Subject and the main tasks of Medical Genetics. Role of heredity in human pathology.
Clinical and genealogical methods. Cytogenetic methods. Molecular genetic methods. Biochemical methods. Semiotics of hereditary diseases.
Morphogenetic development options. Symptomatology and clinical peculiarities of the main forms of inheritable illnesses. Defects of development.
Genetics is defined in dictionaries as the science that deals with heredity and variation in organisms, including the genetic features and constitution of a single organism, species, or group, and with the mechanisms by which they are effected (Encyclopaedia Britannica 15th edition, 1995; Collins English Dictionary, 5th edition2001).
New investigative methods and observations, specially during the last 50 years, have moved genetics into the mainstream of biology and medicine. Genetics is relevant to virtually all fields of medicine and biological disciplines, anthropology, biochemistry, physiology, psychology, ecology, and other fields of the sciences. As both a theoretical and an experimental science, it has broad practical applications in understanding and control of genetic diseases and in agriculture. Knowledge of basic genetic principles and their medical application is an essential part of medical education today. The determination of the nearly complete sequence of the building blocks encoding the genetic information of man in 2004 marked an unprecedented scientific milestone in biology.
The Human Genome Project, an internationalorganization of several countries, reported this major achievement just 50 years after the structure of DNA, the molecule that encodes genetic information, was elucidated (IHGSC, 2004). Although much work remains before we know how the molecules of life interact and produce living organisms, through genetics we now have a good foundation for understanding the living world from a biological perspective.
Each of the approximately ten trillion (1013) cells of an adult human contains a program with life-sustaining information in its nucleus (except red blood cells, which do not have a nucleus). This information is hereditary, transmitted from one cell to its descendent cells, and from one generation to the next. About 200 different types of cells carry out the complex molecular transactions required for life. Genetic information allows organisms to convert atmospheric oxygen and ingested food into energy production, it regulates the synthesis and transport of biologically important molecules, protects against unwarranted invaders, such as bacteria, fungi, and viruses by means of an elaborate immune defense system, and maintains the shape and mobility of bones, muscles, and skin.
Genetically determined functions of the sensory organs enable us to see, to hear, to taste, to feel heat, cold, and pain, to communicate by speech, to support brain function with the ability to learn from experience, and to integrate the environmental input into cognate behavior and social interaction. Reproduction and detoxification of exogenous molecules likewise are under genetic control. Yet, the human brain is endowed with the ability to take free decisions in daily life and developing plans for the future.
The living world consists of two types of cells, the smallest membrane-bound units capable of independent reproduction: prokaryotic cells without a nucleus, represented by bacteria, and eukaryotic cells with a nucleus and complex internal structures, which make up higher organisms. Genetic information is transferred from one cell to both daughter cells at each cell division and from one generation to the next through specialized cells, the germ cells, oocytes, and spermatozoa. The integrity of the genetic program must be maintained without compromise, yet it must be adaptable to long-term changes in the environment.
Errors in maintaining and transmitting genetic information occur frequently in all living systems despite the existence of complex systems for damage recognition and repair. Biological processes are mediated by biochemical reactions performed by biomolecules, called proteins. Each protein is made up of dozens to several hundreds of amino acids arranged in a linear sequence that is specific for its function. Subsequently, it assumes a specific three-dimensional structure, often in combination with other polypeptides. Only this latter feature allows biological function. Genetic information is the blueprint for producing the proteins in a given cell. Most cells do not produce all possible proteins, but a selection, depending on the type of cell. The instructions are encoded in discrete units, the genes. Each of the 20 amino acids used by living organisms recognizes a code of three specific chemical structures. These are the nucleotide bases of a large molecule, DNA (deoxyribonucleic acid).DNA
DNA is a read-only memory device of a genetic information system, called the genetic code. In contrast to the binary system of strings of ones and zeros used in computers (“bits,”which are then combined into “bytes,” which are eight binary digits long), the genetic code in the living world uses a quaternary system of four nucleotide bases with chemical names having the initial letters A, C, G, and T. The quaternary code used in living cells uses three building blocks, called a triplet codon. This genetic code is universal and is used by all living cells, including plants and viruses. A gene is a unit of genetic information.It is equivalent to a single sentence in a text. Thus, genetic information is highly analogous to a linear text and is amenable to being stored in computers.
Genes
Depending on the organizational complexity of an organism, its number of genes ranges from about
termed genomics and proteomics, respectively.
Genes are located on chromosomes. Chromosomes are individual, complex structures located in the cell nucleus, consisting of DNA and special proteins. Chromosomes come in pairs of homologous chromosomes, one derived from the mother, and one from the father. Man has 23 pairs, consisting of chromosomes 1–22 and an X and a Y chromosome in males or two X chromosomes in females. The number and size of chromosomes in different organisms vary, but the total amount of DNA and the total number of genes are the same for a particular species.
Genes are arranged in linear order along each chromosome. Each gene has a defined position, called a gene locus. In higher organisms, genes are structured into contiguous sections of coding and noncoding sequences, called exons (coding) and introns (noncoding), respectively. Genes in multicellular organisms vary with respect to size (ranging from a few thousand to over a millioucleotide base pairs), the number and size of exons, and regulatory DNA sequences. The latter determine the state of activity of a gene, called gene expression. Most genes in differentiated, specialized cells are permanently turned off. Remarkably, more than 90% of the 3 billion base pairs of DNA in higher organisms do not carry known coding information.
The linear text of information contained in the coding sequences of DNA in a gene cannot be read directly. Rather, its total sequence is first transcribed into a structurally related molecule with a corresponding sequence of codons. This molecule is called RNA (ribonucleic acid). RNA is processed by removing the noncoding sections (introns). The coding sections (exons) are spliced together into the final template, called messenger RNA (mRNA). This serves as a template to arrange the amino acids in the sequence specified by the genetic code. This process is called translation.
Genes and Evolution
In The Origin of Species, Charles Darwin wrote in 1859 at the end of chapter IX, On the Imperfection of the Geological Record: “. . .I look at the natural geological record, as a history of the world imperfectly kept, and written in a changing dialect; of this history we possess the last volume alone, relating only to two or three countries. Of this volume, only here and there a short chapter has been preserved; and of each page, only here and there a fewlines.” Advances in genetics and new findings of hominid remains have provided new insights into the process of evolution. Genes with comparable functions in different organisms share structural features. Occasionally they are nearly identical. This is the result of evolution. Living organisms are related to each other by their origin from a common ancestor. Cellular life was established about 3.5 billion years ago when land masses first appeared. Genes required for fundamental functions are similar or almost identical across a,wide variety of organisms, e.g., in bacteria, yeast, insects, worms, vertebrates, mammals, and even plants. They control vital functions such as the cell cycle, DNA repair, or in embryonic development and differentiation. Similar or identical genes present in different organisms are referred to as conserved in evolution.
Genes evolve within the context of the genome of which they are a part. Evolution does not proceed by accumulation of mutations. Most mutations are detrimental to function and usually do not improve an organism’s chance of surviving. Rather, during the course of evolution existing genes are duplicated or parts of genes reshuffled and brought together in a new combination. The duplication event can involve an entire genome, a whole chromosome or a part of it, or a single gene or group of genes. All these events have been documented in the evolution of vertebrates. The human genome contains multiple sites thatwere duplicated during evolution .
Humans, Homo sapiens, are the only living species within the family of Hominidae. All data
available are consistent with the assumption that today’s humans originated in Africa about 100000 to 300000 years ago, spread out over the earth, and populated all continents. Owing to regional adaptation to climatic and other conditions, and favored by geographic isolation, different ethnic groups evolved. Human populations living in different geographic regions differ in the color of the skin, eyes, and hair. This is often mistakenly used to define human races.
However, genetic data do not support the existence of human races. Genetic differences exist mainly between individuals regardless of their ethnic origin. In a study of DNA variation from 12 populations living on five continents of the world, 93–95% of differences were between individuals; only 3–5%were between the populations. Observable differences are literally superficial and do not form a genetic basis for distinguishing races.
Genetically, Homo sapiens is one rather homogeneous species of recent origin. As a result of evolutionary history, humans are well adapted to live peacefully in relatively small groups with a similar cultural and linguistic history. However, humans have not yet adapted to global conditions. They tend to react with hostility to groups with a different cultural background in spite of negligible genetic differences.
Changes in Genes: Mutations
In 1901, H. De Vries recognized that genes can change the contents of their information. For this new observation, he introduced the term mutation. The systematic analysis of mutations contributed greatly to the developing science of genetics. In 1927, H. J. Muller determined the spontaneous mutation rate in Drosophila and demonstrated that mutations can be induced by roentgen rays. C. Auerbach and J. M. Robson in 1941 and, independently, F. Oehlkers in 1943 observed that certain chemical substances also could induce mutations. However, it remained unclear what a mutation actually was, since the physical basis for the transfer of genetic information was not known. Genes of fundamental importance do not tolerate changes (mutations) that compromise function. As a result, deleterious mutations do not accumulate in any substantial number. All living organisms have elaborate cellular systems that can recognize and eliminate faults in the integrity of DNA and genes (DNA repair). Mechanisms exist to sacrifice a cell by programmed cell death (apoptosis) if the defect cannot be successfully repaired.
Genetics in Medicine
Human genetic diseases and normal variations can be placed into one of five categories:
o single gene disorders (diseases or traits where the phenotypes are largely determined by the action, or lack of action, of mutations at individual loci);
o multifactorial traits (diseases or variations where the phenotypes are strongly influenced by the action of mutant alleles at several loci acting in concert);
o chromosomal abnormalities (diseases where the phenotypes are largely determined by physical changes in chromosomal structure – deletion, inversion, translocation, insertion, rings, etc., in chromosome number – trisomy or monosomy, or in chromosome origin – uniparental disomy);
o mitochondrial inheritance (diseases where the phenotypes are affected by mutations of mitochondrial DNA); and
o diseases of unknown etiology that seem to “run in families.”
About 1% of the approximately 4 million annual live births in the
Mendelian traits, or single gene disorders, fall into 5 categories or modes of inheritance based on where the gene for the trait is located and how many copies of the mutant allele are required to express the phenotype:
o autosomal recessive inheritance (the locus is on an autosomal chromosome and both alleles must be mutant alleles to express the phenotype)
o autosomal dominant inheritance (the locus is on an autosomal chromosome and only one mutant allele is required for expression of the phenotype)
o X-linked recessive inheritance (the locus is on the X chromosome and both alleles must be mutant alleles to express the phenotype in females)
o X-linked dominant inheritance (the locus is on the X chromosome and only one mutant allele is required for expression of the phenotype in females), and
o mitochondrial inheritance (the locus is on the mitochondrial “chromosome”).
Mendel based his laws on mathematical probabilities that allowed predictions of resulting phenotypes when certain crosses were made in the garden pea. When he published in 1866, the discovery of the chromosomal basis of inheritance (meiosis and gametogenesis) by Sutton, Boveri, and others was still a generation away. Therefore, there was no physical basis for explaining the Mendelian segregation ratios. The discoveries of Sutton, Boveri, and others allowed a reexamination of Mendel’s apparently forgotten publication. In 1900, Correns, DeVries, and Tschermak, all independently “rediscovered” Mendel’s laws of segregation, and by 1902 the first human Mendelian “inborn error of metabolism”, alcaptonuria, was found by Sir Archibald Garrod. Mendel’s laws are grounded in the chromosomal movements in meiosis, gametogenesis, and fertilization. Understanding the fundamental processes of cell division is the key to understanding Mendelian genetics.
A disease is genetically determined if it is mainly or exclusively caused by disorders in the genetic program of cells and tissues. However, most disease processes result from environmental influences interacting with the individual genetic makeup of the affected individual. These are multigenic or multifactorial diseases. They include many relatively common chronic diseases, e.g., high blood pressure, hyperlipidemia, diabetes mellitus, gout, psychiatric disorders, and certain congenital malformations.
Another common category is cancer, a large, heterogeneous group of nonhereditary genetic disorders resulting from mutations in somatic cells.
Chromosomal aberrations are also an important category. Thus, all medical specialties need to incorporate the genetic foundations of their discipline. As a rule, the genetic origin of a disease cannot be recognized by familial aggregation. Instead, the diagnosis must be based on clinical features and laboratory data. Owing to new mutations and small family size in developed countries, genetic disorders usually do not affect more than one member of a family. About 90% occur isolated within a family. Since genetic disorders affect all organ systems and age groups, and frequently go unrecognized, their contribution to the causes of human diseases appears smaller than it actually is. Genetically determined diseases are not a marginal group, but make up a substantial proportion of diseases. More than one-third of all pediatric hospital admissions are for diseases and developmental disorders that, at least in part, are caused by genetic factors. The total estimated frequency of genetically determined diseases of different categories in the general population is about 3–5% (see Table 1). The large number of individually rare genetically determined diseases and the overlap of diseases with similar clinical manifestations but different etiology cause additional diagnostic difficulties. This principle of genetic or etiological heterogeneity has to be taken into account when a diagnosis is made, to avoid false conclusions about the genetic risk.
Table 1. Categories and frequency of genetically determined diseases
|
Category of disease |
Frequency per 1000 individuals |
|
Monogenic diseases total |
5–17 |
|
Autosomal dominant |
2–10 |
|
Autosomal recessive |
2–5 |
|
X-chromosomal |
1–2 |
|
Chromosome aberrations |
5–7 |
|
Multifactorial disorders |
70–90 |
|
Somatic mutations (cancer) |
200–250 |
|
Congenital malformations |
20–25 |
|
|
Total 300–400 |
Molecular Diagnosis.
From a cell sample much can DNA diagnosis can be obtained using a number of different techniques. Many different types of mutations can be detected easily with new molecular technologies. Point mutations can be detected a variety of ways; 1) RFLP analysis or Allele specific oligo hybridization. Deletions, duplications or insertions can be detected using Southern Blot analysis or PCR analysis. Chromosome aberrations can be detected using in situ hybridization. The techniques for these methods are outlined here.
Methodologies used to test for genetic variants
I. Karyotype Analysis of Human Chromosomes
1. Karyotype preparation and analysis
Cells (from blood, amniotic fluid, etc) are grown in vitro (in a cell culture dish) to increase their number
Cell division is then arrested in metaphase with colchicine (prevents mitotic spindle from forming)
Cells are centrifuged and lysed to release chromosomes
Chromosomes are stained, photographed, and grouped by size and banding patterns
This is a photograph of the 46 human chromosomes in a somatic cell, arrested in metphase. Can you see that they are duplicated sister chromatids?
2. Normal male karyotype (a Cytogeneticist has lined these chromosomes up, matching homologues up and arranging them by size)
3. Normal female karyotype
II. Alterations in chromosome number:
Nondisjunction occurs when either homologues fail to separate during anaphase I of meiosis, or sister chromatids fail to separate during anaphase II. The result is that one gamete has 2 copies of one chromosome and the other has no copy of that chromosome. (The other chromosomes are distributed normally.)
If either of these gametes unites with another during fertilization, the result is aneuploidy (abnormal chromosome number)
A trisomic cell has one extra chromosome (2n +1) = example: trisomy 21. (Polyploidy refers to the condition of having three homologous chromosomes rather then two)
A monosomic cell has one missing chromosome (2n – 1) = usually lethal except for one known in humans: Turner’s syndrome (monosomy XO).
The frequency of nondisjunction is quite high in humans, but the results are usually so devastating to the growing zygote that miscarriage occurs very early in the pregnancy.
If the individual survives, he or she usually has a set of symptoms – a syndrome – caused by the abnormal dose of each gene product from that chromosome.
1. Human disorders due to chromosome alterations in autosomes (Chromosomes 1-22). There only 3 trisomies that result in a baby that can survive for a time after birth; the others are too devastating and the baby usually dies in utero.
A. Down syndrome (trisomy 21): The result of an extra copy of chromosome 21. People with Down syndrome are 47, 21+. Down syndrome affects 1:700 children and alters the child’s phenotype either moderately or severely:
characteristic facial features, short stature; heart defects
susceptibility to respiratory disease, shorter lifespan
prone to developing early Alzheimer’s and leukemia
often sexually underdeveloped and sterile, usually some degree of mental retardation.
Down Syndrome is correlated with age of mother but can also be the result of nondisjunction of the father’s chromosome 21.
Karyotype of a boy with Down Syndrome:
B. Patau syndrome (trisomy 13): serious eye, brain, circulatory defects as well as cleft palate. 1:5000 live births. Children rarely live more than a few months.
C. Edward’s syndrome (trisomy 18): almost every organ system affected 1:10,000 live births. Children with full Trisomy 18 generally do not live more than a few months.
2. Nondisjunction of the sex chromosomes (X or Y chromosome): Can be fatal, but many people have these karyotypes and are just fine!
A. Klinefelter syndrome: 47, XXY males. Male sex organs; unusually small testes, sterile. Breast enlargement and other feminine body characteristics. Normal intelligence.
B. 47, XYY males: Individuals are somewhat taller than average and often have below normal intelligence. At one time (~1970s), it was thought that these men were likely to be criminally aggressive, but this hypothesis has been disproven over time.
3. Trisomy X: 47, XXX females. 1:1000 live births – healthy and fertile – usually cannot be distinguished from normal female except by karyotype
4. Monosomy X (Turner’s syndrome): 1:5000 live births; the only viable monosomy in humans – women with Turner’s have only 45 chromosomes!!! XO individuals are genetically female, however, they do not mature sexually during puberty and are sterile. Short stature and normal intelligence. (98% of these fetuses die before birth)
III. Alterations in chromosome structure:
Sometimes, chromosomes break, leading to 4 types of changes in chromosome structure:
1. Deletion: a portion of one chromosome is lost during cell division. That chromosome is now missing certain genes. When this chromosome is passed on to offspring the result is usually lethal due to missing genes.
Example – Cri du chat (cry of the cat): A specific deletion of a small portion of chromosome 5; these children have severe mental retardation, a small head with unusual facial features, and a cry that sounds like a distressed cat.
2. Duplication: if the fragment joins the homologous chromosome, then that region is repeated
Example – Fragile X: the most common form of mental retardation. The X chromosome of some people is unusually fragile at one tip – seen “hanging by a thread” under a microscope. Most people have 29 “repeats” at this end of their X-chromosome, those with Fragile X have over 700 repeats due to duplications. Affects 1:1500 males, 1:2500 females.
3. Translocation: a fragment of a chromosome is moved (“trans-located”) from one chromosome to another – joins a non-homologous chromosome. The balance of genes is still normal (nothing has been gained or lost) but can alter phenotype as it places genes in a new environment. Can also cause difficulties in egg or sperm development and normal development of a zygote. Acute Myelogenous Leukemia is caused by translocation.
Restriction enzymes
Restriction enzymes are proteins that scan the DNA for specific sequences, usually palindromic sequences of 4 to 8 nucleotides, and then cleave both strands at that position. See Figure 1. There are many different restriction enzymes that can be used. To detect variation in DNA sequence restriction enzyme digestion can be used. Variation in the DNA sequence that gives rise to the creation or destruction of a restriction enzyme digestion site is called a restriction fragment length polymorphism (RFLP). Humans have two copies of each gene, except for those genes on the X and Y chromosomes in males. This must be kept in mind when doing RFLP analysis. In each sample there may be two alleles.
Figure 1. Restriction Enzymes recognition and cut sites.
Southern Blot Analysis
This technique uses a Southern blot technology to identify the RFLP. Southern blots are the transfer of complex DNA to a solid state medium and then probing with a labeled probe to identify the DNA fragments of interest. The result is usually a autoradiograph with bands. This technique can usually be replaced with a PCR derivative .
PCR
This technique has revolutionized the DNA testing. It is based on the principal of DNA replication. Small pieces of DNA are replicated between oligonucleotide primers. See Figure 4-10. One can amplify any piece of the human genome with the appropriate primers and the amplified DNA can be used to test for genetic variation. Oligonucleotides are annealed to the target DNA and syntesis is carried out by a thermostabile polymerase. The PCR cycle is the denaturation of target DNA, the annealing of the oligos, and the synthesis of the new DNA. This cycle is repeated 30 times to give over 1 billion copies of the DNA molecule to use in an analysis.
Due to DNA sequence variation RFLPs can be used to map specific positions in the genome. RFLPs can be used to follow a specific gene through a family due to the linkage. In addition an RFLP can be diagnostic of a specific condition such as sickle cell anemia. See Figure 4
Figure 4. Sickle Cell Anemia mutation in the beta globin gene.
This mutation destroys an MstII site in the gene and can be used as a diagnostic marker for the disease allele. See Figure 5.
Figure 5. The parents are both carriers as noted by the presence of the beta S allele. Child 1 is a homozygote carrying both copies of the beta-S allele while child 2 is a carrier and child 3 carriers two copies of the beta-A allele.
RFLP does not always arise from single nucleotide polymorphism due to a restriction site. Occasionally the disease allele is due to a deletion of DNA causing the DNA fragment to loose a restriction site. See Figure 6.
Figure 6: RFLP due to deletion removing the restriction site. Found in PKU
Allele Specific Oligos analysis
Allele specific oligos can be used to identify mutations in genes where the mutation is known. It is done with specific oligos that are complementary to each of the alleles to be detected. See Figure 4-
This technique can be converted to a PCR derivative where specific amplication of each allele is possible with a specific pair of PCR primers. The result are shown in Figure 10
Figure 10..Allele specific PCR. Oligo primer pairs are use to specifically amplify the wildtype and mutant alleles. Results are show on gel.
PCR detection of triplet repeat expansion.
Triplet repeats are found in a number of human disorders such as
Figure 11. PCR amplification of triplet repeat expansion. The size of the repeat is apparent after gel analysis.
DNA sequence analysis for mutation detection.
Finally DNA sequence analysis can be used to detect mutations. Exons are PCR amplified and then sequenced using an automated sequencing facility. The results are displayed in Figure 12.
Figure 12. Trace of DNA sequence for mutation detection.
This is the preferred method for testing when the mutation does not fall into the ones that are normally found. For example only 70% of all CF mutations are the ∆F508 mutation which deletes codon 508 from the gene. If the mutation that you are looking for does not fall into this category then sequencing iecessary.
ELSI ISSUES of DNA TESTING
UNIQUENESS OF DNA TESTING
- Information may affect an entire family, rather than only the individual.
- Genetic discoveries may be predictive of future adverse events in an individual’s or family member’s health.
- Genetic information and the choices of the present may affect future generations.
- Voluntary
- Medical genetics has a tradition of non-directive in counseling
- Freedom of choice in all matters relevant to Genetics.
- Woman should be an important decision maker in all-reproductive issues.
- Respect diversity.
- No coercion.
- Confidentiality should be maintained in order to avid any discrimination, problems with insurance coverage.
INFORMED CONSENT AND GENETIC TESTING
Following issues need to be covered while obtaining informed consent
- The purpose of the test
- Options and alternatives
- Test’s potential benefits and risks, including social and psychological
- That whatever decision individuals and families make, their care will not be jeopardized.
PRESYMPTOMATIC AND SUSCEPTIBILITY TESTING
This refers to identification of healthy individuals who may have inherited a gene for late-onset disease, and if so will develop the disorder if they live long enough (e.g.
DNA TESTING FOR CHILDREN
- Not usually done for pre-symptomatic testing unless there are potential medical benefits e.g. in the case of newborn screening when early treatment will be of benefit to the child
BANKED DNA
- Blanket informed consent would allow use of a sample in future projects.
- This can be very useful iumber of situations for e.g. (disease identification, forensic purposes).
ASSISTED REPRODUCTION AND MEDICAL GENETICS
- Egg or sperm or embryo donation, or surrogacy.
- Cultural traditions and beliefs play an important role in this area.
- Reproductive cloning (the creation of a fetus whose genome is entirely derived from another individual) has been rejected by many international bodies, including WHO, has aroused fears in many societies, and is not in accord with currently accepted international ethical standards.
EVALUATION OF THE INFANT OR CHILD WITH CONGENITAL HEART DISEASE
The initial evaluation of the infant or child with suspected congenital heart disease involves a systematic approach with three major components. First, congenital cardiac defects can be divided into two major groups based on the presence or absence of cyanosis, which can be determined by physical examination, aided by transcutaneous oximetry. Second, these two groups can be further subdivided based on whether the chest radiograph shows evidence of increased, normal, or decreased pulmonary vascular markings. Finally, the electrocardiogram can be used to determine whether right, left, or biventricular hypertrophy exists. The character of the heart sounds and the presence and character of any murmurs further narrows the differential diagnosis. The final diagnosis is then confirmed by echocardiography and/or cardiac catheterization.
We can classify congenital heart defects into several categories in order to better understand the problems the baby will experience. They include:
- problems that cause too much blood to pass through the lungs
These defects allow oxygen-rich blood that should be traveling to the body to re-circulate through the lungs, causing increased pressure and stress in the lungs. - problems that cause too little blood to pass through the lungs
These defects allow blood that has not been to the lungs to pick up oxygen (and, therefore, is oxygen-poor) to travel to the body. The body does not receive enough oxygen with these heart problems, and the baby will be cyanotic, or have a blue coloring. - problems that cause too little blood to travel to the body
These defects are a result of underdeveloped chambers of the heart or blockages in blood vessels that prevent the proper amount of blood from traveling to the body to meet its needs.
ACYANOTIC CONGENITAL HEART LESIONS
Acyanotic congenital heart lesions can be classified according to the predominant physiologic load they place on the heart. Although many congenital heart lesions induce more than one physiologic disturbance, it is helpful to focus on the primary load abnormality for purposes of classification. The most common lesions are those that produce a volume load, and the most common of these are the left-to-right shunt lesions. Atrioventricular valve regurgitation and some of the cardiomyopathies are other causes of increased volume load. The second major class of lesions causes an increase in pressure load, most commonly secondary to ventricular outflow obstruction (e.g., pulmonic or aortic valve stenosis) or narrowing of one of the great vessels (e.g., coarctation of the aorta). The chest radiograph and electrocardiogram are useful tools for differentiating between these major classes of volume and pressure overload lesions.
LESIONS RESULTING IN INCREASED VOLUME LOAD. The most common lesions in this group are those that cause left-to-right shunts: atrial septal defect (ASD), ventricular septal defect (VSD), atrioventricular septal defects (AVSD, AV canal), and patent ductus arteriosus (PDA). The pathophysiologic common denominator in this group is a communication between the systemic and pulmonary sides of the circulation, resulting in the shunting of fully oxygenated blood back into the lungs. This shunt can be quantitated by calculating the ratio of pulmonary to systemic blood flow, or Qp:Qs. Thus, a 2:1 shunt usually implies that there is twice the normal pulmonary blood flow.
The direction and magnitude of the shunt across such a communication depends on the size of the defect and the relative pulmonary and systemic pressures and pulmonary and systemic vascular resistances. These factors are dynamic and may change dramatically with age: Intracardiac defects may grow smaller with time; pulmonary vascular resistance, which is high in the immediate newborn period, decreases to normal adult levels by several weeks of life; chronic exposure of the pulmonary circulation to high pressure and blood flow will result in a gradual increase in pulmonary vascular resistance . Thus, in a lesion such as a large VSD, there may be little shunting and few symptoms during the 1st wk of life. When the pulmonary vascular resistance declines over the next several weeks, the volume of the left-to-right shunt increases, and symptoms begin to appear.
The increased volume of blood in the lungs decreases pulmonary compliance and increases the work of breathing. Fluid leaks into the interstitial space and alveoli, causing pulmonary edema. The infant develops the symptoms we refer to as “heart failure,” such as tachypnea, chest retractions, nasal flaring, and wheezing. However, the term heart failure is a misnomer; total left ventricular output is actually several times greater thaormal, although much of this output is ineffective because it returns directly to the lungs. To maintain this high level of left ventricular output, heart rate and stroke volume are increased, mediated by an increase in sympathetic nervous system activity. The increase in circulating catecholamines, combined with the increased work of breathing, result in an elevation in total body oxygen consumption, often beyond the oxygen transport ability of the circulation. This leads to the additional symptoms of sweating, irritability, tachycardia, and failure to thrive. If left untreated, pulmonary vascular resistance eventually begins to rise, and by several years of age the shunt volume will decrease and eventually reverse to right-to-left.
Additional lesions that impose a volume load on the heart include the regurgitant lesions and the cardiomyopathies. Regurgitation of the atrioventricular valves is most commonly encountered in patients with partial or complete atrioventricular septal (AV canal) defects. In this lesion, the combination of a left-to-right shunt with atrioventricular valve regurgitation increases the volume load on the heart and leads to more severe symptomatology. Isolated regurgitation of the tricuspid valve is seen in Ebstein anomaly. Regurgitation of one of the semilunar valves is usually also associated with stenosis; however, aortic regurgitation may be encountered in patients with a VSD directly under the aortic valve (supracristal VSD).
As opposed to the left-to-right shunts, in which intrinsic cardiac muscle function is usually either normal or increased, in the cardiomyopathies heart muscle function is decreased. Cardiomyopathies may affect systolic contractility, diastolic relaxation, or both. Decreased cardiac function results in increased atrial and ventricular filling pressures, and pulmonary edema occurs secondary to increased capillary pressure. The major etiologies of cardiomyopathy in infants and children include viral myocarditis, a large range of metabolic disorders, and endocardial fibroelastosis.
LESIONS RESULTING IN INCREASED PRESSURE LOAD. The pathophysiologic common denominator of these lesions is an obstruction to normal blood flow. The most common are obstructions to ventricular outflow: valvar pulmonic stenosis, valvar aortic stenosis, and coarctation of the aorta. Less common are obstruction to ventricular inflow: tricuspid or mitral stenosis and cor triatriatum. Ventricular outflow obstruction can occur at the valve, below the valve (e.g., double-chambered right ventricle, subaortic membrane), or above it (e.g., branch pulmonary stenosis or supravalvar aortic stenosis). Unless the obstruction is severe, cardiac output will be maintained and symptoms of heart failure will be either subtle or absent. This compensation involves an increase in cardiac wall thickness (hypertrophy).
The clinical picture is quite different when obstruction to outflow is severe, usually encountered in the immediate newborn period. The infant may become critically ill within several hours of birth. Severe pulmonic stenosis in the newborn period (critical PS) results in signs of right-sided heart failure (hepatomegaly, peripheral edema) and cyanosis due to right-to-left shunting across the foramen ovale. Severe aortic stenosis in the newborn period (critical AS) presents with signs of left-sided heart failure (pulmonary edema, poor perfusion), rightsided failure (hepatomegaly, peripheral edema), and may progress rapidly to total circulatory collapse.
In older children, coarctation of the aorta usually presents with upper body hypertension and diminished pulses in the lower extremities. In the immediate newborn period, the presentation of coarctation may be delayed due to the presence of a patent ductus arteriosus. In these patients, the aortic end of the ductus may serve as a conduit for blood flow to partially bypass the obstruction. These infants become symptomatic when the ductus finally closes.
CYANOTIC CONGENITAL HEART LESIONS
This group of congenital heart lesions can also be further divided based on pathophysiology: whether pulmonary blood flow is decreased (tetralogy of Fallot, pulmonary atresia with intact septum, tricuspid atresia, total anomalous pulmonary venous return with obstruction) or increased (transposition of the great vessels, single ventricle, truncus arteriosus, total anomalous pulmonary venous return without obstruction). As with the acyanotic lesions, the chest radiograph is a valuable tool for differentiating between these two categories.
CYANOTIC LESIONS WITH DECREASED PULMONARY BLOOD FLOW. These lesions must include both an obstruction to pulmonary blood flow (at the tricuspid valve, right ventricular, or pulmonary valve level) and a pathway by which systemic venous blood can shunt right to left and enter the systemic circulation (via a patent foramen ovale, ASD, or VSD). Common lesions in this group include tricuspid atresia, tetralogy of Fallot, and various forms of single ventricle with pulmonary stenosis. In these lesions, the degree of cyanosis depends on the degree of obstruction to pulmonary blood flow. If the obstruction is mild, cyanosis may be absent at rest. However, these patients may develop hypercyanotic (“tet”) spells during conditions of stress. In contrast, if the obstruction is severe, pulmonary blood flow may be dependent on the patency of the ductus arteriosus. When the ductus closes during the 1st few days of life, the neonate presents with profound hypoxemia and shock.
Anatomy of a heart with tetralogy of Fallot
CYANOTIC LESIONS WITH INCREASED PULMONARY BLOOD FLOW. In this group of lesions, there is no obstruction to pulmonary blood flow. Cyanosis is caused by either abnormal ventricular-arterial connections or by total mixing of systemic venous and pulmonary venous blood within the heart. Transposition of the great vessels (TGV) is the most common of the former group of lesions. In TGV, the aorta arises from the right ventricle and the pulmonary artery from the left ventricle. Systemic venous blood returning to the right atrium is pumped directly back to the body, and oxygenated blood returning from the lungs to the left atrium is pumped back into the lungs. The persistence of fetal pathways (foramen ovale and ductus arteriosus) allows for a small degree of mixing in the immediate newborn period; however, when the ductus begins to close, these infants develop extreme cyanosis.
Anatomy of a heart with transposition of the great arteries
The total mixing lesions include those cardiac defects with a common atria or ventricle, total anomalous pulmonary venous return, and truncus arteriosus. In this group, deoxygenated systemic venous blood and oxygenated pulmonary venous blood mix completely in the heart, resulting in equal oxygen saturations in the pulmonary artery and aorta. If there is no obstruction to pulmonary blood flow, these infants present with a combination of cyanosis and heart failure. In contrast, if pulmonary stenosis is present, these infants present with cyanosis alone, similar to patients with tetralogy of Fallot.
ACYANOTIC CONGENITAL HEART DISEASE
The Left-to-Right Shunt Lesions
Atrial Septal Defect
Atrial septal defects (ASDs) can occur in any portion of the atrial septum (secundum, primum, or sinus venosus). Rarely there may be near absence of the atrial septum, creating a functional single atrium. In contrast, an isolated patent foramen ovale is usually of no hemodynamic significance and is not considered an ASD. However, if right atrial pressure is increased secondary to another cardiac anomaly (e.g., pulmonary stenosis or atresia, tricuspid valve abnormalities, right ventricular dysfunction), venous blood may shunt across the patent foramen ovale into the left atrium with resultant cyanosis. Because of the anatomic structure of a patent foramen ovale, blood normally is not shunted from the left atrium to the right atrium. However, in the presence of a large volume load or a hypertensive left atrium, or both, there may be enough dilatation of the foramen ovale to result in a significant atrial left-to-right shunt. An isolated patent foramen ovale does not require surgical treatment but may be a risk for paradoxical systemic embolization in later life.
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Anatomy of a heart with an atrial septal defect
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Ostium Secundum Defect
This defect, in the region of the fossa ovalis, is the most common form of ASD and is associated with normal atrioventricular valves. Although late myxomatous changes in the mitral valve have been described, this is only rarely an important clinical consideration. The defects may be single or multiple, and in symptomatic older children openings of
PATHOPHYSIOLOGY. The degree of left-to-right shunting is dependent on the size of the defect and also on the relative compliances of the right and left ventricles, and relative vascular resistances in the pulmonary and systemic circulations. In large defects, a considerable shunt of oxygenated blood flows from the left to the right atrium. This blood is added to the usual venous return to the right atrium and is pumped by the right ventricle to the lungs. In large defects, pulmonary blood flow is usually 2–4 times systemic blood flow. The paucity of symptoms in infants with ASDs is related to the structure of the right ventricle in early life when its muscular wall is thick and less compliant, thus limiting the left-to-right shunt. As the infant becomes older, the right ventricular wall becomes thinner as a result of its lower pressure-generating requirements, and the left-to-right shunt across the ASD increases. The large blood flow through the right side of the heart results in enlargement of the right atrium and ventricle and dilatation of the pulmonary artery. Despite the large pulmonary blood flow, the pulmonary arterial pressure remains normal because of the absence of a high pressure communication between the pulmonary and systemic circulations. Pulmonary vascular resistance remains low throughout childhood, although it may begin to increase in adulthood. The left ventricle and aorta are normal in size. Cyanosis is only seen occasionally in adults who have the complicating features of pulmonary vascular disease.
CLINICAL MANIFESTATIONS. A child with an ostium secundum defect is most often asymptomatic, and the lesion may be discovered inadvertently during a physical examination. Even an extremely large secundum ASD rarely produces clinically evident heart failure in childhood; in older children varying degrees of exercise intolerance may be noted. Often the degree of limitation may go unnoticed by the family until after surgical repair, when the child’s activity level increases markedly. In older infants and children the physical findings are usually characteristic but subtle and require careful examination of the heart and special attention to the heart sounds.
The pulses are normal. A right ventricular systolic lift is usually palpable from the left sternal border to the midclavicular line. There is a loud 1st heart sound and sometimes a pulmonic ejection click. In most patients the 2nd heart sound at the upper left sternal edge is widely split and fixed in its splitting in all phases of respiration. This auscultatory finding is characteristic and is due to the defect producing a constantly increased right ventricular diastolic volume and a prolonged ejection time. The systolic murmur is of the ejection type, medium pitched, without harsh qualities, seldom accompanied by a thrill, and best heard at the left mid and upper sternal border. It is produced by the increased flow across the right ventricular outflow tract into the pulmonary artery. A short, rumbling mid-diastolic murmur produced by the increased volume of blood flow across the tricuspid valve is often audible at the lower left sternal border. This finding, which may be subtle and heard best with the bell of the stethoscope, is an excellent diagnostic sign and usually indicates a shunt ratio of at least 2:1.
DIAGNOSIS. The chest roentgenogram shows varying degrees of enlargement of the right ventricle and atrium depending on the size of the shunt; the left ventricle and aorta are of normal size. The pulmonary artery is large, and the pulmonary vascularity is increased. These signs vary and may not be conspicuous in mild cases. Cardiac enlargement is often best appreciated on the lateral view, because the right ventricle protrudes anteriorly as its volume increases. The electrocardiogram shows volume overload of the right ventricle with right axis deviation or a normal axis, and a minor right ventricular conduction delay (usually an rsR´ pattern in the right precordial leads).
The echocardiogram shows findings characteristic of right ventricular volume overload, including increased right ventricular end-diastolic dimension and an abnormal motion of the ventricular septum. The normal septum moves posteriorly during systole and anteriorly during diastole. With right ventricular overload and normal pulmonary vascular resistance, the septal motion is reversed, that is, anterior movement in systole, or the motion is intermediate so that the septum remains straight. The location and size of the atrial defect are readily appreciated by two-dimensional scanning, and the shunt is confirmed by pulsed and color flow Doppler. Patients with classic features of a secundum ASD, including echocardiographic identification of a well-defined defect, need not be catheterized prior to surgical closure.
If the diagnosis is suspect or the shunt size cannot be determined reliably from noninvasive tests, cardiac catheterization will confirm the presence of the defect and allow measurement of the shunt ratio. The oxygen content of blood from the right atrium will be much higher than that from the superior vena cava. This feature is not specifically diagnostic because it may occur with partial anomalous pulmonary venous return to the right atrium, with a ventricular septal defect (VSD) in the presence of tricuspid insufficiency, with atrioventricular septal defects associated with left ventricular-to–right atrial shunts, and with aorta-to–right atrial communications (e.g., ruptured sinus of Valsalva aneurysm). The physical signs produced by the latter three anomalies generally differ greatly from those of ASDs, and their presence can usually be confirmed by selective angiocardiography. Occasionally, mixing of blood is incomplete in the right atrium, and the principal site of shunt appears to be at the ventricular level, even though a VSD is not present.
The catheter can usually be manipulated into the left atrium via the defect. Streaming of inferior vena caval blood across the defect to the left atrium may occur with uncomplicated ASDs. This small right-to-left shunt may be demonstrated by indicator dilution curves but only rarely results in significant arterial desaturation or cyanosis. The pressures in the right side of the heart are usually normal, but small to moderate pressure gradients may be measured across the right ventricular outflow tract. In the absence of associated organic pulmonary stenosis, they are caused by functional stenosis related to excessive blood flow and are usually less than
PROGNOSIS AND COMPLICATIONS. Secundum ASDs are well tolerated during childhood; symptoms usually do not appear until the 3rd decade or later. Pulmonary hypertension, atrial dysrhythmias, tricuspid or mitral insufficiency, and heart failure are late manifestations; these symptoms may first appear during the increased volume load of pregnancy. Infective endocarditis is extremely rare. Postoperative complications, such as late heart failure and atrial fibrillation, are more common in patients operated on after 20 yr of age.
Secundum ASDs are usually isolated, although they may be associated with partial anomalous pulmonary venous return, pulmonary valvular stenosis, VSD, pulmonary arterial branch stenosis, and persistent left superior vena cava, as well as mitral valve prolapse and insufficiency.
TREATMENT. Surgery is advised for all symptomatic patients and also for asymptomatic patients with a shunt ratio of at least 2:1. The timing for elective closure is usually at some time prior to entry into school. Closure is carried out at open heart surgery, and the mortality rate is less than 1%. Repair is preferred during early childhood because the surgical mortality and morbidity are greater in adulthood when late signs are present. Eliminating the increased risks of pregnancy is another important reason to intervene early in females. Mild symptoms with exercise and submaximal physical performance during sports activities are also prevented by early elective repair. Occlusion devices, implanted transvenously at cardiac catheterization, have been used in experimental trials to successfully close secundum ASDs. In patients with small secundum ASDs with minimal left-to-right shunts, the general consensus is that closure is not required. It is unclear at present whether the persistence of a small ASD into adulthood increases the risk for stroke enough to warrant prophylactic closure of all of these defects.
The results after operation in children with large shunts are excellent. Symptoms disappear rapidly, and physical development frequently appears enhanced. The heart size decreases to normal, and the electrocardiogram shows decreased right ventricular forces. Late arrhythmias are less frequent in patients who have had early repair.
Sinus Venosus Defect
The defect is situated in the upper part of the atrial septum in close relation to the entry of the superior vena cava. Often, one or more pulmonary veins (usually from the right lung) drain anomalously into the superior vena cava. Sometimes the superior vena cava straddles the defect; some systemic venous blood then enters the left atrium. The hemodynamic disturbance, clinical picture, electrocardiogram, and roentgenogram are similar to those of secundum ASD. The diagnosis can usually be made by two-dimensional echocardiography. If cardiac catheterization is carried out to better define the venous drainage, the catheter may enter a right pulmonary vein directly from the superior vena cava. Anatomic correction usually requires the insertion of a patch to close the defect while incorporating the entry of anomalous veins into the left atrium; surgical results are generally excellent.
Partial Anomalous Pulmonary Venous Return
A varying number of pulmonary veins may enter the systemic venous circulation or the right atrium and produce a left-to-right shunt of oxygenated blood, which may be further augmented if there is an associated ASD. Partial anomalous pulmonary venous return usually involves some or all of the veins from only one lung, more often the right. An associated ASD usually is of the sinus venosus type. The history, physical signs, electrocardiogram, and roentgenographic findings are indistinguishable from those of an isolated ostium secundum ASD. Occasionally, an anomalous vein draining into the inferior vena cava is visible roentgenographically as a crescentic shadow of vascular density along the right border of the cardiac silhouette (scimitar syndrome); in these cases an ASD is usually not present. The finding of a sinus venosus ASD by echocardiography is often accompanied by the identification or suspicion of associated partial anomalous pulmonary venous return. Echocardiography usually confirms the diagnosis. Magnetic resonance imaging (MRI) is also useful for defining pulmonary venous drainage. At cardiac catheterization, the presence of anomalous pulmonary veins may be demonstrated by selective pulmonary arteriography.
The prognosis is excellent, similar to that for ostium secundum ASDs. When a large left-to-right shunt is present, surgical repair is performed. The associated ASD should be closed in such a way as to direct the pulmonary venous return to the left atrium. A single anomalous pulmonary vein without an atrial communication may be difficult to redirect to the left atrium and, if the shunt size is small, may be left unoperated.
Atrioventricular Septal Defects
(Ostium Primum and AV Canal or Endocardial Cushion Defects)
These abnormalities are grouped together because they represent a spectrum of a basic embryologic abnormality, a deficiency of the atrioventricular (AV) septum. The ostium primum defect is situated in the lower portion of the atrial septum and overlies the mitral and tricuspid valves. In most instances there is also a cleft in the anterior leaflet of the mitral valve. The tricuspid valve is usually functionally normal, although some anatomic abnormality of the septal leaflet is usually present. The ventricular septum is intact.
Atrioventricular Canal Defect
AV septal defect, also known as AV canal defect or endocardial cushion defect, consists of contiguous atrial and ventricular septal defects with markedly abnormal AV valves. The degree of valve abnormalities varies considerably; in the complete form of AV septal defect there is a single AV valve, common to both ventricles, and consisting of an anterior and a posterior bridging leaflet related to the ventricular septum, with a lateral leaflet in each ventricle. The lesion is common among children with Down syndrome and may occasionally occur with pulmonary stenosis.
Transitional varieties of these defects also occur. They include ostium primum defects with clefts in the anterior mitral and septal tricuspid valve leaflets, minor ventricular septal deficiencies, and, less commonly, ostium primum defects with normal AV valves. In some patients, the atrial septum is intact, but the inlet ventricular septal defect simulates that found in the full AV septal defect. These defects are also commonly associated with deformities of the AV valves.
PATHOPHYSIOLOGY. The basic abnormality in patients with ostium primum defects is the combination of a left-to-right shunt across the atrial defect with mitral (or occasionally tricuspid) insufficiency. The shunt is usually moderate to large. The degree of mitral insufficiency is usually mild to moderate. Pulmonary arterial pressures are usually normal or only mildly increased. The physiology of this lesion is, therefore, very similar to that of an ostium secundum ASD.
In AV septal defects the left-to-right shunt is both transatrial and transventricular. Additional shunting may occur directly from the left ventricle to the right atrium because of the absence of the AV septum. Pulmonary hypertension and an early tendency to increase pulmonary vascular resistance are common. AV valvular insufficiency increases the volume load due to regurgitation of blood from the ventricles to both atria. Some right-to-left shunting may also occur at both the atrial and ventricular levels, and lead to mild but significant arterial desaturation. With time, progressive pulmonary vascular disease will increase the right-to-left shunt so that clinical cyanosis develops .
CLINICAL PRESENTATION. Many children with ostium primum defect are asymptomatic, and the anomaly is discovered during a general physical examination. In patients with moderate shunts and trivial mitral insufficiency, the physical signs are similar to those of the secundum ASD, but with an additional apical holosystolic murmur due to mitral insufficiency.
A history of exercise intolerance, easy fatigability, and recurrent pneumonias may be obtained, especially in infants with large left-to-right shunts and severe mitral insufficiency. In these patients cardiac enlargement is moderate or marked, and the precordium is hyperdynamic. The auscultatory signs produced by the left-to-right shunt include a normal or accentuated 1st sound; wide, fixed splitting of the 2nd sound; a pulmonary systolic ejection murmur sometimes preceded by a click; and a low-pitched mid-diastolic rumbling murmur at the lower left sternal edge and/or apex due to increased flow through the atrioventricular valves. Mitral insufficiency may be manifested by an apical holosystolic murmur that radiates to the left axilla.
With complete AV septal defects, congestive heart failure and intercurrent pulmonary infection usually appear in infancy. During these episodes minimal cyanosis may be evident. The liver is enlarged and the infant shows signs of failure to thrive. Cardiac enlargement is moderate to marked, and a systolic thrill is frequently palpable. A lift may be present at the lower left sternal border. The 1st heart sound is normal or accentuated. The 2nd heart sound is widely split if pulmonary flow is massive. A low-pitched, mid-diastolic rumbling murmur is audible at the lower left sternal edge, and a pulmonary systolic ejection murmur is produced by the large pulmonary flow. The apical holosystolic murmur of mitral insufficiency may also be present.
DIAGNOSIS. Chest roentgenograms of children with complete AV septal defects often show marked cardiac enlargement caused by prominence of both ventricles and the right atrium. The pulmonary artery is large, and the pulmonary vascularity is increased.
The electrocardiograms of children with complete AV septal defects are distinctive. The principal abnormalities are (1) superior orientation of the mean frontal QRS axis with left axis deviation to the left upper or right upper quadrant, (2) counterclockwise inscription of the superiorly oriented QRS vector loop, (3) signs of biventricular hypertrophy or isolated right ventricular hypertrophy, (4) right ventricular conduction delay (RSR´ in leads V3R and V1), (5) normal or tall P waves, and (6) occasional prolongation of the P-R interval.
The echocardiogram is characteristic and shows signs of right ventricular enlargement with encroachment of the mitral valve echo on the left ventricular outflow tract; this corresponds to the angiographic “goose-neck” deformity. In normal hearts, the tricuspid valve inserts slightly more towards the apex than the mitral valve. In AV septal defects, both valves insert at the same level due to the absence of the AV septum. In complete AV septal defects, the ventricular septal echo is also deficient and the common AV valve is readily appreciated. Pulsed and color flow Doppler echo will demonstrate left-to-right shunting at atrial, ventricular, or ventricular-to-atrial levels and semiquantitate the degree of AV valve insufficiency. Echocardiography will also aid in assessing for the presence of commonly associated lesions such as patent ductus arteriosus (PDA) or coarctation of the aorta.
Cardiac catheterization and angiocardiography may be required to confirm the diagnosis. These studies demonstrate the magnitude of the left-to-right shunt, the severity of pulmonary hypertension, the degree of elevation of pulmonary vascular resistance, and the severity of insufficiency of the common AV valve. By oximetry, the shunt is usually demonstrable at the atrial level; in some patients, increased oxygen saturations are noted only in the right ventricle because of streaming of blood across the primum defect just proximal to the tricuspid valve. The arterial oxygen saturation is normal or mildly reduced unless severe pulmonary vascular disease is present. Children with ostium primum defects usually have normal or only moderate elevation of pulmonary arterial pressure. On the other hand, complete AV septal defects are associated with right ventricular and pulmonary hypertension, and in older patients with increased pulmonary vascular resistance.
Selective left ventriculography is extremely helpful in the diagnosis of AV septal defects. The deformity of the mitral or common atrioventricular valve and the distortion of the outflow tract of the left ventricle causes a “goose-neck”–appearing deformity of the left ventricular outflow tract. The abnormal anterior leaflet of the mitral valve is serrated, and mitral insufficiency is noted, usually with regurgitation of blood into both the left and right atria. Direct shunting of blood from the left ventricle to the right atrium may also be demonstrated.
PROGNOSIS AND COMPLICATIONS. The prognosis for complete AV septal defects depends on the magnitude of the left-to-right shunt, the degree of elevation of pulmonary vascular resistance, and the severity of AV valve insufficiency. Death from congestive cardiac failure during infancy used to be frequent before the advent of early corrective surgery. Patients who survived without surgery were usually those who developed pulmonary vascular obstructive disease, or more rarely those with pulmonic stenosis. In contrast, most patients with ostium primum defects and minimal AV valve involvement are asymptomatic or have only minor, nonprogressive symptoms until they reach the 3rd to 4th decade of life, similar to the course of patients with secundum atrial septal defects.
TREATMENT. Ostium primum defects are approached surgically from an incision in the right atrium. The cleft in the mitral valve is located through the atrial defect and is repaired by direct suture. The defect in the atrial septum is usually closed by insertion of a patch prosthesis. The surgical mortality rate for ostium primum defects is low. Surgical treatment for complete AV septal defects is more difficult, especially in infants with congestive cardiac failure and pulmonary hypertension. However, successful open heart correction of these defects can be accomplished even in infancy. The atrial and ventricular defects are patched closed and the AV valves reconstructed. Complications are uncommon and include surgically induced heart block requiring placement of a permanent pacemaker, excessive narrowing of the left ventricular outflow tract requiring surgical revision, and eventual worsening of mitral regurgitation requiring replacement with a prosthetic valve.
Ventricular Septal Defect
This is the most common cardiac malformation, accounting for 25% of congenital heart disease. Defects may occur is any portion of the ventricular septum; however, the majority are of the membranous type. These defects are in a posteroinferior position, anterior to the septal leaflet of the tricuspid valve. Defects between the crista supraventricularis and the papillary muscle of the conus may be associated with pulmonary stenosis and the other manifestations of tetralogy of Fallot. Defects superior to the crista supraventricularis (supracristal) are less common; they are found just beneath the pulmonary valve and may impinge on an aortic sinus, causing aortic insufficiency. Defects in the midportion or apical region of the ventricular septum are muscular in type and may be single or multiple (Swiss-cheese septum).
Anatomy of a heart with ventricular septal defect
PATHOPHYSIOLOGY. The physical size of the defect is a major, but not the only, determinant of the size of the left-to-right shunt. The shunt magnitude is also determined by the level of pulmonary vascular resistance compared with systemic vascular resistance. When a small communication is present (usually <0.5 cm2), the defect is called restrictive and right ventricular pressure is normal. The higher pressure in the left ventricle drives the shunt left-to-right; however, the size of the defect limits the magnitude of the shunt. In large nonrestrictive defects (usually >1.0 cm2), right and left ventricular pressures are equalized. In these defects, the direction of shunting and the shunt magnitude are determined by the ratio of pulmonary to systemic vascular resistances.
After birth, in the presence of a large VSD, the pulmonary vascular resistance may remain higher thaormal and thus the size of the left-to-right shunt may be limited. As pulmonary vascular resistance falls in the 1st few weeks after birth because of the normal involution of the media of the small pulmonary arteries and arterioles, the size of the left-to-right shunt increases. Eventually, a large left-to-right shunt ensues, and clinical symptoms become apparent. In most cases during early infancy, the pulmonary vascular resistance is only slightly elevated, and the major contribution to pulmonary hypertension is the extremely large pulmonary blood flow. In some patients with a large VSD, pulmonary arteriolar medial thickness remains increased. With continued exposure of the pulmonary vascular bed to high systolic pressure and high flow, pulmonary vascular obstructive disease begins to develop. When the ratio of pulmonary to systemic resistance approaches 1:1, the shunt becomes bidirectional, signs of heart failure abate, and the patient becomes cyanotic. These progressive increases in pulmonary resistance are rarely seen in the present era when prolonged pulmonary hypertension is prevented by early surgical intervention in patients with large VSDs.
The magnitude of intracardiac shunts is usually described by the ratio of pulmonary to systemic blood flow. If the left-to-right shunt is small (pulmonary to systemic flow ratio <1.75:1), the cardiac chambers will not be appreciably enlarged and the pulmonary vascular bed will likely be normal. If the shunt is large (flow ratio >2.5:1), left atrial and ventricular volume overload occur, as well as right ventricular and pulmonary arterial hypertension. The pulmonary arterial trunk, left atrium, and left ventricle are enlarged because of the large volume of pulmonary blood flow.
CLINICAL MANIFESTATIONS. The clinical presentation of patients with a VSD varies according to the size of the defect and the pulmonary blood flow and pressure. Small defects with trivial left-to-right shunts and normal pulmonary arterial pressures are the most common. These patients are asymptomatic, and the cardiac lesion is usually found during a routine physical examination. Characteristically, there is a loud, harsh, or blowing left parasternal holosystolic murmur, heard best over the lower left sternal border and frequently accompanied by a thrill. In a few instances the murmur ends well before the 2nd sound, presumably because of closure of the defect during late systole. The left-to-right shunt may be limited in the neonate because of higher right-sided pressures, and therefore the systolic murmur may not be audible during the 1st few days of life. In premature infants, however, the murmur may be heard early because pulmonary vascular resistance decreases more rapidly. In patients with small VSDs, the chest roentgenogram is usually normal, although minimal cardiomegaly and a borderline increase in pulmonary vasculature may be observed. The electrocardiogram is usually normal but may suggest left ventricular hypertrophy. The presence of right ventricular hypertrophy is a warning that the defect is not small and that pulmonary hypertension is present or that there is an associated lesion such as pulmonic stenosis.
Large defects with excessive pulmonary blood flow and pulmonary hypertension are responsible for dyspnea, feeding difficulties, poor growth, profuse perspiration, recurrent pulmonary infections, and cardiac failure in early infancy. Cyanosis is usually absent, but duskiness is sometimes noted during infections or crying. Prominence of the left precordium and sternum is common, as are cardiomegaly, a palpable parasternal lift, an apical thrust, and a systolic thrill. The holosystolic murmur may be similar to that of smaller defects, although it is usually less harsh and more blowing iature due to the absence of a significant pressure gradient across the defect. It is even less likely to be audible in the newborn period. The pulmonic component of the 2nd heart sound may be increased, indicating pulmonary hypertension. The presence of a mid-diastolic, low-pitched rumble at the apex is caused by increased blood flow across the mitral valve and indicates a left-to-right shunt of approximately 2:1 or greater. This murmur is best appreciated with the bell of the stethoscope. In large VSDs, the chest roentgenogram shows gross cardiomegaly with prominence of both ventricles, the left atrium, and pulmonary artery. The pulmonary vascular markings are increased and frank pulmonary edema may be present. Pleural effusions may be present. The electrocardiogram shows biventricular hypertrophy; P waves may be notched or peaked.
DIAGNOSIS. The two-dimensional echocardiogram will show the position and size of the VSD. In very small defects, especially of the muscular septum, the defect itself may be difficult to image and is only visualized by color Doppler examination. A thin membrane (ventricular septal aneurysm) consisting of tricuspid valve tissue can partially cover the defect and limit the amount of the left-to-right shunt. The echo is also useful in estimating the shunt size by examining the degree of volume overload of the left atrium and left ventricle; the extent of their increased dimensions reflects the size of the left-to-right shunt. Pulsed Doppler examination will show if the VSD is pressure restrictive by calculating the pressure gradient across the defect. This will allow estimation of right ventricular pressure and help to determine whether the patient is at risk for the development of early pulmonary vascular disease.
The effects of a VSD on the circulation can also be demonstrated by cardiac catheterization. However, this diagnostic procedure is not required in most cases. Catheterization is usually performed when a comprehensive clinical evaluation leaves continued uncertainty regarding the size of the shunt or when laboratory data do not fit well with the clinical findings. Catheterization is also useful for detecting the presence of associated cardiac defects.
When catheterization is performed, oximetry will demonstrate an increase in oxygen content in blood obtained from the right ventricle as compared with that from the right atrium; because some defects eject blood almost directly into the pulmonary artery, this increase is occasionally apparent only when pulmonary arterial blood is sampled (streaming). Small shunts may not result in a detectable increase in oxygen saturation in the right ventricle but may be demonstrated by indicator dilution tests. Small, restrictive defects are associated with normal right-sided heart pressures and pulmonary vascular resistance. Large, nonrestrictive defects are associated with equal or near-equal pulmonary and systemic systolic pressures. Pulmonary blood flow may be 2–4 times systemic blood flow. In these patients, the pulmonary vascular resistance will be only minimally elevated, because resistance is equal to the pressure divided by the flow. If Eisenmenger syndrome is present, pulmonary artery systolic and diastolic pressures will be elevated, the degree of left-to-right shunting will be minimal, and desaturation of blood in the left ventricle will be encountered. The size, location, and number of ventricular defects are demonstrated by left ventriculography. Contrast medium will pass across the defect(s) to opacify the right ventricle and pulmonary artery.
PROGNOSIS AND COMPLICATIONS. The natural course of a VSD depends to a large degree on the size of the defect. A significant number (30–50%) of small defects will close spontaneously, most frequently during the 1st yr of life. The vast majority of defects that close will do so before age 4 yr. These defects will often have ventricular septal aneurysms limiting the magnitude of the shunt. Most children with small defects remain asymptomatic without evidence of an increase in heart size, pulmonary arterial pressure, or resistance. One of the long-term risks for these patients is that of infective endocarditis. Endocarditis occurs in fewer than 2% of children with VSD, is more common in adolescents, and is rare in children under 2 yr of age. The risk is independent of the VSD size.
It is less common for moderate or large defects to close spontaneously, although even defects large enough to result in heart failure may become smaller and rarely will close completely. More commonly, infants with large defects have repeated episodes of respiratory infection and congestive heart failure despite optimal medical management. Heart failure may be manifested in many of these infants, primarily by failure to thrive. In some growth failure may be the only symptom. Pulmonary hypertension occurs as a result of high pulmonary blood flow. These patients are at risk for developing pulmonary vascular disease with time if the defect is not repaired.
A small number of patients with VSD develop acquired infundibular pulmonary stenosis, which then protects the pulmonary circulation from the short-term effects of pulmonary overcirculation and the long-term effects of pulmonary vascular disease. In these patients the clinical picture changes from that of a VSD with a large left-to-right shunt to a VSD with pulmonary stenosis. The shunt may diminish in size, become balanced, or even become a net right-to-left shunt. These patients must be distinguished from those who are developing Eisenmenger physiology.
TREATMENT. In patients with small defects, parents should be reassured of the relatively benigature of the lesion, and the child should be encouraged to live a normal life, with no restrictions of physical activity. Surgical repair is not recommended. As a protection against infective endocarditis, the integrity of primary and permanent teeth should be carefully maintained; antibiotic prophylaxis should be provided for dental visits (including cleanings), tonsillectomy, adenoidectomy, and other oropharyngeal surgical procedures as well as for instrumentation of the genitourinary and lower intestinal tracts. These patients can be followed by a combination of clinical examinations and occasional noninvasive laboratory tests until the defect has closed spontaneously. The electrocardiogram is an excellent means of screening these patients for possible pulmonary hypertension or pulmonic stenosis indicated by right ventricular hypertrophy.
In infants with a large VSD, medical management has two aims: to control congestive heart failure and to prevent the development of pulmonary vascular disease. These patients may show signs of repeated or chronic pulmonary disease and often fail to thrive. Therapeutic measures are aimed at the control of heart failure symptoms and the maintenance of normal growth. If early treatment is successful, the shunt may diminish in size with spontaneous improvement, especially during the 1st yr of life. The clinician must be alert to not confuse clinical improvement due to a decrease in defect size with clinical improvement due to the development of Eisenmenger physiology. Because surgical closure can be carried out at low risk in most infants, medical management should not be pursued in symptomatic infants after an unsuccessful trial. Furthermore, pulmonary vascular disease is prevented when surgery is performed within the 1st yr of life. Thus, large defects associated with pulmonary hypertension should be closed electively at between 6 and 12 mo of age, or earlier if symptoms warrant. Results of primary surgical repair are excellent, and complications resulting in long-term problems (e.g., residual ventricular shunts requiring reoperation or heart block requiring a pacemaker) are extremely rare. Pulmonary arterial banding with repair in later childhood is now reserved only for complicated cases. Surgical risks are higher for defects in the muscular septum, particularly apical defects and multiple (Swiss cheese-type) defects. These patients may require pulmonary arterial banding if symptomatic, with subsequent debanding and repair of multiple VSDs at an older age. Catheter occlusion devices are currently being tested to close apical muscular VSDs.
After obliteration of the left-to-right shunt the hyperdynamic heart becomes quiet, cardiac size decreases toward normal, thrills and murmurs are abolished, and pulmonary artery hypertension regresses. The patient’s clinical status improves markedly. Most infants begin to thrive and cardiac medications are no longer required. Catch-up growth occurs in the majority over the next 1–2 yr. In some instances after successful operation, systolic ejection murmurs of low intensity may persist for months. The long-term prognosis after surgery is excellent.
Patent Ductus Arteriosus (PDA)
During fetal life most of the pulmonary arterial blood is shunted through the ductus arteriosus into the aorta. Functional closure of the ductus normally occurs soon after birth, but if the ductus remains patent when pulmonary vascular resistance falls, aortic blood is shunted into the pulmonary artery. The aortic end of the ductus is just distal to the origin of the left subclavian artery, and the ductus enters the pulmonary artery at its bifurcation. Female patients outnumber males 2:1. PDA is one of the most common congenital cardiovascular anomalies associated with maternal rubella infection during early pregnancy. It is a common problem ieonatal intensive care units, where it has several major sequelae in the premature infant.
When a term infant is found to have PDA, there is deficiency of both the mucoid endothelial layer and the muscular media of the ductus. In the premature infant, however, the patent ductus usually has a normal structural anatomy; in these infants patency is the result of hypoxia and immaturity. Thus a PDA persisting beyond the 1st few weeks of life in a term infant will rarely close spontaneously, whereas in the premature infant, if early pharmacologic or surgical intervention was not required, spontaneous closure would occur in most instances. An obligatory PDA is seen in 10% of patients with other congenital heart lesions. An isolated PDA is also more common in patients born at high altitude.
PATHOPHYSIOLOGY. As a result of the higher aortic pressure, blood flow through the ductus goes from the aorta to the pulmonary artery. The extent of the shunt depends on the size of the ductus and on the ratio of pulmonary to systemic vascular resistances. In extreme cases, 70% of the left ventricular output may be shunted through the ductus to the pulmonary circulation. If the PDA is small, the pressures within the pulmonary artery, the right ventricle, and the right atrium are normal. However, if the PDA is large, pulmonary artery pressures may be elevated to systemic levels during both systole and diastole. These patients are at extremely high risk of developing pulmonary vascular disease if left unoperated. There is a wide pulse pressure due to runoff of blood into the pulmonary artery during diastole.
CLINICAL MANIFESTATIONS. There are usually no symptoms associated with a small patent ductus. A large defect will result in congestive heart failure similar to that encountered in infants with a large VSD. Retardation of physical growth may be a major manifestation in infants with large shunts.
A large PDA will result in striking physical signs attributable to the wide pulse pressure, most prominently bounding arterial pulses. The heart is normal in size when the ductus is small but moderately or grossly enlarged in cases with a large communication. The apical impulse is prominent and, with cardiac enlargement, is heaving. A thrill, maximal in the 2nd left interspace, is often present and may radiate toward the left clavicle, down the left sternal border or toward the apex. It is usually systolic but also may be palpated throughout the cardiac cycle. The classic continuous murmur has been variously described as being like machinery, a humming top, or rolling thunder in quality. It begins soon after onset of the 1st sound, reaches maximal intensity at the end of systole, and wanes in late diastole. It may be localized to the 2nd left intercostal space or radiate down the left sternal border or to the left clavicle. When there is increased pulmonary vascular resistance, the diastolic component of the murmur may be less prominent or absent. In patients with a large left-to-right shunt, a low-pitched mitral mid-diastolic murmur may be audible, owing to the increased volume of blood flow across the mitral valve.
If the left-to-right shunt is small, the electrocardiogram is normal; if the ductus is large, left ventricular or biventricular hypertrophy is present. The diagnosis of an isolated, uncomplicated PDA is untenable when right ventricular hypertrophy is noted.
Roentgenographic studies commonly show a prominent pulmonary artery with increased intrapulmonary vascular markings. The cardiac size depends on the degree of left-to-right shunting; it may be normal or moderately to markedly enlarged. The chambers involved are the left atrium and ventricle. The aortic knob is normal or prominent.
The echocardiographic view of the cardiac chambers is normal if the ductus is small. With large shunts, left atrial and left ventricular dimensions are increased. The left atrial size is usually quantitated by comparison to the size of the aortic root, known as the LA:Ao ratio. Scanning from the suprasternal notch allows direct visualization of the ductus. Doppler examination will demonstrate systolic and/or diastolic retrograde turbulent flow in the pulmonary artery and aortic retrograde flow in diastole.
The clinical pattern is sufficiently distinctive to allow an accurate diagnosis by noninvasive methods in most patients. In patients with atypical findings, or when associated cardiac lesions are suspected, cardiac catheterization may be indicated. Cardiac catheterization demonstrates normal or increased pressures in the right ventricle and pulmonary artery, depending on the size of the ductus. The presence of oxygenated blood shunting into the pulmonary artery confirms a left-to-right shunt. Samples of blood from the venae cavae, right atrium, and right ventricle should have normal oxygen contents. The catheter may pass from the pulmonary artery through the ductus into the descending aorta. Injection of contrast medium into the ascending aorta shows opacification of the pulmonary artery from the aorta and identifies the ductus.
DIAGNOSIS. The diagnosis of uncomplicated PDA is usually not difficult. However, there are other conditions that, in the absence of cyanosis, produce systolic and diastolic murmurs in the pulmonic area and must be differentiated. The characteristics of a venous hum are described in Chapter 380. An aorticopulmonary window defect rarely may be clinically indistinguishable from a patent ductus, although in most cases the murmur is only systolic and is loudest at the right upper sternal border rather than at the left. Similarly, a sinus of Valsalva aneurysm that has ruptured into the right side of the heart or pulmonary artery, coronary arteriovenous fistulas, and an aberrant left coronary artery with massive collaterals from the right coronary display dynamics similar to that of the PDA with a continuous murmur and a wide pulse pressure. Sometimes the murmur is not maximal in the pulmonary area but is heard along the lower left sternal border. Truncus arteriosus with torrential pulmonary flow also has an “aortic runoff” physiology. Pulmonary branch stenosis can be associated with systolic and diastolic murmurs, but the pulse pressure will be normal. A peripheral arteriovenous fistula also results in a wide pulse pressure, but the distinctive murmur of a PDA is not present. VSD with aortic insufficiency and combined rheumatic aortic and mitral insufficiency may be confused with a PDA, but the murmurs should be differentiated by their to-and-fro rather than continuous nature. The combination of a large VSD and a PDA results in findings more like those in isolated VSD. Echocardiography should be able to eliminate these other diagnostic possibilities. If a ductus is suspected clinically but not visualized on echo, a cardiac catheterization is usually indicated.
PROGNOSIS AND COMPLICATIONS. Patients with a small PDA may live a normal span with few or no cardiac symptoms; however, late manifestations may occur. Spontaneous closure of the ductus after infancy is extremely rare. Congestive cardiac failure most often occurs in early infancy in the presence of a large ductus but may occur late in life even with a moderate-sized communication. The chronic left ventricular volume load is less well tolerated with aging.
Infective endarteritis may be seen at any age. Pulmonary or systemic emboli may occur. Rare complications include aneurysmal dilatation of the pulmonary artery or the ductus, calcification of the ductus, noninfective thrombosis of the ductus with embolization, and paradoxic emboli. Pulmonary hypertension (Eisenmenger syndrome) usually occurs in patients with a large PDA who do not undergo surgical treatment.
TREATMENT. Irrespective of age, patients with PDA require surgical closure. In patients with a small PDA, the rationale for closure is prevention of endarteritis or other late complications. In patients with a moderate to large PDA, closure is accomplished to treat congestive heart failure, and/or to prevent the development of pulmonary vascular disease. Once the diagnosis of PDA is made, surgical treatment should not be unduly postponed after adequate medical therapy of congestive cardiac failure has been instituted.
Because the case fatality rate with surgical treatment is considerably less than 1% and the risk without it is greater, ligation and division of the ductus are indicated in the asymptomatic patient, preferably before 1 yr of age. Pulmonary hypertension is not a contraindication to operation at any age if it can be demonstrated at cardiac catheterization that the shunt flow is still predominantly left-to-right and that severe pulmonary vascular disease is not present.
After closure, symptoms of frank or incipient cardiac failure rapidly disappear. There is usually immediate improvement in physical development of the infant who had failed to thrive. The pulse and blood pressure return to normal, and the machinery-like murmur disappears. A functional systolic murmur over the pulmonary area may occasionally persist; it may represent turbulence in a persistently dilated pulmonary artery. The roentgenographic signs of cardiac enlargement and pulmonary overcirculation will disappear over several months and the electrocardiogram becomes normal.
Transcatheter closure in the cardiac catheterization laboratory using either a Teflon plug, an occlusional umbrella, or intravascular coils has been successfully used in selected centers and eliminates the risks of surgery. A relatively new approach involves the use of thoracoscopic surgical techniques to ligate the ductus without the need for a large lateral thoracotomy.
Aorticopulmonary Window Defect
This defect consists of a communication between the ascending aorta and main pulmonary artery. The presence of pulmonary and aortic valves and an intact ventricular septum distinguishes this anomaly from truncus arteriosus. Symptoms similar to those of a large VSD or of PDA appear during early infancy and include recurrent pulmonary infections, congestive heart failure, and, occasionally, minimal cyanosis. The defect is usually large and the cardiac murmur is systolic with a mid-diastolic rumble, reflecting the increased blood flow across the mitral valve. In the rare instance when the communication is somewhat smaller and pulmonary hypertension is absent, the signs can mimic a PDA; a wide pulse pressure, cardiac enlargement, and a right and left upper sternal border continuous murmur may be present. The electrocardiogram shows either left or biventricular hypertrophy. Roentgenographic studies demonstrate cardiac enlargement and prominence of the pulmonary artery and intrapulmonary vasculature. The echocardiogram shows large-volume left-sided heart chambers, and the window defect can often be delineated, especially with color flow Doppler.
Cardiac catheterization reveals a left-to-right shunt at the level of the pulmonary artery, as well as hyperkinetic pulmonary hypertension, because the defect is almost always large. Selective aortography with injection of contrast medium into the ascending aorta demonstrates the lesion, and manipulation of the catheter from the main pulmonary artery directly to the ascending aorta and brachiocephalic vessels is also diagnostic.
The aorticopulmonary window defect is surgically corrected during infancy using cardiopulmonary bypass. If surgery is not carried out in infancy, survivors carry the risk of progressive pulmonary vascular obstructive disease, similar to that of other patients who have large intracardiac or great vessel communications.
Pulmonary Valve Stenosis with Intact Ventricular Septum
Various forms of right ventricular outflow obstruction with intact ventricular septum exist. The most common is valvular pulmonary stenosis. In this entity the valve cusps are deformed to various degrees, resulting in incomplete opening during systole. The valve may be bicuspid or tricuspid with the leaflets partially fused together and with an eccentric outlet. This fusion may be so severe as to leave only a pinhole central opening. If the valve is not severely thickened, it produces a domelike obstruction to right ventricular outflow during systole. Isolated infundibular stenosis, supravalvular pulmonary stenosis, and branch pulmonary artery stenosis are less commonly encountered. In some instances when pulmonary valve stenosis is the dominant lesion, a small associated VSD is present, and this condition is better classified as pulmonary stenosis with VSD than as tetralogy of Fallot. In addition, pulmonary stenosis and ASD are occasionally seen as associated defects. The clinical and laboratory findings will reflect the dominant lesion, but it is important to rule out these associated anomalies. Pulmonary stenosis as a result of valve dysplasia is the common cardiac abnormality of Noonan syndrome.
PATHOPHYSIOLOGY. The obstruction to outflow from the right ventricle to the pulmonary artery results in increased systolic pressure and wall stress, leading to hypertrophy of the right ventricle. The severity of these abnormalities depends on the size of the restricted valvular opening. In severe cases, right ventricular pressure may be much higher than systemic systolic pressure, whereas in milder obstruction right ventricular pressure is only mildly or moderately elevated. Pulmonary arterial pressure is normal or decreased. Arterial oxygen saturation will be normal unless there is an intracardiac communication, such as a VSD or ASD. In severe pulmonic stenosis, markedly decreased right ventricular compliance may lead to right-to-left shunting at the atrial level through a foramen ovale. This is seen most often in the neonate and is referred to as critical pulmonic stenosis.
CLINICAL MANIFESTATIONS. With mild or moderate stenosis there are usually no symptoms. Growth and development are most ofteormal, and usually older infants and children with pulmonary stenosis appear to be especially well developed and healthy. If the stenosis is severe, there may be signs of right-ventricular failure and exercise intolerance. In the neonate or young infant with critical pulmonic stenosis, signs of right ventricular failure may be more prominent and cyanosis is often present due to shunting at the foramen ovale.
With mild pulmonary stenosis the venous pressure and pulse are normal. The heart is not enlarged; the apical impulse is normal, and the right ventricular impulse is not palpable. A relatively short pulmonary systolic ejection murmur is maximally audible over the pulmonic area and may radiate minimally to the lung fields bilaterally. The murmur is usually preceded by a pulmonic ejection click, which is heard best at the left upper sternal border during expiration. The 2nd heart sound is split with a pulmonary element of normal intensity that may be slightly delayed. The electrocardiogram is normal or characteristic of mild right ventricular hypertrophy; there may be inversion of the T waves in the right precordial leads. The only abnormality demonstrable roentgenographically is poststenotic dilatation of the pulmonary artery. Two-dimensional echocardiography shows right ventricular hypertrophy, a domed valve, and Doppler studies demonstrate a right ventricular–pulmonary artery gradient of
In moderate pulmonic stenosis the venous pressure may be slightly elevated, with an intrinsic “a” wave noted in the jugular pulse. A right ventricular lift may be palpable at the lower left sternal border. As the degree of stenosis worsens, the systolic ejection murmur is prolonged later into systole, and becomes louder and harsher (higher frequency). The murmur will radiate to both lung fields. With more severe limitation in valve motion, a pulmonic ejection click will not be appreciated. The 2nd heart sound is split, with a delayed and diminished pulmonary component that may not be audible. The electrocardiogram reveals varying degrees of right ventricular hypertrophy, sometimes with a prominent spiked P wave. Roentgenographically, the heart can vary from normal size to mildly enlarged because of prominence of the right ventricle; intrapulmonary vascularity may be normal or decreased. The echocardiogram will show a thickened pulmonic valve with restricted systolic motion. The Doppler exam will show a ventricular-pulmonary arterial pressure gradient in the 30{endash}–60 mm Hg range. Mild tricuspid regurgitation may be present and allows confirmation of the right ventricular systolic pressure.
In severe stenosis, mild to moderate cyanosis may be noted if there is an interatrial communication. If hepatic enlargement and peripheral edema are present, they are an indication of right ventricular failure. Elevation of the venous pressure is common and is caused by a large presystolic jugular “a” wave. The heart is moderately or greatly enlarged, and there is a conspicuous sternal and parasternal right ventricular lift that frequently extends to the midclavicular line. A loud and long systolic ejection murmur, frequently accompanied by a thrill, is maximally audible in the pulmonic area and may radiate widely over the entire precordium, to both lung fields, into the neck, and to the back. The peak of the murmur occurs later in systole as valve opening becomes more restricted (late systolic accentuation). The murmur frequently encompasses the aortic component of the 2nd sound but is not preceded by an ejection click. The pulmonary element of the 2nd sound is usually inaudible.
The electrocardiogram shows gross right ventricular hypertrophy, frequently accompanied by a tall, spiked P wave. Roentgenographic studies confirm the cardiac enlargement and prominence of the right ventricle and atrium. Prominence of the pulmonary artery segment is due to poststenotic dilatation. The intrapulmonary vascularity is decreased. The two-dimensional echocardiogram shows severe deformity of the pulmonary valve and right ventricular hypertrophy. In the late stages of the disease, dysfunction of the right ventricle is seen and the ventricle may become dilated. Doppler studies demonstrate a large gradient across the pulmonary valve. Tricuspid regurgitation may also be prominent. Fortunately, the classic findings of severe pulmonary stenosis in older children are now rarely seen because of early intervention. The signs of critical pulmonic stenosis are usually encountered in the neonatal period.
Cardiac catheterization demonstrates an abrupt pressure gradient across the pulmonary valve. The pulmonary arterial pressure is either normal or low. The severity is graded based on the right ventricular systolic pressure or the pressure gradient. A gradient of 10–30 mm Hg in mild cases, 30–60 mm Hg in moderate cases, and greater than
PROGNOSIS AND COMPLICATIONS. Congestive cardiac failure, the most common complication, occurs only in severe cases and most often during the 1st mo of life. The development of cyanosis from a right-to-left shunt across a foramen ovale is most often seen in infancy when the stenosis is very severe. Infective endocarditis is a risk but not common in childhood.
Children with mild or moderate stenosis can lead a normal life, but their progress should be evaluated at regular intervals. Patients who have small gradients rarely show progression and do not need intervention, but children having moderate stenosis are more likely to develop a more significant gradient as they grow older. Worsening of obstruction may also be due, in part, to the development of secondary subvalvular muscular and fibrous tissue hypertrophy. In untreated severe stenosis the course may abruptly worsen with the development of right ventricular dysfunction and cardiac failure. Infants with critical pulmonic stenosis require urgent catheter balloon valvuloplasty or surgical valvotomy.
TREATMENT. Patients with moderate or severe isolated pulmonary stenosis require relief of the obstruction. Balloon valvuloplasty is the initial treatment of choice for the vast majority of patients. Patients with severely thickened pulmonic valves, especially common in those with Noonan syndrome, may require surgical intervention instead. In the neonate with critical pulmonic stenosis, emergency treatment with either balloon valvuloplasty or surgical valvotomy is warranted.
Excellent results are obtained in the majority of instances. The gradient across the pulmonary valve is reduced markedly or abolished. In the early period after balloon valvuloplasty a small to moderate residual gradient may remain due to muscular infundibular narrowing; it nearly always resolves with time. A short early decrescendo diastolic murmur at the mid to upper left sternal border due to pulmonary valvular insufficiency may be heard. The degree of insufficiency is usually not clinically significant. There appears to be no difference between valvuloplasty and surgery in patient status at late follow-up, and recurrence is unusual after successful treatment.
Infundibular Pulmonary Stenosis and Double-Chamber Right Ventricle
Infundibular pulmonary stenosis is caused by muscular or fibrous obstruction in the outflow tract of the right ventricle. The site of obstruction may be close to the pulmonary valve or well below it; an infundibular chamber may be present between the right ventricular cavity and the pulmonary valve. In a significant number of cases, a VSD may have been present initially and later closed spontaneously. When the pulmonary valve is also stenotic, the combined defect is primarily classified as valvular stenosis with secondary infundibular hypertrophy. The hemodynamics and clinical manifestations of patients with isolated infundibular pulmonary stenosis are similar, for the most part, to those described under isolated valvular pulmonary stenosis.
A more common variation of right ventricular outflow obstruction below the pulmonary valve is that of double-chamber right ventricle. In this condition there is a muscular band in the mid right ventricular region, which divides the chamber into two parts and creates obstruction between the inlet and outlet portions. There is often an associated VSD that may close spontaneously. Obstruction is not usually seen early in life but may progress rapidly in a similar manner to the progressive infundibular obstruction observed with tetralogy of Fallot.
The diagnosis of isolated right ventricular infundibular stenosis or double-chamber right ventricle can be made by echocardiography and/or cardiac catheterization and angiography. At catheterization, when contrast material is injected into the right ventricle, the site of the stenosis is demonstrated. The ventricular septum must be evaluated to determine whether an associated VSD is present. The prognosis for untreated cases of severe right ventricular outflow obstruction is similar to that for valvular pulmonary stenosis. Thus, when obstruction is moderate to severe, surgery is indicated. After operation the pressure gradient is abolished or markedly reduced and the long-term outlook is excellent.
Peripheral Pulmonary Arterial Stenosis
Single or multiple constrictions may occur anywhere along the major branches of the pulmonary arteries and may be mild, extensive, localized, or multiple. Frequently, these defects are associated with other types of congenital heart disease, including valvular pulmonic stenosis, tetralogy of Fallot, PDA, VSD, ASD, and supravalvular aortic stenosis. A familial tendency has been recognized in some patients with peripheral pulmonic stenosis. A high incidence is found in infants with the congenital rubella syndrome. Supravalvular aortic stenosis with pulmonary arterial branch stenosis has also been observed with idiopathic hypercalcemia of infancy (Williams syndrome).
With a mild constriction there is little effect on the pulmonary circulation. With multiple severe constrictions there is an increase in pressure in the right ventricle and in the pulmonary artery proximal to the site of obstruction. When the anomaly is isolated, the diagnosis is suspected by the presence of murmurs in widespread locations over the chest, both anteriorly or posteriorly. These murmurs are usually systolic but may be continuous. Most often, the physical signs are dominated by the associated anomaly, such as tetralogy of Fallot. If the stenosis is severe, there is electrocardiographic evidence of right ventricular and right atrial hypertrophy.
In the immediate newborn period, a mild and transient form of peripheral pulmonic stenosis may be present. Physical findings are usually limited to a soft systolic ejection murmur, which can be heard over either or both lung fields. It is the absence of other physical findings of valvular pulmonic stenosis (right ventricular lift, soft pulmonic second sound, systolic ejection click, murmur loudest at the upper left sternal border) that supports this diagnosis. This murmur will usually disappear by 1{endash}–2 mo.
On roentgenogram, cardiomegaly and prominence of the main pulmonary artery are present in severe cases. Generally, the pulmonary vasculature is normal; in some cases small intrapulmonary vascular shadows are seen, which may be shown by pulmonary arteriography to be areas of poststenotic dilatation. Pressure gradients across the areas of obstruction are demonstrable by cardiac catheterization. These gradients may not be easily identified if right ventricular outflow obstruction coexists, as the pressure in the main pulmonary artery is normal or low in such patients.
Severe obstruction of the main pulmonary artery and its primary branches can be relieved during corrective surgery for associated lesions such as tetralogy of Fallot or valvular pulmonary stenosis. If peripheral pulmonic stenosis is isolated, it may be treated by catheter balloon dilatation. When peripheral obstruction occurs distally in the intrapulmonary vessels, it is usually not amenable to surgical repair. These obstructions are often multiple and are best treated with repeat balloon angioplasty, although there is a high rate of recurrence. The more recent introduction of expandable intravascular stents, placed by catheter in the distal pulmonary arteries, and then dilated with a balloon to the appropriate size, may prevent restenosis.
Aortic Stenosis
PATHOPHYSIOLOGY. Congenital aortic stenosis accounts for about 5% of cardiac malformations recognized in childhood, but an abnormality of the aortic valve (bicuspid) is one of the most common congenital heart lesions identified in adults. Aortic stenosis is more common in males (3:1). In most cases, aortic stenosis is valvular, the leaflets are thickened, and the commissures are fused to varying degrees.
Subvalvular (subaortic) stenosis with a discrete fibrous shelf below the aortic valve is also an important form of left ventricular outflow tract obstruction. This lesion is frequently associated with other forms of congenital heart disease and is notable for rapid progression in severity. It is virtually never diagnosed during early infancy and may develop despite prior documentation of no left ventricular outflow tract gradient. Subvalvular aortic stenosis may become apparent after successful surgery for other congenital heart defects (e.g., coarctation of the aorta, PDA, and VSD), may develop in association with mild lesions that have not been surgically repaired, and may occur as an isolated abnormality.
Supravalvular aortic stenosis, a less common type, may be sporadic, familial, or associated with Williams syndrome, which includes mental retardation, elfin facies (full face, broad forehead, flattened bridge of nose, long upper lip, and rounded cheeks) and idiopathic hypercalcemia of infancy. Stenoses of other arteries may also be present.
CLINICAL MANIFESTATIONS. Symptomatology among patients with aortic stenosis depends on the severity of the obstruction. Aortic stenosis that presents in early infancy is termed critical aortic stenosis and is associated with severe left ventricular failure. These infants present with signs of low cardiac output. Congestive heart failure, cardiomegaly, and pulmonary edema are severe, and the pulses are weak in all extremities. Urine output may be diminished. Because the cardiac output is decreased, the intensity of the murmur at the right upper sternal border may be minimal. In contrast, most children with less severe forms of aortic stenosis will remain asymptomatic and display a normal growth and development pattern. The murmur is usually discovered during routine physical examination. Rarely, an older child with previously undiagnosed severe obstruction to left ventricular outflow will present with fatigue, angina, dizziness, or syncope. Sudden death has been reported with aortic stenosis but usually occurs in patients with severe left ventricular outflow obstruction in whom surgical relief has been delayed.
The physical findings are dependent on the degree of obstruction to left ventricular outflow. In mild stenosis, the pulses, heart size, and apical impulse are all normal. With increasing degrees of severity, the pulses will become diminished in intensity and the heart may be enlarged with a left ventricular apical thrust. In mild to moderate valvular aortic stenosis, there is usually an early systolic ejection click, best heard at the apex and left sternal edge. Unlike the click associated with pulmonic stenosis, its intensity does not vary with respirations. Clicks are unusual in more severe aortic stenosis or in discrete subaortic stenosis. In severe stenosis the 1st heart sound may be diminished due to decreased compliance of the thickened left ventricle. Normal splitting of the 2nd heart sound is present in mild to moderate obstruction. In patients with severe obstruction, the intensity of aortic valve closure is diminished and, rarely in children, the 2nd sound may be split paradoxically (becoming wider in expiration). A 4th heart sound may be audible when the obstruction is severe.
The intensity, frequency, and duration of the systolic ejection murmur is another indication of severity. Generally, the louder, harsher (higher frequency), and longer the murmur, the greater the degree of obstruction. The typical murmur is audible maximally at the right upper sternal border and radiates to the neck and down the left sternal border. It is usually accompanied by a thrill in the suprasternal notch. In patients with subvalvular aortic stenosis, the murmur may be maximal along the left sternal border or even at the apex. A soft decrescendo diastolic murmur indicative of mild aortic insufficiency is often present when the obstruction is subvalvular or in patients with a bicuspid aortic valve. Occasionally, an apical short mid-diastolic rumbling murmur is audible, even in the presence of a normal mitral valve; however, this should always raise the suspicion of associated mitral stenosis.
DIAGNOSIS. The diagnosis can usually be made on the basis of the physical examination, and the severity of obstruction is confirmed by laboratory tests. If the pressure gradient across the aortic valve is small, the electrocardiogram (ECG) is likely to be normal. The ECG may occasionally be normal, even with more severe obstruction, but evidence of left ventricular hypertrophy and strain (e.g., inverted T waves in the left precordial leads) is usually present if severe stenosis is long-standing. Roentgenograms frequently show a prominent ascending aorta, but the aortic knob is normal. The heart size is usually normal. Valvular calcification has beeoted only in older children. Echocardiography will identify both the site and severity of the obstruction. Two-dimensional imaging will show left ventricular hypertrophy, the thickened and domed aortic valve, the number of valve leaflets, and a subaortic membrane, if present. Associated anomalies of the mitral valve or aortic arch will be detected. In the absence of left ventricular failure, the shortening fraction of the left ventricle may be increased because the ventricle is hypercontractile. In infants with critical aortic stenosis, the left ventricular shortening is usually decreased and the endocardium may be bright, indicating the development of endocardial fibroelastosis (see Chapter 395). Doppler studies will show the specific site of obstruction and determine the peak systolic left ventricular outflow tract gradient. When severe aortic obstruction is associated with left ventricular dysfunction, the Doppler-derived aortic valve gradient may not reflect the severity of the obstruction due to the low cardiac output.
Graded exercise testing is useful in evaluating the severity of left ventricular outflow tract obstruction in older children. As the severity of the gradient increases, working capacity decreases, systolic blood pressure fails to rise adequately, diastolic blood pressure may rise, and ST-segment depression can occur. Because patients with severe aortic stenosis may deny symptoms and have normal electrocardiograms and chest roentgenograms, serial echocardiograms and graded exercise tests may be valuable in determining the timing of cardiac catheterization and surgical or balloon catheter valvuloplasty.
Left heart cardiac catheterization demonstrates the magnitude of the pressure gradient from the left ventricle to the aorta. The site of obstruction is best identified by selective left ventriculography. The aortic pressure curve is abnormal if obstruction is severe. In patients with severe obstruction and decreased left ventricular compliance, the left atrial pressure is increased and there may be pulmonary hypertension. Most infants with critical aortic stenosis do not require diagnostic cardiac catheterization. When a critically ill infant with left ventricular outflow tract obstruction undergoes cardiac catheterization, left ventricular function is often markedly decreased. As with the echocardiogram, the gradient measured across the stenotic aortic valve may be less than severe because of low cardiac output. Actual measurement of the cardiac output by thermodilution and calculation of valve area is helpful in these cases.
PROGNOSIS. The prognosis is good in most children with mild to moderate aortic stenosis. In a small number of patients having a severe obstruction, sudden death has occurred. In such instances there is usually evidence of gross left ventricular hypertrophy. Neonates having critical aortic stenosis who die from congestive heart failure frequently have endocardial fibroelastosis of the left ventricle. Infants who present after the 1st wk or two of life respond well to relief of stenosis, and left ventricular function improves. Reoperations on the aortic valve are often required later in childhood or in adult life, and many patients will eventually require valve replacement.
There may be some danger in allowing patients with significant aortic stenosis to participate in active competitive sports, but otherwise they should lead normal lives. The status of each patient should be reviewed annually and intervention advised if progression of signs or symptoms occurs. Lifetime prophylaxis against infective endocarditis is required.
TREATMENT. Balloon valvuloplasty is indicated for children having moderate to severe valvular aortic stenosis to prevent progressive left ventricular dysfunction and the risks of syncope and sudden death. It is generally agreed that valvuloplasty should be advised when the peak systolic gradient between the left ventricle and aorta exceeds
In the neonatal period, balloon valvuloplasty is made more difficult by problems of arterial access. The risk of femoral arterial complications is much higher than in older children, although the development of low-profile balloons has reduced this risk substantially. Currently, both surgical and catheter approaches are being used at different centers for critical aortic stenosis in the newborn period.
Discrete subaortic stenosis can be resected without damage to the aortic valve, the anterior leaflet of the mitral valve, or the conduction system. This type of obstruction is usually not easily amenable to catheter treatment. Relief of supravalvular stenosis is also achieved surgically, and the results are excellent if the area of obstruction is discrete and is not associated with a hypoplastic aorta.
After either catheter or surgical relief of aortic stenosis, recurrence of obstruction or development of aortic insufficiency is common. When recurrence occurs it may not be associated with early symptoms. Signs of recurrent stenosis include electrocardiographic signs of left ventricular hypertrophy, increase in echo Doppler gradient, deterioration of echocardiographic indices of left ventricular function, and recurrence of signs or symptoms during graded exercise. Evidence of significant aortic regurgitation includes symptoms of congestive heart failure, cardiac enlargement on roentgenogram, and left ventricular dilatation on echocardiogram. The choice of reparative procedure depends on the relative degrees of stenosis and regurgitation.
When aortic valve replacement is necessary, the choice of procedure often depends on the age of the patient. Porcine and homograft valves tend to calcify more rapidly in younger children; however, they do not require chronic anticoagulation. In contrast, mechanical prosthetic valves are much longer lasting, yet require anticoagulation, which can be difficult to manage in young children. In adolescent girls who are nearing childbearing age, consideration of the teratogenic effects of warfarin may warrant the use of a homograft valve. None of these options is perfect for the younger child who requires valve replacement, because they will not grow with the patient. An operation being used by many centers is aorto-pulmonary translocation—{emdash}the Ross procedure. This involves removing the pulmonary valve and using it to replace the abnormal aortic valve. A homograft valve is then placed in the pulmonary position. The possible advantage of this procedure is the potential for growth of the translocated “neo-aortic” valve and the longer longevity of the homograft valve when placed in the lower pressure pulmonary circulation.
Coarctation of the Aorta
Constrictions of the aorta of varying degrees may occur at any point from the transverse arch to the iliac bifurcation, but 98% occur just below the origin of the left subclavian artery at the origin of the ductus arteriosus (juxtaductal coarctation). The anomaly occurs twice as often in males as in females. Coarctation of the aorta may be a feature of Turner (XO) syndrome (see Chapter 538) and is associated with bicuspid aortic valve in over 70% of patients. Mitral valve abnormalities, for example, a supravalvar mitral ring or parachute mitral valve, and subaortic stenosis are not uncommon associated lesions. When this group of left-sided obstructive lesions occurs together, they are referred to as Shone complex.
PATHOPHYSIOLOGY. Coarctation of the aorta can occur as a discrete juxtaductal obstruction or as a tubular hypoplasia of the transverse aorta starting at one of the head or neck vessels and extending to the ductal area (preductal coarctation). Often, both components are present. It is postulated that coarctation is initiated in fetal life by the presence of a cardiac abnormality that results in decreased blood flow anterograde through the aortic valve (e.g., bicuspid aortic valve, VSD).
After birth, in a discrete juxtaductal coarctation, ascending aortic blood will flow through the narrowed segment to reach the descending aorta, although left ventricular hypertension and hypertrophy will result. In the 1st few days of life, the patent ductus arteriosus may serve to widen the juxtaductal area of the aorta and provide a temporary relief from the obstruction. In these infants net left-to-right ductal shunting occurs and they are acyanotic. In contrast, with more severe juxtaductal coarctation or in the presence of transverse arch hypoplasia, right ventricular blood is ejected through the ductus to supply the descending aorta, as it does during fetal life. Perfusion of the lower body is then dependent on right ventricular output (Fig. 386–{endash}6 Fig. 386–{endash}6). In this situation the femoral pulses are palpable, and differential blood pressures may not be helpful in making the diagnosis. However, the ductal right-to-left shunting will be manifest as differential cyanosis, with the upper extremities pink and the lower extremities blue.
Such infants may have severe pulmonary hypertension and high pulmonary vascular resistance. Signs of heart failure are prominent. Occasionally, severely hypoplastic segments of the aortic isthmus may become completely atretic, resulting in an interrupted aortic arch with the left subclavian artery arising either proximal or distal to the interruption. In the past, coarctation associated with arch hypoplasia was referred to as “infantile type” because it usually presented in early infancy due to its severity. “Adult type” referred to the isolated juxtaductal coarctation, which, if mild, usually did not present until later childhood. These terms have been replaced with the more accurate anatomic terms mentioned earlier describing the location and severity of the defect.
The blood pressure is elevated in the vessels that arise proximal to the coarctation; the blood pressure as well as pulse pressure below the constriction are lower. Hypertension is not due to the mechanical obstruction alone, but also involves renal mechanisms. Unless operated on in infancy, coarctation of the aorta usually results in the development of an extensive collateral circulation, chiefly from the branches of the subclavian, the superior intercostal, and the internal mammary arteries. The thoracic and subscapular branches of the axillary artery may also enlarge as collateral channels. These vessels unite with the intercostal branches of the descending aorta and inferior epigastric branches of the femoral artery to create channels for arterial blood to bypass the area of coarctation. The vessels contributing to the collateral circulation may become markedly enlarged and tortuous by early adulthood.
CLINICAL MANIFESTATIONS. Coarctation of the aorta recognized after infancy rarely is associated with significant symptomatology. An occasional child will complain about weakness and/or pain in the legs after exercise, but in most instances even patients with severe coarctation will be asymptomatic. Older children are frequently brought to the cardiologist’s attention when found to be hypertensive on a routine physical examination.
The classic sign of coarctation of the aorta is a disparity in pulsations and blood pressures of the arms and legs. The femoral, popliteal, posterior tibial, and dorsalis pedis pulses are weak (or absent in 40% of patients), in contrast to the bounding pulses of the arms and carotid vessels. The radial and femoral pulses should always be palpated simultaneously for the presence of a radial-femoral delay. Normally, the femoral pulse occurs slightly before the radial pulse. A radial-femoral delay occurs when blood flow to the descending aorta is dependent on collaterals; thus the femoral pulse will be felt after the radial pulse. Iormal persons the systolic blood pressure in the legs obtained by the cuff method is 10{endash}–20 mm Hg higher than that in the arms. In coarctation of the aorta the blood pressure in the legs is lower than that in the arms; frequently, it is difficult to obtain. This differential in blood pressures is common in patients with coarctation over 1 yr of age, about 90% of whom have systolic hypertension in an upper extremity greater than the 95th percentile for age. It is very important to determine the blood pressure in each arm; a pressure higher in the right arm than the left suggests involvement of the left subclavian artery in the area of coarctation. Occasionally, the right subclavian may arise anomalously from below the area of coarctation, resulting in a left arm pressure higher than the right. With exercise, there is a more prominent rise of systemic blood pressure and the upper-to-lower extremity pressure gradient will increase.
The precordial impulse and heart sounds are usually normal; however, the presence of a systolic ejection click or thrill in the suprasternal notch suggests the presence of a bicuspid aortic valve. A short systolic murmur is often heard along the left sternal border at the 3rd and 4th intercostal spaces. The murmur is well transmitted to the left infrascapular area and occasionally to the neck. Often, the typical murmur of mild aortic stenosis can be heard in the 3rd right intercostal space. Occasionally more significant degrees of obstruction across the aortic valve will be present. The presence of a low-pitched mid-diastolic murmur at the apex suggests the presence of mitral valve stenosis. Among older patients with well-developed collateral blood flow, systolic or continuous murmurs may be heard over the left and right sides of the chest laterally and posteriorly. In these patients, a palpable thrill can occasionally be appreciated in the intercostal spaces on the back.
In contrast, neonates or infants with more severe coarctation, usually including some degree of transverse arch hypoplasia, will usually present with signs of lower body hypoperfusion, acidosis, and severe heart failure. This presentation may be delayed until after closure of the ductus arteriosus. If detected before ductal closure, patients may exhibit differential cyanosis, best demonstrated by simultaneous transcutaneous oximetry of upper and lower extremities. On physical examination, the heart is large, and there is a systolic murmur heard along the left sternal border with a loud 2nd heart sound.
DIAGNOSIS. The findings on roentgenographic examination depend on the age of the patient and on the effects of hypertension and collateral circulation. In infants with severe coarctation there is cardiac enlargement and pulmonary congestion. During childhood the findings are not striking until after the 1st decade, when the heart tends to be mildly or moderately enlarged because of left ventricular prominence. The enlarged left subclavian artery commonly produces a prominent shadow in the left superior mediastinum. Notching of the inferior border of the ribs from pressure erosion by enlarged collateral vessels is common by late childhood, except in the upper and lower ribs. In most instances there is an area of poststenotic dilatation of the descending aorta. On a barium esophogram, this may be demonstrated by displacement of the esophagus and by discontinuity of the lateral margin of the aorta below the arch.
The electrocardiogram is usually normal in young children but reveals evidence of left ventricular hypertrophy in older patients. Neonates and young infants will display right or biventricular hypertrophy. Most often, the diagnosis can be made by a careful evaluation of the pulses in all major accessible peripheral arteries and by comparative blood pressure determinations in the arms and legs. The segment of coarctation can usually be visualized by two-dimensional echocardiography; associated anomalies of the mitral and aortic valve can also be demonstrated, if present. The descending aorta will be hypopulsatile. Color Doppler is useful for demonstrating the specific site of the obstruction. Pulsed and continuous-wave Doppler will determine the pressure gradient directly at the area of coarctation. However, in the presence of a patent ductus arteriosus, the pressure gradient may be underestimated. Cardiac catheterization with selective left ventriculography and aortography is useful in selected patients with additional anomalies and as a means of visualizing collateral blood flow. In cases well defined by echocardiography, diagnostic catheterization is usually not required.
PROGNOSIS AND COMPLICATIONS. Abnormalities of the aortic valve are present in most patients. Bicuspid aortic valves are common but usually do not produce clinical signs unless the stenosis is significant. The association of a PDA and coarctation of the aorta is also common. Ventricular and atrial septal defects may be suspected by signs of a left-to-right shunt. Mitral valve abnormalities are also occasionally seen, as is subvalvular aortic stenosis.
Severe neurologic damage or even death rarely may occur from associated cerebrovascular disease. Subarachnoid or intracerebral hemorrhage may result from rupture of congenital aneurysms in the circle of Willis, of other vessels with defective elastic and medial tissue, or of normal vessels; these accidents are secondary to the hypertensive state. Abnormalities of the subclavian arteries may include involvement of the left subclavian artery in the area of coarctation, stenosis of the orifice of the left subclavian artery, and anomalous origin of the right subclavian artery.
Untreated, the great majority of older patients with coarctation of the aorta would succumb between the ages of 20 and 40 yr; some live well into middle life without serious handicap. The common serious complications are related to the hypertensive state, which may result in premature coronary artery disease, congestive heart failure, hypertensive encephalopathy, or intracranial hemorrhage. Heart failure may be worsened by associated anomalies. Infective endocarditis or endarteritis is a significant complication in adults. Aneurysms of the descending aorta or of the enlarged collateral vessels are not unusual. In infants with severe coarctation, congestive heart failure, and hypoperfusion may be life threatening and require immediate medical intervention.
TREATMENT. In neonates with severe coarctation of the aorta, closure of the ductus often results in hypoperfusion, acidosis, and rapid deterioration. These patients should be started on an infusion of prostaglandin E1 in an attempt to reopen the ductus and re-establish adequate lower extremity blood flow. Once a diagnosis has been confirmed and the patient stabilized hemodynamically, surgical repair should be performed. Older infants who present with congestive heart failure but who are not hypoperfused should be managed with anticongestive measures to improve their clinical status prior to surgical intervention.
Older children with significant coarctation of the aorta should be treated relatively soon after diagnosis. Delay is unwarranted, especially after the 2nd decade, when the operation may be less successful because of decreased left ventricular function and degenerative changes. Nevertheless, if cardiac reserve is sufficient, satisfactory repair is possible well into midadult life. Associated valvular lesions increase the hazards of late surgery.
The procedure of choice for isolated juxtaductal coarctation of the aorta is controversial. In many centers, operation is the procedure of choice, and several surgical techniques are used. The area of coarctation can be excised and a primary reanastomosis performed. Often the transverse aorta can be splayed open and a side-to-end anastomosis performed to increase the effective cross-sectional area of the repair. The subclavian flap procedure, which involves division of the left subclavian artery and its incorporation into the wall of the repaired coarctation, is used by some centers, often in the younger age group. Other centers favor a patch aortoplasty, in which the area of coarctation is enlarged with a roof of prosthetic material. Rarely, if the length of aortic constriction precludes primary anastomosis, a homograft or Dacron graft may be utilized.
After operation there is a striking increase in the amplitude of pulsations in the lower extremities. In the immediate postoperative course, “rebound” hypertension is common and usually requires medical management. This exaggerated hypertension gradually subsides and in most patients antihypertensive medications can be discontinued. Residual murmurs are common and may be due to associated cardiac anomalies, to a residual flow disturbance across the repaired area, or to collateral blood flow. Rare additional operative problems include spinal cord injury due to aortic cross-clamping if there are poorly developed collaterals, chylothorax, diaphragm injury, and laryngeal nerve injury. If a left subclavian flap is employed, the radial pulse and blood pressure in the left arm will be diminished or absent.
In some centers, balloon angioplasty has been used for treatment of “native” or unoperated coarctation. Early reports of results in these patients indicate good relief of the obstruction; however, several have reported the subsequent development of aortic aneurysms. Revised techniques have reduced the incidence of this complication, although the use of angioplasty iative coarctation remains controversial.
Repair of coarctation in the 2nd decade of life or beyond may be associated with a higher incidence of premature cardiovascular disease, even in the absence of residual cardiac abnormalities. There may be early onset of adult hypertension, which has occurred even in patients with adequately resected coarctation.
Although restenosis in older patients who had an adequate coarctectomy is extremely rare, a number of infants with end-to-end anastomoses carried out urgently in the 1st mo of life require revision later in childhood. Long-term follow-up is still incomplete; thus, all patients should be followed carefully for development of recoarctation. Should recoarctation occur, balloon angioplasty is the procedure of choice. In these patients, scar tissue from prior surgery makes reoperation more difficult yet makes balloon angioplasty safer because of the lower incidence of aneurysm formation. Relief of obstruction with this technique is usually excellent.
POSTCOARCTECTOMY SYNDROME. Postoperative mesenteric arteritis may be associated with hypertension and abdominal pain in the immediate postoperative period. The pain varies in severity and may be associated with anorexia, nausea, vomiting, leukocytosis, intestinal hemorrhage, bowel necrosis, and small bowel obstruction. Relief is usually obtained with antihypertensive drugs (nitroprusside, esmolol, captopril) and intestinal decompression; corticosteroids may help to alleviate the symptoms and thus avoid surgical exploration for bowel obstruction.
CONGENITAL KIDNEY DISEASES
Congenital means present at birth, so generally refers to those abnormalities that are
permanent birth defects. There are many different kinds and categories:
* Primary defects of the kidney tissue (parenchymal disease)
* Obstruction of the urinary tract (hydronephrosis with obstruction)
* Hydronephrosis without obstruction, including vesicoureteral reflux
* Cystic diseases
* Metabolic diseases
* Syndromes
Primary defects of kidney tissue (parenchymal disease)
In this group of problems of the kidney parenchyma (parenchyma refers to the kidney tissue in general), the basic structure of the kidney looks normal on ultrasound or on an X-ray image, but for some reason on a microscopic level something is wrong and the kidneys don’t work right. The most common problem of this class is renal dysplasia, which is a condition of both kidneys where the tissue is partly normal with some normal filters
(glomeruli) but laced throughout the kidney is fibrosis (like scar tissue), abnormal cell groups such as little pieces of cartilage, and immature tissue where the kidney just didn’t finish developing. There are all levels of severity of this defect, so there are babies who have very poor kidney function at birth and need major support, even sometimes including dialysis, from that time, and there are other children whose kidneys support them through much of life but then eventually as the body grows the kidneys just don’t have enough functional tissue to support it. Occasionally there is a baby with very severe dysplasia and no kidney function at all as a result. In this case, no urine is made in utero either. Since in the last 2/3 of pregnancy the amniotic fluid comes from fetal urine, and since lung formation is dependent on breathing in amniotic fluid, the lungs of these babies with very severe dysplasia may be very underdeveloped, and they may not be able to survive more than a few hours after birth because of their poor lung function. This can also be true with severe obstruction (discussed below) and severely damaged kidneys as a result.
Renal dysplasia is sometimes part of a syndrome, whereby other defects of other organ systems occur simultaneously with the dysplasia (see syndromes).
When children are young (the first months and preschool years especially) with renal dysplasia often the most prominent defect is the inability to concentrate the urine.
The normal kidney has about a million filters, each of which filters the blood and a filtrate in which the waste products and other (electrolyte, mineral and chemical) constituents of blood start down the tubule in a concentration equal to that of blood. The tubule has multiple segments, each with a specific job, and as the filtrate travels down the tubule, water and the other constituents are reabsorbed into blood as needed, so that the final urine is concentrated compared to the initial filtrate of blood. The tubule fine tunes how much sodium and potassium and phosphorus and other substances are kept in the filtrate (urine) as opposed to reabsorbed back into blood. To give you an idea of the work of the tubule, in an adult
When the child has dysplasia, the tubules are affected, and they have a difficult time reabsorbing all that they should, so the child often has a large volume of urine, and that volume is fixed, unable to change based on the circumstance. So, if the child has diarrhea or poor fluid and food intake or both, the kidney is not able to reabsorb most of the salt and water filtered and to reduce the amount of urine, as is a normal renal response.
Instead, the child continues to make large volumes of urine and dehydration comes on very rapidly. (By the way, to make it a double whammy, the kidney with dysplasia, since it is abnormal from the beginning, may be adversely affected by dehydration since dehydration leads to decreased blood flow (carrying oxygen and nutrition) to the kidney, and sustain further damage, temporarily or permanently.)
Dysplasia may be accompanied by hypoplasia, which means that the kidneys are unusually small. Hypoplasia may be isolated or linked to dysplasia Obstruction of the urinary tract (hydronephrosis with obstruction) Hydronephrosis means dilatation of the collecting system or the ureter or both and may be dilatation with or without an obstruction at some point in the system physically to the flow of urine down and out. Hydronephrosis is often seen on prenatal ultrasounds, but is found at least 50% of the time to be dilatation without obstruction, which may simply be due to two facts: 1) that the fetal kidney does not yet concentrate the urine so there is a large flow volume down the ureter, making it dilated by volume, and 2) the immature ureteral tissues are stretchy.
When hydronephrosis is associated with obstruction, it may be either unilateral (one kidney) or bilateral (both).
The most common obstructive lesions are:
* Posterior urethral valves (causes bilateral obstruction and is limited to males)
* Ureteropelvic junction obstruction (present on one or both sides)
* Ureterovesical junction obstruction (present on one of both sides)
* Ureterocele (present on one or both sides)
* Neurogenic bladder-which acts like an obstruction, since the bladder does not empty
If obstruction is unilateral and the contralateral kidney is fine, then there is not a problem with kidney function. The reason that one usually wants to try to fix the situation is to provide the “insurance” of having two functioning kidneys, because one is plenty. In the case of a single kidney, that single kidney increases its function in compensation and can have as much as 90% of the function that two normal kidneys would have. Usually a single kidney has 75-80% of the function of two kidneys. In this circumstance, the child is absolutely healthy, with normal growth and development.
Posterior urethral valves is a fairly common defect, and it occurs because a fold or two of extra tissue grow in the urethra and back up urine flow from the bladder and all the way up the ureters. This fold is present from early in kidney development, and so it causes the urine to back up into the kidneys from the time urine is first made, while the kidneys are still developing. Renal dysplasia, same as the lesion discussed above that may occur independently may occur and in fact, usually does occur, as a result. This means that the kidneys are inherently defective and so unblocking the urethra may improve kidney function somewhat, but it doesn’t usually cause kidney function to return to normal. Even if kidney function comes back to normal or near normal, the problem with the tubules and inability to concentrate the urine is quite commonly persistent. As with primary dysplasia, if the dysplasia is very, very severe and there is little urine production in utero, then lung maturation may be affected and cause difficulty after birth.
Development of the bladder is also affected by the blockage. These boys frequently have defective bladders, which divide into two types: 1) those that are thick walled and have strong muscle so that they don’t hold much and tend to spastically empty frequently, and 2) those that are large and stretched out and hold a lot. Boys with the latter type of bladder have abnormal sensation, too, and often can’t tell when the bladder is full. Their very full ladders may cause backup of urine with pressure up the ureters to the kidneys. Boys with either bladder type may need medication for the bladder; the former may need surgery to augment the bladder with a piece of intestine sewn into the top to make it larger, after which, since the intestine doesn’t contract, they usually have to catheterize the bladder 5 times a day to empty it. Boys with the large bladders without sensation can sometimes make it by voiding on a time schedule, since they don’t get the urge to void; some need intermittent catheterization, too. There are some boys whose bladders work fairly well, but I think that one should always be aware of bladder function in these boys. The bladder dysfunction may play a role in making kidney function worse than it would be with good bladderfunction, so it needs to be watched indefinitely. Bladder dysfunction can also damage a transplanted kidney.
Ureteropelvic junction (UPJ) obstruction is caused by a constriction at the top of the ureter, where it intersects with the renal pelvis, which is the part of the kidney that collects the urine before it starts down the ureter. This can occur because of a constricting band of fibrous (scar-like) tissue or from a crossing blood vessel. Though it is generally present at birth, sometimes it is so mild as to not cause a problem, but the obstruction may worsen with time later in infancy or in childhood as a result of changing relationships of the structures of the urinary tract and of surrounding tissues as growth occurs. A band of tissue or blood vessel near the ureter may impinge on the ureter with time and growth. This is usually a unilateral finding, but it can be bilateral, and it also is associated with problems with the other kidney. Multicystic dysplastic kidneys are associated with a UPJ obstruction of the other kidney. Twenty percent of babies with a multicystic dysplastic kidney have a UPJ obstruction of the other kidney.
UPJ obstruction usually must be fixed surgically. The surgery is safe and successful, requiring only 2-3 days in the hospital. Generally if it is discovered in the newborn period and is unilateral, the surgery is postponed a month or two until the baby is stable and growing and doing well.
Ureterovesical (UVJ) obstruction is much less frequent than is UPJ obstruction, and like UPJ obstruction, can be unilateral or bilateral. It is an abnormality in the insertion of the ureter into the bladder, blocking the flow of the urine into the bladder, and is fixed by surgically reinserting the ureter into the bladder, the same as is done for vesicoureteral reflux (see hydronephrosis without obstruction).
A ureterocele is a cystic dilatation of the ureter as it inserts into the bladder. The cystic area “pouches” into the bladder and causes the opening for urine flow from the ureter into the bladder to be very constricted, resulting in obstruction and hydronephrosis. It can often be handled at cystoscopy, with excision of the abnormal tissue with a small knife passed through the cystoscope. There can be associated dysplasia on the side of the ureterocele, but not always. A neurogenic bladder is usually associated with a problem with the spinal cord, the most common being a myelomeningocele (often referred to by the lay public as spina bifida).
This is a defect where the vertebrae in the lumbosacral area are not properly fused all the way around the spinal cord, and so a sac protrudes from the spinal cord with a mass of nerves all tangled together. In these nerves are those to the bladder, so that it has no functional nerve supply. The bladder then tends to fill and fill and only empty by overflow when it is quite full. There is often backpressure to the kidneys. This can lead to vesicoureteral reflux (explained later in this treatise) and chronic infection and scarring of the kidneys, with eventual renal failure.
Hydronephrosis without obstruction, including vesicoureteral reflux Hydronephrosis without obstruction means dilatation of the ureter and collecting system of the kidney but not because of backup above an area of narrowing and obstruction, rather primary dilatation of the collecting system and ureter.
The conditions causing this are:
* Prune belly syndrome
* Vesicoureteral reflux
* Primary megaureter with or without megacystis
Prune belly syndrome occurs almost exclusively in boys; there is a controversy whether there is a variant in girls. It consists of a group of findings including: decreased or absent abdominal muscles, cryptorchidism (failure of the testicles to descend into the scrotum; they remain in the abdomen), and dilatation of the ureters and bladder, often with associated renal dysplasia. Frequently the dilated ureters come with vesicoureteral reflux (VUR; see below). The boys are sterile and unable to make sperm, even if the testicles are surgically brought down, but they functioormally sexually. The bladder may be large and floppy and not contract and empty like it should, or it may be fine. High-grade reflux is common, but reimplantation of the ureters surgically into the large, floppy bladder may be difficult. With the renal dysplasia, renal failure may be a problem. The renal dysplasia may be of any degree of severity. Some of these boys progress to needing transplantation; others do not.
In boys with prune belly syndrome the abdomen is protuberant because of the decreased or absent abdominal muscles and the lower part of the rib cage in front may flare out a little, causing an abnormal profile. The absence of the muscles of the abdomen causes surprisingly little functional problem. Some boys as they get older wear an elastic support garment around the abdomen to hold it in so that it looks better and clothes fit better.
It also offers some protection to the abdominal organs.
Vesicoureteral reflux (VUR) involves the two-way flow of the urine up and down the ureters, and they should be a one-way down system. The ureter inserts into the bladder dowear its base such that the muscle of the bladder wall does not allow the urine to flow out of the bladder and back up the ureter towards the kidney. This insertion can be abnormal and allow different degrees of back flow, which are graded I to V, depending on severity. When grades I to III happen in an infant or young child, the likelihood is that with time and increasing maturity the problem will resolve itself. Grade IV reflux occasionally spontaneously resolves, and grade V reflux virtually never resolves spontaneously. Grades IV and V usually need surgical correction.
Megaureter and megacystis are two problems that often occur together. Megaureter is the congenital dilatation of all or a portion of the ureter without obstruction.
Megacystis
means enlargement of the bladder, which may affect function in that the bladder may be slow to empty, and in some cases this may mean that intermittent catheterization is needed to empty the bladder. Both megaureter and megacystis are frequently associated with renal dysplasia.
Cystic diseases
Most of the cystic diseases occur in both kidneys, but in the great majority of cases a multicystic dysplastic kidney is confined to one kidney. In this disorder, the kidney is worthless and without any functioning filters and the ureter is atretic, meaning that it stops part way down to the bladder, so is incomplete. The “kidney”, and I put it in parentheses since it is not really a kidney, as we know it, since something went awry very early in its development and it became a group of cysts rather than a kidney. A cyst is a fluid filled round bag-like structure. In most cases the other kidney is normal and grows larger than a normal kidney to make up for the fact that there is only one functioning kidney. Two defects do occur in the functioning kidney with enough frequency to be of concern. The first is vesicoureteral reflux (discussed previously in this article) so every infant found to have a multicystic dysplastic kidney should have a VCUG, a voiding cystourethrogram to look for reflux. The second is ureteropelvic junction obstruction, also discussed previously, which, if present, will have beeoted on the ultrasound examination that was done to pick up the multicystic dysplastic kidney.
A multicystic dysplastic kidney is often picked up on prenatal ultrasound, then confirmed on ultrasound after the baby is born. Since the bags of cysts can be confused with severe dilatation of the kidney related to a severe ureteropelvic junction obstruction, the doctor may want to look at the kidneys with a nuclear renal scan to differentiate between the two. To do this scan, the infant is given an IV injection of a radioactive substance that shows blood flow into the kidney and is filtered by the kidney. The multicystic dysplastic kidney has noblood flow and no function, but the kidney with obstruction has blood flowing through it. The amount of radioactivity given is no more than one receives getting a standard X-ray.
So the infant felt to have a multicystic dysplastic kidney generally has two tests done, a VCUG and a nuclear renal scan. If an associated problem such as reflux or UPJ obstruction is found, they are treated as noted above, with the need for treatment being related to the severity of the problem. The multicystic dysplastic kidney itself is followed with serial ultrasound examinations at intervals over time. Most of the time the cysts shrink progressively and after a few years the end result is a small nubbin of scar tissue which causes no problem If the cysts do not shrink, which happens in a few cases, then the kidney may need to be removed surgically.
Most of the time when cystic kidney disease is mentioned, polycystic kidney disease (PKD) comes to mind. There are two types of polycystic kidney disease are: autosomal dominant disease (ADPKD), formerly called adult PKD, and autosomal recessive PKD. Let me give you a mini-genetics lesson to help explain the two diseases. Each of us has a set of genes from each parent, so we have a double of every gene. In diseases where the trait is dominant, getting an abnormal gene from either parent gives you the disease. So in the typical case of a parent with a dominant disease, the parent got one normal gene from one parent who was healthy and an abnormal gene from a parent with the disease. So the child of that parent has a 50-50 chance of getting the disease, depending on whether he got the diseased gene or the healthy one. Having one gene with the disease means you have the disease. In the case of parents of a child with a recessive disease, both parents have one normal and one abnormal gene, and the normal, rather than the abnormal gene, predominates. A child of such parents has a one out of two chance of getting the abnormal gene from each parent, or a one out of four chance of getting an abnormal gene from both parents. Having both genes of the set abnormal gives the disease. So parents of the child with ARPKD are healthy and do not know that they carry the disease until they have a child with the disease. A parent who has ADPKD knows that there is a 50-50 chance, one out of two of each child born to that parent having the disease.
There have been three different gene defects found that cause ADPKD.
The gene for ARPKD Is being characterized and is on chromosome 6.
ADPKD is a fairly common cause of kidney failure in adults. The cysts of the disease may be seen on a prenatal ultrasound of the developing fetus, but in most cases, the number of cysts in the kidneys increases slowly and kidney function is normal for most or all of childhood and into adulthood. The cysts can start to form in the kidneys in the fetus, or the kidneys may be normal without cysts until as late as 30 years of age. At some age cysts start to form and more and more cysts progressively form in both kidneys. There is a tendency of the pattern
of development of cysts to be the same in members of a family, but it is a tendency and not a rule. As more and more cysts form often hypertension becomes a problem, and then after hypertension, gradual decrease in kidney function. The age at which kidney failure occurs and dialysis and transplantation are needed varies from infancy to old age. A few people die in old age with cysts in the kidneys but with the kidneys working well enough that they do not need dialysis or transplantation. The average age of kidney failure is about 50 years old.
ARPKD is a very uncommon disease. The baby with ARPKD has many small cysts all throughoutthe kidneys right from the time that they form in utero. The kidneys are larger thaormal becauseof the cysts, sometimes very large. In the most severely affected children the kidneys never workand never make urine. This leads to a lack of normal lung development, since lung development isdependent on breathing amniotic fluid, and amniotic fluid comes from baby urine. Without lungdevelopment the baby dies of lack of oxygen soon after birth. In a few cases, fluid has been successfully injected into the uterus around the baby every few days for many weeks during pregnancy, resulting in lung development. This is tricky and may also result in stimulating labor, so that the baby is born quite prematurely with poor lung function and dies
Among the infants with the disease who survive, the severity of the kidney disease and the age at which dialysis and transplantation are needed varies between infancy and adolescence.
Most children with ARPKD also have a condition known as congenital hepatic fibrosis, which means that there are threads of scar tissue through the liver. This usually doesn’t interfere with liver function but may obstruct the flow of blood to the liver through the portal vein from the intestines. This leads to back up of blood in the spleen and in veins of the esophagus and can cause serious problems, too. Backup of blood in the spleen means that platelets get trapped in the spleen and so are not in the general blood circulation. Platelets are important in the circulation as agents of clotting. Meanwhile the blood in the veins of the esophagus is under increased pressure, so that the veins often burst and bleed. With low platelets, the esophagus may bleed and bleed if the veins burst. To prevent this kind of bleeding, some children with ARPKD need surgery to shunt blood flow away from the esophagus while those with a more severe form of hepatic fibrosis also need a liver transplant as well as a kidney transplant.
Another very rare form of bilateral renal cystic disease isglomerulocystic disease, where the cysts are in the glomeruli, the filters of the kidneys. This usually leads to kidney failure early in life.
Other diseases which include bilateral (both kidneys) cystic kidney disease in addition to other health problems include:
* Tuberous sclerosis
* Von Hippel Lindau syndrome.
Metabolic diseases
Metabolic diseases are those diseases where there is a chemical problem in certain or all cells of the body. Most commonly they happen when an enzyme (protein that breaks down a specific chemical) is missing. That can result in the accumulation of that substance in cells, causing all sorts of problems. In some types of metabolic disease a substance accumulates in cells for unknown reasons. In others, an important cellular biochemical process is abnormal.
Cystinosis is a rare disease where cysteine, an amino acid (amino acids are the building blocks of proteins) accumulates in the cells of the body and causes lots of problems, including kidney failure. These children clearly are ill as infants, since they grow poorly, are easily and frequently dehydrated, and develop rickets. The problem with the kidneys early in life is that they leak multiple substances (potassium, bicarbonate, sodium, phosphorus, glucose and amino acids) from the blood into the urine that should stay in the blood. Some of these substances have to be given back as medication: potassium, bicarbonate, sodium, and phosphorus. The kidney also fails to activate vitamin D, so the active form of vitamin D (calcitriol or dihydrotachysterol) must also be given as a medication. As time goes on they develop kidney failure, and generally need kidney transplantation sometime in childhood.
The condition where the kidney tubules leak potassium, glucose (sugar), phosphorus, bicarbonate, and amino acids into the urine is called Fanconi syndrome. Fanconi syndrome is seen in children with cystinosis, Lowe’s syndrome, and is rarely seen temporarily after administration of an antibiotic from the antibiotic grown called aminoglycosides
Oxalosis is another rare disease. In this disease the liver cells lack an enzyme (an active protein) that breaks down oxalate, which is a compound made in the natural functioning of the liver cell. Oxalate then accumulates, spills into blood, links with calcium, and calcium oxalate deposits in the kidney and then in tissues all over the body. The kidney is first, since the kidney tries to get rid of the excess calcium oxalate out of the blood by filtering it out, and in the process the kidney is stopped up with calcium oxalate, Deposits of crystals are found throughout the kidney and stones form also. When there is little or no enzyme in the liver to break down oxalate, the problems ensue quickly in infancy and complete kidney failure can be seen in the first year of life. If there is some enzyme, but not enough, then kidney failure can ensue later in childhood.
In the child with oxalosis, putting in a new kidney alone is not the solution, since the new kidney will be stopped up with calcium oxalate. A liver transplant must be done to give the child the enzyme to handle oxalate, and then a kidney transplant can be done. This is one of the diseases that will be treated with gene therapy. If the gene could be placed in the liver to tell it how to break down oxalate, then there would be no problem, as the liver is otherwise normal.
Other metabolic diseases that may lead to kidney failure include:
Lowe’s syndrome, the mitochondrial myopathies, particularly cytochrome C oxidase deficiency, certain glycogen storage diseases, to name a few. All of these diseases are quite rare.
Syndromes
Prune belly syndrome is one of the commoner syndromes seen as a congenital renal disease. It is described above.
VATER Syndrome stands for vertebral, anal, tracheal, esophageal, and renal and radial (the bigger bone of the forearm) abnormalities. This group of abnormalities tends to occur together. The kidney abnormalities can include hypoplasia, dysplasia, obstruction. The child can be born with one or two kidneys. Not every child with this syndrome has every part of it. The child may also just have one kidney, and it may be normal or abnormal. There are also related syndrome like VACTERAL Syndrome.
LOWE’S Syndrome is a syndrome that includes metabolic (cellular biochemical) abnormalities.
The kidneys start out with partial or complete Fanconi syndrome. In addition the children have developmental delay and eye problems, usually cataracts that are large and present at birth.
Congenital Lung Malformations
The aim here is to provide a concise approach to congenital lung malformations. Therefore, this article discusses bronchogenic cyst, pulmonary agenesis and hypoplasia, polyalveolar lobe, alveolocapillary dysplasia, sequestration including arteriovenous malformation (AVM) and scimitar syndrome, pulmonary lymphangiectasis, congenital lobar emphysema (CLE), and cystic adenomatoid malformation and other lung cysts.
Surgery for congenital lung malformation was made possible relatively recently. Early 20th century thoracic surgery consisted of mainly thoracoplasty to collapse a tuberculoid lung or to drain an empyema. Only with the regular use of endotracheal intubation and mechanical ventilation in the 1950s did intrathoracic procedures become routine. These techniques were not widely applied to newborns until the 1950s. Although Evarts Graham performed pneumonectomy with mass ligature of the hilum, Churchill was the first to regularly perform lobectomy with hilar dissection. Gross and Lewis successfully treated a patient with CLE with lobectomy in 1943.
Bronchogenic cysts are increasingly excised thoracoscopically. Rodgers vigorously promoted endoscopic surgery, which has become prevalent with the plethora of new instrumentation available and with the expansion of minimally invasive laparoscopy and thoracoscopy.1 Most thoracic surgical procedures, such as resection of masses (eg, neurogenic tumors, bronchogenic cysts) and pulmonary lobectomy, are now accomplished with minimally invasive surgery, although the benefits of this approach for cystic adenomatoid malformations (CAMs; see Cystic adenomatoid malformation below) are unclear.
Fetal surgery has been advocated for
Although congenital lung malformations are rare, they are important disorders because they may lead to considerable morbidity and mortality (eg, infection, hemorrhage, respiratory failure). They may occur late, and failure to recognize a malformation may lead to inappropriate intervention. For example, placement of a chest tube to manage suspected tension pneumothorax in a patient with CLE may lead to lung contusion and ventilation through the chest tube instead of into the remaining healthy lung.
Healthy lung is composed of an orderly system of tubes (airways) and sacs (airspaces or alveoli) in a strict relationship to pulmonary blood vessels (arterial from the right ventricle and venous return to the left atrium). Also present is a systemic blood supply (aorta to superior vena cava) and lymphatic drainage. Congenital lung malformations arise whenever one or more of these structures are abnormal or when their relationships are altered.
Bronchogenic cysts
Bronchogenic cysts are also known as foregut duplication. They arise from an abnormal budding of the ventral foregut. Approximately 85% are mediastinal, and 15% are intrapulmonary. The peripheral cysts are multiple and appear late in gestation. They may be filled with air or fluid, or they may have air-fluid levels. The cysts can be central or peripheral. Many are asymptomatic, but incidental findings may be observed on chest radiography. Infection, hemorrhage, and, in rare cases, malignancy can occur. Respiratory distress may result in a stridor or wheeze. Airtrapping may lead to emphysema, atelectasis, or both. Dysphagia, chest pain, and epigastric discomfort can occur.
Pulmonary agenesis and hypoplasia
Both pulmonary agenesis and hypoplasia may be accompanied by renal anomalies, which are usually apparent soon after birth and associated with respiratory distress. Cardiac defects occur in 50% of patients.
Pulmonary agenesis is differentiated from lung aplasia by the absence of the carina in the latter. Lung agenesis is less common than aplasia, about 75% of cases affect the left side, and it is lethal in half of all patients. It may be associated with other manifestations of the syndrome of abnormalities of the vertebrae, anus, cardiovascular tree, trachea, esophagus, renal system, and limb buds (VACTERL syndrome). The survival rate is better with left-sided lung agenesis than with right-sided agenesis because the right lung is the larger of the two.
In pulmonary hypoplasia, development of the distal lung tissue is incomplete. The earlier the delivery of a child, the higher the incidence of lung hypoplasia. In babies delivered before 28 weeks’ gestation, the incidence approaches 20%. Pulmonary hypoplasia results from conditions that restrict lung growth, such as oligohydramnios, Potter syndrome (with bilateral renal agenesis or dysplasia), abnormalities of the thoracic cage, Scimitar syndrome (right-sided pulmonary hypoplasia), and diaphragmatic hernia (usually left-sided hypoplasia). More than 50% of patients have associated cardiac, gut, or skeletal malformations. They may have a small thoracic cage, decreased breath sounds on the affected side, and a mediastinal shift to the side of the lesion. Therefore, aplasia of the right lung can be confused with dextrocardia. Patients may present with lung infections, dyspnea upon exertion, and/or scoliosis.
Pulmonary isomerism
Pulmonary isomerism is an anomaly of the number of lung lobes. In the common variety of pulmonary isomerism, the right lung has 2 lobes, whereas the left has 3. This anomaly may be associated with situs inversus, asplenia, polysplenia, and/or anomalous pulmonary drainage.
Azygous lobe
An azygous lobe is a malformation of the right upper lobe caused by an aberrant azygous vein suspended by a pleural mesentery. An azygous lobe is a radiographic curiosity without clinical significance that occurs in 0.5% of the general population.
Pulmonary sequestration
Pulmonary sequestration accounts for 6% of all congenital lung malformations and mostly occurs in the lower lobes. A sequestration is a bronchopulmonary mass without a normal bronchial communication and with normal or anomalous vascular supply. Sequestered lung may be intralobar or extralobar. The involved lung segments can be classified on the basis of their pleural coverage into intrapulmonary or extrapulmonary types. Variants of pulmonary sequestration are described as disconnected or abnormally communicative bronchopulmonary masses with normal or anomalous vascular supply. The lesions may have some sort of communication with the gut.
Children present with recurrent respiratory problems in the same anatomic location. Associated anomalies include diaphragmatic hernia and eventration. Patients may have exercise intolerance if they have large systemic arterial venous shunts. The extrathoracic variety can be associated with hydrops fetalis or increased lymphatic transudate in the thorax.
About 50% of pulmonary sequestration cases are intrapulmonic, and 60% of intrapulmonic cases occur in the left lower lobe with equal sex distributions. Patients with intrapulmonary sequestration usually present late. They may have a chronic cough, recurrent pneumonias, or poor exercise performance. Systemic arterial flow may produce a murmur, and shunts may lead to congestive cardiac failure. Squamous cell carcinoma, adenocarcinoma, and rhabdomyosarcoma may arise in the sequestration.
Approximately 95% of extrapulmonary cases are left sided. Most extrapulmonary cases are detected in infancy, with boys affected 4 times more than girls. Infants usually present with a chronic cough and recurrent chest infections. Radiographs may show signs of consolidation. If communication with the gut is present, children may present with vomiting, failure to thrive due to poor oral intake, and abdominal pain.
Scimitar syndrome
The constant feature of this syndrome is partial or total anomalous pulmonary venous return to the inferior vena cava. This abnormal vein on the chest radiography creates a gentle curve bulging into the right chest from the mediastinum that some believe resembles the Turkish sword called a scimitar. Other features of the syndrome are variable and may include dextrocardia, hypoplasia of the right lung and/or pulmonary artery, malformation of the bronchi, and systemic arterial supply to the right lung. The clinical features vary according to age. Infants almost always present with congestive heart failure and severe pulmonary hypertension. Adults are generally asymptomatic.
Hamartoma
Hamartomas are lung nodules contain cartilage, respiratory epithelium, and collagen. They may be in the lung tissue or the bronchial lumen. They are presumed to be congenital because they are usually found on chest radiographs in asymptomatic adults. They can cause airway obstruction and are usually excised for diagnosis.
Pulmonary arteriovenous malformation
Pulmonary AVMs are abnormal communications between the pulmonary arterial and venous systems without interposed capillaries. AVMs with a systemic arterial supply are unusual in the lung. As with AVMs elsewhere, they can lead to high-output cardiac failure. Symptoms are unusual in childhood. However, by adulthood, 50% of patients have at least exertional dyspnea. Hemoptysis is most common in patients who also have cutaneous telangiectasis. A continuous bruit is often heard over the lesion.
The fistulas are usually seen as well-defined opacities on chest radiography, and are multiple in as many as 50% of patients and bilateral in 10%. Most of the fistulas are subpleural, and more often occur in the lower lobes. CT findings are usually diagnostic. Complications include bleeding, infection, and embolus. Patients with cutaneous telangiectasis are likely to have Rendu-Osler-Weber disease (also known as hereditary hemorrhagic telangiectasia). They are likely to have multiple pulmonary AVMs and progressive symptoms. Treatment is resection. If this is not possible, the lesions can be embolized.
Alveolar capillary dysplasia
In alveolar capillary dysplasia, a fatal condition, the distal arteriolar blood supply is reduced, the pulmonary veins are misaligned, and the connective tissue between the alveolar epithelium and the capillary endothelium is increased. The alveolar circulation is impaired, and the response to nitric oxide is poor. Affected babies do well with venoarterial extracorporeal membrane oxygenation (ECMO), but they cannot be weaned from it.
The clinical presentation of alveolar capillary dysplasia is that of persistent pulmonary hypertension of the newborn. Hypoxemia leads to arteriolar muscular hypertrophy. Patients may have associated anomalies in the heart or urinary system. Open lung biopsy and cardiac catheterization are suggested as diagnostic tools to look for or exclude pulmonary capillary blush.
Pulmonary lymphangiectasis
Pulmonary lymphangiectasis is a rare disorder in which the normal pulmonary lymphatics are dilated. It may be associated with congenital heart disease in which the pulmonary venous pressure is elevated. Pulmonary lymphangiectasis can also be observed with lymphangiomatosis, in which proliferation of the lymphatic tissue and channels occurs. The disease can also be part of a syndrome of lymphangiomas in many organs; it is sometimes associated with vanishing bones. Pulmonary lymphangiectasis is congenital, but symptoms of respiratory insufficiency usually do not appear until adulthood.
Congenital lobar emphysema
Massive overinflation of one or more lung lobes occurs postnatally in CLE. Causes include intrinsic absence or abnormality (bronchomalacia) of cartilaginous rings or external compression by a large pulmonary artery. (Compression of the cartilage usually leads to malacia.) Hyperexpansion of a pulmonary lobe is present after birth when, with negative inspiratory pressure, air can enter the lung. However, the air cannot exit easily because positive pressure causes the softened airway to collapse. The remaining normal lung is then compressed.
CLE primarily involves the upper lobes. The left upper lobe is involved in 41% of patients; the right middle lobe, in 34%; and the right upper lobe, in 21%. Involvement of the lower lobes is rare, occurring in fewer than 5% of patients. Congenital cardiac anomalies may be present in as many as 10% of patients. Lesions most commonly occur in Caucasians, in male individuals (male-to-female ratio, 3:1), and in young infants.
Most patients with CLE present before 6 months of life. Neonates may present with mild-to-moderate respiratory distress. Mediastinal shift may be present, with hyperresonance and decreased breath sounds on the involved side. Infants present with cough, wheezing, respiratory distress, and cyanosis. Older children may present with recurrent chest infections. On images obtained in neonates, the affected lobe may be slightly opacified, rather than lucent, because it is still filled with fluid. Associated cardiac anomalies occur in as many as 10% of patients.
Cystic adenomatoid malformation
Two main forms of
Polyhydramnios may be present if the
Lung cyst
Lung cysts are rare lesions that may arise from any of the parenchymal tissues of the lung. They can cause symptoms if they enlarge and occupy substantial space. Resection is performed to diagnose lung cyst and to stop the progression of symptoms.
Polyalveolar lobe
In a polyalveolar lobe, the number of alveoli increased to more than 3 times normal. The alveoli are counted microscopically in random lung sections. When extra lung fluid is retained, respiratory distress may occur in the first days of life. This generally benign anomaly may be associated with some cases of CLE.
Congenital lung malformations represent 5-18.7% of all congenital anomalies. This range may be an underestimate because of the high frequency of undetected or asymptomatic lesions.
Bronchogenic cysts represent outpouchings of the ventral foregut in the early part of gestation. These outpouchings generally arise close to the bronchial tree. A cyst may become infected, or it may compress adjacent structures to produce signs and symptoms. Chronic infection and inflammation may predispose the patient to malignancy. Peripheral cysts appear late in gestation and are multiple.
Pulmonary agenesis
In lung agenesis, the entire lung and bronchial tree may be absent on one side. The bronchial tree may form without development of the alveoli. Pulmonary hypertension complicates lung agenesis because of a combination of factors: normal blood volume passing through reduced lung tissue, hypoxemia leading to pulmonary vasoconstriction, and any associated left-to-right shunting cardiac lesion.
Pulmonary hypoplasia
Intrathoracic or extrathoracic lesions can cause pulmonary hypoplasia. Therefore, prolonged rupture of membranes, renal dysplasia, neuromuscular diseases, and congenital diaphragmatic hernia can lead to lung hypoplasia. Reduced urine volume during fetal life may retard lung growth.
Secondary pulmonary causes include
Pulmonary aplasia leads to respiratory distress, which may vary according to the degree of alveolar involvement. Pulmonary hypoplasia may be primary when the entire lung or when one lobe is reduced in size.
Pulmonary sequestration
If an accessory lung bud forms early enough, it leads to the formation of sequestration in the normal lung tissue. Development late in gestation leads to extrapulmonic sequestration. Both types obtain their blood supply from the aorta or its branches. Patients may present with exercise intolerance due to these vascular shunts. Sequestrations may also be connected to the GI tract.
Congenital lobar emphysema
Causes of CLE include bronchial cartilage deficiency, extrinsic compression by a bronchogenic cyst, a large pulmonary artery, or mucus plugs. Lobar overdistention and airtrapping lead to compressive changes in the rest of the lung.
Cystic adenomatoid malformation
Cystic adenomatoid malformation results when the terminal bronchiolar component of the advancing endodermal lung bud proliferates haphazardly because of disruption of humoral factors from the surrounding mesenchyme. Apoptosis in the advancing lung bud is decreased. Glial cell–derived neurotrophic factor is a growth factor that is abnormally expressed in the epithelial cells of the
Resection is recommended because of the potential for infection, hemorrhage, and respiratory compromise. Resection is especially important in the peripheral lesions, which are usually multiple. These can frequently be excised thoracoscopically because they seldom have a major blood supply.
Pulmonary agenesis and pulmonary hypoplasia
Patients with pulmonary agenesis and pulmonary hypoplasia seem to have one of 3 presentations. The first group consists of patients with insufficient lung tissue who may have received mechanical ventilation for some time. However, ventilator-induced lung injury results in slow decompensation and death. The second group of patients is identified serendipitously when chest radiography is obtained to assess a minor complaint. These patients require no intervention. The third group does not have respiratory distress requiring mechanical ventilation, but they have respiratory limitations to activity or kinking of the airway with shift of the lung to the contralateral side of the chest. In addition to the aplasia or hypoplasia, congenital narrowing of the upper airway also affects many patients.
Pulmonary sequestration
Resection is recommended, even in asymptomatic patients, to prevent infection, hemorrhage, shunting from arteriovenous anastomoses, or compression of normal lung mass leading to respiratory distress. Lobectomy can usually be performed. For patients with intralobar sequestration, segmentectomy may suffice. Segmentectomy is relatively difficult, but preserves additional functioning lung tissue.
Since the advent of staplers, most surgeons wedge out the lesion with staplers rather than perform the tedious dissection and stripping of segmentectomy that is prone to air leakage and often bloody. In many sequestrations, the mass is airless and separate from the other lung tissue. The surgeon must remain vigilant in searching for the systemic arterial supply. Its origin cannot be predicted, and it may be from below the diaphragm. Bleeding from inadvertently crossing this vessel may be troublesome or even dangerous. For this reason, some surgeons insist on obtaining an arteriogram before surgery.
At least a few thoracoscopic surgeons have accomplished pulmonary resection, even in children. In children, the difficulty in finding enough space in the chest to work while the lungs are being ventilated and the risk of injuring the delicate pulmonary vessels has limited wide adoption of this technique.
Scimitar syndrome
When symptoms of scimitar syndrome are related to anomalous pulmonary venous return, this return can be redirected surgically. Symptoms are often related to the bronchial abnormalities and chronic infection. In these cases, pneumonectomy is indicated.
Hamartoma and pulmonary arteriovenous malformation
Resection is usually performed for diagnosis when a lesion is noted on chest radiography. Symptoms of airway obstruction or high cardiac output are occasionally indications for surgery as well.
Congenital lobar emphysema
Progressive airtrapping leads to respiratory and circulatory compromise in infancy. Emergency lobectomy may be required. A patient with respiratory distress whose chest radiograph reveals a hyperlucency on one side and mediastinal shift usually has a tension pneumothorax. However, one must consider CLE, especially in the newborn. The diagnosis can usually be determined by looking at the edges of the hyperlucent area. In pneumothorax, the edges are convex and outline the chest wall, whereas in CLE, they are concave and outline the cystic structure of an overexpanded lobe.
Placing a chest tube in the hyperlucent airspace of CLE decreases ventilation as air takes the path of least resistance out the chest tube from the bronchus rather than expanding the stiff infant lung in the remaining lobes. Prompt thoracotomy relieves the pressure inside a hyperexpanded lobe and allows the other compressed areas to ventilate. This overexpansion often stretches and dissects the bronchi and vessels, facilitating lobectomy. In cases that are detected early or surgically treated because of radiographic findings and not because of symptoms, the abnormal lobe may be difficult to identify during surgery. Therefore, in these cases, radiographs and CT scans must be carefully reviewed preoperatively.
Cystic adenomatoid malformation
In
Lung cysts
During surgery, lung cysts are often found to be CAMs, though simple cysts do occur. Some lesions can be shelled out or unroofed. If they are not congenital but related to barotrauma, they may communicate directly with small bronchi. In this case, unroofing leads to major airleaks. These lesions can sometimes be controlled with figure-8 sutures, but wedge resection, segmentectomy, or even lobectomy may be required to avoid a bronchopleural fistula.
Fetal intervention for congenital lung malformations
Many centers perform antenatal aspiration of lung cysts. This procedure is often successful in that no lung cyst appears on postnatal chest radiographs. However, many cysts observed on antenatal sonograms also resolve spontaneously. The few groups who are pursuing open fetal surgery also perform in utero lobectomy to manage
The lungs continue to mature after birth. Embryologic development progresses from the conductive initial lung bud down to the highly functional respiratory alveoli. Major bronchiolar development ceases around 16 weeks’ gestation. Vascular beds form, and the basic acinus framework is then laid down from 17-28 weeks’ gestation. Alveolar development starts at 24 weeks’ gestation and may continue until adolescence. Most of this increase in the alveoli occurs in the first 8 years of life. Aortic branches initially supply the bronchial buds; later, the pulmonary arteries take over as the lung develops.
The timing and severity of various insults may determine the resultant lesions. These lesions may vary from complete agenesis to bronchial stenosis and sequestration of a lung lobe with retention of the aortic flow. Peripheral pulmonary lesions, such as CLE, appear late in development.
Other theories try to account for the abnormal lung vessel communications. The vascular traction theory suggests that the lung tissue is sequestered when the systemic blood vessels move caudally. Another theory is that the pulmonary vessels fail to develop and lead to abnormal persistence of systemic vessels.
Bronchogenic cysts
Bronchogenic cysts are most commonly mediastinal in a pericarinal, paratracheal, or retrocardiac location. The cysts are thin walled and lined with columnar epithelium. The common central cysts represent outpouchings of the ventral foregut in the early part of gestation.
Pulmonary agenesis and hypoplasia
The entire lung and bronchial tree may be absent on one side. The bronchial tree may form without development of the alveoli. Agenesis is a primary defect in organogenesis, and hypoplasia is often secondary to extrinsic compression. Both lesions may be associated with other anomalies. In physiologic terms, the 2 lesions behave similarly.
Schechter has pointed out the many possible variations. In addition to absence of the entire lung and bronchial tree, an interrupted bronchial tree may be present, but the alveoli are absent or the lung may be reduced in size, or one lobe may be absent.
Pulmonary hypertension complicates lung agenesis because of a combination of factors, including normal blood volume passing through reduced lung tissue, hypoxemia leading to pulmonary vasoconstriction, and any associated left-to-right shunting cardiac lesion.
Pulmonary isomerism
In pulmonary isomerism, the lungs are asymmetric, and the number of lobes on both sides may vary. Associated findings may include situs inversus and splenic anomalies. Anomalous pulmonary venous drainage is almost always present.
Scimitar syndrome
A constant feature of Scimitar syndrome is aplasia of one or more lobes of the right lung. Variable features include the following:
· Partial anomalous pulmonary venous return (scimitar-shaped vein) draining to the inferior vena cava and leading to a left-to-right shunt
· Small pulmonary artery
· Arterial supply from aorta
· Anomalies of hemidiaphragm on affected side
· Rib cage anomalies
Pulmonary sequestration
Pulmonary sequestration may be present in the normal lung or outside it, in the thoracic cavity, in the diaphragm, or in a subdiaphragmatic position. Alveoli and bronchioles have normal histology. However, they do not communicate with the normal airways, or they may have an abnormal communication with the gut. Sequestration is fundamentally an abnormal vascular supply to the affected lung, and accelerated atherosclerosis may be found in vessels exposed to high systemic pressures. Branches from the descending thoracic aorta supply the intralobar sequestration, which is drained by pulmonary veins. An infradiaphragmatic source may supply the extralobar variety in as many as 20% of patients, and the azygous venous system drains it.
Congenital lobar emphysema
In CLE, a single lobe is commonly involved. The bronchi at the involved site may be devoid of cartilage. The number of alveoli may be fewer thaormal (hypoalveolar) or greater thaormal (polyalveolar). Cardiac anomalies may be present in 10% of patients. The lung parenchyma is normal, unlike what is seen in
Cystic adenomatoid malformation
One lobe, multiple lobes, or multiple segments on both sides may be affected. The upper lobes are usually involved. The bronchiolar proliferation is terminal without much alveolar development. The abnormal hamartomatous proliferation usually retains its communication with the normal bronchiolar tree. However, no cartilage or bronchiolar tubular glands are present in the malformation itself. Columnar mucinous epithelium is present.
Three types of
In a study of 12 patients with late-onset
General contraindications include severe sepsis and bleeding disorders. Specific contraindications are discussed below.
Bronchogenic cysts
Lung cysts usually do not need to be differentiated for surgical purposes because the presentations and outcomes are the same. However, resection is not feasible in cases of diffuse bilateral pulmonary lymphangiectasis manifesting as cystic disease of the lung because the outcome is often poor.
Pulmonary hypoplasia
Severe pulmonary hypertension may be a contraindication to operate in cases of pulmonary hypoplasia resulting from congenital diaphragmatic hernia. Associated anomalies may modify the course and the surgical procedures.
Pulmonary sequestration
Resistant congestive cardiac failure may need to be stabilized before surgical resection is undertaken. This stabilization may necessitate the use of a heart-lung machine.
Congenital lobar emphysema
CLE poses no specific contraindications and the prognosis after surgery is generally excellent. Surgery may not be required in asymptomatic patients, for whom close follow-up usually suffices.
Cystic adenomatoid malformation
Fetal hydrops is the only consistent predictor of mortality associated with
· Hemoglobin testing is always valuable in respiratory illness because the result is an important factor in oxygen delivery and in planning surgery, which often involves major vessels.
· Renal function tests to measure BUN, serum creatinine, and electrolyte levels are important because of the frequent association of renal anomalies with pulmonary anomalies (usually pulmonary hypoplasia).
o Bronchogenic cysts: Bronchogenic cysts are usually fluid-filled lesions and are well circumscribed in the mediastinum. Solid masses may be difficult to differentiate from fluid. Intrapulmonic cysts appear as solitary nodules unless they contain air. Large cysts may be difficult to differentiate from macrocystic
o Pulmonary hypoplasia: In pulmonary hypoplasia, a mediastinal shift to the side of a homogenous density may be depicted, with compensatory herniation of the uninvolved lung. The associated anomalies (cardiac, skeletal, gut) may be seen.
o Pulmonary sequestration: In pulmonary sequestration, an opaque or cystic lesion is seen, depending on the presence of infection.
o CLE: In CLE, the involved lobe crossing the midline and the compressed normal lung can be seen. This appearance does not change during expiration or in the decubitus position. Vascularity of the involved site is attenuated. The intercostal spaces in the involved site appear widened, and the hemidiaphragm is flattened. Lucent, anteriorly herniated lung pushes the lung posteriorly, as seen on the lateral view. The lesion must be differentiated from contralateral lung hypoplasia and ipsilateral pneumothorax.
o CAM:
· Chest CT scanning
o Bronchogenic cysts: In patients with bronchogenic cysts, CT findings are characteristic. The lesions are sharply marginated and nonenhancing. If the lesions are seen as soft-tissue attenuation instead of water attenuation, differentiating from lymph nodes may be difficult.
o Pulmonary hypoplasia: In lung hypoplasia, loss of lung volume and associated anomalies can be seen.
o Pulmonary sequestration: In pulmonary sequestration, the findings may be only an unusual solid attenuation. Therefore, CT may have little to add to sonographic and plain radiographic results unless the anomalous vascular supply can be visualized with vascular contrast enhancement.
o CLE: In CLE, the involved lobe and its vascularity can be easily outlined as compared to normal lung parenchyma.
o CAM: Different types of
· MRI: MRI is particularly useful when delineation of blood vessels is important. It is the study of choice in difficult cases of bronchogenic cysts. The cysts appear bright on T2-weighted images and do not enhance after the administration of gadolinium-based contrast material.
o Pulmonary sequestration: MRI and MRA (magnetic resonance angiography) can be performed to identify pulmonary pathology, and aberrant systemic vessels. MRI and MRA have been suggested as the diagnostic procedures of choice for evaluating sequestration of the lung.
o CLE: In CLE, MRI is used to depict the involved lung and its vascular supply.
o
· Prenatal ultrasonography: Lesions on prenatal sonograms may shrink or disappear with advancing gestational age. Most pulmonary parenchymal lesions appear as echogenic fetal chest masses. The masses may be unilateral (eg, in
o Pulmonary hypoplasia: In lung hypoplasia, renal malformations, oligohydramnios, decreased fetal movements ieuromuscular disease, dysmorphisms in trisomies, and skeletal dysplasias may be identified. The thoracic-to-abdomen ratio and lung area are useful parameters. Pulmonary arterial flow can be measured by using Doppler studies.
o CLE: In CLE, a large fluid-filled lobe may be seen.
o CAM: In
· Isotope ventilation scanning: Although specific changes occur on isotope ventilation scanning, this modality seldom adds clinically useful information. In CLE, decreased ventilation initially occurs, followed by isotope retention. Attenuated vascularity results in decreased perfusion. Sequestration does not fill up at all during the early pulmonary phase, but it does during the systemic (late) phase. The value of radionuclide imaging is limited because of the lack of anatomic details.
· Aortography and angiography: Aortographic and angiographic findings are often definitive in sequestration and AVM, yet MRI usually makes these studies unnecessary. In pulmonary hypoplasia, aortography and angiography may be performed to evaluate for reduced pulmonary flow, aberrant pulmonary vessels, and scimitar syndrome. In pulmonary sequestration, arterial supply and venous drainage can be outlined.
o Pulmonary hypoplasia: In lung hypoplasia, aortography and angiography may be performed to evaluate for reduced pulmonary flow, aberrant pulmonary vessels, and scimitar syndrome.
o Pulmonary sequestration: In pulmonary sequestration, the arterial supply and venous drainage can be outlined. However, MRA has replaced interventional angiography as the diagnostic modality of choice for identifying sequestration vasculature in many centers.
· Barium esophagraphy: This test can assist in defining mediastinal masses and blood vessels. The images also outline communication between a pulmonary sequestration and the gut. However, with the availability of CT scanning, barium esophagraphy is no longer necessary.
· Echocardiography: Cardiac anomalies are associated with pulmonary hypoplasia in many patients. In addition, some cardiac malformations (eg, tetralogy of Fallot, and scimitar syndrome) may lead to pulmonary hypoplasia.
· Pulmonary function tests: Residual volume, vital capacity, total lung capacity, forced expiratory volume in 1 second (FEV1), and midexpiratory flow can be used to compare volumes in selected lung lesions before and after surgical resection.
· Monoclonal antibody testing: The ultimate usefulness of testing for elevated levels of cancer antigen (CA) 19-
· ECG: This test may be performed to evaluate for associated cardiac lesions or pulmonary hypertension. In cases of right-sided pulmonary hypoplasia, ECG is performed to distinguish between dextrocardia and dextroposition.
· Bronchoscopy: Bronchoscopy can be performed to detect airway malacia, which is present in patients with CLE, abnormal bronchial branching (eg, eparterial bronchus where the right upper lobe bronchus comes directly off the trachea). The study can also be performed to detect purulent material, which indicates infection complicating a congenital malformation of the lung, or to diagnose an acquired lesion, such as bronchiectasis.
· Bronchography: Bronchography is seldom indicated any longer because CT scanning can demonstrate most (but not all) cases of bronchiectasis. Bronchography is useful if a bronchial anomaly is suspected. These anomalies are rare but include bronchial agenesis, which leaves a poorly aerated lobe receiving only collateral ventilation, and bridging bronchus, in which the left mainstem bronchus originates from the right side.
Medical Therapy
Nonsurgical therapy is limited to the treatment of complications and associated respiratory failure. Antenatal prevention of preterm delivery (tocolytics) is important to avoid adding the complications of prematurity to any respiratory compromise that might be associated with the congenital lung malformation. If preterm delivery seems likely, maternal steroid administration may improve newborn surfactant and decrease hyaline membrane disease.
After birth, antibiotics are indicated for infection. Supplemental oxygen and mechanical ventilation are used for respiratory failure. In pulmonary sequestration and AVM, systemic arterial blood supply can be embolized, although thoracotomy and resection is usually just as rapid and more definitive than embolization.
In CLE, the infant is placed in a decubitus position with the involved side dependent, and the noninvolved side is selectively intubated. Gentle ventilation and respiratory monitoring are required.
Most lesions can be approached by means of a posterior lateral thoracotomy through the fifth intercostal space without resecting a rib. If thoracoscopy is performed, collapsing the lung with a double-lumen bifurcated endotracheal tube is usually not possible. For this reason, the authors use ports so that carbon dioxide can be introduced to gently depress the lung. In most cases, 5-
If pulmonary hypoplasia is diagnosed antenatally and judged to be incompatible with extrauterine life, some have suggested in utero intervention. This is done by occluding the fetal trachea with a balloon or clip. The accumulating fetal lung fluid seems to induce growth of the lung beyond normal. Because the lesion is rare and because the outcome is difficult to predict, this technique has not become popular. Some have tried to accomplish the same objective postnatally when a patient is receiving ECMO. One can then instill a perfluorocarbon for liquid ventilation under pressure and expect some lung growth and development. Serial amnioinfusions have been helpful in certain cases of oligohydramnios.
In the EXIT procedure, the fetal head, neck, and shoulders are delivered through a uterine opening to allow for an assessment of the airway while the fetus is still attached to placental circulation. This technique has been used as a primary procedure to treat tracheal occlusion, to manage neck masses, and to facilitate the safe delivery of conjoined twins. For respiratory management, ECMO may be required after delivery.
Procedures to enlarge the thorax have been tried when an abnormal chest wall causes lung hypoplasia. These procedures include thoracoplasty and median sternotomy. In CLE,
Posterolateral thoracotomy is performed to excise a bronchogenic cyst. The skin is incised from an inframammary point to a point about
Pulmonary hypoplasia
Surgical intervention may be necessary to manage airway narrowing. This narrowing can also be managed by placing a spacer on the contralateral side of the chest so that the airway does not become kinked and so that the lung does not hyperexpand. Tissue expanders have been used for this purpose. They offer the advantage that they can be slowly expanded over time by injecting saline through a subcutaneous port.
The authors have been disappointed with the longevity of tissue expanders. Leaks frequently occur, and the tissue expander must be replaced. The authors prefer to use the old but stable technique of placing ping-pong balls. This method creates a stable and long-lasting mass. As the patient grows, repeat operation to place more ping-pong balls is occasionally required, but this is unusual. The authors have had 1 patient who had to undergo repeat operation to remove 1 ball because overcorrection had occurred.
Placing a spacer on the contralateral side of the chest may also prevent the scoliosis that many of these children develop.
Pulmonary sequestration
Lobectomy is required to manage intrapulmonary lesions. Segmentectomy can be done in a few patients. The extrapulmonary sequestration can be resected without the loss of normal lung tissue.
Most children can be extubated in the recovery room. If this is not possible, supplemental oxygen or mechanical ventilation is provided as needed. Meticulous pain management increases the likelihood of extubation, including thoracic epidural or intrapleural infusion or even just local infiltration of intercostals nerves.
The authors then administer intravenous morphine 0.05 mg/kg/h in children younger than 6 months or 0.1 mg/kg/h in older children. In children school age, patient-controlled analgesia is best.
Full expansion of the lung should be achieved to seal air leaks. The chest tube is changed from suction to an underwater seal wheo air leak is present. When chest output is more than 2 mL/kg/d, the chest tube can be removed.
Maintenance fluids are provided intravenously to keep the patient a little dry and oral liquids are started the next day.
The authors encourage early ambulation. Many patients can be discharged in 3-5 days.
The prognosis is usually excellent after resection of congenital lung lesions when indicated. Attention is focused on any associated anomalies. If pneumonectomy was required, mediastinal shift may lead to cardiorespiratory compromise. This can be managed by placing an intrathoracic balloon prosthesis or by performing a tracheal-suspension procedure to relieve tracheal kinking.
Infants with limited remaining lung (eg, those with hypoplasia or extensive
General risks of thoracotomy and lung resection include empyema, pneumothorax, bleeding, and bronchopleural fistula. With respiratory insufficiency due to insufficient pulmonary tissue, pulmonary-artery hypertension and gastroesophageal reflux may occur and cause further deterioration. Failure to thrive can occur just as it does in congenital heart disease. Patients with failure to thrive may require supplemental feeding, even by means of a gastrostomy. Scoliosis can be a late complication when lung tissue is decreased in one thoracic cavity. Orthopedic intervention with bracing or open surgery may be necessary.
The incidence of complications after lung resection has decreased from 20-40% to 5-10% with modern care. Long-term pulmonary function after lobar resection is excellent.
Bronchogenic cyst
Because the normal lung parenchyma is not removed, the prognosis after surgical resection of bronchogenic cyst is excellent.
Pulmonary hypoplasia
The prognosis of patients with pulmonary hypoplasia depends on several factors, as follows:
· Associated anomalies
· Pulmonary hypertension
· Severe oligohydramnios, which increases the mortality rate
· Preterm delivery or rupture of the membranes earlier than 28 weeks’ gestation
· Sidedness (Because the right lung is normally larger than the left, hypoplasia of the right lung is associated with a worsened outcome.)
Pulmonary sequestration
If the pulmonary sequestration is resected before repeated infections occur, morbidity can be prevented. In addition, the patient’s prognosis depends on associated anomalies. The survival rate approaches 100% in the absence of other medical problems. Extralobar resection does not involve the removal of normal lung, and postoperative pulmonary function is excellent.
Congenital lobar emphysema
Frenckner and Freyschuss and then McBride showed that the lung volumes were 90-100% of predicted values in patients who underwent lobectomy for CLE as neonates.3,4 This change results from compensatory growth of lung tissue and not from residual lung distention. However, the flow rates were low compared with predicted values (FEV1 at 72% of expected). These findings may have resulted from the fact that alveoli continue to form, whereas airway formation ceases after birth.
Cystic adenomatoid malformation
The overall probability of survival is 80-100% in most studies. Most children have excellent long-term pulmonary function after lobectomy.
Factors in the natural history that may modify the patient’s prognosis include the type (type 3 has the worst prognosis), size (large lesions produce respiratory compromise and mediastinal shift), timing of surgery (early surgical resection may improve outcomes), hydrops fetalis (this worsens the prognosis), and bilateral involvement (this results in a poor outcome).
Advancements in obstetric care, early detection of anomalies, noninvasive diagnostic modalities, early definitive surgery, and intensive care have improved the outcome of patients with congenital lung malformations. In minimally invasive thoracoscopic surgery, tiny holes are drilled in the chest to provide surgical access to internal structures. This technique is as effective as open thoracotomy in selected cases.
Fetal surgery
Perhaps one of the most controversial areas still evolving is fetal surgery.
Fetal endoscopic surgery (ie, fetendo) obviates a large uterine incision and may reduce the overall risks of fetal surgery by reducing uterine trauma and, ultimately, preterm labor. Fetal endoscopic surgery, the EXIT procedure and the plug (ie, tracheal occlusion) procedure have improved the outlook in a number of cases of congenital lung malformation. However, fetal surgery is still limited to relatively few tertiary care centers.
A randomized controlled trial of 24 fetuses with congenital diaphragmatic hernia failed to show an appreciable effect on 90-day survival rates after tracheal occlusion to induce lung growth.5 Tracheal occlusion was compared with standard care (planned delivery and intensive postnatal care at a tertiary care center) in this study.
Total or partial lobectomy may be performed in patients with
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Basic:
1. Medical Genetics + Student Consult, 4th Edition. Lynn B. Jorde, John C. Carey, MPH and Michael J. Bamshad, 2010, p. 368. ISBN: 978-032-305-373-0
2. Essential Medical Genetics, 6 edition. Edward S. Tobias, Michael Connor, Malcolm Ferguson Smith. Published by Wiley-Blackwell, 2011, p. 344. ISBN: 978-140-516-974-5
3. Emery’s Elements of Medical Genetics + Student Consult, 14th Edition Peter D Turnpenny, 2012 p. 464. ISBN: 978-070-204-043-6
4. Genes, Chromosomes, and Disease: From Simple Traits, to Complex Traits, to Personalized Medicine. Nicholas Wright Gillham. Published by FT Press Science, 2011. p. 352.
5. Management of Genetic Syndromes. Suzanne B. Cassidy, Judith E. Allanson; 3 edition. Published by Wiley-Blackwell. 2010 p. 984 ISBN: 978-047-019-141-5.
6. Genetic Disorders and the Fetus: Diagnosis, Prevention and Treatment (Milunsky, Genetic Disorders and the Fetus) 6 edition. Aubrey Milunsky and Jeff Milunsky. Published by Wiley-Blackwell, 2010 p. 1184 ISBN: 978-140-519-087-9
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8. Passarge E. Color Atlas of Genetics – Thieme, 2007 Р. 497
Additional:
1. Atlas of Inherited Metabolic Diseases 3 edition William L Nyhan Bruce A Barshop, Aida I Al-Aqeel. Published by CRC. Press 2011, p 888. ISBN: 978-144-411-225-2.
2. Inborn Metabolic Diseases: Diagnosis and Treatment Jean-Marie Saudubray, Georges van den Berghe, John H. Walter. 5th ed. Published by Springer, 2012, p. 684. ISBN: 978-364-215-719-6.
3. Chromosome Abnormalities and Genetic Counseling (Oxford Monographs on Medical Genetics). 4 edition R. J. M. Gardner, Grant R Sutherland and Lisa G. Shaffer. Published by Oxford University Press, USA; 2011 p.648. ISBN: 978-019-537-533-6.
4. Mitochondrial Medicine: Mitochondrial Metabolism, Diseases, Diagnosis and Therapy Editored by Anna Gvozdjáková. Published by Soringer, 2008, p. 409 ISBN 978-1-4020-6713-6
5. Mitochondrial DNA, Mitochondria, Disease and Stem Cells (Stem Cell Biology and Regenerative Medicine) Editor Justin C. St. John. Published by Humana Press, 2012 p.199. ISBN: 978-162-703-100-4.
6. Genetic Counseling Practice: Advanced Concepts and Skills. Bonnie S. LeRoy, Patricia M. Veach, Dianne M. Bartels. Published by Wiley-Blackwell, 2010, p. 415. ISBN: 978-047-018-355-7
7. A Guide to Genetic Counseling 2 edition; Wendy R. Uhlmann, Jane L. Schuette, Beverly Yashar. Published by Wiley-Blackwell, 2010, p. 644. ISBN: 978-047-017-965-9
8. http://www.downtv.org/
