Lecture 3
General characterization of monogenic pathology. Clinical symptoms and genetics of the main forms of monogenic diseases.
Neurofibromatosis
Neurofibromatosis was first described in 1882 by the German pathologist Friedrich Daniel von Recklinghausen.
Joseph Merrick, the Elephant Man, was once considered to have been affected with either elephantiasis or neurofibromatosis type I. However, it is now generally believed that Merrick suffered from the very rare Proteus syndrome. This however has given rise to the common misconception that Neurofibromatosis and “Elephant Man Disease” are one and the same.
Neurofibromatosis-1 is found in approximately
NF-2 is less common, having one case in 50,000-120,000 live births.
Neurofibromatosis (commonly abbreviated NF) is a genetically-inherited disease in which nerve tissue grows tumors (e.g. neurofibromas) that may be harmless or may cause serious damage by compressing nerves and other tissues. The disorder affects all neural crest cells (Schwann cells, melanocytes, endoneurial fibroblasts). Cellular elements from these cell types proliferate excessively throughout the body forming tumors and the melanocytes function abnormally resulting in disordered skin pigmentation.The tumors may cause bumps under the skin, colored spots, skeletal problems, pressure on spinal nerve roots, and other neurological problems.
Neurofibromas are the subcutaneous lumps that are characteristic of the disease and increase in number with age.
Back of an elderly woman with Neurofibromatosis.
ETHIOLOGY Neurofibromatosis is autosomal dominant, which means that it affects males and females equally and is dominant (only one copy of the affected gene is needed to get the disorder). Therefore, if only one parent has neurofibromatosis, his or her children have a 50% chance of developing the condition as well. Disease severity in affected individuals, however, can vary (this is called variable expressivity). Moreover, in around half of cases there is no other affected family member because a new mutation has occurred.
Diagnostic Criteria
Neurofibromatosis type 1 – mutation of neurofibromin chromosome 17q11.2.
The diagnosis of NF1 is made if any two of the following seven criteria are met:
Two or more neurofibromas on the skin or under the skin or one plexiform neurofibroma (a large cluster of tumors involving multiple nerves);
Freckling of the groin or the axilla (arm pit).
Café au lait spots (pigmented birthmarks). Six or more measuring
Skeletal abnormalities, such as sphenoid dysplasia or thinning of the cortex of the long bones of the body (i.e. bones of the leg, potentially resulting in bowing of the legs)
Lisch nodules (hamartomas of iris), freckling in the iris.
Tumors on the optic nerve, also known as an optic glioma
A first-degree relative with a diagnosis of NF1
Neurofibromatosis type 2 – mutation of merlin chromosome 22q12
Bilateral tumors, acoustic neuromas on the vestibulocochlear nerve (the eighth cranial nerve) leading to hearing loss
the hallmark of NF 2 is hearing loss due to acoustic neuromas around the age of twenty
the tumors may cause: headache, balance problems, and Vertigo, facial weakness/paralysis
patients with NF2 may also develop other brain tumors, as well as spinal tumors
Deafness and Tinnitus
Any relative with NF-2, diagnosed or not NF-2 may be inherited in an autosomal dominant fashion, as well as through random mutation.
Both NF1 and NF2 can also appear to be spontaneous mutation, with no family history. These cases account for about one half of neurofibromatosis cases (ibid).
Effects
People with Neurofibromatosis can be affected in many different ways.There is a high incidence of learning disabilities in people with NF. It is believed that at least 50% of people with NF have learning disabilities of some type. Increased chances of development of petit mal epilepsy (a Partial absence seizure disorder) The tumors that occur can grow anywhere a nerve is present.
This means that:
They can grow in places that are very visible.
The tumors can also grow in places that can cause other medical issues that may require them to be removed for the patient’s safety.
Affected individuals may need multiple surgeries, depending on where the tumors are located.
Treatment
Because there is no cure for the disease itself, the only therapy for those people with neurofibromatosis is a program of treatment by a team of specialists to manage symptoms or complications. Surgery may be needed when the tumors compress organs or other structures. Less than 10% of people with neurofibromatosis develop cancerous growths; in these cases, chemotherapy may be successful. Some people may find something in the herbal remidies that can slow down the growth of these tumors.
Related disorders
Neurofibromatosis is considered a member of the neurocutaneous syndromes (phakomatoses). In addition to the types of neurofibromatosis, the phakomatoses also include tuberous sclerosis, Sturge-Weber syndrome and von Hippel-Lindau disease. This grouping is an artifact of an earlier time in medicine, before the distinct genetic basis of each of these diseases was understood.
Neurofibromatosis is also associated with pheochromocytoma.
Cystic fibrosis
Cystic fibrosis (also known as CF, mucovoidosis, or mucoviscidosis) is a genetic disorder known to be an inherited disease of the secretory glands, including the glands that make mucus and sweat.
Cystic fibrosis (CF) was recognized as specific entity during the 1930s. There is nothing resembling CF described in the 1032 pages of Sir Frederick Still’s 1927 Edition of Common Disorders and Diseases of Childhood. Formerly known as “cystic fibrosis of the pancreas,” this entity has increasingly been labeled simply “cystic fibrosis.”
Although technically a rare disease, cystic fibrosis is ranked as one of the most widespread life-shortening genetic diseases. It is most common among nations in the Western world; one in twenty-two people of Mediterranean descent is a carrier of one gene for CF, making it the most common genetic disease in these populations.
An exception is Finland, where only one in 80 people carry a CF mutation. In the United States,
Genetics and Hereditability
Cystic Fibrosis has an autosomal recessive pattern of inheritance.
CF is caused by a mutation in the gene cystic fibrosis transmembrane conductance regulator (CFTR). The product of this gene is a chloride ion channel important in creating sweat, digestive juices and mucus. Although most people without CF have two working copies (alleles) of the CFTR gene, only one is needed to prevent cystic fibrosis. CF develops wheeither allele can produce a functional CFTR protein.
PATHOGENESIS.
Four long-standing observations are of fundamental pathophysiologic importance: failure to clear mucous secretions, a paucity of water in mucous secretions, an elevated salt content of sweat and other serous secretions, and chronic infection limited to the respiratory tract. The relationships among these findings were unclear until the early 1980s when it was demonstrated that there is a greater negative potential difference across the respiratory epithelia of CF than of control subjects. Aberrant electrical properties were also demonstrated for CF sweat gland duct epithelium. Subsequent studies demonstrated that the apical membranes of CF epithelial cells are unable to secrete chloride ions in response to cAMP-mediated signals, and that, at least in the respiratory tract, excessive amounts of sodium are absorbed through these membranes.
Signs and symptoms
The hallmarks of cystic fibrosis are salty tasting skin, normal appetite but poor growth and poor weight gain, excess mucus production, and coughing/shortness of breath. Males can be infertile due to the condition congenital bilateral absence of the vas deferens. Often, symptoms of CF appear in infancy and childhood. Meconium ileus is a typical finding iewborn babies with CF.
Lung and sinus disease
Lung disease results from clogging the airways due to mucosa buildup and resulting inflammation. Inflammation and infection cause injury to the lungs and structural changes that lead to a variety of symptoms. In the early stages, incessant coughing, copious phlegm production, and decreased ability to exercise are common. Many of these symptoms occur when bacteria that normally inhabit the thick mucus grow out of control and cause pneumonia. In later stages of CF, changes in the architecture of the lung further exacerbate chronic difficulties in breathing. Other symptoms include coughing up blood (hemoptysis), changes in the major airways in the lungs (bronchiectasis), high blood pressure in the lung (pulmonary hypertension), heart failure, difficulties getting enough oxygen to the body (hypoxia), and respiratory failure requiring support with breathing masks such as bilevel positive airway pressure machines or ventilators. In addition to typical bacterial infections, people with CF more commonly develop other types of lung disease. Among these is allergic bronchopulmonary aspergillosis, in which the body’s response to the common fungus Aspergillus fumigatus causes worsening of breathing problems. Another is infection with Mycobacterium avium complex (MAC), a group of bacteria related to tuberculosis, which can cause further lung damage and does not respond to common antibiotics. Mucus in the paranasal sinuses is equally thick and may also cause blockage of the sinus passages, leading to infection. This may cause facial pain, fever, nasal drainage, and headaches. Individuals with CF may develop overgrowth of the nasal tissue (nasal polyps) due to inflammation from chronic sinus infections. These polyps can block the nasal passages and increase breathing difficulties.
Gastrointestinal, liver and pancreatic disease
Prior to prenatal and newborn screening, cystic fibrosis was often diagnosed when a newborn infant failed to pass feces (meconium). Meconium may completely block the intestines and cause serious illness. This condition, called meconium ileus, occurs in 10% of newborns with CF. In addition, protrusion of internal rectal membranes (rectal prolapse) is more common in CF because of increased fecal volume, malnutrition, and increased intra–abdominal pressure due to coughing.
The thick mucus seen in the lungs has a counterpart in thickened secretions from the pancreas, an organ responsible for providing digestive juices which help break down food. These secretions block the movement of the digestive enzymes into the duodenum and result in irreversible damage to the pancreas, often with painful inflammation (pancreatitis). The lack of digestive enzymes leads to difficulty absorbing nutrients with their subsequent excretion in the faeces, a disorder known as malabsorption. Malabsorption leads to malnutrition and poor growth and development because of calorie loss. Individuals with CF also have difficulties absorbing the fat-soluble vitamins A, D, E, and K. In addition to the pancreas problems, people with cystic fibrosis experience more heartburn, intestinal blockage by intussusception, and constipation. Older individuals with CF may also develop distal intestinal obstruction syndrome when thickened feces cause intestinal blockage.
Thickened secretions also may cause liver problems in patients with CF. Bile secreted by the liver to aid in digestion may block the bile ducts, leading to liver damage. Over time, this can lead to cirrhosis, in which the liver fails to rid the blood of toxins and does not make important proteins such as those responsible for blood clotting.
Endocrine disease and growth
The pancreas contains the islets of Langerhans, which are responsible for making insulin, a hormone that helps regulate blood glucose. Damage of the pancreas can lead to loss of the islet cells, leading to diabetes that is unique to those with the disease. Cystic Fibrosis Related Diabetes (CFRD), as it is known as, shares characteristics that can be found in Type 1 and Type 2 diabetics and is one of the principal non-pulmonary complications of CF. Vitamin D is involved in calcium and phosphorus regulation. Poor uptake of vitamin D from the diet because of malabsorption leads to the bone disease osteoporosis in which weakened bones are more susceptible to fractures. In addition, people with CF often develop clubbing of their fingers and toes due to the effects of chronic illness and low oxygen in their tissues.
Poor growth is a hallmark of CF. Children with CF typically do not gain weight or height at the same rate as their peers, and occasionally are not diagnosed until investigation is initiated for poor growth. The causes of growth failure are multi–factorial and include chronic lung infection, poor absorption of nutrients through the gastrointestinal tract, and increased metabolic demand due to chronic illness.
Diagnosis
Cystic fibrosis may be diagnosed by many different categories of testing including those such as, newborn screening, sweat testing, or genetic testing.
Infants with an abnormal newborn screeeed a sweat test in order to confirm the CF diagnosis. Sweat-testing involves application of a medication that stimulates sweating (pilocarpine) to one electrode of an apparatus and running electric current to a separate electrode on the skin. This process, called iontophoresis, causes sweating; the sweat is then collected on filter paper or in a capillary tube and analyzed for abnormal amounts of sodium and chloride. People with CF have increased amounts of sodium and chloride in their sweat. CF can also be diagnosed by identification of mutations in the CFTR gene.
A multitude of tests are used to identify complications of CF and to monitor disease progression.
X-rays and CAT scans are used to examine the lungs for signs of damage or infection.
Examination of the sputum under a microscope is used to identify which bacteria are causing infection so that effective antibiotics can be given.
Pulmonary function tests measure how well the lungs are functioning, and are used to measure the need for and response to antibiotic therapy.
Blood tests can identify liver abnormalities, vitamin deficiencies, and the onset of diabetes.
DEXA scans can screen for osteoporosis and testing for fecal elastase can help diagnose insufficient digestive enzymes.
Prenatal diagnosis
Couples who are pregnant or who are planning a pregnancy can themselves be tested for CFTR gene mutations to determine the likelihood that their child will be born with cystic fibrosis. Testing is typically performed first on one or both parents and, if the risk of CF is found to be high, testing on the fetus can then be performed.
Couples who are at high risk for having a child with CF will often opt to perform further testing before or during pregnancy. In vitro fertilization with preimplantation genetic diagnosis offers the possibility to examine the embryo prior to its placement into the uterus. The test, performed 3 days after fertilization, looks for the presence of abnormal CF genes. If two mutated CFTR genes are identified, the embryo is not used for embryo transfer and an embryo with at least one normal gene is implanted.
monitoring
The cornerstones of management are proactive treatment of airway infection, and encouragement of good nutrition and an active lifestyle. The treatment for cystic fibrosis continues throughout a patient’s life, and is aimed at maximizing organ function, and therefore quality of life. At best, current treatments delay the decline in organ function. Treatment typically occurs at specialist multidisciplinary centres, and is tailored to the individual, because of the wide variation in disease symptoms.
Targets for therapy are the lungs, gastrointestinal tract (including insulin treatment and pancreatic enzyme supplements), the reproductive organs and psychological support.
The most consistent aspect of therapy in cystic fibrosis is limiting and treating the lung damage caused by thick mucus and infection with the goal of maintaining quality of life. Intravenous, inhaled, and oral antibiotics are used to treat chronic and acute infections. Mechanical devices and inhalation medications are used to alter and clear the thickened mucus. These therapies, while effective, can be extremely time consuming to the patient. One of the most important battles that CF patients face is finding the time to comply with all the prescribed treatments while balancing a normal life.
Many CF patients are on one or more antibiotics at all times, even when they are considered healthy, to suppress the infection as much as possible. Antibiotics are absolutely necessary whenever pneumonia is suspected or there has been a noticeable decline in lung function.
Reversible airway obstruction occurs in many patients with CF, sometimes in conjunction with frank asthma or acute bronchopulmonary aspergillosis. Reversible obstruction is suggested by improvement of 15% or more in flow rates after inhalation of a bronchodilator. Treatment may include use of b{beta}-adrenergic agonists by aerosol. Cromolyn sodium or ipratropium hydrochloride are alternative agents, but their efficacy has not been studied systematically.
Corticosteroids are useful for the treatment of allergic bronchopulmonary aspergillosis and other severe reactive airways disease occasionally encountered in patients with CF. Prolonged treatment of standard CF lung disease using an alternate-day regimen initially appeared to improve pulmonary function and diminish hospitalization rates.
Systemic drugs, such as iodides and guaiphenesin, do not effectively assist with the removal of secretions from the respiratory tract.
Other methods to treat lung disease
Treatment of obstructed airways sometimes includes tracheobronchial suctioning or lavage, especially if atelectasis or mucoid impaction is present. Bronchopulmonary lavage may be performed by the instillation of saline or by a mucolytic agent through a fiberoptic bronchoscope. Antibiotics (usually gentamicin or tobramycin) may also be directly instilled at lavage, transiently achieving a much higher endobronchial concentration than can be obtained by using intravenous therapy. There is no evidence for sustained benefit from repeated endoscopic or lavage procedures.
Several mechanical techniques are used to dislodge sputum and encourage its expectoration. In the hospital setting, chest physiotherapy (CPT) is utilized; a respiratory therapist percusses an individual’s chest with his or her hands several times a day, to loosen up secretions. Physiotherapy is essential to help manage an individuals chest on a long term basis, and can also teach techniques for the older child and teenager to manage themselves at home. Aerobic exercise is of great benefit to people with cystic fibrosis. Not only does exercise increase sputum clearance but it also improves cardiovascular and overall health.
As lung disease worsens, breathing support from machines may become necessary. Individuals with CF may need to wear special masks at night that help push air into their lungs. During severe illness, people with CF may need to have a tube placed in their throats (a procedure known as a tracheostomy) and their breathing supported by a ventilator.
A typical breathing treatment for cystic fibrosis, using a mask nebuliser and the ThAIRapy Vest
Treatment of other aspects of CF
Newborns with meconium ileus typically require surgery, whereas adults with distal intestinal obstruction syndrome typically do not. Treatment of pancreatic insufficiency by replacement of missing digestive enzymes allows the duodenum to properly absorb nutrients and vitamins that would otherwise be lost in the faeces. Even so, most individuals with CF take additional amounts of vitamins A, D, E, and K and eat high-calorie meals.
It should be noted, however, that nutritional advice given to patients is, at best, mixed: Often, literature encourages the eating of high-fat foods without differentiating between saturated, unsaturated fat, and trans-fats; this lack of clear information runs counter to health advice given to the general population, and creates the risk of further serious health problems for people with cystic fibrosis as they grow older. So far, no large-scale research involving the incidence of atherosclerosis and coronary heart disease in adults with cystic fibrosis has been conducted. This is likely due to the fact that the vast majority of people with cystic fibrosis do not live long enough to develop clinically significant atherosclerosis or coronary heart disease.
The diabetes common to many CF patients is typically treated with insulin injections or an insulin pump.Development of osteoporosis can be prevented by increased intake of vitamin D and calcium, and can be treated by bisphosphonates. Poor growth may be avoided by insertion of a feeding tube for increasing calories through supplemental feeds or by administration of injected growth hormone.
Sinus infections are treated by prolonged courses of antibiotics. The development of nasal polyps or other chronic changes within the nasal passages may severely limit airflow through the nose. Sinus surgery is often used to alleviate nasal obstruction and to limit further infections. Nasal steroids such as fluticasone are used to decrease nasal inflammation. Female infertility may be overcome by assisted reproduction technology, particularly embryo transfer techniques. Male infertility may be overcome with intracytoplasmic sperm injection. Third party reproduction is also a possibility for women with CF.
Transplantation and gene therapy
Lung transplantation often becomes necessary for individuals with cystic fibrosis as lung function and exercise tolerance declines. Although single lung transplantation is possible in other diseases, individuals with CF must have both lungs replaced because the remaining lung would contain bacteria that could infect the transplanted lung. A pancreatic or liver transplant may be performed at the same time in order to alleviate liver disease and/or diabetes. Lung transplantation is considered when lung function approaches a point where it threatens survival or requires assistance from mechanical devices. This point is typically when lung function declines to approximately 20 to 30 percent, however there is a small time frame when transplantation is feasible as the patient must be healthy enough to endure the procedure.
Gene therapy holds promise as a potential avenue to cure cystic fibrosis. Gene therapy attempts to place a normal copy of the CFTR gene into affected cells. Studies have shown that to prevent the lung manifestations of cystic fibrosis, only 5–10% the normal amount of CFTR gene expression is needed. Multiple approaches have been tested for gene transfer, such as liposomes and viral vectors in animal models and clinical trials. However, at this time gene therapy is still a relatively inefficient treatment option. Ideally, transferring the normal CFTR gene into the affected epithelium cells would result in the production of functional CFTR in all target cells, without adverse reactions or an inflammation response. But if too few cells take up the vector and express the gene, the treatment has little effect. Additionally, problems have beeoted in cDNA recombination, such that the gene introduced by the treatment is rendered unusable.
Prognosis
In most cases, CF causes an early death. Average life expectancy is around 36.8 years according to the Cystic Fibrosis Foundation, although improvements in treatments mean a baby born today could expect to live longer
Marfan syndrome
Marfan syndrome (or Marfan’s syndrome) is a genetic disorder of the connective tissue.
It is named after Antoine Marfan, the French pediatrician who first described the condition in 1896 after noticing striking features in a 5-year-old girl. The gene linked to the disease was first identified by Francesco Ramirez at the Mount Sinai Medical Center in New York City in 1991.
Epidemiology
Marfan syndrome affects males and females equally, and the mutation shows no geographical bias. Estimates indicate that approximately 60,000 (
Genetics and Hereditability
It is sometimes inherited as a dominant trait. It is carried by a gene called FBN1, which encodes a connective protein called fibrillin-1. People have a pair of FBN1 genes. Because it is dominant, people who have inherited one affected FBN1 gene from either parent will have Marfan’s. This syndrome can run from mild to severe.
In addition to being a connective protein that forms the structural support for tissues outside the cell, fibrillin-1 binds to another protein, transforming growth factor beta (TGF-β). TGF-β is important in termination of acute inflammation.
Researchers now believe that the inflammatory effects of fibrillin disabling TGF-β, at the lungs, heart valves, and aorta, weaken the tissues and cause the features of Marfan syndrome. Since angiotensin II receptor blockers (ARBs) also reduce TGF-β, they have tested this by giving ARBs (losartan, etc.) to a small sample of young, severely affected Marfan syndrome patients. In some patients, the growth of the aorta was indeed reduced.
Pathogenesis
Diagnosis
A diagnosis of Marfan syndrome is based on family history and a combination of major and minor indicators of the disorder, rare in the general population, that occur in one individual. For example: four skeletal signs with one or more signs in another body system such as ocular and cardiovascular in one individual.
People with Marfan’s are typically tall, with long limbs and long thin fingers.
The most serious complications are the defects of the heart valves and aorta. It may also affect the lungs, eyes, the dural sac surrounding the spinal cord, skeleton and the hard palate.
Although there are no unique signs or symptoms of Marfan syndrome, the constellation of long limbs, dislocated lenses, and aortic root dilation is sufficient to make the diagnosis with confidence. There are more than 30 other clinical features that are variably associated with the syndrome, most involving the skeleton, skin, and joints. There is a great deal of clinical variability even within families that carry the identical mutation.
The following conditions may result from Marfan syndrome but may also occur in people without any known underlying disorder.
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Aortic aneurysm or dilation Bicuspid aortic valve Cystic medial necrosis Ectopia lentis Gigantism Hernias Malocclusion Myopia Osteoarthritis Pneumothorax Scoliosis Stretch marks |
Arachnodactyly Cysts Dural ectasia Flat feet Glaucoma Hypermobility of the joints Mitral valve prolapse Obstructive lung disease Pectus carinatum or excavatum Retinal detachment Sleep apnea |
Skeletal system
The most readily visible signs are associated with the skeletal system. Many individuals with Marfan syndrome grow to above average height. Some have long slender limbs with fingers and toes that are also abnormally long and slender (arachnodactyly).
This long, slender body habitus and long, slender limbs are known as dolichostenomelia. An individual’s arms may be disproportionately long, with thin, weak wrists. In addition to affecting height and limb proportions.
Abnormal curvature of the spine (scoliosis) is common, as is abnormal indentation (pectus excavatum) or protrusion (pectus carinatum) of the sternum. Other signs include abnormal joint flexibility, a high palate, malocclusions, flat feet, hammer toes, stooped shoulders, unexplained stretch marks on the skin and thin wrists. It can also cause pain in the joints, bones and muscles in some patients. Some people with Marfan have speech disorders resulting from symptomatic high palates and small jaws.
Eyes
Lens dislocation in Marfan’s syndrome, the lens was kidney-shaped and was resting against the ciliary body.
Marfan syndrome can also seriously affect the eyes and vision. Nearsightedness and astigmatism are common, but farsightedness can also result. Subluxation (dislocation) of the crystalline lens in one or both eyes (ectopia lentis) (in 80% of patients) also occurs and may be detected by an ophthalmologist or optometrist using a slit-lamp biomicroscope. In Marfan’s the dislocation is typically superotemporal whereas in the similar condition homocystinuria, the dislocation is inferonasal. Sometimes eye problems appear only after the weakening of connective tissue has caused detachment of the retina. Early onset glaucoma can be another related problem.
Cardiovascular system
The most serious signs and symptoms associated with Marfan syndrome involve the cardiovascular system. Undue fatigue, shortness of breath, heart palpitations, racing heartbeats, or Angina pectoris with pain radiating to the back, shoulder, or arm. Cold arms, hands and feet can also be linked to Marfan’s syndrome because of inadequate circulation. A heart murmur, abnormal reading on an EKG, or symptoms of angina can indicate further investigation. The signs of regurgitation from prolapse of the mitral or aortic valves (which control the flow of blood through the heart) result from cystic medial degeneration of the valves which is commonly associated with Marfan’s syndrome (see mitral valve prolapse). However, the major sign that would lead a doctor to consider an underlying condition is a dilated aorta or an aortic aneurysm. Sometimes, no heart problems are apparent until the weakening of the connective tissue (cystic medial degeneration) in the ascending aorta causes an aortic aneurysm or aortic dissection, a medical emergency. An aortic dissection is most often fatal and presents with pain radiating down the back, giving a tearing sensation.
Lungs
Marfan syndrome is a risk factor for spontaneous pneumothorax. In spontaneous unilateral pneumothorax, air escapes from a lung and occupies the pleural space between the chest wall and a lung. The lung becomes partially compressed or collapsed. This can cause pain, shortness of breath, cyanosis, and, if not treated, death. Marfan syndrome has also been associated with sleep apnea and idiopathic obstructive lung disease.
Central nervous system
Another condition that can reduce the quality of life for an individual, though not life-threatening, is dural ectasia, the weakening of the connective tissue of the dural sac, the membrane that encases the spinal cord. Dural ectasia can be present for a long time without producing any noticeable symptoms. Symptoms that can occur are lower back pain, leg pain, abdominal pain, other neurological symptoms in the lower extremities, or headaches. Such symptoms usually diminish when the individual lies flat on his or her back. These types of symptoms might lead a doctor to order an X-ray of the lower spine. Dural ectasia is usually not visible on an X-ray in the early phases. A worsening of symptoms and the lack of finding any other cause should eventually lead a doctor to order an upright MRI of the lower spine. Dural ectasia that has progressed to the point of causing these symptoms would appear in an upright MRI image as a dilated pouch that is wearing away at the lumbar vertebrae.[9] Other spinal issues associated with Marfan include degenerative disk disease and spinal cysts. Marfan syndrome is also associated with dysautonomia.
Differential diagnosis
The following disorders have similar signs and symptoms of Marfan syndrome:
Congenital Contractural Arachnodactyly (CCA) or Beals Syndrome
Ehlers-Danlos syndrome
Homocystinuria
Loeys-Dietz syndrome
MASS phenotype
Stickler syndrome
Multiple endocrine neoplasia, type 2B
Management
There is no cure for Marfan syndrome, but life expectancy has increased significantly over the last few decades, and clinical trials are underway for a promising new treatment. The syndrome is treated by addressing each issue as it arises, and, in particular, considering preventive medication, even for young children, to slow progression of aortic dilation.
Regular checkups by a cardiologist are needed to monitor the health of the heart valves and the aorta. The goal of treatment is to slow the progression of aortic dilation and damage to heart valves by eliminating arrythmias, minimizing the heart rate, and minimizing blood pressure. Beta blockers have been used to control arrythmias and slow the heart rate. Other medications might be needed to further minimize blood pressure without slowing the heart rate, such as ACE inhibitors and angiotensin II receptor antagonists, also known as angiontensin receptor blockers (ARBs). If the dilation of the aorta progresses to a significant diameter aneurysm, causes a dissection or a rupture, or leads to failure of the aortic or other valve, then surgery (possibly a composite aortic valve graft [CAVG] or valve-sparing procedure) becomes necessary. Although aortic graft surgery (or any vascular surgery) is a serious undertaking it is generally successful if undertaken on an elective basis.
Surgery in the setting of acute aortic dissection or rupture is considerably more problematic. Elective aortic valve/graft surgery is usually considered when aortic root diameter reaches
The skeletal and ocular manifestations of Marfan syndrome can also be serious, although not life-threatening. These symptoms are usually treated in the typical manner for the appropriate condition, such as with various kinds of pain medication or muscle relaxants. It is also common for patients to receive treatment from a physiotherapist, using TENS therapy, ultrasound and skeletal adjustment.[citatioeeded] This can also affect height, arm length, and life span. A physiotherapist can also help improve function and prevent injuries in individuals with Marfan’s. The Nuss procedure is now being offered to people with Marfan syndrome to correct ‘sunken chest’ or (pectus excavatum).Because Marfan may cause spinal abnormalities that are asymptomatic, any spinal surgery contemplated on a Marfan patient should only follow detailed imaging and careful surgical planning, regardless of the indication for surgery.
Clinical trials have been conducted of the drug acetazolamide in the treatment of symptoms of dural ectasia. The treatment has demonstrated significant functional improvements in some sufferers. Other medical treatments, as well as physical therapy, are also available.
Treatment of a spontaneous pneumothorax is dependent on the volume of air in the pleural space and the natural progression of the individual’s condition. A small pneumothorax might resolve without active treatment in one to two weeks. Recurrent pneumothoraces might require chest surgery. Moderately sized pneumothoraces might need chest drain management for several days in a hospital. Large pneumothoraces are likely to be medical emergencies requiring emergency decompression.
Ehlers-Danlos Syndrome
Ehlers-Danlos Syndrome (EDS) (also known as “Cutis hyperelastica”) is a group of inherited connective tissue disorders, caused by a defect in the synthesis of collagen (a protein in connective tissue). Connective tissue helps support the skin, muscles, ligaments and organs of the body. Depending on the individual mutation, the severity of the syndrome can vary from mild to life-threatening. There is no known cure. Treatment is supportive.
The syndrome is named after two doctors, Edvard Ehlers of Denmark, and Henri-Alexandre Danlos of France, who identified it at the turn of the 20th century.
Epidemiology
Ehlers-Danlos Syndrome is an inherited disorder estimated to occur in about
Symptoms
Symptoms vary widely based on which type of EDS the patient has. In each case, however, the symptoms are ultimately due to faulty or reduced amounts of Type III collagen. EDS most typically affects the joints, skin, and blood vessels, with symptoms such as loose, overly-flexible joints; smooth or stretchy, easily-bruised skin; abnormal wound healing and scar formation; and small, fragile blood vessels. All forms of EDS affect the joints, causing hypermobility, or joints that extend beyond the normal range of motion. As a result of their hypermobility, individuals with EDS are more susceptible to injuries such as: dislocations, subluxations, sprains, strains, and sometimes fractures. Because it is often undiagnosed in childhood, some instances of Ehlers-Danlos syndrome have been mischaracterized as child abuse.
Genetics
Mutations in the following can cause Ehlers-Danlos syndrome:
Fibrous proteins: COL1A1, COL1A2, COL3A1, COL5A1, COL5A2, and TNXB
Enzymes: ADAMTS2, PLOD1
Mutations in these genes usually alter the structure, production, or processing of collagen or proteins that interact with collagen. Collagen provides structure and strength to connective tissue throughout the body. A defect in collagen can weaken connective tissue in the skin, bones, blood vessels, and organs, resulting in the features of the disorder.
Inheritance patterns depend on the type of Ehlers-Danlos syndrome. Most forms of the condition are inherited in an autosomal dominant pattern, which means only one of the two copies of the gene in question must be altered to cause the disorder. The minority are inherited in an autosomal recessive pattern, which means both copies of the gene must be altered for a person to be affected by the condition. It can also be an individual (de novo or “sporadic”) mutation. Please refer to the summary for each type of Ehlers-Danlos syndrome for a discussion of its inheritance pattern.
Treatment/management
There is no known cure for Ehlers Danlos Syndrome. The treatment is supportive. Physical therapy, occupational therapy, and orthopedic instruments (e.g., wheelchairs, bracing) may be helpful. One should avoid activities that cause the joint to lock or overextend.
A physician may prescribe bracing to stabilize joints. Surgical repair of joints may be necessary at some time. Physicians may also consult a physical and/or occupational therapist to help strengthen muscles and to teach people how to properly use and preserve their joints. To decrease bruising and improve wound healing, some patients have responded to ascorbic acid (vitamin C) by taking 1 to
In general, medical intervention is limited to symptomatic therapy. Prior to pregnancy, patients with EDS should have genetic counseling. Children with EDS should be provided with information about the disorder, so they can understand why contact sports and other physically stressful activities should be avoided. Children should be taught early on that demonstrating the unusual positions they can maintain due to loose joints should not be done as this may cause early degeneration of the joints. Family members, teachers and friends should be provided with information about EDS so they can accept and assist the child as necessary.
Prognosis
The outlook for individuals with EDS depends on the type of EDS with which they have been diagnosed. Symptoms vary in severity, even within one sub-type, and the frequency of complications changes on an individual basis. Some individuals have negligible symptoms while others are severely restricted in their daily life. Extreme joint instability, pain, and spinal deformities may limit a person’s mobility. Most individuals will have a normal lifespan. However, those with blood vessel involvement have an increased risk of fatal complications.
EDS is a lifelong condition. Affected individuals may face social obstacles related to their disease on a daily basis. Some people with EDS have reported living with fears of significant and painful ruptures, becoming pregnant, their condition worsening, becoming unemployed due to physical and emotional burdens, and social stigmatization in general.
Prader-Willi syndrome
Prader-Willi Syndrome (PWS) is an uncommon genetic disorder. It causes poor muscle tone, low levels of sex hormones and a constant feeling of hunger. The part of the brain that controls feelings of fullness or hunger does not work properly in people with PWS. They overeat, leading to obesity.
There are generally two stages of symptoms for people with Prader-Willi syndrome:
Stage 1–As newborns, babies with Prader-Willi can have low muscle tone, which can affect their ability to suck properly. As a result, babies may need special feeding techniques to help them eat, and infants may have problems gaining weight. As these babies grow older, their strength and muscle tone usually get better. They meet motor milestones, but are usually slower in doing so.
Stage 2–Between the ages of 1 and 6 years old, the disorder changes to one of constant hunger and food seeking. Most people with Prader-Willi syndrome have an insatiable appetite, meaning they never feel full. In fact, their brains are telling them they are starving. They may have trouble regulating their own eating and may need external restrictions on food, including locked kitchen and food storage areas.
This problem is made worse because people with Prader-Willi syndrome use fewer calories than those without the syndrome because they have less muscle mass. The combination of eating massive amounts of food and not burning enough calories can lead to life-threatening obesity if the diet is not kept under strict control.
There are other symptoms that may affect people with Prader-Willi, including:
Behavioral problems, usually during transitions and unanticipated changes, such as stubbornness or temper tantrums
Delayed motor skills and speech due to low muscle tone
Cognitive problems, ranging from near normal intelligence to mild mental retardation; learning disabilities are common
Repetitive thoughts and verbalizations
Collecting and hoarding of possessions
Picking at skin
Low sex hormone levels
Prader-Willi syndrome is considered a spectrum disorder, meaning not all symptoms will occur in everyone affected and the symptoms may range from mild to severe.
People with Prader-Willi often have some mental strengths as well, such as skills in jigsaw puzzles. If obesity is prevented, people with the syndrome can live a normal lifespan.
Babies with PWS are usually floppy, with poor muscle tone, and have trouble sucking. Boys may have undescended testicles. Later, other signs appear. These include
Short stature
Poor motor skills
Weight gain
Underdeveloped sex organs
Mild mental retardation and learning disabilities
There is no cure for PWS. Growth hormone and exercise can help build muscle mass and control weight.
TABLE 3. Suggested New Criteria to Prompt DNA Testing for PWS
Age at Assessment Features Sufficient to Prompt DNA Testing
|
Birth to 2 y |
1. Hypotonia with poor suck. |
|
2y–6 y |
1. Hypotonia with history of poor suck. 2. Global developmental delay. |
|
6y–12 y
|
1. History of hypotonia with poor suck (hypotonia often persists). 2. Global developmental delay. 3. Excessive eating (hyperphagia; preoccupation with food) with central obesity if uncontrolled. |
|
13 y through adulthood |
1. Cognitive disabilities; usually mild mental retardation. 2. Excessive eating (hyperphagia; preoccupation with food) with central obesity if uncontrolled. 3. Hypothalamic hypogonadism and/or typical behavior problems (including temper tantrums, perseverative and compulsive-like behaviors). |
TABLE 2. Sensitivities and the Percentages of Documentation of the Published Criteria
|
|
% Affected
|
|
Major criteria |
|
|
Neonatal hypotonia |
88 |
|
Feeding problems in infancy |
79 |
|
Excessive weight gain |
67 |
|
Facial features |
88 |
|
Hypogonadism |
51 |
|
Developmental delay |
99 |
|
Hyperphagia |
84 |
|
Minor criteria |
|
|
Decreased fetal activity |
62 |
|
Behavior problems |
87 |
|
Sleep disturbance/sleep apnea |
76 |
|
Short stature |
63 |
|
Hypopigmentation |
73 |
|
Small hands and/or feet |
88 |
|
Narrow hands/straight |
82 |
|
ulnar borders |
|
|
Eye abnormalities |
68 |
|
Thick viscous saliva |
89 |
|
Articulation defects |
80 |
|
Skin-picking |
83 |
Modified from PEDIATRICS (ISSN 0031 4005) Vol. 108 No. 5, Pages 5, Copyright © 2001 by the AAP
Treatments
Prader-Willi syndrome cannot be cured. But, early intervention can help people build skills for adapting to the disorder. Early diagnosis can also help parents learn about the condition and prepare for future challenges. A health care provider can do a blood test to check for Prader-Willi syndrome.
Exercise and physical activity can help control weight and help with motor skills. Speech therapy may be needed to help with oral skills.
Human growth hormone has been found to be helpful in treating Prader-Willi syndrome. It can help to increase height, decrease body fat, and increase muscle mass. However, no medications have yet been found to control appetite in those with Prader-Willi
IMPRINTING
Prader-Willi syndrome affects between 1/10,000 and 1/30,000 live births. The study of this disease led to the discovery that, for some genes, the origin of the gene may be important. For some loci the gene inherited from the father acts differently from the gene inherited from the mother, even though they may have the same DNA. This phenomenon is called imprinting. About 75% of patients with Prader-Willi syndrome have a small deletion of the long arm of chromosome
Congenital hypothyroidism
The fetal hypothalamic-pituitary-thyroid system develops independently of the mother’s pituitary-thyroid axis. During embryogenesis, primordial thyroid cells arise from epithelial cells on the pharyngeal floor; they then migrate caudally to fuse with the ventral aspect of the fourth pharyngeal pouch by 4 weeks’ gestation. The thyroid continues to develop anteriorly to the third tracheal cartilage. Thyroglobulin is produced by 8 weeks’ gestation. Trapping of iodine occurs by 10-12 weeks’ gestation, followed by the synthesis of iodothyronines. Colloid formation and pituitary secretion of thyrotropin, also termed thyroid-stimulating hormone (TSH), occur by the 12 weeks’ gestation.
Normal physiology
The primary function of the thyroid gland is synthesis of thyroxine (T4) and triiodothyronine (T3). Pituitary thyrotropin regulates thyroid hormone production. TSH synthesis and secretion are stimulated by thyrotropin-releasing hormone (TRH), which is synthesized by the hypothalamus and is secreted into the hypophyseal portal vasculature for transport to the anterior pituitary gland. Serum T4 concentration modulates secretion of both TRH and TSH by means of a classic negative feedback loop.
Circulating T4 is predominantly bound to T4-binding globulin (TBG). T4 is deiodinated in peripheral tissue to T3, the more bioactive thyroid hormone. T3 carries 3-4 times the metabolic potency of T4, freely enters cells, and binds to receptors of the hormone into the cell nucleus. Thyroid hormone exerts profound effects on the regulation of gene transcription. Some major clinical phenomena of thyroid hormone action include differentiation of the CNS and maintenance of muscle mass. Thyroid hormone also controls skeletal growth and differentiation and metabolism of carbohydrates, lipids, and vitamins.
Thyroid hormone synthesis absolutely requires iodine. Dietary iodine deficiency is endemic in several areas of the world, particularly high mountain plateaus. In the United States, supplementation of salt with iodine has nearly eliminated dietary deficiency of this essential element. The recommended dietary allowance of iodine is 40-50 mcg daily in infants, 70-120 mcg daily for children, and 150 mcg daily for adolescents and adults. The daily intake in North America varies from 240 mcg to more than 700 mcg.
In the thyroid gland, iodide is trapped, transported, and concentrated in the follicular lumen for thyroid hormone synthesis. Before trapped iodide can react with tyrosine residues, it must be oxidized by thyroidal peroxidase. Iodination of tyrosine forms mono-iodotyrosine and di-iodotyrosine. Two molecules of di-iodotyrosine combine to form T4, and one molecule of mono-iodotyrosine combines with one molecule of di-iodotyrosine to form T3. Formed thyroid hormones are stored within thyroglobulin in the lumen of the thyroid follicle until release. TSH stimulates uptake and organification of iodide as well as liberation of T4 and T3 from thyroglobulin.
Pathophysiology
Congenital hypothyroidism most commonly results from agenesis, dysplasia, or ectopy of the thyroid; however, it is also caused by autosomal recessive defects in the organification of iodine (thyroid hormone synthesis) and defects in other enzymatic steps in T4 synthesis and release.
Frequency
Congenital hypothyroidism has a frequency of 1 case per 3500 live births in United States
.
International
Hypothyroidism can be congenital. Thyroid dysgenesis affects 1 per 4000 newborns worldwide. Hypothalamic or pituitary insufficiency, which results in secondary or tertiary hypothyroidism, respectively, affects 1 per 60,000-140,000 newborns worldwide.
Mortality/Morbidity
Untreated congenital hypothyroidism in early infancy results in profound growth failure and disrupted development of the CNS, leading to developmental cognitive delay (cretinism). Untreated hypothyroidism in older children leads to growth failure as well as slowed metabolism and impaired memory.
Race
In descending order, thyroid dysgenesis occurs more frequently in Hispanics than in whites, followed by blacks.
Sex
Thyroid dysgenesis occurs more frequently in females than in males, with a female-to-male ratio of 2:1. CLT also has a 2:1 female-to-male preponderance.
Age
Congenital hypothyroidism can present with goiter at birth or with the gradual development of symptoms over the first several months of life. The age of symptom onset is unpredictable in a child who has thyroid dysgenesis with a hypoplastic and/or ectopic thyroid gland because initial increases in TSH may be able to initially overcome the relative insufficiency of the thyroid gland. CLT typically presents during adolescence; however, it may present any time in life.
Clinics
Most infants with congenital hypothyroidism are asymptomatic during the neonatal period or display subtle and nonspecific symptoms of thyroid hormone deficiency.
The lack of symptoms initially may result, in part, from an ectopic thyroid gland with clinically significant reserve function, partial defects in thyroid hormone synthesis, or to the moderate amount of maternal T4 that crosses the placenta and is able to boost fetal levels within 25-50% of normal levels observed at birth.
Detection of congenital hypothyroidism based on signs and symptoms alone may be delayed until age 6-12 weeks or older because of the protean clinical presentation and requires a high index of suspicion by the health care provider.
Only about 5% of infants with hypothyroidism are detected by clinical criteria before the biochemical screen alerts the clinician to confirm the diagnosis.
The following are among the earliest signs of hypothyroidism:
Prolonged gestation
Elevated birth weight
Delayed stooling after birth, constipation
Prolonged indirect jaundice
Poor feeding, poor management of secretions
Hypothermia
Decreased activity level
Noisy respirations
Hoarse cry
Acquired hypothyroidism: The clinical features of acquired hypothyroidism are typically insidious in onset.
Goiter: Patients with CLT (ie, Hashimoto thyroiditis) most commonly present with an asymptomatic goiter. Parents may report that their child’s neck looks “full” or “swollen.” Children may complain of local symptoms of dysphagia, hoarseness, or of a pressure sensation in their neck and/or throat. A patient with other causes of hypothyroidism may have an enlarged thyroid gland.
Slow growth, delayed osseous maturation, and increased weight: Mild weight gain despite decreased appetite is characteristic of the child who has a hypothyroid condition. Moderate-to-severe obesity in children is not typical for hypothyroidism. Furthermore, children with hypothyroidism manifest a decreased growth rate, a more constant finding than weight gain. In contrast, children with exogenous obesity typically have an increased growth velocity.
Lethargy
Decreased energy, dry skin, and puffiness
Sleep disturbance, typically obstructive sleep apnea
Cold intolerance and constipation
Heat intolerance, weight loss, and tremors: These are typical symptoms of hyperthyroidism. However, approximately 5-10% of children with CLT initially present with symptoms of toxic thyroiditis. This clinical picture may suggest a diagnosis of Graves disease. The thyrotoxic phase of CLT can be differentiated from Graves disease in that CLT is transient, is not associated with exophthalmos, and is usually associated with a decreased and nonuniform uptake of radioactive iodine. This hashitoxicosis phase is usually followed by the more characteristic hypothyroid phase.
Sexual pseudoprecocity
Parents may bring their child in for evaluation secondary to concern about testicular enlargement in boys or early breast development or onset of vaginal bleeding in girls.
The exact mechanism of sexual pseudoprecocity is not fully understood.
Serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels are elevated into the pubertal range. Mounting evidence suggests that increased serum levels of prolactin produce resistance to LH stimulation of the gonads, perhaps leading to hypothalamic gonadotropin-releasing hormone (GnRH) production and stimulation of pituitary LH and FSH release.
The short stature and delayed bone age observed in children with hypothyroidism help distinguish sexual pseudoprecocity from true precocious puberty.
Sexual pseudoprecocity reverses with adequate thyroid replacement.
Galactorrhea: This condition develops in primary hypothyroidism secondary to TRH secretion from the hypothalamus. TRH stimulates the anterior pituitary to release TSH and prolactin. Galactorrhea resolves as prolactin concentrations fall with thyroid replacement.
Physical
If the newborn with congenital hypothyroidism is not identified by newborn screening and receives no replacement therapy, clinical manifestations of congenital hypothyroidism evolve during the first weeks after birth. Note that although the signs listed below are classic for congenital hypothyroidism, they may be subtle or absent. Recognition of this disorder has been enhanced by systematic newborn screening for the past 30 years.
Physical signs of congenital hypothyroidism include the following:
Bradycardia
Elevated weight
Sluggish behavior
Rare cry or hoarse cry (hoarse cry is secondary to myxedema of the vocal cords)
Large fontanelles
Myxedema of the eyelids, hands, and/or scrotum
Large protruding tongue (secondary to accumulation of myxedema in the tongue)
Goiter
Umbilical hernia
Delayed relaxation of deep tendon reflexes (The Achilles tendon reflex appears to be most sensitive to effects of hypothyroidism.)
Cool dry skin
Enlarged cardiac silhouette, usually because of pericardial effusion
Prolonged conduction time and low voltage on electrocardiogram (ECG)
Hypothermia
The signs of acquired hypothyroidism can include many physical findings observed with congenital hypothyroidism, such as the following:
Decreased growth velocity
Bradycardia
Mild obesity (5-
Immature upper-to-lower body proportions
Dry coarse hair
Delayed dentition
Precocious sexual development
Cool, dry, carotenemic skin
Brittle nails
Delayed relaxation phase of deep tendon reflexes
Goiter formation
This may occur secondary to the effects of TSH receptor–stimulating antibodies, inflammatory lymphocytic infiltration, or compensatory hyperplasia because of decreased serum T4 and increased TSH concentrations.
Typically, the thyroid gland is enlarged diffusely, although it may not be enlarged symmetrically.
Upon palpation, the thyroid gland may initially be soft but then takes on a firm feeling with rubbery consistency and a seedlike surface secondary to hyperplasia of the normal lobular architecture
Myxedema (much more rare in children than in adults)
Dull facial expression
Causes
Congenital hypothyroidism: Approximately 75% of infants with congenital hypothyroidism have defects in thyroid gland development, 10% have hereditary defects in thyroid hormone synthesis or uptake, 5% have secondary (pituitary) or tertiary (hypothalamus) hypothyroidism, and 10% have transient hypothyroidism.
Thyroid dysgenesis: Defective thyroid gland development accounts for most instances of congenital hypothyroidism. Thyroid dysgenesis occurs sporadically in most cases but is occasionally familial because of mutations or deletions of genes (PAX8, TTF1, TTF2) that are involved in fetal thyroid formation. Thyroid dysgenesis ranges in severity from thyroid aplasia or hypoplasia to functional ectopic thyroid tissue. Approximately 40-60% of infants with thyroid gland dysgenesis have some functioning tissue. Laboratory and imaging studies facilitate the determination of the degree of dysgenesis. Thyroid agenesis is suggested by a low serum T4 level with an elevated serum TSH level and undetectable serum thyroglobulin. Newborns with ectopic or hypoplastic thyroid glands manifest low serum T4, elevated serum TSH, and measurable levels of circulating thyroglobulin. Imaging aids in confirming the diagnosis of aplastic, hypoplastic, or ectopic thyroid.
Familial thyroid dyshormonogenesis: Rare autosomal recessive inborn errors of thyroid hormone synthesis, secretion, or uptake also cause congenital hypothyroidism. The following 8 inborn errors have been identified:
Failure to respond to TSH secondary to defective activation of the thyroid receptor and related cyclic adenosine monophosphate (cAMP) signal transduction pathway
Defect in trapping of iodide secondary to sodium-iodide symporter failure
Defective oxidation of iodide to iodine secondary to thyroid peroxidase deficiency
Defective coupling of iodotyrosines
Deiodination defects
Defective thyroglobulin synthesis
Defective proteolysis of thyroglobulin
Release of T3 and T4 into the circulation
Partial peripheral resistance to thyroid hormones (autosomal dominant defect): Patients relate a family history of goiter with euthyroidism or hypothyroidism in the face of elevated serum levels of T4 or T3 but nonsuppressed serum TSH concentrations.
Differential Diagnoses
Constipation Malabsorption Syndromes
Constitutional Growth Delay Malnutrition
Growth Hormone Deficiency Mood Disorder: Depression
Hyposomatotropism Short Stature
Laboratory Studies
For all measures of thyroid function, age must be considered to interpret the results. In the term neonate, laboratory tests best reflect true thyroid function when performed in infants older than 24 hours.
Serum thyrotropin (TSH) concentration remains the most sensitive screening test for hypothyroidism and for establishing the diagnosis of primary hypothyroidism. The sample can be obtained at any time of day. A value within the reference range does not exclude TSH deficiency or TRH deficiency.
A physiologic surge of TSH occurs within the first 30 minutes of life and appears to be related to the stress of delivery and exposure to the cold temperature of the extrauterine environment. Serum TSH levels peak at levels as much as 70 mIU/L within the first 24 hours of life and then rapidly drop to less than 10 mIU/L within the first 3 days of life. Beyond the neonatal period, healthy serum levels of TSH are less than 6 mIU/L. Serum TSH levels are elevated in primary hypothyroidism or compensated hypothyroidism and should be low or within the reference range in cases of pituitary (TSH deficiency) or hypothalamic (TRH deficiency) etiologies. Isolated TSH deficiency is far less common than multiple anterior pituitary hormone deficiencies.
Serum TSH is the optimal parameter to guide dosing of thyroid hormone replacement, except in patients with secondary or tertiary hypothyroidism. In these patients, measuring serum free T4 by means of equilibrium dialysis is the superior testing method. Adequate thyroid hormone replacement results iormalization of serum TSH. In the rare syndromes of thyroid hormone resistance, serum TSH levels are elevated in the presence of normal-to-high serum total T4 concentration.
Serum TSH levels are often mildly abnormal (£ 7 mIU/L) in children and adolescents who are morbidly obese (>
T4 is present in both the free state and bound to TBG. Total T4 assays measure T4 in both states and are useful to establish the diagnosis of primary hypothyroidism and to assess response to treatment. Free T4 should be directly measured with the equilibrium dialysis method. Many laboratories report a calculated value termed the free T4 index, which is an estimate of the free T4 concentration, not a measurement. The free T4 index is calculated by multiplying the T4 by the T3 resin uptake. Serum free T4 by equilibrium dialysis should be measured when secondary hypothyroidism (pituitary TSH deficiency) or tertiary hypothyroidism (hypothalamic TRH deficiency) is suggested.
Measurement of serum T3 concentration, free or total, is not required to confirm the diagnosis of hypothyroidism.
Newborn screening for congenital hypothyroidism includes the following:
Required by US law in all 50 states, these programs measure total T4 levels using a filter paper–based assay. In those neonates whose serum T4 level falls within the lowest 10th percentile for newborns screened that day by the program, T4 is reassayed, and TSH is simultaneously determined. Remember that, even with the best screening programs, infants with hypothyroidism can be missed. Therefore, the occurrence of a normal screening result must not preclude thyroid function testing in any infant with signs or symptoms of hypothyroidism.
Infants with abnormal or borderline screening results should have total T4 and TSH obtained for definitive testing. Thyroid hormone replacement may be empirically initiated while awaiting the confirmatory studies.
In infants, if the serum total T4 is less than 85 nmol/L (<7 mg/dL), with TSH more than 40 mIU/L, congenital hypothyroidism is likely. If total T4 is low, and serum TSH is not elevated, TBG deficiency, central hypothyroidism, or euthyroid sick syndrome should be considered, and repeat testing may be needed. Serum free T4 concentration is normal in TBG deficiency. Normal TSH (<20 mIU/L) in the presence of low total T4 and free T4 concentrations suggest secondary or tertiary causes of hypothyroidism. In the latter, signs of associated hypopituitarism (eg, poor feeding, hypoglycemia) and physical findings (eg, midline defects, micropenis) support the diagnosis. All such infants should be screened for other pituitary hormone deficiencies (see Hypopituitarism).
Serum antithyroid antibody test findings do not facilitate the diagnosis of hypothyroidism and only serve to establish a diagnosis of CLT and indicate the risk of subsequent development of hypothyroidism. Antithyroid peroxidase and antithyroglobulin antibody titers are elevated in 90-95% of children with CLT. A small proportion of children with test results that are initially negative become positive later. As many as 20% of individuals who have antibody-positive test results do not develop hypothyroidism or hyperthyroidism.
Serum total T4 levels and serum free T4 levels are both low in patients with hypothyroidism. In compensated hypothyroidism, total T4 may remain within the reference range in the presence of elevated TSH.
Newborns with an elevated TSH should be treated empirically with thyroid hormone replacement until they are aged 2 years to eliminate any possibility of permanent cognitive deficits as a result of hypothyroidism.
Low or low-normal serum total T4 levels in the setting of a serum TSH within the reference range suggests TBG deficiency. This congenital disorder causes no pathologic consequence; however, it should be recognized to avoid unnecessary thyroid hormone administration. TBG deficiency affects 1 individual per 3000 population; therefore, occurrence is nearly as frequent as that in congenital hypothyroidism. TBG deficiency results in low serum total T4; however, serum TSH and serum free T4 concentrations are normal. Assessment of the serum TBG concentration, preferably with simultaneous serum free and serum total T4 concentrations, confirms the diagnosis.
Imaging Studies
In vivo radionucleotide studies: The iodide-trapping or concentrating mechanism of normal thyroid tissue can be evaluated by radioisotope (iodine-123 or technetium-99m pertechnetate). In children, technetium-99m is a useful radioisotope because it is trapped by the thyroid but not organified; thus, the child is exposed to lower amounts of radiation.
In congenital organification defects and lymphocytic thyroiditis, the amount of radioisotope uptake is within reference range; however, the half-life of the radioisotope within the thyroid is decreased because of the lack of organification. This can be demonstrated by means of a perchlorate washout study.
Radioisotope-based thyroid scanning is useful to detect the absence or ectopic location of healthy thyroid tissue in congenital hypothyroidism.
Iodine-123 scanning of the thyroid can be used to identify ectopic thyroid tissue, such as lingual thyroid. Absence of a signal on this study confirms athyreosis.
Treatment & Medication
In congenital hypothyroidism, treatment should be initiated as soon as the diagnosis is suggested, immediately after obtaining blood for confirmatory tests. Delaying treatment after 6 weeks of life is associated with a substantial risk of delayed cognitive development. Newborns with elevated TSH should be treated empirically with thyroid hormone replacement until they are aged 2 years to eliminate any possibility of permanent cognitive deficits caused by hypothyroidism.
Once treatment is initiated for congenital hypothyroidism, serum total T4 and TSH concentrations should be assessed monthly until the total or free T4 levels normalize, then every 3 months until the patient is aged 3 years. Thereafter, total T4 and TSH should be measured every 6 months.
Bone age may confirm the diagnosis of congenital hypothyroidism or can be used to assess excessive thyroid hormone replacement.
Therapeutic goals are normalization of thyroid function test results and elimination of all signs and symptoms of hypothyroidism.
Therapy should correct growth, pseudoprecocious puberty, and galactorrhea. Goiter may be reduced; however, replacement therapy often does not result in complete normalization of size.
When indicated by an elevated serum TSH, dosage adjustments of 0.0125 mg levothyroxine are usually sufficient. Because the half-life of T4 in the serum is about 6 days, approximately 3.5 weeks are required for serum T4 values to reach a new steady state. Depending on the degree of hypothyroidism and the time spent in the hypothyroid state, suppression of elevated TSH levels may take longer; therefore, repeat measurements of total T4 and TSH should be obtained no sooner than 1 month after any dosage adjustment or change in brand of thyroid hormone.
Levothyroxine tablets are easily crushed and can be given in a spoon with a small amount of water, formula, or cereal. Suspensions are not commercially available and are not recommended because maintaining a consistent concentration of levothyroxine in solution is difficult.
Approximately 20% of children with CLT recover to the euthyroid state and do not require lifelong thyroid hormone replacement. After treatment beyond the completion of puberty, a 6-month trial off thyroid hormone replacement therapy should be considered, with monitoring of serum TSH and total T4 levels every 3 months. If serum TSH levels rise above the reference range, levothyroxine treatment should be resumed and continued for life. Patients with CLT should undergo at least yearly monitoring of thyroid function with serum total T4 and TSH assessment to assure adequate treatment and maintenance of euthyroidism.
Surgical Care
Rarely, a massive goiter may require surgical resection for cosmetic indications. Generally, surgical therapy has no role in the treatment of hypothyroidism. Case reports have documented surgical resection of an enlarged pituitary gland, which subsequently demonstrated physiologic thyrotroph hypertrophy related to primary hypothyroidism. This condition is best treated by adequate T4 replacement.
Consultations
Consultation with a nuclear medicine physician is indicated for performance of radioiodine scan. Surgical consultation is advised during evaluation of a single cold nodule in the adolescent or young adult.
Thyroid Hormone
Levothyroxine is the preferred form of thyroid hormone replacement in all patients with hypothyroidism. Rarely, patients with congenital hypothyroidism display a “reset thyrostat” (ie, the serum TSH is not suppressed to reference range even with supraphysiologic replacement of levothyroxine). The primary therapeutic goal in patients with congenital hypothyroidism is to maintain the free serum T4 level within the high end of the reference range without resulting in symptoms of hyperthyroidism.
Thyroid hormones only should be used as replacement therapy in children with hypothyroidism. In active form, thyroid hormone influences growth and maturation of tissues, metabolism, and development. It does not enhance final adult height in euthyroid children.
Levothyroxine (Levothroid, Levoxyl, Synthroid)
Synthetic drug identical to human T4. Adjust dose on basis of total T4 and TSH (if primary hypothyroidism) or free T4 (if secondary or tertiary hypothyroidism); target range is normal total or free T4, with TSH <5 mcU/mL. Use a single brand to avoid variations in potency between brands. Several commercial preparations are available and share equal efficacy, despite different potency. With age, dose decreases on a weight basis, although daily dose approximates 100 mcg/m2, IV dose is approximately 40-50% of the PO dose.
Dosing
Pediatric
Neonates: Initial dose 10-15 mcg/kg PO every am ac
Term infants-2 years: 37.5-50 mcg PO every am ac; titrate on basis of thyroid function tests; check serum total T4 and TSH q3mo until 2 y; therapeutic goals are normal total T4 and TSH less than 5 mcU/mL
2-6 years: 5 mcg/kg PO every am ac; typically 50-100 mcg/d
6-12 years: 4-5 mcg/kg PO every am ac; typically 75-150 mcg/d
Adolescents: 100-150 mcg PO every am acMore on Hypothyroidism
Interactions
Absorption can be inhibited by concurrent soy ingestion (eg, soy-based formulas); cholestyramine, iron salts, sucralfate, or aluminum hydroxide may decrease liothyronine absorption; estrogens may decrease response to thyroid hormone therapy in patients with nonfunctioning thyroid glands; effect of anticoagulants increased when administered with liothyronine; activity of some beta-blockers may decrease when hypothyroidism converted to euthyroid state
Contraindications
Documented hypersensitivity; uncorrected adrenal insufficiency; hyperthyroidism
Use cautiously in angina pectoris or cardiovascular disease; in adults with long-standing hypothyroidism, rapid initiation of full thyroid hormone replacement therapy can precipitate heart failure; by contrast, diagnosis of hypothyroidism in infants and children is typically recognized promptly (as a result of growth failure), and pediatric heart usually more resilient to challenge; therefore, full replacement doses in children may be initiated and not gradually titrated ; treatment of compensated hypothyroidism rests the gland and may decrease autoimmune inflammatory process and diminish goiter size; avoid overtreatment, which may advance skeletal maturation and thereby compromise final adult height and decrease ultimate bone mineral density; periodically monitor thyroid status
References
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
7. Molecular Diagnostics: Fundamentals, Methods, & Clinical Applications. 1st edition. Buckingham L, Flaws ML. F.A. Davis. 2007.
8. Passarge E. Color Atlas of Genetics – Thieme, 2007 Р. 497
9. http://intranet.tdmu.edu.ua/data/kafedra/internal/index.php?&path=pediatria2/classes_stud
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 (
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
