Reed E. Pyeritz, MD, PhD
ACUTE INTERMITTENT PORPHYRIA
ESSENTIALS OF DIAGNOSIS
Unexplained abdominal crisis, generally in young women.
Acute peripheral or central nervous system dysfunction; recurrent psychiatric illnesses.
Porphobilinogen in the urine during an attack.
Though there are several different types of porphyrias, the one with the most serious consequences and the one that usually presents in adulthood is acute intermittent porphyria (AIP), which is inherited as an autosomal dominant, though it remains clinically silent in most patients who carry a mutation in HMBS. Clinical illness usually develops in women. Symptoms begin in the teens or 20s, but onset can begin after menopause in rare cases. The disorder is caused by partial deficiency of hydroxymethylbilane synthase activity, leading to increased excretion of aminolevulinic acid and porphobilinogen in the urine. The diagnosis may be elusive if not specifically considered. The characteristic abdominal pain may be due to abnormalities in autonomic innervation in the gut. In contrast to other forms of porphyria, cutaneous photosensitivity is absent in AIP. Attacks are precipitated by numerous factors, including drugs and intercurrent infections. Harmful and relatively safe drugs for use in treatment are listed in Table 40–1. Hyponatremia may be seen, due in part to inappropriate release of antidiuretic hormone, although gastrointestinal loss of sodium in some patients may be a contributing factor.
Table 40–1. Some of the “unsafe” and “probably safe” drugs used in the treatment of acute porphyrias.
Patients show intermittent abdominal pain of varying severity, and in some instances it may so simulate acute abdomen as to lead to exploratory laparotomy. Because the origin of the abdominal pain is neurologic, there is an absence of fever and leukocytosis. Complete recovery between attacks is usual. Any part of the nervous system may be involved, with evidence for autonomic and peripheral neuropathy. Peripheral neuropathy may be symmetric or asymmetric and mild or profound; in the latter instance, it can even lead to quadriplegia with respiratory paralysis. Other central nervous system manifestations include seizures, altered consciousness, psychosis, and abnormalities of the basal ganglia. Hyponatremia may further cause or exacerbate central nervous system manifestations.
Often there is profound hyponatremia. The diagnosis can be confirmed by demonstrating an increased amount of porphobilinogen in the urine during an acute attack. Freshly voided urine is of normal color but may turn dark upon standing in light and air.
Most families have different mutations in HMBS causing AIP. Mutations can be detected in 90% of patients and used for presymptomatic and prenatal diagnosis.
Avoidance of factors known to precipitate attacks of AIP—especially drugs—can reduce morbidity. Sulfonamides and barbiturates are the most common culprits; others are listed in Table 40–1 and on the Internet (www.drugs-porphyria.org). Starvation diets or prolonged fasting also cause attacks and so must be avoided. Hormonal changes during pregnancy can precipitate crises.
Treatment with a high-carbohydrate diet diminishes the number of attacks in some patients and is a reasonable empiric gesture considering its benignity. Acute attacks may be life-threatening and require prompt diagnosis, withdrawal of the inciting agent (if possible), and treatment with analgesics and intravenous glucose in saline and hematin. A minimum of 300 g of carbohydrate per day should be provided orally or intravenously. Electrolyte balance requires close attention. Hematin therapy should be undertaken with full recognition of adverse consequences, especially phlebitis and coagulopathy. The intravenous dosage is up to 4 mg/kg once or twice daily. Liver transplantation may provide an option for patients with disease poorly controlled by medical therapy.
When to Refer
When to Admit
The patient should be hospitalized when he or she has an acute attack accompanied by mental status changes, seizure, or hyponatremia.
Kuo HC et al. Neurological complications of acute intermittent porphyria. Eur Neurol. 2011;66(5):247–52. [PMID: 21986212]
Stein PE et al. Acute intermittent porphyria: fatal complications of treatment. Clin Med. 2012 Jun;12(3):293–4. [PMID: 22783787]
Whatley SD et al. Role of genetic testing in the management of patients with inherited porphyria and their families. Ann Clin Biochem. 2013 May;50(Pt 3):204–16. [PMID: 23605133]
ESSENTIALS OF DIAGNOSIS
Ochronosis (gray-black discoloration of connective tissue, including the sclerae, ears, and cartilage).
Characteristic radiologic dense intervertebral disks in the spine.
Urine darkens on standing.
Alkaptonuria is caused by a recessively inherited deficiency of the enzyme homogentisic acid oxidase. This acid derives from metabolism of both phenylalanine and tyrosine and is present in large amounts in the urine throughout the patient’s life. A dark oxidation product accumulates slowly in cartilage and other connective tissues throughout the body, leading to degenerative joint disease of the spine and peripheral joints. Examination of patients in the third and fourth decades shows a slight darkish blue color below the skin in areas overlying cartilage, such as in the ears, a phenomenon called ochronosis. In some patients, a more severe hyperpigmentation can be seen in the sclera, conjunctiva, and cornea. Kidney, biliary, and salivary stones can occur. Accumulation of metabolites in heart valves can lead to aortic or mitral stenosis. A predisposition to coronary artery disease may also be present. Although the syndrome causes considerable morbidity, life expectancy is reduced only modestly. Symptoms are more often attributable to spondylitis with back pain, leading to a clinical picture difficult to distinguish from that of ankylosing spondylitis, though on radiographic assessment the sacroiliac joints are not fused in alkaptonuria. The disorder is uncommon in most populations (< 1 per 100,000) but much more common in Slovakia and the Dominican Republic.
The diagnosis is established by demonstrating homogentisic acid in the urine, which turns black spontaneously on exposure to the air; this reaction is particularly noteworthy if the urine is alkaline or when alkali is added to a specimen. Molecular analysis of the homogentisic acid oxidase gene (HGD) is available but not necessary for diagnosis.
Carrier screening and prenatal diagnosis are possible by testing for genetic mutations.
Treatment of the arthritis is similar to that for other arthropathies and joint replacement can be effective. Although, in theory, rigid dietary restriction or medications might reduce accumulation of the pigment, this has not proved to be of practical benefit. Since the aortic valve becomes involved by the fifth decade, screening echocardiography of affected adults is indicated. Nitisinone, a drug that inhibits the formation of homogentisic acid, is in development.
Pettit SJ et al. Cardiovascular manifestations of alkaptonuria. J Inherit Metab Dis. 2011 Dec;34(6):1177–81. [PMID: 21506017]
ESSENTIALS OF DIAGNOSIS
Typical craniofacial features (flat occiput, epicanthal folds, large tongue).
Congenital heart disease (eg, atrioventricular canal defects) in 50% of patients.
Dementia of the Alzheimer type in early-to-mid adulthood.
Three copies of chromosome 21 (trisomy 21) or a chromosome rearrangement that results in three copies of a region of the long arm of chromosome 21.
Nearly 0.5% of all human conceptions are trisomic for chromosome 21. Because of increased fetal mortality, birth incidence of Down syndrome is 1 per 700 but varies from 1 per 1000 in young mothers to more than three times as frequent in women of advanced maternal age. The presence of a fetus with Down syndrome can be detected in many pregnancies in the first or early second trimester through screening maternal serum for alpha-fetoprotein and other biomarkers (“multiple marker screening”) and by detecting increased nuchal thickness and underdevelopment of the nasal bone on ultrasonography. Prenatal diagnosis with high sensitivity and specificity can be achieved by assaying fetal DNA that is circulating in maternal blood. The chance of bearing a child with Down syndrome increases exponentially with the age of the mother at conception and begins a marked rise after age 35. By age 45 years, the odds of having an affected child are as high as 1 in 40. The risk of other conditions associated with trisomy also increases, because of the predisposition of older oocytes to nondisjunction during meiosis. There is little risk of trisomy associated with increased paternal age. However, older men do have an increased risk of fathering a child with a new autosomal dominant condition. Because there are so many distinct conditions, though, the chance of fathering an offspring with any given one is extremely small.
Down syndrome is usually diagnosed at birth on the basis of the typical craniofacial features, hypotonia, and single palmar crease. Several serious problems that may be evident at birth or may develop early in childhood include duodenal atresia, congenital heart disease (especially atrioventricular canal defects), and hematologic malignancy. The intestinal and cardiac anomalies usually respond to surgery. A transient neonatal leukemia generally responds to conservative management. The incidences of both acute lymphoblastic and myeloid leukemias are increased in childhood. Intelligence varies across a wide spectrum. Many people with Down syndrome do well in sheltered workshops and group homes, but few achieve full independence in adulthood. Other frequent complications include atlanto-axial instability, celiac disease, frequent infections due to immune deficiency, and hypothyroidism. An Alzheimer-like dementia usually becomes evident in the fourth or fifth decade. Patients with Down syndrome who survive childhood and who develop dementia have a reduced life expectancy; on average, they live to about age 55 years.
Cytogenomic analysis should always be performed—even though most patients will have simple trisomy for chromosome 21—to detect unbalanced translocations; such patients may have a parent with a balanced translocation, and there will be a substantial recurrence risk of Down syndrome in future offspring of that parent and potentially that parent’s relatives.
Duodenal atresia should be treated surgically. Congenital heart disease should be treated as in any other patient. No medical treatment has been proven to affect the intellectual capacity.
When to Refer
When to Admit
An affected young patient should be hospitalized when he or she has failure to thrive, regurgitation, breathlessness, or easy bruising.
Andriolo RB et al. Aerobic exercise training programmes for improving physical and psychosocial health in adults with Down syndrome. Cochrane Database Syst Rev. 2010 May 12;5:CD005176. [PMID: 20464738]
Bartesaghi R et al. Is it possible to improve neurodevelopmental abnormalities in Down syndrome? Rev Neurosci. 2011;22(4):419–55. [PMID: 21819263]
Lott IT et al. Cognitive deficits and associated neurological complications in individuals with Down’s syndrome. Lancet Neurol. 2010 Jun;9(6):623–33. [PMID: 20494326]
Ram G et al. Infections and immunodeficiency in Down syndrome. Clin Exp Immunol. 2011 Apr;164(1):9–16. [PMID: 21352207]
FRAGILE X MENTAL RETARDATION
ESSENTIALS OF DIAGNOSIS
Expanded trinucleotide repeat (> 200) in the FMR1 gene.
Mental retardation and autism in males; large testes after puberty.
Learning disabilities or mental retardation in females; premature ovarian failure.
Late-onset tremor and ataxia in males and females with moderate trinucleotide repeat (55–200) expansion (premutation carriers).
This X-linked condition accounts for more cases of mental retardation in males than any condition except Down syndrome; about 1 in 4000 males is affected. The central nervous system phenotype includes autism spectrum, impulsivity and aggressiveness, and repetitive behaviors. The condition also affects intellectual function in females, although less severely and about 50% less frequently than in males. Affected (heterozygous) young women show no physical signs other than early menopause, but they may have learning difficulties, anxiety, sensory issues, or frank retardation. Affected males show macro-orchidism (enlarged testes) after puberty, large ears and a prominent jaw, a high-pitched voice, autistic characteristics, and mental retardation. Some males show evidence of a mild connective tissue defect, with joint hypermobility and mitral valve prolapse.
Women who are premutation carriers (55–200 CGG repeats) are at increased risk for premature ovarian failure and mild cognitive abnormalities. Male and female premutation carriers are at risk for mood and anxiety disorders and the development of tremor and ataxia beyond middle age (fragile-X tremor-ataxia syndrome, FXTAS). Changes in the cerebellar white matter may be evident on MRI before symptoms appear. Because of the relatively high prevalence of premutation carriers in the general population (1/130–1/600), older people in whom any of these behavioral or neurologic problems develop should undergo testing of the FMR1 locus.
The first marker for this condition was a small gap, or fragile site, evident near the tip of the long arm of the X chromosome. Subsequently, the condition was found to be due to expansion of a trinucleotide repeat (CGG) near a gene called FMR1. All individuals have some CGG repeats in this location, but as the number increases beyond 52, the chances of further expansion during spermatogenesis or oogenesis increase.
Being born with one FMR1 allele with 200 or more repeats results in mental retardation in most men, and in about 60% of women. The more repeats, the greater the likelihood that further expansion will occur during gametogenesis; this results in anticipation, in which the disorder can worsen from one generation to the next.
DNA diagnosis for the number of repeats has supplanted cytogenetic analysis for both clinical and prenatal diagnosis. This should be done on any male or female who has unexplained mental retardation. Newborn screening based on hypermethylation of the FMR1 gene is being considered as a means of early detection and intervention.
Several treatments that address the imbalances in neurotransmission have been developed based on the mouse model and are in clinical trials. Valproic acid may reduce symptoms of hyperactivity and attention deficit, but standard therapies should be tried first.
When to Refer
Gallagher A et al. Fragile X-associated disorders: a clinical overview. J Neurol. 2012 Mar;259(3):401–13. [PMID: 21748281]
Hagerman R et al. Advances in clinical and molecular understanding of the FMR1 premutation and fragile X-associated tremor/ataxia syndrome. Lancet Neurol. 2013 Aug;12(8):786–98. [PMID: 23867198]
ESSENTIALS OF DIAGNOSIS
Deficiency of beta-glucocerebrosidase.
Anemia and thrombocytopenia; hypersplenism.
Gaucher disease has an autosomal recessive pattern of inheritance. A deficiency of beta-glucocerebrosidase causes an accumulation of sphingolipid within phagocytic cells throughout the body. Anemia and thrombocytopenia are common and may be symptomatic; both are due primarily to hypersplenism, but marrow infiltration with Gaucher cells may be a contributing factor. Cortical erosions of bones, especially the vertebrae and femur, are due to local infarctions, but the mechanism is unclear. Episodes of bone pain (termed “crises”) are reminiscent of those in sickle cell disease. A hip fracture in a patient with a palpable spleen—especially in a Jewish person of Eastern European origin—suggests the possibility of Gaucher disease. Peripheral neuropathy may develop in patients.
Two uncommon forms of Gaucher disease, called type II and type III, involve neurologic accumulation of sphingolipid and a variety of neurologic problems. Type II is of infantile onset and has a poor prognosis. Heterozygotes for Gaucher disease are at increased risk for developing Parkinson disease.
Bone marrow aspirates reveal typical Gaucher cells, which have an eccentric nucleus and periodic acid–Schiff (PAS)-positive inclusions, along with wrinkled cytoplasm and inclusion bodies of a fibrillar type. In addition, the serum acid phosphatase is elevated. Definitive diagnosis requires the demonstration of deficient glucocerebrosidase activity in leukocytes. Hundreds of mutations have been found to cause Gaucher disease and some are highly predictive of the neuronopathic forms. Thus, mutation detection, especially in a young person, is of potential value. Only four mutations in glucocerebrosidase account for more than 90% of the disease among Ashkenazi Jews, in whom the carrier frequency is 1:15.
Most clinical complications can be prevented by early institution of enzyme replacement therapy. Carrier screening, especially among Ashkenazi Jews, detects those couples at 25% risk of having an affected child. Prenatal diagnosis through mutation analysis is feasible. Because of an increased risk of malignancy, especially multiple myeloma and other hematologic cancers, regular screening of adults with Gaucher disease may be warranted.
A recombinant form of the enzyme glucocerebrosidase (imiglucerase) for intravenous administration on a regular basis reduces total body stores of glycolipid and improves orthopedic and hematologic manifestations. Unfortunately, the neurologic manifestations of types II and III have not improved with enzyme replacement therapy. The major drawback is the exceptional cost of imiglucerase, which can exceed $100,000 per year for a severely affected patient. Early treatment of affected children normalizes growth and bone mineral density and improves liver and spleen size, anemia, and thrombocytopenia. In adults with thrombocytopenia due to splenic sequestration, enzyme replacement often obviates the need for splenectomy. Alternative or complementary therapies, including methods to reduce substrate and to provide a chaperone for a defective enzyme, are being developed. One approved medication, miglustat, does reduce the production of glucocerebroside in some patients, but can be poorly tolerated because of adverse effects.
Mistry PK et al. A reappraisal of Gaucher disease-diagnosis and disease management algorithms. Am J Hematol. 2011 Jan;86(1):110–5. [PMID: 21080341]
Mistry PK et al. Gaucher disease and malignancy: a model for cancer pathogenesis in an inborn error of metabolism. Crit Rev Oncog. 2013;18(3):235–46. [PMID: 23510066]
Sidransky E et al. Multicenter analysis of glucocerebrosidase mutation in Parkinson’s disease. N Engl J Med. 2009 Oct 22;361(17):1651–61. [PMID: 19846850]
Suzuki Y. Chaperone therapy update: Fabry disease, GM1-gangliosidosis and Gaucher disease. Brain Dev. 2013 Jun;35(6):515–23. [PMID: 23290321]
DISORDERS OF HOMOCYSTEINE METABOLISM
ESSENTIALS OF DIAGNOSIS
For homocystinuria, dislocated ocular lenses.
Elevated homocysteine in the urine or plasma.
Considerable evidence has accumulated to support the observation that patients with clinical and angiographic evidence of coronary artery disease tend to have higher levels of plasma homocysteine than persons without coronary artery disease. The relationship has been extended to cerebrovascular and peripheral vascular diseases. Although this effect was initially thought to be due at least in part to heterozygotes for cystathionine beta-synthase deficiency (see below), there is little supporting evidence. Rather, an important factor leading to hyperhomocysteinemia is folate deficiency. Pyridoxine (vitamin B6) and vitamin B12 are also important in the metabolism of methionine, and deficiency of any of these vitamins can lead to accumulation of homocysteine. A number of genes influence utilization of these vitamins and can predispose to deficiency. For example, having one—and especially two—copies of an allele that causes thermolability of methylene tetrahydrofolate reductase predisposes people to elevated fasting homocysteine levels. Both nutritional and most genetic deficiencies of these vitamins can be corrected by dietary supplementation of folic acid and, if serum levels are low, vitamins B6and B12. In the United States, cereal grains are fortified with folic acid. However, therapy with B vitamins and folate lowers homocysteine levels significantly but does not reduce the risk of either venous thromboembolism or complications of coronary artery disease. The role of lowering homocysteine as primary prevention for sequelae of atherosclerosis has received little direct support in clinical trials. Hyperhomocysteinemia occurs with end-stage chronic kidney disease.
Homocystinuria in its classic form is caused by cystathionine beta-synthase deficiency and exhibits an autosomal recessive pattern of inheritance. This results in extreme elevations of plasma and urinary homocystine levels, a basis for diagnosis of this disorder. Homocystinuria is similar in certain superficial aspects to Marfan syndrome, since patients may have a similar body habitus and ectopia lentis is almost always present. However, mental retardation is often present in homocystinuria, and the cardiovascular events are those of repeated venous and arterial thromboses whose precise cause remains obscure. Thus, the diagnosis should be suspected in patients in the second and third decades of life who have arterial or venous thromboses without other risk factors. Life expectancy is reduced, especially in untreated and pyridoxine-unresponsive patients; myocardial infarction, stroke, and pulmonary embolism are the most common causes of death. This condition is diagnosed by newborn screening for hypermethioninemia; however, pyridoxine-responsive infants may not be detected. In addition, homozygotes for a common mutant allele, p.I278T, show marked clinical variability, with some unaffected as adults.
Although many mutations have been identified in the cystathionine beta-synthase gene (CBS), amino acid analysis of plasma remains the most appropriate diagnostic test. Patients should be studied after they have been off folate or pyridoxine supplementation for at least 1 week. Relatively few laboratories currently provide highly reliable assays for homocysteine. Processing of the specimen is crucial to obtain accurate results. The plasma must be separated within 30 minutes; otherwise, blood cells release the amino acid and the measurement will then be artificially elevated.
About 50% of patients have a form of cystathionine beta-synthase deficiency that improves biochemically and clinically through pharmacologic doses of pyridoxine (50–500 mg/d) and folate (5–10 mg/d). For these patients, treatment from infancy can prevent retardation and the other clinical problems. Patients who are pyridoxine nonresponders must be treated with a dietary reduction in methionine and supplementation of cysteine, also from infancy. The vitamin betaine is also useful in reducing plasma methionine levels by facilitating a metabolic pathway that bypasses the defective enzyme.
Patients with classic homocystinuria who have suffered venous thrombosis receive anticoagulation therapy, but there are no studies to support prophylactic use of warfarin or antiplatelet agents.
Blom HJ et al. Overview of homocysteine and folate metabolism. With special references to cardiovascular disease and neural tube defects. J Inherit Metab Dis. 2011 Feb;34(1):75–81. [PMID: 20814827]
Lee M et al. Efficacy of homocysteine-lowering therapy with folic acid in stroke prevention: a meta-analysis. Stroke. 2010 Jun;41(6):1205–12. [PMID: 20413740]
Schiff M et al. Treatment of inherited homocystinurias. Neuropediatrics. 2012 Dec;43(6):295–304. [PMID: 23124942]
Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) Collaborative Group et al. Effects of homocysteine-lowering with folic acid plus vitamin B12 vs placebo on mortality and major morbidity in myocardial infarction survivors: a randomized trial. JAMA. 2010 Jun 23;303(24):2486–94. [PMID: 20571015]
ESSENTIALS OF DIAGNOSIS
Males with hypergonadotropic hypogonadism and small testes.
Boys with an extra X chromosome are normal in appearance before puberty; thereafter, they have disproportionately long legs and arms, sparse body hair, a female escutcheon, gynecomastia, and small testes. Infertility is due to azoospermia; the seminiferous tubules are hyalinized. The incidence is 1 in 660 newborn males, but the diagnosis is often not made until a man is evaluated for inability to conceive. Intellectual disability is somewhat more common than in the general population. Many men with Klinefelter syndrome have language-based learning problems. However, their intelligence usually tests within the broad range of normal. As adults, detailed psychometric testing may reveal a deficiency in executive skills. The risk of osteoporosis, breast cancer and diabetes mellitus is much higher in men with Klinefelter syndrome than in 46,XY men.
Low serum testosterone is common. The karyotype is typically 47,XXY, but other sex chromosome anomalies cause variations of Klinefelter syndrome.
Screening for cancer (especially of the breast), deep venous thrombosis, and glucose intolerance are indicated.
Treatment with testosterone after puberty is advisable but will not restore fertility. However, men with Klinefelter syndrome have had mature sperm aspirated from their testes and injected into oocytes, resulting in fertilization. After the blastocysts have been implanted into the uterus of a partner, conception has resulted. However, men with Klinefelter syndrome do have an increased risk for aneuploidy in sperm, and therefore genomic analysis of a blastocyst should be considered before implantation.
Aksglaede L et al. Testicular function and fertility in men with Klinefelter syndrome: a review. Eur J Endocrinol. 2013 Mar 15;168(4):R67–76. [PMID: 23504510]
Gravholt CH. Sex chromosome abnormalities. In: Rimoin DL et al (editors). Emery and Rimoin’s Principles and Practice of Medical Genetics, 6th ed. Philadelphia: Churchill Livingstone, 2013.
Radicioni AF et al. Consensus statement on diagnosis and clinical management of Klinefelter syndrome. J Endocrinol Invest. 2010 Dec;33(11):839–50. [PMID: 21293172]
Sigman M. Klinefelter syndrome: how, what, and why? Fertil Steril. 2012 Aug;98(2):251–2. [PMID: 22726951]
Sokol RZ. It’s not all about the testes: medical issues in Klinefelter patients. Fertil Steril. 2012 Aug;98(2):261–5. [PMID: 22704628]
ESSENTIALS OF DIAGNOSIS
Disproportionately tall stature, thoracic deformity, and joint laxity or contractures.
Ectopia lentis and myopia.
Aortic root dilation and dissection; mitral valve prolapse.
Mutation in FBN1, the gene encoding fibrillin-1.
Marfan syndrome, a systemic connective tissue disease, has an autosomal dominant pattern of inheritance. It is characterized by abnormalities of the skeletal, ocular, and cardiovascular systems; spontaneous pneumothorax; dural ectasia; and striae atrophicae. Of most concern is disease of the ascending aorta, which begins as a dilated aortic root. Histology of the aorta shows diffuse medial degeneration. Mitral valve leaflets are also abnormal and mitral prolapse and regurgitation may be present, often with elongated chordae tendineae, which on occasion may rupture.
Affected patients are typically tall, with particularly long arms, legs, and digits (arachnodactyly). However, there can be wide variability in the clinical presentation. Commonly, scoliosis and anterior chest deformity, such as pectus excavatum, are found. Ectopia lentis is present in about half of patients; severe myopia is common and retinal detachment can occur. Mitral valve prolapse is seen in about 85% of patients. Aortic root dilation is common and leads to aortic regurgitation or dissection with rupture. To diagnose Marfan syndrome, people with an affected relative need features in at least two systems. People with no family history need features in the skeletal system, two other systems, and one of the major criteria of ectopia lentis, dilation of the aortic root, or aortic dissection. Patients with homocystinuria due to cystathionine beta-synthase deficiency also have dislocated lenses, tall, disproportionate stature, and thoracic deformity. They tend to have below normal intelligence, stiff joints, and a predisposition to arterial and venous occlusive disease. Males with Klinefelter syndrome do not show the typical ocular or cardiovascular features of Marfan syndrome and are generally sporadic occurrences in the family.
Mutations in the fibrillin gene (FBN1) on chromosome 15 cause Marfan syndrome. Nonetheless, no simple laboratory test is available to support the diagnosis in questionable cases because related conditions may also be due to defects in fibrillin. The nature of the FBN1 mutation has little predictive value in terms of prognosis. The pathogenesis of Marfan syndrome involves aberrant regulation of transforming growth factor (TGF)-beta activity. Mutations in either of two receptors for TGF-beta (TGFBR1 and TGFBR2) can cause conditions that resemble Marfan syndrome in terms of aortic aneurysm and dissection and autosomal dominant inheritance.
There is prenatal and presymptomatic diagnosis for patients in whom the molecular defect in FBN1 has been found.
Children with Marfan syndrome require regular ophthalmologic surveillance to correct visual acuity and thus prevent amblyopia, and annual orthopedic consultation for diagnosis of scoliosis at an early enough stage so that bracing might delay progression. Patients of all ages require echocardiography at least annually to monitor aortic diameter and mitral valve function. Long-term beta-adrenergic blockade, titrated to individual tolerance but enough to produce a negative inotropic effect (atenolol, 1–2 mg/kg orally daily) retards the rate of aortic dilation. A dozen clinical trials comparing the effectiveness of atenolol and losartan or other angiotensin receptor blockers, drugs that reduces activity of TGF-beta, are underway, and results from several are being reported. Restriction from vigorous physical exertion protects from aortic dissection. Prophylactic replacement of the aortic root with a composite graft when the diameter reaches 45–50 mm in an adult (normal: < 40 mm) prolongs life. A procedure to reimplant the patient’s native aortic valve and replace just the aneurysmal sinuses of Valsalva and ascending aorta avoids the need for lifelong anticoagulation.
People with Marfan syndrome who are untreated commonly die in the fourth or fifth decade from aortic dissection or heart failure secondary to aortic regurgitation. However, because of earlier diagnosis, lifestyle modifications, beta-adrenergic blockade, and prophylactic aortic surgery, life expectancy has increased by several decades in the past 25 years.
When to Refer
When to Admit
Any patient with Marfan syndrome in whom severe or unusual chest pain develops should be hospitalized to exclude pneumothorax and aortic dissection.
Benedetto U et al. Surgical management of aortic root disease in Marfan syndrome: a systematic review and meta-analysis. Heart. 2011 Jun;97(12):955–8. [PMID: 21228428]
David TE et al. Long-term results of aortic root repair using the reimplantation technique. J Thorac Cardiovasc Surg. 2013 Mar;145(3 Suppl):S22–5. [PMID: 23260437]
Groenink M et al. Losartan reduces aortic dilatation rate in adults with Marfan syndrome: a randomized controlled trial. Eur Heart J. 2013 Dec;34(45):3491–500. [PMID: 23999449]
Pyeritz RE. Evaluation of the adolescent or adult with some features of Marfan syndrome. Genet Med. 2012 Jan;14(1):171–7. [PMID: 22237449]
Pyeritz RE. Marfan syndrome and related disorders. In: Rimoin DL et al (editors). Emery and Rimoin’s Principles and Practice of Medical Genetics, 6th ed. Philadelphia: Churchill Livingstone, 2013.
HEREDITARY HEMORRHAGIC TELANGIECTASIA
ESSENTIALS OF DIAGNOSIS
Visceral arteriovenous malformations (especially lung, liver, brain, bowel).
Hereditary hemorrhagic telangiectasia (HHT), formerly termed “Osler-Weber-Rendu syndrome,” is an autosomal dominant disorder of development of the vasculature. Epistaxis may begin in childhood or later in adolescence. Punctate telangiectases of the lips, tongue, fingers, and skin generally appear in later childhood and adolescence. Arteriovenous malformations (AVMs) can occur at any age in the brain, lungs, and liver. Bleeding from the gastrointestinal tract is due to mucosal vascular malformations and usually is not a problem until mid-adult years or later. Pulmonary AVMs can cause hypoxemia (with peripheral cyanosis, dyspnea, and clubbing) and right-to-left shunting (with embolic stroke or brain abscess). The criteria for diagnosis require presence of three of the following four features: (1) recurrent epistaxis, (2) visceral AVMs, (3) mucocutaneous telangiectases, and (4) being the near relative of a clearly affected individual. Mutation analysis can be used for presymptomatic diagnosis or exclusion of the worry of HHT.
MR or CT arteriography detects AVMs. Mutations in at least five genes can cause HHT. Three have been identified and molecular analysis to identify them is available; these mutations in ENG, ALK1, andSMAD4 account for about 87% of families with HHT. When the familial mutation is known, molecular testing is far more cost effective than repeated screening of relatives who are at risk.
Embolization of pulmonary AVMs with wire coils or other occlusive devices reduces the risk of stroke and brain abscess. Treatment of brain AVMs reduces the risk of hemorrhagic stroke. All patients with HHT with evidence of a pulmonary shunt should practice routine endocarditis prophylaxis (see Table 33–6). All intravenous lines (except those for transfusion of red blood cells and radiographic contrast) should have an air-filter to prevent embolization of an air bubble. Prenatal diagnosis through mutation detection is possible.
All patients in whom the diagnosis of HHT is considered should have an MRI of the brain with contrast. A contrast echocardiogram will detect most pulmonary AVMs when “bubbles” appear on the left side of the heart after 3–6 cardiac cycles. A positive contrast echocardiogram should be followed by a high-resolution CT angiogram for localization of pulmonary AVMs. Patients who have AVMs with a feeding artery of 1–2 mm diameter or greater should undergo embolization. After successful embolization of all treatable pulmonary AVMs, the CT angiogram should be repeated in 3 years. A person with a negative contrast echocardiogram should have the test repeated every 5 years. Several recent studies suggest that treatment with anti-estrogenic agents (eg, tamoxifen), thalidomide, or anti-vascular endothelial growth factor agents (eg, bevacizumab) can reduce epistaxis and gastrointestinal bleeding and improve hepatic shunting.
Dupuis-Girod S et al. Bevacizumab in patients with hereditary hemorrhagic telangiectasia and severe hepatic vascular malformations and high cardiac output. JAMA. 2012 Mar 7;307(9):948–55. [PMID: 22396517]
Faughnan ME et al; HHT Guidelines Working Group. International guidelines for the diagnosis and management of hereditary haemorrhagic telangiectasia. J Med Genet. 2011 Feb;48(2):73–87. [PMID: 19553198]
Guttmacher AE et al. Hereditary hemorrhagic telangiectasia. In: Rimoin DL et al (editors). Emery and Rimoin’s Principles and Practice of Medical Genetics, 6th ed. Philadelphia: Churchill Livingstone, 2013.
Trerotola SO, Pyeritz RE. PAVM embolization: an update. AJR Am J Roentgenol. 2010 Oct;195(4):837–45. [PMID: 20858807]
Velthuis S et al. Role of transthoracic contrast echocardiography in the clinical diagnosis of hereditary hemorrhagic telangiectasia. Chest. 2013 Dec;144(6):1876–82. [PMID: 23907523]
Yaniv E et al. Anti-estrogen therapy for hereditary hemorrhagic telangiectasia—a long-term clinical trial. Rhinology. 2011 Jun;49(2):214–6. [PMID: 21743879]