Vol. 16: Summer, 1998

Management of Common Genetic Disorders

Marfan Syndrome

Introduction
Marfan syndrome is an autosomal dominant, highly penetrant, disorder of connective tissue with extremely variable clinical expression. The frequency is 1 to 10 per 100,000 live births. About 15% of individuals with Marfan syndrome have new mutations; the rest are familial. It is caused by a defect in the fibrillin-1 gene (FBN1) on chromosome 15. Many different mutations of FBN1 have been identified, which may contribute to the variability seen in the disorder.
Currently, no single gene probe or group of probes can detect most FBN1 mutations. Sequencing the entire gene for mutations is tedious, and often detects mutations that may represent normal variation, resulting in both false positives and false negatives. Immunohistological evaluation of skin for abnormal fibrillin has been reported but is not widely available. For now, diagnosis of Marfan syndrome remains a clinical one.
Clinical Features
Marfan syndrome typically affects three major body systems: cardiovascular, skeletal, and ocular. Lungs and/or skin may also be involved.
Individuals with Marfan syndrome may be diagnosed at birth because of the presence of long thin, bones (dolichostenomelia). Others, however, are more subtle in their presentation and require years of close follow-up to diagnose.
The diagnosis of Marfan syndrome is difficult due to extreme variability in presentation and the existence of several disorders similar to Marfan syndrome (e.g. homocystinuria). Detailed diagnostic criteria are now available. Diagnosis is based on manifestations in tissue and organ systems as well as family history. A series of major and minor criteria is used.
- Skeletal System
  - Major Criteria: At least 4 of the following: 1) pectus carinatum, 2) pectus excavatum requiring surgery, 3) reduced upper-to-lower segment ratio or arm span to height ratio >1.05, 4) wrist and thumb signs, 5) scoliosis >20 degrees or spondylolisthesis, 6) reduced elbow extension (<170 degrees), 7) medial displacement of the medial malleolus causing pes planus, or 8) protrusio acetabulae (ascertained on radiographs).
  - Minor Criteria: Moderate pectus excavatum, joint hypermobility, high arched palate with dental crowding, or characteristic facial appearance.
- Ocular System
  - Major Criterion: Ectopia lentis
  - Minor Criteria: Abnormally flat corneas, increased axial length of the globe, or hypoplastic iris or ciliary muscle causing miosis.
- Cardiovascular System
  - Major Criterion: Dilatation of the ascending aorta involving at least the sinuses of valsalva or dissection of the ascending aorta.
  - Minor Criteria: Mitral valve prolapse, dilatation of the main pulmonary artery without valvular or peripheral pulmonic stenosis or other obvious cause before 40 years, or dilatation or dissection of the descending aorta before 50 years.
- Pulmonary System
  - Major Criterion: None
  - Minor Criteria: Spontaneous pneumothorax and apical blebs.
- Skin and Integument
  - Major Criterion: None
  - Minor Criterion: Striae atrophicae (stretch marks) not associated with marked weight changes, pregnancy, or repetitive stress or recurrent or incisional hernias.
- Dura
  - Major Criterion: Lumbosacral dural ectasia seen on CT or MRI imaging.
  - Minor Criterion: None
- Family and Genetic History
  - Major Criteria: 1) A first degree relative who meets the criteria independently, 2) a mutation in FBN1 known to cause Marfan syndrome, or 3) a haplotype around FBN1, inherited by descent, known to be associated with confirmed Marfan syndrome in the family.
  - Minor Criterion: None
- Requirements for the Diagnosis of Marfan Syndrome
  For the index case: If the family and genetic history is not contributory, major criteria in at least two different organ systems and involvement in a third system.
  If a mutation known to cause Marfan syndrome is present in other family members, major criterion in one organ system and involvement of another organ system.
- Common Medical Complications
  Cardiovascular abnormalities are the principle cause of mortality in Marfan syndrome. Dilatation of the aortic root can develop at any time and may result in death in the mid 30's without treatment. The use of b-blockers in patients with aortic dilatation and surgical repair of aortic aneurysms has increased life expectancy by at least 10 years. Patients need long-term cardiology follow-up and regular echocardiograms. Mitral valve prolapse requires antibiotic prophylaxis prior to dental or invasive procedures. Blood pressure should be monitored at each encounter and cardiac symptoms such as chest pain and syncope need further study. Non-strenuous exercise should be emphasized.
  Eye abnormalities include myopia and subluxation of the lenses (ectopia lentis), but other findings such as sunken eyes (enophthalmos), down slanting palpebral fissures, and retinal detachments occur with increased frequency. Annual evaluation by an ophthalmologist is recommended. Ectopic lenses are of diagnostic significance and may cause visual impairment; myopia is usually treatable with refraction. The primary care physician should inquire about visual symptoms at each encounter and emphasize the importance of protective eyeware to prevent retinal detachment.
  Skeletal complications include tall stature, scoliosis, pectus abnormalities, joint abnormalities, and malocclusion. Growth should be plotted on a Marfan syndrome growth curve. Rarely, hormone therapy may be used to accelerate puberty and limit height.
  Annual assessment of spine alignment, with referral to an orthopedist for rapid progression or curvature greater than 15 degrees, is indicated. Occasionally pectus anomalies compromise cardiac or respiratory function requiring surgical intervention during childhood. Cosmetic repair, however, should wait until at least mid-adolescence.
  Joint dislocations decrease with increasing muscle strength. Shoes with adequate arch supports are recommended for individuals with flat feet.
  Early orthodontic referral is beneficial.
  The recurrence risk for Marfan syndrome is 50% for each pregnancy. Prenatal or preimplantation diagnosis are possible if the family's mutation is known. Affected women need a thorough cardiovascular evaluation before conception and those with an aortic root diameter <40 mm usually tolerate pregnancy well. Nonetheless, these women require close surveillance during pregnancy with echocardiography every 6 to 10 weeks. Delivery should be managed to minimize the second stage. There is an increased risk for aortic dissection for 6 to 8 weeks post partum.
References:
Rossiter JP, et al. A prospective longitudinal evaluation of pregnancy in the Marfan syndrome. Am J Obstet Gynecol 173(5):1599-1606, 1995
Shores J, et al. Progresssion of aortic dilitation and the benefit of long-term beta-adrenergic blockade in Marfan syndrome. N Eng J Med 330(19):1335-1341, 1994
Health Supervision for Children With Marfan Syndrome. Committee on Genetics. Pediatrics 98 (5): 978-982, 1996

Contributed by Kirk Aleck, MD (AZ)

The Genetic Drift Newsletter is not copyrighted. Readers are free to duplicate all or parts of its contents. The Genetic Drift Newsletter is published semiannually by the Mountain States Genetics Network for associates & those interested in Human Genetics. In accordance with accepted publication standards, we request acknowledgement in print of any article reproduced in another publication. The views expressed in the newsletter do not necessarily reflect local, state, or federal policy. For additional information, contact Carol Clericuzio, M.D., Editor, Department of Pediatrics, The University of New Mexico, Albuquerque, NM, 87131

Table of Contents
Management of Common Genetic Disorders

Introduction
Achondropasia
Down Syndrome / Trisomy 21
Fragile X Syndrome
Marfan Syndrome
Neurofibromatosis
Turner Syndrome
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