Genetic Disorders: Toddler With Skeletal, Ocular, and Cardiac Anomalies

A 15-month-old girl presents for evaluation of macrocephaly and unusual facial features. Her prenatal and natal history are unremarkable. The child is now developing normally after mild gross motor delays during the first 6 months of life. Mild scoliosis was noted on a babygram taken at 8 months during an evaluation for possible nonaccidental trauma.

The child is 80 cm long (75th percentile); weight, 10.8 kg (65th percentile); head circumference, 50.2 cm (2.5 standard deviations above the mean). She appears healthy, with a prominent forehead and brow. Her face has a "serious" expression and her eyes are deep-set. There is no obvious iridodonesis. The patient brings objects up very close to her eyes to focus on them. Her ears have mildly thin cartilage. The palate is narrow and steep. There is a 2/6 systolic murmur. The abdomen is protuberant, with lax musculature. The spine has a right thoracolumbar rib hump on forward bend. The fingers are long, with mild flexion contractures at the distal interphalangeal joints and the feet are narrow with long toes. Muscle mass is mildly diminished. Results of the neurologic examination are normal and the skin is unremarkable.

TO WHAT DIAGNOSIS DO THESE CLINICAL FINDINGS POINT?

ANSWER: SEVERE INFANTILE MARFAN SYNDROME

The infantile form of Marfan syndrome is typically quite severe. "Serious" facial expression, prominent brow with deep-set eyes, flexion contractures of digits, early-onset scoliosis, and severe cardiac involvement are characteristic. Macrocephaly is an unrelated finding in this patient.

The patient ultimately underwent spinal fusion when she was 11 years old. She has spontaneously anteriorly dislocating lenses, which she has learned to reposition by lying supine, and she has been receiving b-blockers for aortic dilatation since she was 15 months old. She also has severe mitral valve prolapse and insufficiency.

ETIOLOGY AND PREVALENCE

Marfan syndrome is an autosomal dominant disorder most frequently caused by mutations in the FBN1 gene that codes for fibrillin 1--an important component of microfibrils. Several hundred different mutations in FBN1 have been identified in persons with Marfan syndrome, as well as in those with milder phenotypes who do not meet the diagnostic criteria for Marfan syndrome.

Persons with Marfan syndrome have a 50% chance of passing on the mutant FBN1 gene to offspring, and there is frequently marked interfamilial and intrafamilial variation in severity of the manifestations. The severe neonatal and infantile forms are usually caused by new mutations. Recently, Marfan syndrome caused by mutations in transforming growth factor b receptor 2 gene (TGFBR2) has been described.

Marfan syndrome affects approximately 1 to 2 persons per 10,000. Males and females are affected equally, and there is no ethnic predilection. New mutations are observed with increased frequency in the offspring of older fathers.

CLINICAL FEATURES AND DIAGNOSIS

Marfan syndrome is a multisystem disorder that primarily affects the skeletal, ocular, and cardiovascular systems. Persons with Marfan syndrome are at increased risk for lens dislocation, severe myopia, retinal detachment, glaucoma, and early cataract formation. Scoliosis is common and can be mild or severe and progressive.

The cardiovascular system is the major contributor to early mortality. Cardiovascular manifestations of Marfan syndrome include dilatation of the aorta at the level of the sinuses of Valsalva, aortic dissection, mitral valve prolapse with or without regurgitation, tricuspid valve prolapse, and enlargement of the proximal pulmonary artery. With good management--frequently involving b-blockers--the life expectancy for an affected person may approximate that of the general population.

Most clinical geneticists make the diagnosis based on fulfillment of clinical criteria set forth by experts meeting in Ghent, Belgium (referred to as the "Ghent Criteria"). Affected persons must meet major clinical criteria in 2 of the 3 systems noted above, with involvement of the third system. Fewer clinical criteria are needed to diagnose Marfan syndrome in the offspring of affected parents. FBN1 mutation testing is available and may be helpful in identifying at-risk children in Marfan syndrome families--particularly because features develop over time and affected young children often do not fully meet the clinical criteria.

In view of shared features (skeletal findings and lens dislocation), all persons with suspected Marfan syndrome should undergo screening for homocystinuria. This involves quantitative measurement of plasma homocysteine levels.

References:

FOR MORE INFORMATION:

De Paepe A, Devereux RB, Dietz HC, et al. Revised diagnostic criteria for the Marfan syndrome. Am J Med Genet. 1996;62:417-426.

Mizuguchi T, Collod-Beroud G, Akiyama T, et al. Heterozygous TGFBR2 mutations in Marfan syndrome. Nat Genet. 2004;36:855-860.

National Institutes of Health. GENETests. Available at: http://www.genetests.

org/servlet/access?db=geneclinics&site=gt&id=8888891&key=z5fS2X-zvo0B2& gry=&fcn=y&fw=IjLA&filename=/profiles/marfan/index.html. Accessed December 15, 2005.