Marfan syndrome (MFS) is an autosomal dominant (AD) systemic condition of connective tissue that affects multiple organs, including the eye, skeleton, and cardiovascular system. The estimated prevalence of MFS ranges from 1 in 5,000 to 10,000. Clinical diagnosis is based on the revised Ghent criteria, which delineates minor and major criteria. Findings other than aortic root enlargement or ectopia lentis are considered in a systemic score. As many manifestations of MFS appear with age, it may take years for the systemic diagnosis of MFS to become clear.
Major skeletal features include pectus carinatum, pectus excavatum requiring surgery, reduced upper-to-lower body segment ratio, combination of both positive wrist and thumb signs, scoliosis of greater than 20 degrees or spondylolisthesis, and reduced extension at the elbows. The thumb sign is considered positive when the entire distal phalanx of the adducted thumb extends beyond the ulnar border. The wrist sign is positive when the tip of the thumb covers the entire fingernail of the fifth finger when wrapped around the contralateral wrist (▶ Fig. 12.1). Minor features include pectus excavatum of moderate severity, joint hypermobility, high arched palate with crowding of teeth, and facial appearance (dolichocephaly, malar hypoplasia, enophthalmos, retrognathia, downslanting palpebral fissures). Skeletal anomalies can appear even in infancy and tend to progress during growing periods. Patients with MFS are not necessarily tall as familial background is also a determinant. Many of the skeletal findings of MFS are frequently found in the normal general population.
Fig. 12.1 Ectopia lentis in a patient with Marfan syndrome. Note zonules are stretched rather than broken.
The only major ocular finding is ectopia lentis (▶ Fig. 12.2). Minor features include flat cornea, increased globe axial length, and hypoplasia of pupillary dilator resulting in miosis. Myopia may be lenticular, due to ectopia lentis, or axial. It may progress rapidly during infancy due to progressive ectopia lentis. Ectopia lentis is only found in approximately 60% of patients. Although the typical lens subluxation is superotemporal, the lens can move in any direction. As flat keratometry may “counteract” myopia, measuring axial length and careful examination for subtle ectopia lentis is required. Patients with MFS are also at increased risk for retinal detachment (with or without lens surgery), adult-onset open angle glaucoma, and cataract within the ectopic lens.
Fig. 12.2 (a) Positive thumb sign in a patient with Marfan syndrome. Part of the thumb is visible beyond the ulnar border of the hand. (b) Positive wrist sign in the same patient. The thumb is able to pass the distal phalangeal joint of the middle finger of the opposite hand when grasping the wrist.
Major cardiovascular findings include dilatation of the ascending aorta with or without aortic regurgitation or dissection of the ascending aorta. Minor features are mitral valve prolapse with or without mitral valve regurgitation, dilatation of the main pulmonary artery, calcification of the mitral annulus below the age of 40 years, and dilatation or dissection of the descending thoracic or abdominal aorta below the age of 50 years. Aortic root dilatation tends to progress over time, although the onset and rate are extremely variable. Medical and surgical advances have increased life expectancy.
Dural ectasia is considered a major criterion, and can lead to low back pain, proximal leg pain, weakness and numbness, headache, and genital/rectal pain. Pulmonary and skin abnormalities are minor features. Pulmonary findings include spontaneous pneumothorax and apical blebs. Skin features are striae atrophicae (not associated with marked weight changes, pregnancy, or repetitive stress), and recurrent or incisional hernias.
12.2 Molecular Genetics
MFS is caused by mutation of FBN1 (15q21.1), which can be detected by thorough sequencing in over 95% of patients. Intron mutations, large deletions, and promoter mutations may occur. Even in the presence of an FBN1 mutation, clinical confirmation by the revised Ghent criteria is recommended. TGFBR1, TGFBR2, or TGFB2 mutations have also been seen in patients with clinical MFS although ectopia lentis is rarely seen with these genes.
Approximately 25% of MFS is due to de novo mutation. Because of variable expression, in the absence of genetic testing, both parents should have a comprehensive clinical examination and echocardiogram. Few genotype–phenotype correlations exist in MFS. Severe early-onset MFS usually presents alterations in exons 24 and 32, although some patients with mutations in this region have classic or even mild MFS. Nonsense mutations result in rapid degradation of mutated transcripts and can be associated with mild conditions.
12.3 Differential Diagnosis
12.3.1 Homocystinuria (OMIM 236200)
Homocystinuria (OMIM 236200) is an autosomal recessive (AR) disorder associated with cystathionine β-synthase (21q22.3) deficiency, and affects the transsulfuration pathway, resulting in elevated serum and urine homocysteine and plasma methionine. 5,10-Methylenetetrahydrofolate reductase (MTHFR) deficiency can also result in homocystinuria, usually with more mild ectopia lentis. Frequency of cystathionine β-synthase is variable, ranging from 1:30,000 to 60,000 live births. Unlike MFS, approximately 50% of patients have a variable degree of intellectual disability. Ectopia lentis is seen in up to 40% of children and almost all patients by adulthood. Whereas the zonules are stretched in MFS, they are broken in homocystinuria and often seen clumped on the lens edge with crenulations of lens edge (▶ Fig. 12.3). Other findings that differentiate this disorder from MFS include coarse hair with premature graying, and most importantly, the increased risk of thromboembolic events. As the latter is aggravated by general anesthesia, and can result in significant stroke or death, all patients should have serum and urine homocysteine levels measured preoperatively unless another cause of their ectopia lentis is clear. The phenotype may overlap with MFS, because individuals with homocystinuria may have Marfanoid habitus, myopia, pectus deformity, scoliosis, mitral valve prolapse, and highly arched palate although their wrist and thumb signs are negative. Although the lens usually luxates down and nasally (approximately half of individuals), posteriorly in 20%, and anteriorly in 10% of patients, any direction is possible. If the lens dislocates into the anterior chamber, pupillary block, acute glaucoma, and secondary corneal decompensation may occur. Approximately half of patients with homocystinuria are responsive to vitamin B6 supplementation.
Fig. 12.3 Ectopia lentis in a patient with homocystinuria. Note the broken lens zonules resulting in crenulations of the lens edge.
12.3.2 Weill–Marchesani Syndrome (OMIM 277600; 608328; 614819)
This condition includes microspherophakia with progressive anterior movement of the lens (▶ Fig. 12.4) resulting in angle closure glaucoma and iris atrophy. Other features include short stature, brachydactyly, joint stiffness, and lack of vascular manifestations of MFS. Mutation in FBN1 can cause AD Weill–Marchesani Syndrome (WMS). Mutations in ADAMTS10 and ADAMTS17 are known to cause AR WMS. The AD form is less severe. Mild cardiac abnormalities, not including aneurysm, can occur in the AR form.
Fig. 12.4 Microspherophakia with progressive anterior movement of the lens and iris in a patient with autosomal recessive Weill–Marchesani syndrome. This may result in angle closure glaucoma and iris atrophy.
12.3.3 Autosomal Dominant Isolated Ectopia Lentis (OMIM 129600)
Caused by heterozygous mutation in FBN1, these patients lack the systemic features of MFS, although, as a fibrillinopathy, some have later shown signs of aortic root enlargement. It has been argued that the presence of ectopia lentis and an identified FBN1 mutation meets criteria for diagnosis of MFS and therefore ongoing screening with echocardiography is recommended.
12.3.4 Autosomal Recessive Isolated Ectopia Lentis (OMIM 225100)
This entity can be caused by mutations in ADAMTSL4 and is not associated with systemic manifestations. Mutations in this gene may also result in ectopia lentis et pupillae