A 16-year-old boy presents to an ophthalmologist with blurry vision. Over the past several months, he has had increasing difficulty seeing the board from the back of the classroom at school. The patient is otherwise doing well in school and enjoys playing basketball. His medical history is otherwise significant for scoliosis which is managed by an orthopedic surgeon. His family history is significant for a mother with type 2 diabetes mellitus and a father who underwent aortic valve replacement last year. His temperature is 98.6°F (37°C), blood pressure is 115/71 mmHg, pulse is 72/min, and respirations are 12/min. On physical exam, the patient is tall for his age and has long arms. He has 20 degrees of thoracic scoliosis, which is stable from previous exams. On slit-lamp examination, the patient is found to have bilateral upward lens subluxation and is prescribed corrective lenses. Which of the following is the most likely cause of this patient’s symptoms?
Extra copy of sex chromosome
Mutation of RET proto-oncogene
Defective metabolism of methionine
Mutation of chromosome 15
Mutation of chromosome 15
This patient presents with tall stature, upward lens subluxation, and a family history of aortic valve disease, which suggests a diagnosis of Marfan syndrome. Marfan syndrome is caused by an autosomal dominant mutation in the fibrillin-1 gene on chromosome 15.

The fibrillin-1 gene codes for a glycoprotein in the extracellular matrix of connective tissue. Patients with Marfan syndrome classically present with a triad of musculoskeletal, ocular, and cardiovascular symptoms. The musculoskeletal findings include tall stature, long limbs, arachnodactyly, pectus excavatum, joint hypermobility, skin hyperelasticity, and scoliosis. Patients with Marfan syndrome also often present with upward lens subluxation, and they are at increased risk of cardiac disease, including aortic regurgitation and aortic dissection. Treatment is symptomatic with avoidance of contact sports, beta-blockers, and valve repair to prevent cardiac complications.

Bitterman and Sponseller review the evidence regarding the diagnosis and treatment of Marfan syndrome. They discuss how skeletal manifestations are often the initial presentation of this condition leading to diagnosis. They recommend screening for patients who are suspected to have this disease.

Incorrect Answers:
Answer A: Defective metabolism of methionine describes homocystinuria, an autosomal recessive deficiency of cystathionine synthase. Although patients with homocystinuria may also have tall stature, arachnodactyly, and pectus deformity, the lens dislocation in homocystinuria is downward rather than upwards. Patients with homocystinuria also tend to have a fair complexion, intellectual disability, and thrombophilia. Treatment includes vitamin B6 supplementation.

Answer B: Extra copy of a sex chromosome describes Klinefelter syndrome (47,XXY). Although patients with Klinefelter syndrome classically present with tall stature, they do not have the other clinical features found in this patient, including joint hypermobility and lens subluxation. Patients with Klinefelter also present with hypogonadism and azoospermia. Treatment is supportive

Answer D: Mutation of COL5A1 or COL5A2 leads to Ehlers-Danlos syndrome, a collagen disorder that commonly presents with joint hypermobility, skin hyperextensibility, and skin fragility with easy bruising. Ehlers-Danlos would not explain this patient’s lens subluxation. Treatment may include bracing of unstable joints.

Answer E: Mutation of RET proto-oncogene describes multiple endocrine neoplasia type 2B (MEN2B). Patients with MEN2B may present with Marfanoid habitus and are predisposed to medullary thyroid cancer, pheochromocytoma, and mucosal neuromas. MEN2B would not explain lens subluxation. Treatment is with surgical resection of tumors.

Bullet Summary:
Marfan syndrome is caused by an autosomal dominant mutation in the fibrillin-1 gene on chromosome 15 and presents with a triad of musculoskeletal, ocular, and cardiovascular findings.