A 3-year-old boy presents with his parents to a pediatrician for a new patient visit. The child was recently adopted and little is known about his medical or family history. The child seems to be doing well, but the patient is much larger than any of the other 3-year-olds in his preschool class. He eats a varied diet at home and with limited juice and snack foods. His temperature is 98.6°F (37°C), blood pressure is 101/67 mmHg, pulse is 110/min, and respirations are 24/min. On physical exam, the patient is in the 73rd percentile for weight, 99th percentile for height, and 86th percentile for head circumference. He appears mildly developmentally delayed. He has a fair complexion and tall stature with a prominent sternum. The patient also has joint hypermobility and hyperelastic skin. He appears to have poor visual acuity and is referred to an ophthalmologist, who finds downward lens subluxation of the right eye. This child is most likely to develop which of the following complications?
Thromboembolic stroke
Wilms tumor
Osteoarthritis
Aortic dissection
Thromboembolic stroke
This patient presents with Marfanoid habitus, joint hypermobility, hyperelastic skin, developmental delay, and downward lens subluxation, which suggests a diagnosis of homocystinuria. Homocystinuria predisposes to thromboembolic events such as stroke.

Although homocystinuria shares many features with Marfan syndrome, patients with homocystinuria also present with a fair complexion, intellectual disability, and downward subluxation of the lens (instead of the upward subluxation seen in Marfan syndrome). Patients with homocystinuria are also at an increased risk of thromboembolic events that disproportionally affect the cerebral vessels. Similar to Marfan syndrome, patients have phenotypic features of a Marfanoid habitus, including tall stature, long limbs, arachnodactyly, joint hypermobility, skin hyperelasticity, pectus deformity, and scoliosis. Treatment includes vitamin B6 supplementation.

Hasan et al. review the evidence regarding diseases associated with homocystinuria. They discuss how this disease is associated with cancer and Alzheimer disease. They recommend screening for this disease.

Incorrect Answers:
Answer A: Aortic dissection is a complication of Marfan syndrome, an autosomal dominant mutation of the fibrillin-1 gene. It is also associated with elevated homocysteine levels. Although Marfan syndrome shares many features with homocystinuria, the fair complexion, and intellectual disability seen in this patient are specific to homocystinuria. Treatment involves avoidance of contact sports and beta blockers.

Answer B: Medullary thyroid cancer is part of the syndrome of multiple endocrine neoplasia type 2B (MEN2B), which is caused by a mutation in the RET proto-oncogene. Patients with MEN2B present with Marfanoid habitus, but they do not present with the other features described in this vignette, including fair complexion, intellectual disability, and downward lens subluxation. Treatment is with surgical excision of tumors.

Answer C: Osteoarthritis is a complication of Ehlers-Danlos syndrome (EDS). Although patients with EDS may present with many of the phenotypic features of both Marfan syndrome and homocystinuria, patients are much less likely to have lens subluxation. Osteoarthritis may be seen with higher incidence in patients with homocystinuria. Treatment is with brace support of unstable joints.

Answer E: Wilms tumor is associated with Beckwith-Wiedemann syndrome (BWS), a pediatric overgrowth disorder usually caused by a mutation at chromosome 11p15. BWS presents with macrosomia (“gigantism”), which is defined as height and weight > 97th percentile. BWS additionally presents with omphalocele, hemihyperplasia, visceromegaly, neonatal hypoglycemia, and other embryonal tumors, including hepatoblastoma and neuroblastoma. Treatment is with surgical correction of defects.

Bullet Summary:
Homocystinuria presents with Marfanoid habitus, fair complexion, intellectual disability, downward lens subluxation, and an increased risk of thromboembolic events.