A 3-year-old boy is brought to the office by his mother for follow-up after an emergency department visit for a lower extremity fracture. One week ago, the patient fell while running on the stairs and was found to have a closed tibial fracture. He was placed in a cast and has been doing well since. His history is also notable for a femur fracture shortly after learning to walk at age 13 months. The patient has speech delay and mild hearing loss. His mother has had multiple fractures since childhood and has hearing loss as well. Vital signs are normal. Height and weight are at the 5th and 20th percentiles, respectively. Examination shows a young boy with no dysmorphic features. Bilateral upper and proximal lower extremities have 5/5 strength. Hypermobility of the joints in the hands is noted. The right leg is casted from below the knee to the foot, and capillary refill of the toes is

Question

A 3-year-old boy is brought to the office by his mother for follow-up after an emergency department visit for a lower extremity fracture.  One week ago, the patient fell while running on the stairs and was found to have a closed tibial fracture.  He was placed in a cast and has been doing well since.  His history is also notable for a femur fracture shortly after learning to walk at age 13 months.  The patient has speech delay and mild hearing loss.  His mother has had multiple fractures since childhood and has hearing loss as well.  Vital signs are normal.  Height and weight are at the 5th and 20th percentiles, respectively.  Examination shows a young boy with no dysmorphic features.  Bilateral upper and proximal lower extremities have 5/5 strength.  Hypermobility of the joints in the hands is noted.  The right leg is casted from below the knee to the foot, and capillary refill of the toes is <2 seconds.  Based on this clinical presentation, this patient most likely has a defect in which of the following genes?

Quizplus · Accepted Answer

11ec25c8_d741_9957_bc81_0fc950c7b167_MD0003_00 Osteogenesis imperfecta is an autosomal dominant connective tissue disorder caused by a type I collagen (COL1A1) gene mutation. This mutation results in a structural defect in type I collagen, an important component of the musculoskeletal system, skin, and sclera. In bone, type I collagen contributes to tensile and torsional strength; therefore, patients with osteogenesis imperfecta have decreased bone strength and flexibility that results in frequent fractures from minor trauma. Recurrent fractures, continued bone turnover, and decreased bone volume result in short stature. Dislocation or fracture of the ossicles results in conductive hearing loss and associated speech delay. Patients have joint hypermobility due to type I collagen defects in the tendons and ligaments. Additional clinical features include blue sclerae (ie, scleral thinning causing visualization of underlying vessels) and dentinogenesis imperfecta (ie, discolored teeth due to dentin exposure). (Choice A) Duchenne and Becker muscular dystrophy are due to dystrophin gene mutations that result in skeletal and cardiac muscle fiber degradation. Patients with muscular dystrophy can have frequent fractures due to a combination of proximal muscle weakness (leading to falls) and decreased bone density (secondary to glucocorticoids). This patient's strength is normal, making these diagnoses unlikely. (Choice B) Marfan syndrome is an autosomal dominant condition caused by a fibrillin-1 gene mutation. The defective fibrillin results in the weakening of microfibrils surrounding elastic fibers; therefore, patients with Marfan syndrome have joint hypermobility. However, patients are typically taller than average and are not at risk for frequent fractures. (Choice C) Achondroplasia is caused by a fibroblast growth factor receptor 3 (FGFR3) gene mutation that inhibits endochondral bone formation, primarily in long bones. Therefore, patients have disproportionate short stature (ie, shortening of the extremities relative to the trunk). Common dysmorphic features include frontal bossing and macrocephaly. Fractures and hearing loss are not typical. Achondroplasia (Choice D) An unstable trinucleotide repeat expansion of the fragile X mental retardation 1 (FMR1) gene results in fragile X syndrome, an X-linked disorder. This syndrome is associated with intellectual disability and joint hyperlaxity (particularly of the hands); however, patients often have characteristic dysmorphic features (eg, long and narrow face, large ears). There is no association with recurrent fractures. Educational objective: Osteogenesis imperfecta is an autosomal dominant connective tissue disorder caused by mutations in the type I collagen (COL1A1) gene. Patients typically present with recurrent fractures, joint hypermobility, short stature, and hearing loss. References: Osteogenesis imperfecta. (http://www.ncbi.nlm.nih.gov/pubmed/28820180) Osteogenesis imperfecta. (http://www.ncbi.nlm.nih.gov/pubmed/26542481)

A 3-Year-Old Boy Is Brought to the Office by His