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You are called by the neonatal intensive care unit to consult on a newborn girl with fractures. The baby’s parents state concerns were initially raised after a 20-week prenatal ultrasound showed femoral bowing and undermineralization of the skull. There were no additional complications with the pregnancy, and the baby was born full term by spontaneous vaginal delivery. On physical examination, you note shortened, bowed extremities; a small chest; and a triangular-shaped skull with a soft calvarium. You review her skeletal survey, which shows multiple rib fractures, mildly reduced lung volumes, and a right humerus fracture. You discuss your suspected diagnosis with the family and order genetic testing.
This patient’s type of disease is most commonly associated with which of the following?
- Strong genotype-phenotype correlation
- Fewer fractures in infants born via cesarean delivery
- Severe short stature
- Hearing loss
- A decrease in fracture rate with age
Severe short stature
This patient’s presentation is consistent with osteogenesis imperfecta (OI), a congenital disorder resulting from defects in production or processing of connective tissue. The primary clinical feature of OI is bone fragility, which leads to fractures and deformities. Affected persons may also develop extraskeletal features including muscle weakness, hyperlaxity, dental abnormalities, hearing loss, and restrictive lung disease. OI occurs along a broad clinical spectrum and is classified into 8 different types.
Types 1 through 4 are the most common and result from mutations in the COL1A1 and COL1A2 genes, leading to abnormalities in type 1 collagen. The mildest form of OI is type 1, which typically presents with fractures in childhood. Patients with type 1 have normal to mildly shortened stature, and long bone deformity is uncommon. Childhood fractures in patients with type 1 are variable, ranging from few to numerous, and the fracture rate typically decreases in adulthood. However, this newborn’s presentation is more severe than that of type 1 OI (thus, Answer E is incorrect). Blue sclerae and hearing loss are prominent features of type 1 OI. The most severe form is type 2 OI, which frequently results in neonatal lethality due to pulmonary hypoplasia. Type 3 is the most severe type of OI in children who survive past the neonatal period, and it presents with fractures in utero and at birth. Physical features in affected newborns include shortened, bowed limbs; a small thorax; and a relatively large, triangular-shaped head with a soft calvarium. This patient’s presentation with in utero and perinatal fractures is consistent with type 3 OI. Neonates with this type of OI may develop respiratory and/or feeding issues, and children develop severe short stature that persists into adulthood (thus, Answer C is correct). Patients with type 4 OI are moderately affected with a variable clinical presentation ranging from few fractures in childhood (similar to type 1 OI) to a more severe phenotype (similar to type 3 OI). Short stature is generally moderate to severe, which may distinguish these patients from those with type 1 OI. Long-bone deformities may occur but are generally mild in type 4 OI.
The genotype-phenotype correlation in OI has not been well characterized (thus, Answer A is incorrect). While the optimal mode of delivery for neonates with OI has not been determined, currently available data do not support a decrease in fracture rates with cesarean delivery compared with vaginal delivery (thus, Answer B is incorrect). Hearing loss can occur in any type of OI, but it is most common in type 1 (thus, Answer D is incorrect).
Differentiate among the clinical features of various forms of osteogenesis imperfecta.
Harrington J, Sochett E, Howard A. Update on the evaluation and treatment of osteogenesis imperfecta. Pediatr Clin North Am. 2014;61(6):1243-1257.