Clinical Scenario:
A boy is noted at birth to have marked hypotonia, poor feeding, and bilateral cryptorchidism. During infancy, feeding difficulties gradually improve. By 2 years of age, he develops an intense appetite with rapid weight gain despite short stature. Examination shows small hands and feet. His growth velocity is reduced, and investigations demonstrate a low insulin-like growth factor 1 level.
Which of the following best explains the underlying genetic abnormality?
A. Autosomal dominant FGFR3 mutation
B. Loss of paternally expressed genes at chromosome 15q11-q13
C. Primary growth hormone receptor resistance
D. Leptin receptor deficiency
E. Loss of maternally expressed UBE3A
Correct answer & Explanation:
Answer: B. Loss of paternally expressed genes at chromosome 15q11-q13
Explanation
The combination of neonatal hypotonia, poor feeding, cryptorchidism, followed later by hyperphagia, obesity, short stature, and small hands and feet is characteristic of Prader-Willi syndrome (PWS).
PWS results from loss of expression of paternally inherited genes in the 15q11-q13 region. This occurs most commonly through a paternal deletion, maternal uniparental disomy, or an imprinting defect.
Growth failure in PWS is partly related to hypothalamic dysfunction and growth hormone deficiency, which explains the low insulin-like growth factor 1 and reduced linear growth. However, the fundamental genetic abnormality is the loss of paternal gene expression.
By contrast, loss of the maternally expressed UBE3A gene in the same chromosomal region causes Angelman syndrome.
Exam pearl:
Prader-Willi → paternal allele lost
Angelman → maternal UBE3A allele lost
