A 3-year-old boy with disproportionate short stature is brought to the pediatric clinic. On examination, he has frontal bossing, midface hypoplasia, and markedly shortened proximal limbs compared to distal segments. Pelvic radiography shows the characteristic finding marked as **A** in the diagram — a champagne-glass pelvis with narrow sacrosciatic notches and horizontal acetabular roofs. Which of the following best explains the skeletal phenotype in this child?
A. Gain-of-function mutation in FGFR3 on chromosome 4p16.3 causing constitutive activation and suppression of endochondral ossification at the growth plate
B. Loss-of-function mutation in COL2A1 causing defective type II collagen and impaired membranous ossification
C. Gain-of-function mutation in IHH (Indian hedgehog) causing excessive chondrocyte proliferation and metaphyseal expansion
D. Autosomal recessive mutation in DTDST causing defective sulfate transport and disproportionate dwarfism
Explanation
Why Option 1 is correct
Achondroplasia is the most common non-lethal skeletal dysplasia (incidence ~1 in 25,000 live births) and the most common cause of disproportionate short stature. It is caused by a gain-of-function missense mutation in FGFR3 on chromosome 4p16.3 (>95% are the G380R mutation). Constitutive FGFR3 activation inhibits endochondral ossification at the growth plate by suppressing chondrocyte proliferation and differentiation, while sparing membranous ossification (explaining normal skull vault and clavicles). This selective inhibition of endochondral ossification produces the characteristic rhizomelic (proximal limb) shortening and the radiographic hallmark of champagne-glass pelvis with narrow sacrosciatic notches and horizontal acetabular roofs, as marked in A (Pauli Genet Med 2019 Achondroplasia Guidelines).
Why each distractor is wrong
Option 2 (COL2A1 loss-of-function): COL2A1 mutations cause spondyloepiphyseal dysplasias and achondrogenesis, not achondroplasia. These conditions affect both endochondral and membranous ossification and do not produce the characteristic champagne-glass pelvis or rhizomelic shortening pattern of achondroplasia.
Option 3 (DTDST autosomal recessive): DTDST mutations cause diastrophic dysplasia and atelosteogenesis, which present with severe skeletal deformities, clubfoot, and cleft palate — not the classic achondroplasia phenotype. The inheritance is autosomal recessive, not dominant, and the pelvic morphology differs.
Option 4 (IHH gain-of-function): IHH mutations do not cause achondroplasia. Excessive hedgehog signaling would increase rather than suppress chondrocyte proliferation, producing the opposite phenotype (tall stature with metaphyseal expansion, not short stature with rhizomelic shortening).
High-YieldNEET PG
Achondroplasia = FGFR3 gain-of-function → inhibited endochondral ossification → rhizomelic shortening + champagne-glass pelvis; 80% sporadic de novo mutations associated with advanced paternal age.
Pauli Genet Med 2019 Achondroplasia Guidelines; Vosoritide FDA Approval 2021
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