Sagittal and Lambdoid Synostosis, Low set ears

 # A two-month-old boy is referred for evaluation because he has an abnormal head shape. Physical examination shows low-set ears, and short-webbed fingers. A CT scan shows sagittal and lambdoid synostosis. Which of the following genes is most likely to cause this syndrome ?

A. TWIST1

B. FGFR1

C. FGFR2

D. RAB23

The correct answer C. FGFR2.

The most likely gene to cause the syndrome described, characterized by sagittal and lambdoid synostosis, low-set ears, and short-webbed fingers in a two-month-old boy, is C. FGFR2.

Explanation:

The clinical presentation suggests a craniosynostosis syndrome, with sagittal and lambdoid synostosis indicating premature fusion of cranial sutures, and additional features like low-set ears and short-webbed fingers (syndactyly) pointing toward a syndromic form. Among the options, mutations in FGFR2 (Fibroblast Growth Factor Receptor 2) are strongly associated with syndromic craniosynostoses, particularly Apert syndrome and Crouzon syndrome, both of which can present with multisuture synostosis (including sagittal and lambdoid) and distinctive features.

Apert syndrome (caused by FGFR2 mutations) is characterized by coronal synostosis (though sagittal and lambdoid can also be involved), syndactyly (webbed fingers/toes), midface hypoplasia, and occasionally low-set ears due to associated craniofacial anomalies. The short-webbed fingers in the question align well with Apert’s syndactyly.

Crouzon syndrome (also FGFR2-related) involves craniosynostosis (often coronal, but sagittal and lambdoid can occur) and facial anomalies like low-set ears, though syndactyly is less common.

Analysis of other options:

A. TWIST1: Associated with Saethre-Chotzen syndrome, which typically involves coronal synostosis and milder limb anomalies (e.g., partial syndactyly or brachydactyly). Multisuture involvement (sagittal and lambdoid) is less common, and severe syndactyly is not typical.

B. FGFR1: Linked to Pfeiffer syndrome in some cases, but FGFR2 is more commonly implicated. Pfeiffer includes broad thumbs/toes and partial syndactyly, but sagittal and lambdoid synostosis as the primary sutures is less frequent.

D. RAB23: Associated with Carpenter syndrome, a rare condition with craniosynostosis (often sagittal or coronal), polysyndactyly (extra digits), and other anomalies. The absence of polysyndactyly or obesity in the description makes this less likely, and short-webbed fingers align better with Apert’s syndactyly.

Conclusion: FGFR2 mutations are most likely to cause a syndrome with sagittal and lambdoid synostosis, low-set ears, and short-webbed fingers, as seen in Apert syndrome, making C. FGFR2 the best answer.