An 18-month-old boy has tall stature, macro-orchidism, and intellectual disability. His maternal grandfather had tremor and ataxia. His mother has premature ovarian insufficiency. The most likely molecular diagnosis is:

• A Down syndrome (trisomy 21)
• B Klinefelter syndrome (47,XXY)
• C Neurofibromatosis type 1
• D Fragile X syndrome (FMR1 gene CGG repeat expansion) ✓

Explanation

Fragile X syndrome is caused by >200 CGG repeats in the FMR1 gene on chromosome Xq27.3, causing methylation and gene silencing. It is the most common inherited cause of intellectual disability in males. Macro-orchidism is a hallmark post-pubertally but can be appreciated earlier. The family history clues are: grandfather with tremor-ataxia (FXTAS — Fragile X Tremor Ataxia Syndrome, premutation 55–200 repeats) and mother with premature ovarian insufficiency (FXPOI — also premutation). This triad across generations is pathognomonic of FMR1 premutation pedigree.

Reference: Ghai Essential Pediatrics, 10th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.