Clinical Scenario:
An 18-month-old girl who had previously acquired age-appropriate developmental milestones is brought because of progressive loss of speech and social interaction over the past 4 months. She has also lost purposeful use of her hands and repeatedly brings her hands to the midline, where she makes stereotypic wringing and washing movements. Neurological examination shows no focal deficit.
Which of the following genetic abnormalities is most likely responsible?
A. FMR1 CGG repeat expansion
B. MECP2 mutation
C. NF1 mutation
D. PTEN mutation
E. UBE3A mutation
Correct answer & Explanation:
Answer: B. MECP2 mutation
Explanation
The combination of normal early development followed by regression, loss of purposeful hand use, loss of language, and stereotypic hand-wringing movements is highly characteristic of Rett syndrome.
Rett syndrome is most commonly caused by pathogenic variants in the MECP2 gene, located on the X chromosome. It predominantly affects girls and typically becomes apparent during infancy or early childhood after a period of apparently normal development.
- FMR1 → Fragile X syndrome, usually associated with developmental delay, intellectual disability, autistic features, and characteristic physical features.
- UBE3A → Angelman syndrome, characterized by severe developmental delay, ataxia, seizures, and a happy/excitable demeanor.
- PTEN → associated with certain macrocephaly-intellectual disability/autism syndromes.
- NF1 → neurofibromatosis type 1, characterized by café-au-lait macules, neurofibromas, and other neurological complications.
The key diagnostic clue is developmental regression with loss of purposeful hand skills followed by stereotypic hand movements.
