Clinical scenario:
A 2-year-old girl is brought with loss of previously acquired speech and hand skills. She was developing normally during infancy. Her head circumference was at the 90th centile at birth but has progressively crossed downwards and is now at the 50th centile. Examination shows reduced purposeful hand use with repetitive hand movements. Which of the following is the most likely diagnosis?
A. Achondroplasia
B. Benign familial macrocephaly
C. Fragile X syndrome
D. Rett syndrome
E. Sotos syndrome
Correct answer & Explanation:
Correct answer: D. Rett syndrome
This is a classic presentation of Rett syndrome, a neurodevelopmental disorder associated most commonly with pathogenic variants in the MECP2 gene.
Explanation
The key diagnostic clues are the combination of:
- Normal early development
- Developmental regression around 1–4 years of age
- Loss of previously acquired speech
- Loss of purposeful hand skills
- Development of repetitive/stereotypic hand movements
- Deceleration of head growth, with the head circumference crossing downward through percentiles
These features closely match the characteristic clinical pattern of classic Rett syndrome. GeneReviews identifies regression with loss of acquired purposeful hand skills and spoken language, together with stereotypic hand movements, as the major clinical findings. Deceleration of head growth is also a common feature.
In this case, the fall in head circumference from the 90th to the 50th percentile is particularly important. The child does not necessarily need to have absolute microcephaly; deceleration of head growth is the relevant clinical clue. GeneReviews reports deceleration of head growth in approximately 80% of females with classic Rett syndrome.
Why the other options are less likely
| Option | Why it is less likely |
|---|---|
| A. Achondroplasia | Characterized primarily by disproportionate short stature and skeletal features; it does not cause this characteristic pattern of developmental regression and hand stereotypies. |
| B. Benign familial macrocephaly | Causes a persistently large head circumference with normal development; it does not explain developmental regression or loss of purposeful hand use. |
| C. Fragile X syndrome | Usually causes developmental delay/intellectual disability, characteristic behavioral features and, in boys, macroorchidism. Progressive loss of acquired speech and purposeful hand skills with stereotypic hand movements is not the classic pattern. |
| D. Rett syndrome | Normal early development → regression → loss of speech/purposeful hand use → stereotypic hand movements + deceleration of head growth. |
| E. Sotos syndrome | Typically features overgrowth, macrocephaly and developmental delay, rather than progressive developmental regression with loss of purposeful hand skills. |
High-yield exam pearl
Rett syndrome = “normal development → regression + hand stereotypies + decelerating head growth.”
You can also practice another MCQ on Phenylketonuria.
References
- Kaur S, Christodoulou J. MECP2 Disorders. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Updated 2025 Dec 4.
- Mims C. Rett Syndrome: The Epidemiology, Clinical Features, and Management. Pediatr Rev. 2025;46(10):586-588. doi:10.1542/pir.2024-006437
