FFinalistSouthampton · 2027
Child health
AKT · Child health/Genetic syndromes

Fragile X syndrome

FMR1 CGG trinucleotide-repeat expansion — X-linked

Overview

The commonest INHERITED cause of learning disability (Down syndrome is commoner overall but usually not inherited). An expansion of the CGG repeat in the FMR1 gene silences it; shows anticipation. Boys are more severely affected than girls.

Recognise

  • Moderate–severe learning disability; autism/ADHD features common
  • Long narrow face, large everted ears, prominent forehead/jaw
  • Macro-orchidism (large testes) AFTER puberty
  • Joint hypermobility, mitral valve prolapse, hypotonia; gaze avoidance, hand-flapping/biting

Red flags

  • Unexplained learning disability/ASD with the dysmorphic pattern → test for Fragile X

Differentials & how to tell them apart

Down syndrometrisomy 21 — commonest cause of LD overall but usually NOT inherited; different facies (epicanthic folds, single palmar crease)
Autism spectrum disorder (idiopathic)no FMR1 expansion, no macro-orchidism/typical facies
Other X-linked intellectual disabilitygene panel/array distinguishes
Klinefelter (47,XXY)tall, small firm testes (opposite of macro-orchidism), gynaecomastia

Investigations

FMR1 molecular genetic testing (CGG repeat number) is diagnostic. Offer genetic counselling (X-linked, anticipation, premutation carriers risk FXTAS/POI).

Management

FMR1 genetic testing to confirm; MDT support + genetic counselling

  1. 1Suspect in unexplained LD/ASD with the dysmorphic pattern → FMR1 testing.Gate: Premutation carriers (mothers) can have affected children and themselves risk fragile-X tremor/ataxia (FXTAS) or premature ovarian insufficiency → genetic counselling
  2. 2Multidisciplinary support: education, SALT, behavioural and ADHD management; family genetic counselling.
No specific cure — manage ADHD/behaviour symptomatically; MDT support

Key points

Macro-orchidism is post-pubertal — absent in young boys, so a normal exam does not exclude it. Anticipation: repeats expand across generations.

Monitor & prognosis

Developmental/educational progress; cardiac review (MVP); family cascade testing.

Lifelong learning disability; supportive management improves function.

Source: NICE CKS (learning disabilities); clinical genetics