How can I differentiate Fragile X Syndrome from other causes of intellectual disability in children?

Fragile X Syndrome (FXS) can be differentiated from other causes of intellectual disability in children primarily through its distinctive clinical features combined with confirmatory genetic testing. Clinically, children with FXS often present with a characteristic pattern of intellectual disability that ranges from mild to severe, accompanied by specific physical and behavioural features such as a long face, large ears, macroorchidism (in post-pubertal males), and connective tissue signs like joint hypermobility and flat feet (Hagerman, 1987). Behaviourally, features overlap with autism spectrum disorder but include social anxiety, gaze avoidance, and repetitive behaviours that are somewhat distinct from idiopathic autism (Terracciano et al., 2005). These phenotypic clues help differentiate FXS from other genetic or environmental causes of intellectual disability.

Definitive differentiation requires molecular genetic testing for the FMR1 gene mutation, specifically the CGG trinucleotide repeat expansion. This test is the gold standard and distinguishes FXS from other intellectual disabilities that do not involve this mutation (Laxova, 1994). Unlike other causes of intellectual disability, FXS is caused by a full mutation (>200 CGG repeats) leading to silencing of the FMR1 gene and absence of the fragile X mental retardation protein (FMRP), which is critical for normal neural development.

In clinical practice, the presence of intellectual disability with suggestive physical and behavioural features should prompt referral for genetic testing to confirm FXS, differentiating it from other syndromic or non-syndromic intellectual disabilities. This approach aligns with UK guidelines recommending developmental assessment and targeted genetic testing when specific syndromic features are present ¹.