Casus 10

Je bent klinisch geneticus. Op je spreekuur komt een persoon in wiens familie het fragiele X syndroom voorkomt voor erfelijkheidsadvies.

Zie ook casus 9

Tekst afkomstig van Illustrated textbook of paediatrics. blz 124

Fragile X syndrome The prevalence  of  significant  learning  difficulties  in males due to fragile X syndrome is about 1 in 4000 (Fig 8.13 and Box 8.9). This condition was initially diagnosed on the  basis  of  the  appearance  of  an  apparent  gap  or break (a fragile site) in the distal part of the long arm of the  X  chromosome. Diagnosis is  now  achieved  by molecular  analysis  of  the  CGG  trinucleotide  repeat expansion in the relevant gene (FMR1).

Although it is inherited as an X­linked recessive dis­order, a  substantial  proportion  of  obligate  female  car­riers have learning difficulties (usually mild to moderate) and around one­fifth of males who inherit the mutation are  phenotypically  normal  but  may  pass  the  disorder on to their grandsons through their daughters.

These unusual findings are explained by the nature of the  mutation,  which  occurs  in  ‘pre­mutation’  and ‘full mutation’ forms. The normal copy of the gene con­tains fewer  than  50  copies  of  the  CGG  trinucleotide repeat sequence and is stable when transmitted to off­spring. Genes with  the  pre­mutation  contain  55–199 copies  of  the  repeat  sequence. This expansion  causes no intellectual disability in male or female carriers, but is unstable and may become larger during transmission through females. Genes with the full mutation contain more than  200  copies  of  the  repeat  sequence. This affects gene  function,  causing  the  clinical  features  of fragile X syndrome in virtually all males and around half of  female  carriers. These full  mutations  always  arise from  expansion  of  pre­mutations,  and  never  arise directly  from  normal  genes. Hence all  mothers  of affected males are carriers.

Fragile X syndrome is the commonest familial form of learning difficulties and the second most common genetic cause of severe learning difficulties after Downsyndrome. *									•  Moderate–severe learning difficulty (IQ 20–80, mean 50) *									•  Macrocephaly *									•  Macro­orchidism – postpubertal *									•  Characteristic facies – long face, large

everted ears, prominent mandible and broad forehead, most evident in affected adults *									•  Other features – mitral valve prolapse, joint laxity, scoliosis, autism, hyperactivity. A child with fragile X syndrome. At this age, the main physical feature is often the prominent ears.