Paeds · genetics-dysmorphology-and-metabolism
Fragile X syndrome
Also known as FMR1-related disorders · FRAXA syndrome · Martin-Bell syndrome · Fragile X-associated disorders · FXS
A fellowship approach to fragile X syndrome: recognise the X-linked FMR1 CGG-repeat expansion as the commonest inherited cause of intellectual disability, confirm the molecular diagnosis with PCR plus methylation analysis, build multidisciplinary developmental and behavioural support around the child, and run cascade testing of the wider family — because no curative therapy exists and every at-risk relative is a candidate for counselling.
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Red flags
- Global developmental delay or intellectual disability of unexplained cause in any child, especially a boy — fragile X testing is indicated
- A boy with autism spectrum disorder plus intellectual disability, or a girl with otherwise unexplained intellectual disability
- Family history of intellectual disability in males across generations, or a known carrier or premutation mother
- Post-pubertal boy with long face, large or protruding ears, macro-orchidism, joint laxity, and mitral valve prolapse
- Maternal premutation carrier — her offspring are at risk of full-mutation expansion, and she herself risks FXTAS and FXPOI
- Infant or child with seizures, hypotonia, and gaze aversion or social anxiety alongside developmental delay
- Relatives of an index case who have not yet had cascade testing — affected premutation and full-mutation carriers are routinely missed
Life stages
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Board mappings
- Common inherited causes of intellectual disability
- Indications for fragile X testing
- Genetic counselling of an X-linked condition
- FMR1 CGG-repeat classification and premutation biology
- Multidisciplinary management of fragile X syndrome
- Cascade testing and premutation surveillance (FXTAS, FXPOI)
- Recognising and investigating fragile X syndrome
- Counselling a family on an X-linked diagnosis
- Coordinating developmental and educational support
- Long case of a child with global developmental delay and dysmorphism
- Discussing cascade testing and reproductive risk with a carrier mother
- Genetic causes of neurodevelopmental disorder
- Communication in complex chronic disability
- Safeguarding and advocacy for the disabled child
- FMR1 genetics and CGG-repeat biology
- Investigation of intellectual disability
- Fragile X premutation-associated conditions
- Developmental assessment of the child with delay
- Counselling on genetic testing results
- Inherited intellectual disability
- Fragile X syndrome genetics and management
- Indications for genetic testing in developmental delay
- Fragile X syndrome
- Evaluation of the child with developmental delay
- Genetic counselling and family testing
- Fragile X syndrome and FMR1-related disorders
- Multidisciplinary care of genetic neurodevelopmental disability
The fellowship mark goes to the candidate who thinks in three layers at once. The first layer is the child in front of you: their intellectual level, their autism and ADHD comorbidity, their seizures and sensory profile, and the supports that change their trajectory. The second is the molecular mechanism: a CGG expansion that expands across generations, a silenced gene, and a missing synaptic brake. The third is the family: a premutation mother at risk of fragile X-associated tremor/ataxia syndrome (FXTAS) and ovarian insufficiency, siblings who may be carriers or affected, and relatives who deserve cascade testing and counselling. [1] [9]
References10ShowHide
- [1]Hersh JH, Saul RA Health supervision for children with fragile X syndrome. Pediatrics, 2011.PMID 21518720
- [2]Hunter J, Rivero-Arias O, Angelov A, et al. Epidemiology of fragile X syndrome: a systematic review and meta-analysis. Am J Med Genet A, 2014.PMID 24700618
- [3]Santoro MR, Bray SM, Warren ST. Molecular mechanisms of fragile X syndrome: a twenty-year perspective. Annu Rev Pathol, 2012.PMID 22017584
- [4]Maurin T, Zongaro S, Bardoni B. Fragile X Syndrome: from molecular pathology to therapy. Neurosci Biobehav Rev, 2014.PMID 24462888
- [5]Pirozzi F, Tabolacci E, Neri G. The FRAXopathies: definition, overview, and update. Am J Med Genet A, 2011.PMID 21739597
- [6]Protic D, Salcedo-Arellano MJ, Dy JB, Potter LA, Hagerman RJ. New targeted treatments for fragile X syndrome. Curr Pediatr Rev, 2019.PMID 31241016
- [7]Zhang JY, Wu DW, Yang RL, et al. FMR1 allele frequencies in 51,000 newborns: a large-scale population study in China. World J Pediatr, 2021.PMID 34738199
- [8]Castagnola S, Bardoni B, Maurin T. The search for an effective therapy to treat fragile X syndrome: dream or reality? Front Synaptic Neurosci, 2017.PMID 29163124
- [9]Tassone F, Protic D, Allen EG, et al. Insight and recommendations for fragile X-premutation-associated conditions from the Fifth International Conference. Cells, 2023.PMID 37759552
- [10]Sachdeva A, Jain P, Gunasekaran V, et al. Consensus statement of the Indian Academy of Pediatrics on diagnosis and management of fragile X syndrome in India. Indian Pediatr, 2019.PMID 30954995