At age 3 years, Fragile X was diagnosed, based on 20% of 54 cells tested having a fragile site on Xq27. When reviewed at age 14 years, DNA testing for Fragile X A was applied. Direct fluorescent polymerase chain reaction (PCR) analysis and Southern blot analysis showed that she was homozygous for normal sized fragments (test sensitivity >95%). Therefore FRAXA was excluded and the diagnosis of Fragile X was withdrawn.

Persistent clinical concerns led to re-evaluation at 15 years. She had serious behavioural problems, being very aggressive, destructive, not showing much emotional attachment, and befriending children several years her junior. She was tall and obese. There were no dysmorphic features and the neurological examination was normal.

She had normal female karyotype (46XX). Testing for Smith Magenis syndrome showed normal hybridisation signals on chromosome 17p11.2. Karyotyping confirmed a fragile site at Xq28 in 16/30 cells. Southern blot analysis using probe OxE20 detected a large DNA expansion of approximately 1.7 kb above the normal size in the FMR2 gene, showing a full mutation at the FRAXE locus and confirming a diagnosis of Fragile X E.

Using the same PCR tests, her mother was found to be a carrier. By then her biological father had left the family. Her mother remarried and had a male child with her new partner.

The term Fragile X derives from the appearance of the X chromosome which expresses a folate sensitive fragile site at Xq27.3 in folate deprived culture conditions.

Fragile X syndrome (FRAXA) is nearly always characterised by moderate mental retardation in affected males and mild mental retardation in affected females. Affected males may have a characteristic appearance (large head, long face, prominent forehead, jaw and ears), joint laxity and large testes (macroorchidism) after puberty. Neurobehavioral features include hyperactivity, mild autistic features and difficulty in social interaction. Girls with autistic features may have a worse developmental outcome.⁴

Fragile X associated tremor/ataxia syndrome (FXTAS) occurs in males who have an FMR1 premutation and is characterised by late onset, progressive cerebellar ataxia and intention tremor. FMR1 related premature ovarian failure (POF) (age at cessation of menses <40 years) occurs in approximately 20% of females who have an FMR1 premutation. More than 99% of individuals with FRAXA have a loss-of-function mutation in the FMR1 gene caused by an increased number of CGG trinucleotide repeats (typically >200) accompanied by aberrant methylation of the FMR1 gene. Recent studies estimate a prevalence of 16–25:100,000 males.

In patients with the cytogenetic changes of Fragile X syndrome but who lack an expansion of the FMR1 gene, a second distinct site of fragility, FRAXE, was identified.⁵ It lies 150–600 kb distal to the FRAXA site. This site showed a possible aetiological relationship with non-specific mental impairment.

The FRAXE gene, FMR2, is distal to FRAXA at Xq28. Normal individuals have 6–25 copies of a GCC repeat adjacent to a CpG island. Mentally retarded individuals have more than 200 repeats and the CpG island is methylated. FMR2 is downregulated by repeat expansion and methylation. The GCC repeat is unstable, with copy number increasing from one generation to the next, when transmitted through females. Two to four times as many females carry the gene abnormality as males. The Fragile X premutation can be passed through the generations in a family before a child is affected.

FRAXE is relatively rare and has no distinct dysmorphology, making clinical diagnosis difficult. FRAXE causes a wide range of intellectual and behavioural problems including mild mental retardation and learning difficulty/developmental delay. Speech impairment seems to be a common feature. Boys are typically more severely affected than girls, and descriptions of affected females are rare.

There may be no correlation between genotype and phenotype perhaps because of mosaicism, differential tissue expression or because clinical evaluation has been lacking.⁶

This individual was not dysmorphic and was neurologically normal, reducing the likelihood that she had a disorder caused by birth injury or a chromosome abnormality. Having been assessed by a clinical geneticist (HS) she was not thought to have an alternative syndromic diagnosis.

Significant family, developmental, cognitive, and neuropsychological histories are keys to diagnosis. The diagnosis is made earlier if there is a family history of male relatives with mental retardation or a mother with learning difficulty. During infancy, developmental milestones are achieved as expected. After the first year of life delays in speech and language are notable, and fine motor skills are impaired. Physical and cognitive/behavioural signs are more obvious during adolescence. Lifespan is generally unaffected by the disorder.

Chromosome analysis using modified culture techniques to induce fragile sites had several limitations: it was positive in <60% of cells in most affected individuals; it was not able to identify a carrier status or identify the various subtypes of Fragile X. It is no longer used for diagnosis of Fragile X syndrome, being less sensitive and more costly than molecular genetic testing.

Currently testing involves PCR analysis which can detect carriers and affected individuals. A positive test is diagnostic for a disease or identifies a carrier state. However, a negative result does not rule out the diagnosis due to a sensitivity that is <100% or the involvement of more than one gene (genetic heterogeneity).

Because the symptoms can be subtle it is recommended that testing for Fragile X (FRAXA) be considered for any individual of either sex with otherwise unexplained developmental delay, mental retardation or autism. Individuals seeking reproductive counselling who have a family history of Fragile X syndrome or mental retardation or fetuses of known carrier mothers could also be tested. Population screening is not recommended.

Routine screening for FRAXE and FRAX subtypes is not warranted but is indicated in selected FRAXA negative cases, especially those with cytogenetic features of Fragile X syndrome but who are FMR1 negative.

In a child with global developmental delay identified by routine paediatric screening, a careful search for an underlying aetiology is usually undertaken. Accurate diagnosis limits further unnecessary testing and has implications regarding treatment, prognosis, management of associated conditions, and counselling of families regarding recurrence risks, and empowers the affected family in planning for their child and future pregnancies. Appropriate education and anticipatory guidance can help maximise the potential of each child.