Can You Diagnose This Genetic/Developmental Disorder?

February 11, 2010

A 6-year-old boy presents with tall stature (97th percentile for age), motor delays (walking at 16 months), speech delays (expressive vocabulary of 30 to 40 words with recent use of 2-word phrases), and behavioral differences (poor eye contact, lack of pointing, hyperactive behavior with hand-flapping).

A 6-year-old boy presents with tall stature (97th percentile for age), motor delays (walking at 16 months), speech delays (expressive vocabulary of 30 to 40 words with recent use of 2-word phrases), and behavioral differences (poor eye contact, lack of pointing, hyperactive behavior with

hand-flapping). Appearance is as shown. Aside from several episodes of otitis media, his medical history is noncontributory. His family history is significant for mild mental disability in his mother and severe disability in a maternal uncle.


 Q: What diagnoses would you consider, and what laboratory tests and referrals would you order?

(Answer on next page.)







 A: This child has developmental delays that require recognition by his primary care physician, initiation of discussions with the parents, and judgment as to how to proceed with the workup. Important developmental milestones were not met (walking by 11 to 13 months, and use of 2-word phrases by age 2 years). Such a situation mandates prompt and supportive discussion with the patient's parents, with an emphasis on working as a physician-parent team to coordinate assessment and therapy (ie, the "medical home" model). Behavioral differences in the areas of communication, social interaction, and repetitive movements/ interests suggest the presence of a pervasive developmental disorder (PDD), with autism disorder most strongly suspected.

In children with developmental delays, the medical and family history can sometimes refine the differential diagnosis. Here, the family history of a severely affected male relative and apparent female transmission of the disability (Figure) suggest an X-linked inheritance pattern. This raises suspicion of fragile X syndrome.

Overview of fragile X syndrome. This disorder is characterized by intellectual disability (IQ range in males, 30 to 60; in carrier females, 70 or higher) that is often accompanied by behavioral differences suggestive of PDD/autism spectrum disorder, connective-tissue problems (eg, joint laxity, mitral valve prolapse, flatfoot, skeletal problems), and/or subtle yet distinctive physical features.1-3 The disorder exhibits X-linked recessive inheritance, with subtle changes (such as mild mental disability or primary ovarian insufficiency) in symptomatic carrier females. The family history may exhibit "anticipation," with worse symptoms in affected descendants compared with their ancestors: ie, asymptomatic premutation males have apparently normal carrier daughters whose sons have full fragile X syndrome with significant mental disability. In premutation males, fragile X ataxia syndrome may develop in middle age.

Physical findings. In boys with fragile X syndrome, physical examination may detect subtle variations (minor anomalies), such as the large ears and prominent jaw seen in this child. Findings such as these, along with increased testicular volume (often not obvious until after puberty) and moderate to severe developmental-behavioral differences can distinguish boys with fragile X syndrome from those with Klinefelter (47,XXY) syndrome (who have small testes) and those with 47,XYY syndrome (who have few physical differences).

The child shown here had normal testicular size, but his affected maternal uncle had large testes, and both had increased joint laxity. In addition, the uncle had mitral valve prolapse.

Testing and referrals. Consider baseline genetic testing and referral to a pediatric geneticist, neurologist, and developmental pediatrician for any child with significant developmental delays.
The order of referrals is determined by the accompanying symptoms: children with dysmorphology/
metabolic symptoms should be referred first to a geneticist; those with seizure/tone/movement symptoms should be referred first to a neurologist; and those with autism or cerebral palsy symptoms should be referred first to a developmental pediatrician. A striking family history, as in this case, also supports a referral for genetic counseling because of the 25% recurrence risk in carrier females.

Baseline genetic testing should include a routine chromosome study (karyotype); in addition, fragile X DNA testing should be considered for any boy with significant developmental delays.4,5 Fragile X DNA testing quantifies the number of trinucleotide (triplet) repeats near the fragile X–mental retardation gene (FMR-1). Normal males have fewer than 60 repeats at their single FMR-1 locus, while affected males have 400 to 2000 repeats. Premutation males have 60 to 2000 repeats that are transmitted to all their daughters, making these girls carriers with one normal FMR-1 locus and one FMR-1 locus with 60 to 200 repeats (symptomatic carrier females have closer to 200 repeats). The repeats can undergo dramatic expansion during female meiosis, giving carrier women a 25% risk of having an affected male child in whom a high number of repeats inactivates FMR-1 protein expression in the brain.

The boy in this case had 600 triplet repeats by DNA testing, which was diagnostic of fragile X syndrome. His mother and uncle declined testing.

Follow-up and preventive care for children with fragile X syndrome. Preventive health care for children in whom fragile X syndrome has been diagnosed should include monitoring for hearing and vision problems and for signs of connective-tissue dysplasia (pectus excavatum, scoliosis, flatfoot, cardiac valve dysplasia).

Be alert for autistic symptoms, which are common in these children, as illustrated by the triad of social deficits (lack of eye contact and pointing), communication deficits (speech delay), and movement differences (hand-flapping) in this patient.



1. D'Hulst C, Kooy RF. Fragile X syndrome: from molecular genetics to therapy. J Med Genet. 2009;46:577-584.
2. Chudley AE, Hagerman RJ. Fragile X syndrome. J Pediatr. 1987;110:821-831.
3. American Academy of Pediatrics Committee on Genetics. Health supervision for children with fragile X syndrome. Pediatrics. 1996;98(2, pt 1):297-300.
4. Sex chromosome aneuploidy and X-linked mental retardation syndromes: fragile X syndrome. In: Wilson GN, Cooley WC, eds. Preventive Health Care for Children with Genetic Conditions: Providing a Primary Care Medical Home. 2nd ed. Cambridge, UK: Cambridge University Press; 2006:214-229.
5. Muhle R, Trentacoste SV, Rapin I. The genetics of autism. Pediatrics. 2004; 113:e472-e486.