Photoclinic: Fragile X Syndrome

During a routine physical examination, a 3-year-old boy was noted to have speech delay and hyperactive behavior. The child was born at term to a 25-year-old mother with epilepsy, which was managed with phenytoin. His birth weight was 3.5 kg (7.8 lb); he had no neonatal problems or features of fetal Dilantin syndrome. However, he had undergone bilateral hydrocele and inguinal hernia repair and tube placement for recurrent ear infections. His half sister (from his mother's previous marriage) needs help in reading and math. His father is healthy.

The child's weight was 15.5 kg (34.4 lb) (75th percentile); height, 98 cm (75th percentile); and head circumference, 53 cm (95th percentile). He avoided eye-to-eye contact and would not look at the camera when photographed. Generalized hypotonia and poor motor coordination were also noted. Other systems were normal.

Bhagwan Das Bang, MD, of Opp, Ala, writes that developmental delay--particularly affecting speech or in the setting of a maternal history of mental retardation--strongly suggests fragile X syndrome in an infant or toddler. In this child, DNA analysis revealed an expansion to the full fragile X mutation to 469 CGG repeats and full methylation.

Fragile X syndrome is the most common inherited cause of mental retardation. The prevalence is 1:3500 to 1:4000 in males, 1:4000 to 1:6000 in females who show the full mutation, and 1:800 in men and 1:260 in women who are carriers¹; however, the disorder is frequently undetected. It is caused by abnormal expansion of the CGG trinucleotide repeat in the FMR1 gene at Xq27.3 (fragile site). Children without the mutation have fewer than 40 CGG repeats, whereas children with full mutation have more than 200 CGG repeats. Marked amplification of the CGG repeat leads to abnormal methylation and halt of transcription of the FMR1 gene and its products. Children with fewer than 200 but more than 40 CGG repeats are considered carriers of a premutation.² Affected male patients can present later in life with tremor/ataxia syndrome.

Physical features of fragile X syndrome are subtle and may not be apparent at an early age. These features may include characteristic facies (usually apparent after 8 years of age) and macroorchidism (apparent after puberty); the exact cause is unclear, but it does not affect fertility or sexual function. Affected children may also have a high-arched palate, mitral valve prolapse, seizure, hyperextensible finger, hand calluses as a result of biting or chewing on the hand, flat feet, soft skin over the dorsum of the hand, and hypotonia.

Girls and women with fragile X syndrome have social anxiety and shyness as their major clinical features, whereas boys and men show speech delay and huge behavioral challenges (such as hyperactivity, social awkwardness, and autistic-like behavior).

Timely diagnosis permits the initiation of early intervention services for children and genetic counseling for families.³

References:

REFERENCES:

1.

The National Fragile X Foundation. Available at:

http://www.fragilex.org/ html/prevalence.htm

. Accessed on June 8, 2006.

2.

Hall JG. Chromosomal clinical abnormalities. In: Behrman RE, Kliegman R, Jenson HB, eds.

Nelson Textbook of Pediatrics.

16th ed. Philadelphia: WB Saunders Co; 2000:331.

3.

Visootsak J, Warren ST, Anido A, Graham JM Jr. Fragile X syndrome: an update and review for the primary pediatrician.

Clin Pediatr (Phila).

2005;44:371-381.