Case 2: Developmental delay, especially language, in a toddler

An 18-month-old girl was first referred at eight months of age to a developmental centre because of general developmental delay. She was born after a normal pregnancy and delivery. Her birth weight was 3.7 kg, with Apgar scores of 9 and 10 at 1 min and 5 min, respectively. The neonatal period was uneventful. Her parents are non-consanguineous and have two older healthy sons. There are no known individuals with developmental delay or mental retardation in the enlarged families of both parents.

Beginning at four months of age, the infant suffered recurrent episodes of otitis media, and was hospitalized twice with pneumonia and purulent otitis media. A hearing test performed at seven months of age revealed profound hearing loss mainly in her right ear (70 dB), and a brainstem auditory evoked response test confirmed the hearing loss; ventilatory tubes were inserted. Her physical examination when she was first seen in the developmental centre was normal, with no dysmorphic features or abnormal neurological signs. Repeated developmental examinations and follow-up at 18 months of age confirmed a general developmental delay corresponding to motor developmental skills of a 12-month level and language skills at a nine-month level. The neurological examination showed mild hypotonia. Laboratory tests including a complete blood count, chemistry, thyroid function and urinalysis were normal. Toxoplasma, rubella, cytomegalovirus and herpes simplex virus titres were negative. Metabolic work-up including lactate, ammonia, amino acids and biotinidase in the blood, and organic and amino acids in the urine were normal. At this point, a blood test was ordered, which confirmed the suspected diagnosis.

CASE 2 DIAGNOSIS: FEMALE FRAGILE X SYNDROME

The developmental delay and recurrent episodes of otitis media, with hearing loss that persisted after the ventilatory tubes were inserted, led us to think of a syndromic cause for the patient’s symptoms. Chromosomal analysis revealed a normal female 46,XX karyotype, and molecular studies found a full mutation in the FMR1 gene (more than 200 copies of the CGG trinucleotide repeat sequence at the fragile X locus on the X chromosome), thus establishing the diagnosis of fragile X syndrome (FXS).

In 1991, the gene for FXS, designated FMR1, which codes for the fragile X MR protein (FMRP) was discovered. The lack of FMRP production causes the syndrome. The DNA sequence at the FMR1 gene is a CGG trinucleotide repeat sequence. Normal individuals have between six and 55 CGG repeats, and carriers of the ‘premutation’ have 56 to 199 repeats, in which FMRP production still occurs. Those who have 200 CGG repeats or more have the ‘full mutation’, and in this situation, the DNA nucleotides are methylated, resulting in the absence of the FMRP. Forty per cent of patients with the full mutation are mosaics with cells containing variable length of full or premutation alleles.

FXS is the most common inherited cause of intellectual disability affecting males and females, with a prevalence of 1:3500 to 1:4000 in males, and 1:8000 to 1:9000 in females who show the full mutation. The overall prevalence may be as high as 1:2000 to 1:3000 because many prevalence studies have not screened children with milder cognitive deficits. The syndrome is characterized by certain physical features and impaired cognition, with language and behavioural problems. Approximately 80% of males have a dysmorphic appearance in contrast with most females who are not dysmorphic. Physical features may not be apparent at an early age. The characteristic facies are usually apparent by eight to 10 years of age, and may consist of macrocephaly, long face, prominent forehead, epicanthal folds, prognathism, dental crowding and large protruding ears. Entering puberty at approximately nine years of age, macroorchidism may become evident, increasing until a mean testicular volume of 50 mL in adulthood. Other features that may be seen in FXS include strabismus, mitral valve prolapse, high arched palate, soft velvety skin over the dorsum of the hands, hyperextensible joints, flat feet, scoliosis and simian creases of the palms. Recurrent otitis media (in 60% to 80% of individuals) and sinusitis (in 23% of individuals) are common in infancy and childhood.

Neurological abnormalities such as seizures (25%), hypotonia and motor dyspraxia may occur. The seizures appear mainly in boys. Partial seizures have been described in two girls who are fragile X carriers. In girls with the pre-mutation, the typical physical characteristics are more subtle, and they may exhibit premature ovarian insufficiency later in life. Approximately 30% of males who carry a pre-mutation allele will develop fragile X-associated tremor and ataxia syndrome after 50 years of age. Cognitive function in boys is more severely impaired, and most of them have moderate to severe intellectual disability with an average IQ of 30, whereas girls are borderline to mild, and 35% to 50% of those with the full mutation may have IQ scores of less than 85. With regard to language skills, boys may show greater delays in gaining expressive language skills compared with receptive language. Their speech may be rapid; dysfluent; characterized by repetitions of sounds, words and phrases; and they occasionally may have garbled, slurred and disorganized speech. Language impairment is also noted in affected girls.

Behavioural problems in boys are manifested by social avoidance, and deficits in attention and hyperactivity. Nearly 25% of boys meet the criteria for autism. Girls express social anxiety, social avoidance, withdrawal and depression. Shyness and social discomfort appear more in those with the premutation. Selective mutism has also been described in girls with the full mutation. Girls express more attentional difficulties, without the hyperactivity and impulsivity of attention-deficit hyperactivity disorder. Autistic behaviours may be reported in girls by six to 16 years of age, but unlike boys with the syndrome, they are usually not severly affected.

There are still reports in the literature of delayed diagnosis of the syndrome because of nonspecific features, unremarkable physical examination, noncontributory family history and delayed molecular testing. The case presented is one of the earliest ages of diagnosis in a female described in the literature.

There is no specific treatment for the syndrome. However, affected children do benefit from early developmental treatments in physical, speech and occupational therapy. More specific therapy includes psychopharmacological treatments for those with attention-deficit hyperactivity disorder symptoms; selective serotonin reuptake inhibitors for those with anxiety, perseveration, compulsive and depressive symptoms; and risperidone for aggressive behaviours.

CLINICAL PEARLS

• Consider FXS in any child, boy or girl, with a delay in language, social anxiety, hyperactivity or hand flapping.

• Girls generally have a milder presentation than boys because they have two X chromosomes and the normal X produces variable amounts of FMRP, depending on the amount of X inactivation. The level of FMRP correlates with the degree of cognitive involvement in both males and females.

• Early diagnosis is important for genetic counselling, particularly in young couples, and it is also useful for early intervention for those children who have special educational and psychosocial needs.

• In girls presenting with partial seizures of unknown cause, consider the possibility that they may be fragile X carriers.