Xq28 Duplication Syndrome, Int22h1/int22h2 Mediated

Clinical characteristics.

The int22h1/int22h2-mediated Xq28 duplication syndrome is a recently recognized X-linked intellectual disability syndrome characterized in males by cognitive impairment, behavioral and psychiatric problems, recurrent infections and atopic diseases, obesity, and distinctive facial features. Females heterozygous for this duplication exhibit a milder phenotype (with learning difficulties and distinctive facies) or are clinically unaffected. To date 26 individuals (14 males and 12 females) with this recurrent duplication have been described.

Diagnosis/testing.

The diagnosis of the int22h1/int22h2-mediated Xq28 duplication is established by detection of a 0.5-Mb duplication (hemizygous in males and heterozygous in females) at chromosome Xq28 extending from 154.1 Mb to 154.6 Mb in the reference genome (NCBI Build GRCh37/hg19).

Management.

Treatment of manifestations: Early intervention with speech and physical therapy for young children with developmental delay; special education programs for school-aged children with intellectual disability. Recurrent bacterial infections are treated with standard antibiotics; recurrent ear infections are treated in the standard manner. Nutritional counseling and regular exercise for obese individuals. Standard management for behavioral and psychiatric problems.

Surveillance: The following monitoring is recommended: assessment of developmental progress and cognitive abilities; screening for behavioral and psychiatric problems; and routine audiologic and ophthalmologic evaluations.

Evaluation of relatives at risk: Clinically asymptomatic children who have the familial duplication should be assessed and monitored for developmental delay with the goal of early initiation of therapies and support if needed.

Genetic counseling.

The int22h1/int22h2-mediated Xq28 duplication is inherited in an X-linked manner. The father of an affected male will not have the disorder nor will he be hemizygous for this Xq28 duplication. All mothers (tested to date) of individuals with this Xq28 duplication were found to be heterozygous for the duplication. When mothers are heterozygous for this Xq28 duplication, the chance of transmission in each pregnancy is 50%: sons who inherit the duplication will be affected; daughters who inherit the duplication will be heterozygotes and may have a milder phenotype or may be clinically unaffected. Prenatal testing using genomic testing that will detect this Xq28 duplication is possible when the mother is known to be heterozygous for the duplication.

Suggestive Findings

The int22h1/int22h2-mediated Xq28 duplication syndrome should be suspected in males with the following clinical findings:

• Cognitive impairment
• Behavioral and psychiatric problems: aggressiveness, attention deficit hyperactivity disorder (ADHD), autism spectrum disorder, sleep disturbance, anxiety, and psychotic disorders
• Recurrent respiratory infections and atopic diseases
• Obesity
• Distinctive facial features: tall forehead, upper eyelid fullness, wide nasal bridge, and thick vermilion of the lower lip (see Figure 1A-E)

Figure 1.

Facial features of males (A-E) and females (F-K) with int22h1/int22h2-mediated Xq28 duplication A and B are brothers ages 11 and 3 years, respectively.

The int22h1/int22h2-mediated Xq28 duplication syndrome should be suspected in females with the following clinical findings:

• Learning difficulties
• Distinctive facial features: tall forehead, upper eyelid fullness, wide nasal bridge, and thick vermilion of the lower lip (see Figure 1F-K)

Establishing the Diagnosis

The diagnosis of the int22h1/int22h2-mediated Xq28 duplication is established by detection of a 0.5-Mb duplication (hemizygous in males and heterozygous in females) at chromosome Xq28 extending from 154.1 Mb to 154.6 Mb in the reference genome (NCBI Build GRCh37/hg19).

The duplicated segment extends from a low copy repeat (LCR) region located within intron 22 of F8 (known as intron 22 homologous region 1 [int22h1]) and another LCR region situated 0.5 Mb telomeric to the int22h1 region (known as intron 22 homologous region 2 [int22h2]). This duplication is mediated by nonallelic homologous recombination between the int22h1 and int22h2 LCR regions.

Note: A 0.8-Mb Xq28 duplication that overlaps with the int22h1/int22h2-mediated Xq28 duplication has been reported in individuals who shared some of the clinical findings of individuals with the int22h1/int22h2-mediated Xq28 duplication syndrome (see Genetically Related Disorders).

The duplicated region between int22h1 and int22h2 includes several genes. The cognitive impairment in individuals with the int22h1/int22h2-mediated Xq28 duplication syndrome is likely due to increased dosage of one or more of these genes; the most likely candidates are CLIC2 and RAB39B (see Molecular Genetics).

Genomic testing methods that determine the copy number of sequences can include chromosomal microarray (CMA) or targeted duplication analysis by quantitative PCR (qPCR), multiplex ligation-dependent probe amplification (MLPA), or other targeted quantitative methods. Although fluorescence in situ hybridization (FISH) using metaphase chromosomes is NOT reliable for detecting this duplication, it can be used to determine if the duplicated segment is inserted elsewhere in the genome (insertion translocation). Note: The int22h1/int22h2-mediated Xq28 duplication cannot be identified by routine analysis of G-banded chromosomes or other conventional cytogenetic banding techniques.

Chromosomal microarray (CMA) using oligonucleotide arrays or SNP (single nucleotide polymorphism) genotyping arrays can detect the int22h1/int22h2-mediated Xq28 duplication. The ability to size the duplication depends on the type of microarray used and the density of probes in the Xq28 region.

Note: (1) Most individuals with the int22h1/int22h2-mediated Xq28 duplication are identified by CMA performed for the indication of developmental delay or intellectual disability. (2) Prior to 2011, CMA platforms did not include coverage for this region and thus could not detect this duplication. The earlier BAC (bacterial artificial chromosome)-based arrays could not detect this duplication.

Targeted duplication analysis. Quantitative PCR (qPCR), multiplex ligation-dependent probe amplification (MLPA) or other targeted quantitative methods may be used to test relatives of a proband known to have the int22h1/int22h2-mediated Xq28 duplication.

Note: (1) Metaphase FISH is not a reliable method for detecting a duplication of this size; interphase FISH (iFISH) may be used if appropriate control studies are performed. (2) Targeted duplication testing is not appropriate for an individual in whom the int22h1/int22h2-mediated Xq28 duplication was not detected by CMA designed to target this region. (3) It is not possible to size the duplication routinely by use of targeted methods.

Evaluating at-risk relatives. qPCR, iFISH or other quantitative methods of targeted duplication analysis can be used to identify the int22h1/int22h2-mediated Xq28 duplication in at-risk relatives of the proband. Testing of maternal samples is important in determining recurrence risk (see Genetic Counseling).

Clinical Description

The int22h1/int22h2-mediated Xq28 duplication syndrome is a recently recognized X-linked intellectual disability syndrome characterized in males by cognitive impairment, behavioral and psychiatric problems, recurrent infections, atopic diseases, obesity, and distinctive facial features. Females heterozygous for this duplication exhibit a milder phenotype (with learning difficulties and distinctive facies) or are clinically unaffected.

To date 26 individuals (14 males and 12 females) with this recurrent duplication have been described. The clinical description below is based on the clinical phenotype described in these 26 individuals (see Table 2) [El-Hattab et al 2011, Lannoy et al 2013, Vanmarsenille et al 2014, El-Hattab et al 2015].

Cognitive impairment. Cognitive impairment has been reported in all males with the int22h1/int22h2-mediated Xq28 duplication. Developmental delay is typically observed in early childhood. The majority of affected males require special education. Intellectual disability in the affected males is typically in the mild to moderate range.

Females heterozygous for this duplication have milder cognitive impairment (i.e., learning difficulties in 6 of 12 affected females) or no cognitive impairment.

Behavioral and psychiatric problems. Behavioral problems are common in affected males; they include aggressiveness, attention deficit hyperactivity disorder (ADHD), autism spectrum disorder, and sleep disturbance.

Only one heterozygous female was reported to have ADHD.

Additionally, two males and one female were reported to have psychotic disorders including mood disorders and schizophrenia (Table 2).

Recurrent infections and atopic diseases. Approximately 70% of males with the int22h1/int22h2-mediated Xq28 duplication have experienced recurrent infections including otitis media and pneumonia. Atopic diseases, including asthma, eczema, and allergic rhinitis, are also common in these males.

None of the heterozygous females were reported to have recurrent infections or atopic diseases (Table 2).

Growth abnormalities. Obesity was reported in four affected males and one female heterozygous for the Xq28 duplication.

Tall stature was observed in three affected males and microcephaly in one (Table 2).

Characteristic facial features. The most common facial features in both males and females are listed in Diagnosis and represented in Figure 1.

Less common facial features are listed in Table 3 (pdf).

Other infrequent manifestations. Hand and foot anomalies have been infrequently observed in males with this duplication. Clinodactyly was reported twice; single palmar crease, fetal finger pads, rocker bottom feet, pes valgus, pes planus, metatarsus adductus, sandal gap, 2-3 toe syndactyly, short second toe, and short heel cords were each reported once in a male with this duplication.

Hearing loss was reported in one affected boy.

Strabismus, myopia, and astigmatism were each reported once in a male with this duplication.

Patent ductus arteriosus (PDA), atrial septal defect (ASD), esophageal atresia with tracheoesophageal fistula, Pierre Robin sequence with cleft palate, cryptorchidism, phimosis, hip dysplasia, kyphoscoliosis, and polyhydramnios were each reported once in an affected male.

Hemihyperplasia, hypothyroidism, and kyphoscoliosis were each reported once in a heterozygous female.

X-chromosome inactivation in heterozygous females. X-chromosome inactivation analyses were reported to be skewed in nine of 12 females heterozygous for the int22h1/int22h2-mediated Xq28 duplication; however, skewing of X-chromosome inactivation was inconsistent; that is, it was observed with the normal X chromosome and the X chromosome with the duplication. Additionally, no clear correlation between the X-chromosome inactivation pattern and the cognitive phenotypes was evident: random and skewed patterns occurred in both cognitively normal and cognitively impaired females [El-Hattab et al 2015].

Penetrance

Int22h1/int22h2-mediated Xq28 duplication syndrome is completely penetrant for cognitive impairment in males.

Cognitive impairment is incompletely penetrant in females heterozygous for this duplication with only 50% reported to have learning difficulties [El-Hattab et al 2011, Lannoy et al 2013, Vanmarsenille et al 2014, El-Hattab et al 2015].

Prevalence

Int22h1/int22h2-mediated Xq28 duplication has been reported in 26 individuals (14 males and 12 females) to date [El-Hattab et al 2011, Lannoy et al 2013, Vanmarsenille et al 2014, El-Hattab et al 2015].

The prevalence of this duplication is not known, but has been estimated at 1:1000 among males with intellectual disability [Vanmarsenille et al 2014]; this may, however, be an overestimate.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with the int22h1/int22h2-mediated Xq28 duplication syndrome, the following evaluations are recommended:

• Review of medical history for behavioral and psychiatric problems, recurrent infections, and atopic diseases
• Comprehensive physical examination with emphasis on growth parameters, hands and feet, and possible kyphoscoliosis
• Neuropsychological evaluation to assess level of cognitive functioning and for any behavioral problems
• Psychiatric evaluation if psychiatric illness is suspected
• Echocardiogram
• Audiologic evaluation
• Ophthalmologic examination
• Spine x-ray and orthopedic evaluation if kyphoscoliosis is present
• Nutritional evaluation and counseling if obesity is present
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Early intervention with speech and physical therapy is recommended for young children with developmental delay. Special education programs are subsequently recommended for school-aged children with intellectual disability.

Recurrent bacterial infections are treated with standard antibiotics. Children with recurrent ear infections should be referred to ENT to assess need for tympanostomy tubes.

Nutritional counseling and regular exercise are needed when obesity is an issue.

Standard management is recommended for the following:

• Behavioral and psychiatric problems
• Kyphoscoliosis
• Cardiac malformations
• Hearing impairment
• Eye problems

Surveillance

The following routine monitoring is recommended:

• Assessment of developmental progress and cognitive abilities
• Screening for behavioral and psychiatric problems
• Audiology evaluation
• Ophthalmologic evaluation

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of apparently asymptomatic children who are relatives of an affected individual by genomic testing for the int22h1/int22h2-mediated Xq28 duplication. Clinically asymptomatic children who have the familial duplication should be assessed and monitored for developmental delay with the goal of early initiation of therapies and support if needed.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.