Xq28 Duplication Syndrome, Int22h1/Int22h2 Mediated

Excerpt

Clinical characteristics: Clinical features of int22h1/int22h2-mediated Xq28 duplication syndrome in males can include mild-to-moderate developmental delay / intellectual disability, a characteristic behavioral profile (aggression, irritability, ADHD, autism, anxiety, sleep disturbance, and socialization issues), recurrent sinopulmonary infections (e.g., otitis media, sinusitis, recurrent upper respiratory tract infections), atopic conditions (i.e., asthma, allergic rhinitis, and eczema), obesity with or without tall stature, and nonspecific facial dysmorphic features. However, several adult males with this duplication have been reported who have no discernable cognitive or neurobehavioral manifestations, suggesting reduced penetrance with respect to cognition and neurobehaviors. Most heterozygous females are clinically unaffected or have inconspicuous findings. However, some heterozygous females can display a milder phenotype predominantly consisting of mild learning disabilities, inattentive-type childhood ADHD-like manifestations, and nonspecific facial dysmorphic features similar to those seen in affected males.

Diagnosis/testing: The diagnosis of int22h1/int22h2-mediated Xq28 duplication syndrome is established in hemizygous males or heterozygous females by detection of a 0.5-Mb duplication of the subregion extending from 154.1 Mb to 154.6 Mb within the q28 region of the X chromosome in the reference genome (NCBI Build GRCh37/hg19).

Management: Treatment of manifestations: Regular exercise and referral for nutritional counseling in those with obesity. Consider conservative treatment with proper sleep hygiene practices for sleep disturbance. Standard treatment for developmental delay / intellectual disability, kyphoscoliosis, recurrent sinopulmonary infections, asthma, allergic rhinitis, eczema, hearing loss, refractive errors / strabismus, undervirilization in males, and congenital heart defects.

Surveillance: At each visit, measure growth / anthropometric parameters; monitor progress along age-expected neurodevelopmental milestones; assess and screen for anxiety, irritability, aggression, self-injurious behaviors, attention deficits, hyperactivity, impulsivity, and sleep disturbances; PT/OT assessment of gross and fine motor skills, mobility, and self-care skills. Annually in childhood and adolescence, reassess special educational needs. At least annually or as clinically indicated, orthopedics follow up; audiology evaluation; ophthalmology evaluation; repeat pulmonary function testing as needed in those with moderate-to-severe asthma; assess response to prescribed medications.

Evaluation of relatives at risk: Targeted duplication analysis of apparently asymptomatic at-risk male and female relatives of an affected individual is appropriate in order to identify as early as possible those who would benefit from early intervention services.

Genetic counseling: Int22h1/int22h2-mediated Xq28 duplication syndrome is inherited in an X-linked manner. Most affected individuals reported to date exhibit maternal inheritance of the duplication. Paternal inheritance of the duplication has been reported in eight affected individuals. Hemizygous males transmit the int22h1/int22h2-mediated Xq28 duplication to all of their daughters and none of their sons. Heterozygous females have a 50% chance of transmitting the duplication to offspring in each pregnancy. Once the int22h1/int22h2-mediated Xq28 duplication has been identified in an affected family member, prenatal and preimplantation genetic testing for a pregnancy at increased risk are possible.