Xq28 duplication syndrome

Inspired by a patient

Ballout RA, El-Hattab AW, Schaaf CP, et al. Xq28 Duplication Syndrome, Int22h1/Int22h2 Mediated. 2016 Mar 10 [Updated 2021 Feb 25]. In: Adam MP, Everman DB, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022. Available from: https://www.ncbi.nlm.nih.gov/books/NBK349624/

Summary

Clinical characteristics.

The int22h1/int22h2-mediated Xq28 duplication syndrome is an X-linked intellectual disability syndrome characterized by variable degrees of cognitive impairment (typically more severe in males), a wide spectrum of neurobehavioral abnormalities, and variable facial dysmorphic features. Affected males also exhibit a peculiar combination of recurrent sinopulmonary infections and atopy, findings that have not been observed in affected females. All males reported to date with the syndrome have moderate-to-severe intellectual disability; in contrast, a minority of heterozygous females have been reported to have mild intellectual disability, while the majority have no discernible health or learning issues and are considered clinically unaffected. 

Diagnosis/testing.

The diagnosis of int22h1/int22h2-mediated Xq28 duplication in a hemizygous male or a heterozygous female is established by detection of a 0.5-Mb duplication within the q28 region of the X chromosome extending between 154.1 Mb and 154.6 Mb in the reference genome (NCBI Build GRCh37/hg19). 

Management.

Treatment of manifestations: Early intervention with speech and physical therapy for children with neurodevelopmental delays; enrollment in special education programs of school-aged children with intellectual disability; cognitive behavioral therapy and standard treatment with antidepressants and/or antipsychotics for individuals with mood and psychotic disorders; standard treatment per orthopedist for those with kyphoscoliosis; bacterial culture-driven antibiotic treatment of affected individuals who have recurrent infections; vaccinations against Strep pneumoniae, Haemophilus influenzae, and Neisseria meningitidis and annual influenza A vaccine; standard medical treatment of sleep issues, asthma, allergic rhinitis, eczema, hearing loss, and refractive error; standard surgical correction of congenital malformations (e.g., strabismus, hypospadias, cryptorchidism, heart defects, limb anomalies). 

Surveillance: Measurement of growth parameters and assessment of neurodevelopmental progress, cognitive abilities, behavioral/psychiatric symptoms, and motor functioning at each visit; reassessment of special education needs annually in childhood and adolescence; routine follow up with orthopedist for those with contractures and/or kyphoscoliosis; pulmonary function testing as clinically indicated for those with severe asthma; at least annual audiologic and ophthalmologic evaluations. 

Evaluation of relatives at risk: Clinically asymptomatic sibs of affected individuals who also have the duplication should be regularly assessed and carefully monitored for achievement of neurodevelopmental milestones with the goal of instituting early intervention if or when neurodevelopmental delays are noted. 

Genetic counseling.

The int22h1/int22h2-mediated Xq28 duplication syndrome is inherited in an X-linked manner. Most affected individuals inherited the duplication from their heterozygous and often asymptomatic mother. However, individuals with de novo duplications have also been identified. Because offspring inherit one X chromosome from the mother, each child of a mother with an int22h1/int22h2-mediated Xq28 duplication has a 50% chance of inheriting the duplication. In other words, a female with an int22h1/int22h2-mediated Xq28 duplication has a 50% chance of passing the duplication to her offspring at each conception. Being hemizygous for X-linked genes, males who inherit the duplication are affected. In contrast, females who inherit the duplication will be heterozygous and thus, will either exhibit a milder phenotype or be clinically unaffected. Females in whom the X-inactivation pattern is skewed toward inactivation of the X chromosome bearing the duplication are more likely to be clinically unaffected. Once an int22h1/int22h2-mediated Xq28 duplication has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.