Clinical Description
Int22h1/int22h2-mediated Xq28 duplication syndrome, also referred to as distal Xq28 duplication syndrome, is commonly characterized by cognitive impairment, neurobehavioral abnormalities, a combination of recurrent sinopulmonary infections (e.g., otitis media, sinusitis, recurrent upper respiratory tract infections) and atopic conditions (i.e., asthma, allergic rhinitis, and eczema), obesity, and nonspecific facial dysmorphic features (see Tables 2 and 3). However, Billes et al [2024] and Levy et al [2024] both reported several adult males with this duplication who had no discernable cognitive or neurobehavioral manifestations, suggesting that this duplication may display reduced penetrance with respect to cognition and neurobehaviors.
Most heterozygous females are clinically unaffected or have inconspicuous abnormalities. However, heterozygous females can display a milder phenotype predominantly consisting of mild learning disabilities, inattentive-type childhood attention-deficit/hyperactivity disorder (ADHD)-like manifestations, and nonspecific facial dysmorphic features similar to those seen in affected males (see Tables 2 and 3).
To date, approximately 73 living individuals (34 males and 39 females) with the typical 0.5-Mb int22h1/int22h2-mediated Xq28 duplication have been identified and reported within the literature. The clinical features discussed below are based on the phenotypic manifestations reported in these individuals [El-Hattab et al 2011, Lannoy et al 2013, Vanmarsenille et al 2014, El-Hattab et al 2015, Ballout et al 2020, Chien et al 2022, Billes et al 2024, Levy et al 2024].
Note: Features of individuals who have nested or elongated versions of the classic duplication are discussed in Genetically Related Disorders.
Males
For a detailed list of manifestations by sex, click here.
Developmental delay / intellectual disability. The vast majority of reported affected males have developmental delay / intellectual disability. Developmental delay (with language delay in about 20%) is most often in the mild-to-moderate range and is usually recognized in early childhood. However, Billes et al [2024] reported four adult males hemizygous for the int22h1/int22h2-mediated Xq28 duplication who had no associated neurocognitive findings. Subsequently Levy et al [2024] described a further three hemizygous males who were seemingly unaffected with respect to cognition and neurobehaviors [Levy et al 2024], suggesting reduced penetrance for neurocognitive manifestations in hemizygous males.
Neurobehavioral/psychiatric abnormalities. A characteristic neurobehavioral profile has been observed, consisting of:
Aggression and irritability
Attention-deficit/hyperactivity disorder (ADHD)
Autism spectrum disorder
Anxiety
Socialization deficits
Sleep disturbances (See Sleep disturbanes below.)
Less common findings may include:
Various socialization deficits
Mood disorder (mainly depression or bipolar disorder)
Motor tics
Psychotic disorder, including schizophrenia
Obsessive compulsive disorder (OCD)
Recurrent sinopulmonary infections and atopic diseases. Most males with a history of recurrent sinopulmonary infections also had atopic diseases, making this particular combination somewhat a "signature" in affected males.
Almost 50% of affected males have a positive history of recurrent sinopulmonary infections including:
Nearly 40% of affected males have a history of atopic diseases, including:
Asthma
Eczema
Allergic rhinitis
Sleep disturbances. Sleep disturbances, observed in about 15% of hemizygous males, are most often characterized as insomnia that involves difficulty remaining asleep (i.e., sleep maintenance).
Anthropometric findings
Nonspecific facial dysmorphic features. The most common facial features in affected males are as follows (see ):
Other less common facial features include:
Sparse scalp hair and sparse eyebrows
Long eyelashes
Bulbous nose
Thin vermilion of the upper lip
Elongated and smooth philtrum
Micrognathia or retrognathia
Eye anomalies/refractive error are less common; four males have strabismus and three males have astigmatism. Myopia and unilateral ptosis have been reported in one male each [Ballout et al 2020, Billes et al 2024].
Other rarely reported features (either rare manifestations of Xq28 duplication syndrome or rare, unrelated co-occurrences) that have each been described in one or two affected males each [Ballout et al 2020, Billes et al 2024]:
Limb and digital anomalies
Sensorineural hearing loss
Genitourinary malformations
Esophageal atresia with tracheoesophageal fistula, associated with cleft lip and cleft palate (2 males)
Minor
congenital heart defects, including atrial septal defect, ventricular septal defect, and/or patent ductus arteriosus
Axial hypotonia with peripheral hypertonia
Heterozygous Females
As is typical for X-linked disorders, heterozygous females may have no discernable features at all or may have milder and/or fewer features compared to hemizygous males. A small subset of heterozygous females reported to date exhibited findings that almost mirror those seen in affected males [Billes et al 2024].
Developmental delay / intellectual disability. Fewer than one third of heterozygous females have some degree of intellectual disability, typically in the mild range (if present) and more likely to become apparent in later life. Fewer than 10% of affected females have language delays noted in childhood.
Neurobehavioral/psychiatric abnormalities. A small proportion of heterozygous females have ADHD/ADD, anxiety, socialization deficits, and/or autism. Less common findings may include:
Mood disorders (mainly depression or bipolar disorder) (2 females)
Self-mutilation or self-harming behaviors (1 female)
Aggression and irritability (1 female)
No heterozygous females have been reported to date to have a psychotic disorder.
Sleep disturbances have been reported in ~8% of heterozygous females and are more likely to involve difficulty falling asleep (i.e., sleep initiation), although one reported heterozygous female had interrupted sleep secondary to sleep apnea.
Anthropometric findings. Only one heterozygous female was overweight, and one had microcephaly. Tall stature has not been reported in heterozygous females.
Nonspecific facial dysmorphic features. The most common facial features in heterozygous females are the same as in affected males (see ):
Other less common facial features may include:
Sparse scalp hair and sparse eyebrows
Long eyelashes
Thin vermilion of the upper lip
Elongated and smooth philtrum
Micrognathia or retrognathia
Other rarely reported features (either rare manifestations of Xq28 duplication syndrome or rare, unrelated co-occurrences) that have each been described in one heterozygous female each [Ballout et al 2020, Billes et al 2024]:
X-chromosome inactivation analyses were skewed in ten of 13 heterozygous females, although the skewed inactivation was inconsistent with nearly equal frequencies of inactivation of the normal X chromosome and the X chromosome containing the duplication. Moreover, no association could be appreciated between the X-chromosome inactivation pattern and the corresponding cognitive phenotype in the studied females, with random and skewed inactivation patterns being seen at nearly equal rates in heterozygous females with or without intellectual disability [El-Hattab et al 2015]. Billes et al [2024] evaluated the X-chromosome inactivation in a further four heterozygous females and found similar results, thereby supporting prior observations. However, X-chromosome inactivation analyses have not been performed for all heterozygous females, making it difficult to ascertain whether this conclusion will remain valid.
