Associated Syndrome

CLINICAL CHARACTERISTICS

-associated syndrome (SAS) is a multisystem disorder in which all affected individuals have developmental delay / intellectual disability that can range from mild to profound but is most commonly moderate to profound. Speech delay and/or absent speech is observed in all affected individuals. Other neurobehavioral manifestations can include jovial or friendly personality, autistic tendencies, agitation or aggressive outbursts, self-injury, impulsivity, hyperactivity, anxiety, difficulty falling asleep or maintaining sleep, and sensory issues. Most affected individuals have hypotonia. EEG abnormalities are frequent but may be without clinically recognizable seizures. While only about 20% of affected individuals have clinical seizures, a subset of affected individuals have electrical status epilepticus in sleep. Craniofacial findings can include nonspecific dysmorphic features, palatal anomalies (cleft palate, high-arched palate, velopharyngeal insufficiency, bifid uvula), and dental anomalies (abnormal shape or size or the upper central incisors, dental crowding, hypodontia, and delayed teeth eruption, among others). Skeletal anomalies can include scoliosis, tibial bowing, and joint contractures. At least one third of individuals have a history of previous fractures and about one quarter of affected individuals have documented low bone mineral density. Other finding can include pre- and postnatal growth restriction, feeding issues, and eye anomalies (strabismus, refractive error). In those with a larger deletion involving and adjacent genes, cardiovascular, genitourinary, and ectodermal findings may also be present.

DIAGNOSIS/TESTING: The diagnosis of SAS is established in a proband with suggestive findings and identification of one of the following by molecular genetic testing: a heterozygous intragenic pathogenic variant; a heterozygous non-recurrent deletion at 2q33.1 that includes ; a chromosome translocation or inversion with a 2q33.1 breakpoint that disrupts ; a chromosomal duplication with breakpoints that encompass

MANAGEMENT

Standard treatment for developmental delay / intellectual disability, neurobehavioral issues, cleft palate, micrognathia, dental anomalies, scoliosis, tibial bowing, joint contractures, spasticity, epilepsy, undescended testes, inguinal hernia, hypospadias, refractive error, strabismus, and congenital heart defects. For those with feeding issues and/or poor weight gain, feeding therapy is typically recommended, with a low threshold for clinical feeding evaluation and/or radiographic swallowing study if there are signs or symptoms of dysphagia. A gastrostomy tube placement may be required for persistent feeding issues. Sleep disturbance may respond to sleep hygiene healthy habits and potential medical management, as needed. In those with restless sleep, an overnight EEG to explore potential epileptogenic abnormalities may be considered. To address osteopenia / frequent fractures, optimize physical activity and calcium / vitamin D levels; denosumab and bisphosphonates have also been used with no direct comparison between the different options. At each visit, measure growth parameters, nutrition status, and safety of oral intake; assess for new manifestations, such as seizures or changes in tone; monitor developmental progress and educational needs; assess for anxiety, ADHD, ASD, aggression, & self-injury; evaluate for scoliosis and spine deformities; and assess for signs/symptoms of sleep disturbance. At least annually, dental evaluation with consideration of orthodontics; ophthalmology evaluation; obtain a DXA scan for bone mineral density if z score is below −1; measure alkaline phosphatase level (if previously elevated). Every two years, obtain a DXA scan for bone mineral density if z score is above −1; measure alkaline phosphatase level (if previously normal).

GENETIC COUNSELING

SAS is an autosomal dominant disorder. Almost all probands with SAS reported to date have the disorder as the result of a genetic event. In approximately 1% of affected individuals, SAS is the result of a genetic alteration inherited from a mosaic parent. To date, individuals with SAS are not known to reproduce. Once the genetic alteration has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.