AFF4-Related CHOPS Syndrome

Excerpt

Clinical characteristics: AFF4-related CHOPS syndrome is characterized by coarse facial features / cognitive impairment, heart defects, obesity, pulmonary involvement, and short stature / skeletal abnormalities. All individuals reported to date have mild-to-moderate developmental delay and intellectual disability without regression. Neurobehavioral features include disruptive and self-absorbed behaviors, communication disturbance, and food-seeking behaviors leading to obesity. Characteristic facial features include synophrys, highly arched eyebrows, long eyelashes, proptosis, and anteverted nares. Coarse facies and round face with full cheeks become more noticeable with age. Other common features include growth deficiency, respiratory issues, congenital heart defects, small hands, brachydactyly, ocular abnormalities, genitourinary abnormalities, and gastrointestinal manifestations.

Diagnosis/testing: The diagnosis of AFF4-related CHOPS syndrome is established in a proband with suggestive clinical findings and a heterozygous pathogenic variant in AFF4 identified by molecular genetic testing. To date, all CHOPS-related pathogenic variants are located in the AFF4 ALF homology domain.

Management: Treatment of manifestations: Developmental and educational support; feeding therapy; gastrostomy tube placement as needed; nutritional management for obesity; standard treatments for chronic lung disease and sleep apnea; standard vaccinations; tracheostomy as needed for laryngomalacia; standard treatment for congenital heart defects and vertebral anomalies; treatment of refractive errors and strabismus per ophthalmologist; treatment of cataract per ophthalmic subspecialist; hearing aids as needed for hearing loss; standard treatment of genitourinary anomalies and bowel dysfunction; transitional care plan by age ten years; social work and family support.

Surveillance: Assess developmental progress, educational needs, behavior issues, growth, evidence of aspiration or respiratory insufficiency, musculoskeletal manifestations, nutritional status, safety of oral intake, gastrointestinal manifestations, and family needs at each visit. Assess for myopia and strabismus per ophthalmologist and at least annually; annual audiology evaluation.

Genetic counseling: AFF4-related CHOPS syndrome is an autosomal dominant disorder. All probands reported to date with AFF4-related CHOPS syndrome whose parents have undergone molecular genetic testing have the disorder as the result of a de novo pathogenic variant. Risk to the parents of the proband of having another affected pregnancy is presumed to be low for the parents of the proband as the proband most likely has a de novo AFF4 pathogenic variant. There is, however, a recurrence risk (~1%) to sibs based on the possibility of parental gonadal mosaicism. Given this risk, prenatal and preimplantation genetic testing may be considered.