Zhu-Tokita-Takenouchi-Kim Syndrome

Excerpt

Clinical characteristics: Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome is characterized by developmental delay and intellectual disability. Behavioral issues and seizures are reported in more than half of affected individuals. Characteristic facial features include facial asymmetry, prominent forehead, horizontal eyebrows, ptosis, downslanted palpebral fissures, epicanthal folds, deep-set eyes, midface retrusion, depressed or other abnormality of the nasal bridge, low-set ears that may be posteriorly rotated, short and/or smooth philtrum, thin vermilion of the upper lip, bifid uvula, and high palate. Skeletal and ocular abnormalities, short stature, and genitourinary and kidney manifestations are common. Hematologic, cardiac, immune, gastrointestinal, and hearing abnormalities have also been reported.

Diagnosis/testing: The diagnosis of ZTTK syndrome is established in a proband with characteristic features and a heterozygous pathogenic variant in SON identified by molecular genetic testing.

Management: Treatment of manifestations: None of the treatments available directly address SON deficiency. Supportive measures include developmental and educational support; standard treatment for seizures and movement disorder; treatment of craniosynostosis per craniofacial team; treatment of musculoskeletal manifestations per orthopedist; treatment of refractive errors and strabismus per ophthalmologist; low vision services as needed; nutritional support for feeding issues; treatment of growth hormone deficiency per endocrinologist; treatment of genitourinary and kidney manifestations per nephrologist and/or urologist; treatment of hematologic disorders per hematologist; surgical and/or medical treatment for cardiac anomalies; treat infections aggressively; in those with immune deficiency irradiated blood products are recommended; standard treatment of recurrent otitis media; management of bowel dysfunction and other gastrointestinal issues per gastroenterologist; hearing aids may be helpful; family and social work support.

Surveillance: Assess developmental progress, educational needs, behavioral issues, neurologic manifestations, musculoskeletal evaluation, growth, nutrition, gastrointestinal and hematologic issues, and for recurrent infections at each visit; ophthalmologic evaluation per ophthalmologist; endocrine evaluation in those with growth hormone deficiency; kidney ultrasound annually or as needed; audiology evaluation annually; assess family and social work needs at each visit.

Genetic counseling: ZTTK syndrome is an autosomal dominant disorder. Almost all probands reported to date with ZTTK syndrome whose parents have undergone molecular genetic testing have the disorder as the result of a de novo SON pathogenic variant. Each child of an individual with ZTTK syndrome has a 50% chance of inheriting the SON pathogenic variant (data on reproduction in affected individuals are currently lacking, as most reported individuals are not yet of reproductive age). Once the SON pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.