Clinical characteristics: Schaaf-Yang syndrome (SYS) is a rare neurodevelopmental disorder that shares multiple clinical features with the genetically related Prader-Willi syndrome. It usually manifests at birth with muscular hypotonia in all and distal joint contractures in a majority of affected individuals. Gastrointestinal/feeding problems are particularly pronounced in infancy and childhood, but can transition to hyperphagia and obesity in adulthood. Respiratory distress is present in many individuals at birth, with approximately half requiring intubation and mechanical ventilation, and approximately 20% requiring tracheostomy. Skeletal manifestations such as joint contractures, scoliosis, and decreased bone mineral density are frequently observed. All affected individuals show developmental delay, resulting in intellectual disability of variable degree, from low-normal intelligence to severe intellectual disability. Other findings may include short stature, seizures, eye anomalies, and hypogonadism.

Diagnosis/testing: The diagnosis of Schaaf-Yang syndrome is established in a proband by identification of a heterozygous pathogenic variant in the paternally derived MAGEL2 allele by molecular genetic testing. The 15q11.2 locus that includes MAGEL2 is maternally imprinted, meaning that only the paternally derived allele is expressed while the maternally derived allele is inactivated.

Management: Treatment of manifestations: Feeding therapy or supplemental tube feeding may be required for persistent feeding issues; assisted ventilation to include either noninvasive or invasive intervention; CPAP for sleep apnea; growth hormone therapy in those with short stature and/or linear growth concerns; standard therapy for gastroesophageal reflux disease, metabolic syndrome, constipation, skeletal abnormalities, low bone mineral density, developmental delay/cognitive impairment, seizures, eye anomalies, undescended testes, hypogonadism and pubertal abnormalities, and hypothyroidism.

Surveillance: At each visit: measurement of growth parameters and evaluation of nutritional status & safety of oral intake; assessment of developmental progress, educational needs, and self-help skills; monitor for signs and symptoms of constipation, sleep apnea, respiratory insufficiency, scoliosis, progression of contractures, and puberty (from ages 10-17 years). Behavioral assessment annually; DXA scan every two years starting at the age five years, transitioning to every three to five years in adulthood; ophthalmology evaluation as recommended by an ophthalmologist; polysomnography annually for those on long-term GH therapy or as recommended by a sleep specialist.

Genetic counseling: Schaaf-Yang syndrome is inherited in an autosomal dominant, maternally imprinted manner (i.e., a heterozygous pathogenic variant on the paternally derived MAGEL2 allele results in disease; a pathogenic variant on the maternally derived MAGEL2 allele does not result in disease because normally the maternally derived MAGEL2 allele is silenced). Approximately 50% of individuals diagnosed with SYS inherited a MAGEL2 pathogenic variant from a clinically unaffected father and the remainder are de novo. If the father of the proband is heterozygous for the MAGEL2 pathogenic variant identified in the proband, the risk to both male and female sibs is 50%. The recurrence risk within the family of the proband's mother is that of the general population. Once the MAGEL2 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.