Snapshot A 33-year-old woman delivers a baby girl at full-term without complications. During a breastfeeding session, a lactation specialist notes that the neonate has poor muscle tone, poor suck, and a weak cry. Her basic laboratory results are normal. As hypotonia is classically associated with a genetic condition, a geneticist is consulted for further discussion. Introduction Overview Prader-Willi syndrome is a disorder of imprinting associated with mutation or deletion of chromosome 15q11-13 Epidemiology Incidence 1 in 16,000-25,000 ETIOLOGY Pathogenesis the maternal allele on chromosome 15q11.2-13 is normally methylated or silenced mutation or deletion of the paternal allele then results in complete absence or defective gene expression, leading to Prader-Willi syndrome Genetics inheritance pattern sporadic mutations 25% due to maternal uniparental disomy (2 copies of maternal chromosome 15) majority of cases are due to a mutation or deletion in paternal chromosome 15q11.2-13 genes identified include SNRPN, UBE3A, and necdin genes Associated conditions growth hormone deficiency Presentation Symptoms intellectual disability hyperphagia behavioral problems Physical exam neonate and infant hypotonia poor suck failure to thrive weak cry genital hypoplasia cryptorchidism toddlers delayed developmental milestones children obesity small hands and feet short stature strabismus scoliosis Imaging Radiograph indication assess for scoliosis findings curvature of spine Studies Serum labs fasting levels of insulin-like growth factor 1 and insulin-like growth factor binding protein-3 screen for underlying growth hormone deficiency confirm with provacative growth hormone stimulation test Genetic testing chromosomal or microarray analysis prenatal testing via chorionic villus sampling or amniocentesis Differential Angelman syndrome key distinguishing factors silenced maternal genomic material at chromosome 15q11.2-13 characterized by excessive laughter, hyperexcitability, and hand flapping Treatment Lifestyle behavioral therapy critical for conditioning child to normal eating habits and avoiding hyperphagia diet and exercise often requires coordination between home and school calorie restriction Medical growth hormone indications growth failure growth hormone deficiency hormone-replacement therapy indications delayed puberty Surgical feeding tube indication growth failure in infancy Complications Hypopituitarism with deficiency in growth hormone Scoliosis Obstructive sleep apnea Cor pulmonale Prognosis Patients are typically able to function well into adulthood