Updates on Obesity in Prader-Willi Syndrome: From Genetics to Management

Abstract

Prader-Willi syndrome (PWS), which is considered the most common genetic form of obesity, results from the absence of imprinted genes in the paternally derived PWS critical region located on chromosome 15q11.2-13. Infants with PWS exhibit poor sucking, neonatal hypotonia, and delayed motor milestones. These patients begin to experience hyperphagia and obesity from 2 to 3 years of age. PWS is a multisystemic disorder, and its clinical manifestations include developmental delay/intellectual disability, behavioral problems, dysmorphic facial features, short stature, scoliosis, and endocrine abnormalities such as hypogonadism, growth hormone deficiency, hypothyroidism, and central adrenal insufficiency. Although the underlying mechanism of hyperphagia is not completely understood, hypothalamic and endocrine dysregulation is believed to be responsible for the lack of satiety and abnormal food-seeking behaviors that lead to severe obesity. The management of PWS requires a multidisciplinary team approach. Early diagnosis and comprehensive early intervention are essential to prevent the development of obesity-related morbidities, including metabolic syndrome, diabetes mellitus, obstructive sleep apnea, respiratory failure, pulmonary hypertension, and cardiovascular complications. Although several clinical trials have been conducted on the pharmacologic treatment of obesity in PWS, no drugs have demonstrated a consistently beneficial effect to date. Nevertheless, ongoing research efforts should be directed toward understanding the mechanism of the unique obesity phenotype of PWS and developing pharmacological therapies.

Keywords: Genomic imprinting; Hyperphagia, obesity; Prader-Willi syndrome.

Fig. 1.. Endocrine changes in Prader-Willi syndrome. Changes in orexigenic and anorexigenic hormone levels in PWS. ↑, increased; ↓, decreased; =, unchanged; GLP-1, glucagon-like peptide 1; PYY, peptide YY; BDNF, brain-derived neurotrophic factor; PWS, Prader-Willi syndrome.