Prader-Willi Syndrome
Prader-Willi Syndrome (PWS) is a complex multisystem genetic disorder characterized primarily by hypotonia, hyperphagia leading to obesity, cognitive impairment, short stature, hypogonadism, and behavioral difficulties. PWS results from the absence of expression of paternally inherited genes in the chromosome 15q11-q13 region, most commonly due to a paternal deletion, maternal uniparental disomy, or imprinting defects. The pathogenesis involves disruption of hypothalamic function, leading to deficits in satiety regulation, growth hormone secretion, and endocrine homeostasis. Health impacts are profound and lifelong, with affected individuals experiencing significant risks of morbid obesity, type 2 diabetes, cardiovascular disease, respiratory complications, osteoporosis, infertility, and psychosocial challenges. PWS requires multidisciplinary management to address its diverse clinical manifestations and improve quality of life.
This type of Prader-Willi Syndrome occurs when there is a deletion of the paternal copy of the 15q11-q13 region on chromosome 15. It accounts for approximately 65-75% of PWS cases. The deletion leads to the loss of several genes that are crucial for normal neurodevelopment and metabolic regulation. Clinical features are generally typical of PWS, but some studies suggest that individuals with this type may have more pronounced cognitive and behavioral difficulties compared to other types.
In this variant, both copies of chromosome 15 are inherited from the mother, with no paternal contribution in the critical region. Maternal UPD accounts for about 20-30% of cases. The absence of paternal gene expression leads to the PWS phenotype. Individuals with UPD may have a higher risk of developing psychiatric illnesses, including psychosis, and may present with milder physical symptoms compared to those with the deletion type.
This rare form, comprising 1-3% of PWS cases, results from defects in the imprinting center that controls the parent-specific expression of genes in the 15q11-q13 region. This defect can be due to microdeletions or epigenetic errors, leading to both chromosomes being functionally maternal. Clinical features are similar to other types, but imprinting defects may have implications for recurrence risk in families.
Prader-Willi Syndrome is a rare disorder, with an estimated prevalence ranging from 1 in 10,000 to 1 in 30,000 live births worldwide. The incidence does not significantly differ by sex or ethnicity. Advances in molecular diagnostic techniques have improved detection rates, but underdiagnosis and misdiagnosis remain concerns, especially in milder cases or in populations with limited access to genetic testing. Mortality in PWS is increased compared to the general population, with obesity-related complications, respiratory failure, and choking being leading causes of death. Life expectancy has improved with early diagnosis and comprehensive care.
Diagnosis of Prader-Willi Syndrome is based on a combination of clinical features and confirmatory genetic testing. Initial clinical suspicion arises from hallmark signs such as severe neonatal hypotonia, feeding difficulties in infancy, followed by hyperphagia, rapid weight gain, developmental delays, and characteristic physical features including almond-shaped eyes, narrow bifrontal diameter, small hands and feet, and hypogonadism. The definitive diagnosis is established through molecular genetic testing. Methylation analysis of the 15q11-q13 region is the first-line test, as it detects abnormal imprinting in more than 99% of cases, regardless of the underlying genetic mechanism. If methylation analysis is positive, further testing such as fluorescence in situ hybridization (FISH), chromosomal microarray, or DNA polymorphism studies are used to distinguish between paternal deletion, maternal uniparental disomy, and imprinting defects. Early diagnosis is crucial for initiating appropriate interventions and genetic counseling.
Diazoxide choline is utilized as a pharmacological intervention to address hyperphagia and related metabolic disturbances in Prader-Willi Syndrome, acting by modulating insulin secretion and potentially improving glucose homeostasis. Recombinant human growth hormone, including recombinant somatropin and somatropin (rbe), is indicated for managing growth hormone deficiency commonly observed in affected individuals; its administration promotes linear growth, increases muscle mass, reduces body fat, and may enhance physical strength and mobility. Somatropin (epr), a recombinant form of growth hormone, is also employed to support growth and metabolic outcomes in patients with this syndrome. These treatments form part of a comprehensive strategy aimed at mitigating the clinical manifestations and improving the overall health and quality of life of individuals with Prader-Willi Syndrome.
| Structure | Generic Name | Molecular Formula | Molecular Weight |
|---|---|---|---|
 | diazoxide choline (USAN) | C8 H6 Cl N2 O2 S . C5 H14 N O | 333.834 |
| recombinant human growth hormone; recombinant somatropin; somatropin (rbe) | |||
| somatropin (epr) (Rec INN; USAN; BAN) |
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