Prader-Willi syndrome due to imprinting mutation

Prader-Willi syndrome due to imprinting mutation (also called Prader-Willi syndrome due to imprinting defect or epimutation) is a specific genetic subtype of Prader-Willi syndrome (PWS) caused by abnormal DNA methylation (an epigenetic defect) in the Prader-Willi critical region on chromosome 15q11-q13. In this subtype, both copies of chromosome 15 are present and structurally normal, but the paternal copy carries an abnormal imprinting pattern that silences genes that should normally be active. This imprinting defect accounts for approximately 1–3% of all Prader-Willi syndrome cases. The clinical features are consistent with those seen in other forms of Prader-Willi syndrome. In the neonatal period, affected infants typically present with severe hypotonia (low muscle tone), feeding difficulties, and failure to thrive. During early childhood, the clinical picture shifts dramatically to hyperphagia (an insatiable appetite) and progressive obesity if caloric intake is not strictly controlled. Additional features include short stature, hypogonadism, intellectual disability (usually mild to moderate), behavioral problems (such as temper tantrums, stubbornness, and obsessive-compulsive tendencies), and characteristic facial features including a narrow forehead, almond-shaped eyes, and a thin upper lip. Multiple body systems are affected, including the endocrine, neurological, musculoskeletal, and reproductive systems. There is no cure for Prader-Willi syndrome due to imprinting mutation. Management is multidisciplinary and includes growth hormone therapy to improve height, body composition, and muscle tone; strict dietary supervision to prevent life-threatening obesity; sex hormone replacement for hypogonadism; and behavioral, educational, and psychological support. Early intervention with physical therapy, speech therapy, and occupational therapy can improve developmental outcomes. Notably, some imprinting defect cases occur without a detectable microdeletion in the imprinting center, and these cases may have a lower recurrence risk compared to those with an identifiable imprinting center deletion, which is an important consideration for genetic counseling.

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