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Key Points

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  • Disease summary:

    • Prader-Willi syndrome (PWS)

      • Characteristic face with a small upturned nose, narrow bifrontal diameter, thin upper lip with downturned corners of mouth, sticky saliva, and enamel hypoplasia.

      • Hypogonadism or hypogenitalism, hypopigmentation, hypotonia, poor suck and feeding difficulties, and growth hormone deficiency noted during infancy.

      • Short stature and small hands and feet noted during childhood without growth hormone treatment. Growth hormone therapy increases muscle mass, decreases fat mass, and improves strength in children.

      • Hyperphagia is noted in early childhood with subsequent obesity, if diet restriction and behavior modifications are unsuccessful addressing the eating issues.

      • Developmental delay noted during infancy with mental deficiency (average IQ = 65) and behavioral problems (skin picking, outbursts, obsessive-compulsive disorder) observed during childhood, adolescence, and adulthood.

      • Paternal 15q11-q13 deletion (in about 70% of cases), maternal uniparental disomy 15 (in 25%), and imprinting defects or other chromosome 15 abnormalities in the remaining subjects.

      • Genetic subtypes such as maternal disomy 15 and typical 15q11-q13 deletions (type I or type II) produce variation in clinical phenotype with compulsions, and self-injury being more common and adaptive and cognitive assessment scores reported lower in those with the type I deletion compared with maternal disomy 15 or type II deletions.

      • Adults with PWS are at increased risk of osteoporosis, sleep apnea, and psychosis. Increased pain threshold and impaired temperature sensitivity can delay the recognition of illnesses among PWS adults.

    • Angelman syndrome (AS)

      • Characteristic face with acquired microcephaly, a broad-appearing head, a prominent nose, large mouth with a protruding tongue and swallowing difficulties, widely spaced teeth, frequent drooling, and prognathism.

      • Seizures, abnormal electroencephalogram (EEG) (high-amplitude spikes and slow waves at 2 to 3 Hz noted anteriorly), severe developmental delay or intellectual disability, absent or nearly absent speech, inappropriate laughter, and sleep problems.

      • Unsteady wide-based gait with abnormal jerky arm movements, hypotonia with occasional hyper-reflexia, and abnormal head computed tomography (CT) scan (cerebral atrophy).

      • Maternal 15q11-q13 deletion (in about 70% of cases), paternal disomy 15 (about 5%), UBE3A gene mutations (about 10%), imprinting center defects (about 5%), and other chromosome 15 abnormalities in the remaining subjects.

      • Clinical differences correlate with genetic subtypes as seen in PWS with typical 15q11-13 deletions having more seizures (particularly in type I deletions), microcephaly, and hypopigmentation than in the other genetic subtypes.

      • Adults with AS typically retain the facial features, lack of speech and seizures (seizures may get worse with age), but are also at increased risk of obesity and decreased mobility due to ataxia, contractures, and scoliosis.

  • Hereditary basis:

    • Prader-Willi and Angelman syndromes are genomic imprinting disorders due to alterations of an epigenetic phenomenon controlling methylation of CpG-rich regions of genes regulating gene allele expression based on the gender of the transmitting parent. This phenomenon evolved over 150 million years ago. Many imprinted gens are arranged in clusters or imprinted domain areas.

  • Differential diagnosis:

    • Several disorders can strongly resemble PWS including Cohen, Bardet-Biedl, fragile X, and Alström syndromes. Cytogenetic abnormalities in similarly affected individuals include duplications of 3p25.3-p26.2 and ...

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