Hypotonia of infancy in a one-month-old male with PWS. Note frogleg position and need for a feeding tube. Also note dolichocephaly and hypoplastic, empty scrotum.

Classical facial phenotype of PWS in adolescence and adulthood. (a) A 15-year-old male. (b) A 41-year-old female. Note narrow bifrontal diameter, almond-shaped and slightly upslanting eyes, narrow nasal bridge, and thin upper lip.

Summary of the genetic and expression map of chromosomal region 15q11.2–q13. The position of genes and genetic markers (circles) are shown. In the PWS region (shown in blue), there are six paternal-only (PWS region) expressed unique copy genes (MKRN3, MAGEL2, NECDIN, C15ORF2 and SNURF- SNRPN and a family of five paternal-only expressed snoRNA genes). Only UBE3A and ATP10A (shown in red), related to Angelman syndrome (AS), have maternal-only expression in mouse and humans, and this imprinted expression is limited to certain tissue-specific regions (ie, brain). The bipartite imprinting center (IC) lies proximal to SNURF-SNRPN and within the 3 Mb PWS/AS imprinted region. The cluster of GABA receptor genes (GABRB3, GABRA5 and GABRG3), OCA2 (type II albinism) and HERC2 are not imprinted and have biparental expression (shown in black). The jagged vertical lines denote the common 5–7 Mb AS and PWS deletion breakpoints, which lie within the segmental duplications associated with BP1, BP2 and BP3.⁴⁵ There are two common proximal breakpoints and one distal common breakpoint.⁴⁴ In between BP1 and BP2 lie four additional, non-imprinted genes GCP5 (TUBGCP5), CYFIP1, NIPA2 and NIPA1.⁴⁶ Type 1 deletions extend from BP1 to BP3 and type 2 deletions extend from BP2 to BP3. Note that there are more copies of the HBII-85 and HBII-52 genes than are shown.

Central obesity of PWS in (a) a 2 ½ year old girl and (b) a 21-year-old male. Note also typical facial appearance, active skin picking lesions and gastrostomy feeding tube scar in the girl, pseudogynecomastia and genus valgus in the male.

Molecular classes of PWS and their frequencies. Deletion 15q11.2–q13, maternal uniparental disomy (UPD), imprinting defect (ID) and single gene mutation. The parent of origin of each chromosome is indicated with M (maternal) or P (paternal). Note that there is biparental contribution of the two chromosomes 15 in the case of ID, but the paternal (P) contribution in 15q11.2–q13 has maternal (M) epigenetic markings (eg, DNA methylation) and behaves accordingly.

Normalization of the body and facial phenotype of PWS following treatment with growth hormone from infancy. (a) A 7-year-old unaffected sibling on the left and his 8-year-old brother with PWS on the right. Note lighter pigmentation in affected brother who has a typical deletion, and scar from the gastrostomy tube used in infancy. The unaffected brother has 24% body fat and the brother with PWS has 20% body fat. (b) A 2-year-old boy. (c) A 4-year-old unrelated boy.