Systematic review of the clinical and genetic aspects of Prader-Willi syndrome

Abstract

Prader-Willi syndrome (PWS) is a complex multisystem genetic disorder that is caused by the lack of expression of paternally inherited imprinted genes on chromosome 15q11-q13. This syndrome has a characteristic phenotype including severe neonatal hypotonia, early-onset hyperphagia, development of morbid obesity, short stature, hypogonadism, learning disabilities, behavioral problems, and psychiatric problems. PWS is an example of a genetic condition caused by genomic imprinting. It can occur via 3 main mechanisms that lead to the absence of expression of paternally inherited genes in the 15q11.2-q13 region: paternal microdeletion, maternal uniparental disomy, and an imprinting defect. Over 99% of PWS cases can be diagnosed using DNA methylation analysis. Early diagnosis of PWS is important for effective long-term management. Growth hormone (GH) treatment improves the growth, physical phenotype, and body composition of patients with PWS. In recent years, GH treatment in infants has been shown to have beneficial effects on the growth and neurological development of patients diagnosed during infancy. There is a clear need for an integrated multidisciplinary approach to facilitate early diagnosis and optimize management to improve quality of life, prevent complications, and prolong life expectancy in patients with PWS.

Keywords: Clinical manifestations; Genetics; Growth hormone treatment; Prader-Willi syndrome.

Fig. 1

Hypotonia of infancy in patients with PWS. Note the head-lag position in traction.

Fig. 2

Characteristic facial features of patients with PWS.

Fig. 3

Summary of the genetic and expression map of chromosomal region 15q11.2-q13. There are 6 paternal-only (PWS region) expressed unique copy genes (MKRN3, MAGEL2, NECDIN, C15ORF2, and SNRPN and a family of 5 paternal-only expressed snoRNA genes). Only UBE3A and ATP10A, related to Angelman syndrome (AS), have maternal-only expression in mice and humans. The bipartite imprinting center lies proximal to 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. Type 1 deletions extend from BP1 to BP3, and type 2 deletions extend from BP2 to BP3 (Cassidy et al. 2009 Eur J Hum Genet17;3-13).

Fig. 4

Molecular classes of PWS and their frequencies (Buiting et al. 2010. Am J Med Genet Part C Semin Med Genet 154C:365-376).