Prader-Willi syndrome: current understanding of cause and diagnosis

Abstract

Prader-Willi syndrome (PWS) is characterized by hypotonia, obesity, hypogonadism, short stature, small hands and feet, mental deficiency, a characteristic face, and an interstitial deletion of the proximal long arm of chromosome 15 in about one-half of the patients. The incidence is estimated to be about 1 in 25,000, and PWS is the most common syndromal cause of human obesity. DNA abnormalities, usually deletions or duplications of chromosome 15, have been identified in individuals with PWS with or without recognizable chromosome 15 deletions. Paternal origin of the chromosome 15 deletion by cytogenetic and DNA studies has been found in nearly all PWS individuals studied. No cytogenetic evidence for chromosome breakage has been identified, although an environmental cause (e.g., paternal hydrocarbon-exposed occupations) of the chromosome 15 abnormality has been proposed. PWS patients with the chromosome 15 deletion are more prone to hypopigmentation compared with PWS individuals with normal chromosomes, but no other clinical differences are consistently identified between those with and without the chromosome deletion. Anthropometric, dermatoglyphic, and other clinical findings indicate homogeneity of PWS patients with the chromosome deletion and heterogeneity of the nondeletion patients. A review of our current understanding of the major clinical, cytogenetic, and DNA findings is presented, and clinical manifestations and cytogenetic abnormalities are summarized from the literature.

Fig. 1

A prometaphase chromosome 15 idiogram (850 band level) and representative prometaphase chromosomes of a normal control individual and a Prader-Willi syndrome individual with an interstitial deletion of chromosome 15 are shown. The 15q12 band is indicated by the arrow in each of the normal chromosomes. Known DNA probes and loci on proximal 15q(11–13) [Cox and Gedde-Dahl, 1988; Donlon, 1988; Nicholls et al., 1989]. D15S15–18 lie outside of 15q11.1–12 but within 15q11–13. IGHDY2, immunoglobulin heavy chain diversity region 2.

Fig. 2

Frontal and profile views of two males (patient A is 8.5 years of age, with the chromosome 15[q11–13] deletion; patient B is 11 years of age, with apparently normal chromosomes) with Prader-Willi syndrome. Note the typical facial appearance (e.g., narrow bifrontal diameter, almond-shaped eyes, triangular mouth), small hands and feet, characteristic obesity, and hypopigmentation (in patient A).