INTRODUCTION — Prader-Willi syndrome (PWS), also known as Prader-Willi-Labhart syndrome, is the most common syndromic form of obesity and is caused by absence of expression of the paternally active genes in a discrete region on the long arm of chromosome 15, either due to deletions from the paternal chromosome or maternal disomy. The vast majority of cases occur sporadically. In adults and children, the primary clinical features are hyperphagia, usually leading to early-onset obesity; hypogonadism; developmental delay; and characteristic facial features. In infants, the most prominent findings are hypotonia and feeding difficulties.

The epidemiology and genetics of PWS will be reviewed here. The clinical features, diagnosis, and approaches to treatment of this disorder are discussed separately. (See "Clinical features, diagnosis, and treatment of Prader-Willi syndrome".)

HISTORY — In 1887, Langdon-Down described the first girl with probable PWS, manifest by mental impairment, short stature, hypogonadism, and obesity; he termed the condition polysarcia [1]. Seventy years later, Prader and colleagues reported a series of patients with similar phenotypes [2]. In 1981, Ledbetter, et al, identified microdeletions within chromosome 15 as the site for PWS [3].

EPIDEMIOLOGY — PWS is the most common syndromic form of obesity and affects between 350,000 and 400,000 individuals worldwide. Males and females are affected equally [4].

Although prevalence estimates differ among studies, this is likely due to using different methods for case identification, and there is no strong evidence for increased risk in specific countries or gene pools. Within the United States, the rate of prevalence has been reported between 1 in 16,062 [5] to 1 in 25,000 [6]. Outside of the United States, reported prevalence rates for PWS range from 1 per 8000 in rural Sweden [7] to 1 per 16,000 in Western Japan [8], 1:15,830 in Australia [9], and a birth incidence of 1 per 27,000 in Flanders [10]. Within the United Kingdom, a lower population prevalence of 1 in 52,000 was estimated, with a proposed true prevalence of 1 in 45,000 [11]. In each of these populations, PWS represents a very small fraction of children with obesity or even severe obesity.

The prevalence of PWS is higher in populations referred for the key clinical features. One study reported PWS in 11 percent of infants referred for hypotonia [12]. The prevalence of PWS among individuals with intellectual disability is less than 1 percent [13].

GENETICS AND PATHOGENESIS

Genetics and phenotypic implications — PWS (MIM #176270) was the first genetic disorder attributed to genomic imprinting, meaning that the expression of the gene depends on the sex of the parent donating the gene. PWS arises due to the loss of the paternal copy of the PWS "critical region" on chromosome 15q11.2-13, whereas loss of the maternal copy of 15q11.2-13 results in Angelman syndrome. The majority of cases of PWS arise sporadically. Monozygotic twins are concordantly affected. (See "Inheritance patterns of monogenic disorders (Mendelian and non-Mendelian)", section on 'Parent-of-origin effects (imprinting)' and "Microdeletion syndromes (chromosomes 12 to 22)", section on '15q11-13 paternal deletion syndrome (Prader-Willi syndrome)'.)

PWS can be caused by several types of genetic defects involving the PWS critical region (table 1):

●Deletion of paternal 15q11.2-13 – 50 to 75 percent of cases.

●Maternal uniparental disomy – 20 to 50 percent of cases. In the most recent case series, the proportion caused by maternal uniparental disomy is as high as 50 percent and this was attributed to advancing maternal age as well as improved techniques for molecular diagnosis [9,14].

●Imprinting center defects – Approximately 2 percent of cases. Most of these are epimutations, and a small fraction (<0.5 percent of PWS cases) are caused by deletions.

●Balanced translocation – <0.1 percent of cases [15].

Determining the type of mutation has implications for recurrence risk. (See 'Risk of recurrence in future pregnancies' below.)

There appears to be some association between the type of genetic defect and the phenotypic features seen in an individual with PWS. Individuals with uniparental disomy generally have less distinct physical features, higher intelligence quotients (IQs), and milder behavioral problems than individuals with PWS caused by deletions. However, patients with uniparental disomy are also more likely to exhibit autistic-like behaviors and psychosis [16,17].

PWS-like phenotypes, especially during infancy, have been reported with maternal uniparental disomy of chromosome 14 or microdeletions of the 14q32.2 imprinted region [18,19]. Schaaf-Yang syndrome (MIM #615547) is characterized by PWS-like features (intellectual disability, infantile hypotonia, and early-onset obesity), as well autism spectrum disorder; it is caused by truncating variants of the MAGEL2 gene in the PWS-critical region [20-23].

Risk of recurrence in future pregnancies — The risk of PWS in siblings of an affected child depends on the type of molecular defect causing PWS in that individual. Thus, genetic testing is important not only to establish the diagnosis of PWS but to determine the risk of recurrence in future pregnancies.

The recurrence risk is less than 1 percent if the affected child has a deletion or maternal disomy, or an imprinting defect without a deletion (an epimutation). Two rare molecular defects that cause PWS are associated with a higher recurrence risk: If the affected child has a deletion of the imprinting control center (representing a small fraction of those with imprinting defects and less than 0.5 percent of PWS cases), the recurrence risk for siblings is up to 50 percent; if the affected child has a parental chromosomal rearrangement (representing less than 1 percent of PWS cases), the recurrence risk for siblings is up to 25 percent (table 1) [16,24]. (See "Clinical features, diagnosis, and treatment of Prader-Willi syndrome", section on 'Genetic testing'.)

Molecular pathogenesis — Several genes have been mapped to the 15q11.2-13 region. Genetic analysis of many different individuals with PWS progressively narrowed the candidate region, and it now appears that the major manifestations of PWS are caused by paternal deficiency for SNORD116-1 (HBII-85) "small nucleolar RNA" (snoRNA) cluster [25,26]. SnoRNAs are noncoding molecules that guide post-transcriptional modification of ribosomal RNA and other small nuclear RNAs. The modifications include methylation, which is the mechanism for sex-specific imprinting. The precise mechanisms through which SNORD116-1 deletions cause the clinical features of PWS have not been established.

SNORD116-1 and several other snoRNA clusters are located just downstream of the SNURF-SNRPN, NDN, MAGEL2, and MKRN3 genes, explaining the apparent association of PWS with these candidate genes in previous studies [16,24]. These genes, or others in the PWS region, may account for some associated features but are unlikely to be exclusive causes. As an example, truncating mutations in MAGEL2 cause Schaaf-Yang syndrome, which shares several phenotypic features of PWS (see 'Genetics and phenotypic implications' above). Also, the P gene encodes for tyrosinase-positive albinism and is likely responsible for the hypopigmentation observed in 30 percent of individuals with PWS.

MOLECULAR GENETIC TESTING — Molecular testing for PWS is highly sensitive and standard panels with a methylation analysis will detect over 99 percent of PWS cases [16]. For probands with a strong clinical suspicion of PWS, the testing is done in a sequence that allows identification of all potential genetic defects. (See "Clinical features, diagnosis, and treatment of Prader-Willi syndrome", section on 'Indications for genetic testing'.)

Diagnostic panel — Molecular testing is a stepwise process designed to detect the most common molecular defects causing PWS with the fewest steps (algorithm 1). This technique is likely to evolve in the near future with new next-generation sequencing techniques [27].

Diagnosis — The first and most important step in molecular diagnosis is a methylation analysis, which detects abnormal parent-specific methylation imprinting within the PWS critical region on 15q11.2-13. This can be done by the Southern method using a methylation-sensitive probe (SNRPN or PW71B) or by polymerase chain reaction (PCR) using parent-specific primers. (See "Tools for genetics and genomics: Cytogenetics and molecular genetics".)

Mutation identification — If abnormal methylation is detected, further studies are performed to determine the type of mutation, which is important for the purposes of genetic counseling:

●Deletion (65 to 75 percent of PWS cases) – Deletions of the PWS-critical region are detected by fluorescence in situ hybridization (FISH) using the probe SNRPN, or by chromosomal microarray (CMA). If FISH or CMA are positive, then other family members should be evaluated to exclude the possibility of a translocation.

●Uniparental disomy (20 to 30 percent of PWS cases) – Testing for uniparental disomy (DNA polymorphism analysis) involves microsatellite probes or single-nucleotide polymorphisms (SNPs) and is conducted on the parents and affected child.

●Imprinting center defects (2 percent of PWS cases) – If microsatellite markers detect no uniparental disomy, then a mutation or deletion in the imprinting center is suspected. Further diagnostic studies such as whole-exome sequencing, high-resolution CMA, or droplet digital PCR may be required to establish this cause and determine the risk of recurrence in future pregnancies [28]. The majority of imprinting defects are "epimutations," in which the imprint, but not the underlying DNA sequence, is abnormal; in these cases, the recurrence risk for future pregnancies is low [16,29]. A minority of imprinting defects (<1 percent of PWS cases) are caused by deletions in the imprinting center, which carry a higher risk of recurrence.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Obesity in children".)

SUMMARY

●Epidemiology – The prevalence of Prader-Willi syndrome (PWS) is approximately 1 in 25,000 live births, and males and females are equally affected. The vast majority of cases are sporadic rather than familial. (See 'Epidemiology' above.)

●Genetics – PWS is caused by the absence of expression of the paternally active genes in the "PWS-critical" region of chromosome 15q11.2-13. This dependence of the phenotype on the sex of the parent of origin is known as "genomic imprinting." (See 'Genetics and phenotypic implications' above.)

Between 50 and 75 percent of cases of PWS are caused by deletions within the PWS-critical chromosome region, and 20 to 50 percent are caused by uniparental disomy (in which the paternal copy of the gene is replaced by a second maternal copy) (table 1). The remaining PWS cases are caused by defects in the imprinting process or chromosomal translocations. (See 'Genetics and phenotypic implications' above.)

●Risk of recurrence in siblings – The risk of PWS occurring in a sibling of an affected individual is very low unless a deletion affecting the imprinting center is present (table 1) (less than 1 percent of PWS cases). (See 'Risk of recurrence in future pregnancies' above.)

●Molecular diagnosis – The diagnosis of PWS is made by genetic testing of individuals that exhibit typical clinical features. Genetic testing is highly sensitive and detects PWS in over 99 percent of cases. The first and most important step in molecular diagnosis is a methylation analysis, which detects abnormal parent-specific methylation imprinting within the PWS critical region on 15q11.2-13 (algorithm 1). (See 'Molecular genetic testing' above and "Clinical features, diagnosis, and treatment of Prader-Willi syndrome".)