Prader-Willi Syndrome (PWS)

Prader-Willi syndrome (PWS) is a rare, complex neurobehavioral disorder characterized by hypotonia and feeding difficulties in infancy, growth hormone deficiency, hypogonadism, behavioral problems, cognitive impairment, and hyperphagia leading to obesity in early childhood.¹

PWS is caused by a lack of expression of imprinted genes on chromosome 15q11-q13. The variability of genetic abnormalities affecting this gene expression defines the characteristics of the different PWS subtypes.² 

PWS subtypes include²:

• Paternal deletions (65% to 75% of cases), which are subdivided into type I, type II, and atypical deletions;
• Maternal uniparental disomy (UPD; 20% to 30%, which are genetically subdivided into cases of heterodisomy and cases of isodisomy);
• Imprinting center defects (1% to 3%); and
• Rare paternal chromosome 15 translocations (0.1%).

No genetic error has been linked to any exclusive symptoms.³ For example, hypotonia and motor delay occur in all patients with PWS regardless of genetic subtype.² However, PWS genetic subtypes are associated with statistically significant differences in the frequency or severity of certain phenotype-genotype characteristics.^1,2 

Paternal Deletions

Hypopigmentation and skin picking occur more frequently in all 3 subtypes of paternal deletion errors than in UPD subtypes.² Feeding problems, sleep disturbances, and speech and language deficits are also more often associated with paternal deletions.³

Cognitive deficits are more likely to occur in individuals with paternal deletions, although depressed cognitive functioning is a clinical feature of all types. A 2006 study found that only 9.52% of studied individuals with paternal deletions had Full-Scale Intelligence Quotient (FSIQ) over 70 vs 61.53% of studied individuals with UPD or imprinting defects had FSIQ over 70.⁴

Polysomnographic studies comparing paternal deletions with other subtypes indicated that the frequency of central events with desaturations of 10% or higher was higher in the deletion subtype, suggesting that central nervous system parameters differ between groups.⁴

Read more about PWS clinical features

Type I Deletions

Type I deletions affect a larger genomic region than type II deletions. PWS with type I paternal deletions tends to be diagnosed at an earlier age, and speech delay is more frequent and/or symptoms are more severe in patients with type I deletions than in those with type II deletions.² Although some studies did not find any behavioral differences between patients with type I and those with type II deletions,² others noted worse adaptive behaviors and more frequent obsessive-compulsive behaviors in patients with type I deletions.^2,3,5 

Academic performance and intellectual abilities have been reported to be better in patients with type I deletions than in those with type II deletions.³

Type II Deletions

Type II deletions occur more frequently than type I deletions.² Type II deletions are on average approximately 500 kb smaller than type I deletions.⁵

Atypical Deletions 

Atypical deletions are the least frequent subtype of paternal deletions. These deletions can be smaller than type II or larger than type I deletions. Some of the phenotypic characteristics associated with this genotype are severe, including the need for tube feeding and absence of speech.²

Read more about PWS complications

Maternal UPD

Compared with individuals with deletion subtypes, individuals with the UPD subtype of PWS presented with phenotypic characteristics including older maternal age, less frequent hypopigmentation and skin picking, and more frequent autistic traits and anxiety.^2,5

Studies have provided conflicting evidence whether UPD genotypes are more likely than deletion genotypes to be associated with temperature dysregulation, feeding problems, sleep disorders, older age at PWS diagnosis, and dysmorphic facial features.^2,3

Post-term delivery, higher verbal IQ, and psychosis are more frequent in individuals with maternal UPD, whereas facial dysmorphism is less frequent.³

Maternal UPD can be subgrouped into two genetic subtypes by genotyping polymorphic microsatellite markers. These microsatellite markers are found heterozygous in the mothers of patients. The heterodisomy subgroup includes patients who maternally inherited both heterozygous alleles. The isodisomy subgroup includes patients who maternally inherited either allele, but present homozygous alleles.² 

Read more about PWS genetics

Heterodisomy 

Heterodisomy results from a meiosis I error without crossover events, whereas mixed UPD involves a meiosis I error with crossover events. Phenotypic variations of heterodisomy and isodisomy UPD are rarely reported.^2,5 In the 2022 study by Zhang et al., microsatellite genotyping found 57.89% of UPD cases were a result of heterodisomy and 42.11% of UPD cases were due to isodisomy.²

Isodisomy

Isodisomy results from a meiosis II error and subsequent monosomy rescue.² Anxiety was more frequent in patients with isodisomy UPD than in those with heterodisomy UPD (83.33% vs 50%, respectively), although the difference was not statistically significant.²

Imprinting Center Defects

Microdeletions of a region called the imprinting center on chromosome 15q11-q13 result in a relatively rare PWS subtype. Promoter elements on the SNRPN gene contribute to the initiation of imprint switching during spermatogenesis.⁶ 

Patients with mutations at the imprinting center on chromosome 15 exhibit the classic PWS phenotype.^6,7

Read more about PWS epidemiology

Chromosome 15 Translocations

Reports of translocations between chromosome 15 and other chromosomes, including chromosomes 6, 11, 13, 14, and 19, are exceedingly rare.^8-12 Some of these translocations occurred in families with a history of consanguineous parents¹¹ or a family history of translocations in cousins with nonconsanguineous parents.⁸

Of 2 cousins with a family history of translocations between chromosomes 6 and 15, one exhibited typical PWS features while the other exhibited features typical of Angelman syndrome, such as severe cognitive impairment, microcephaly, seizures, and paroxysms of laughter.⁸

The phenotype of an individual with a translocation between chromosomes 13 and 15 (resembling a Robertsonian translocation) correlated well with the phenotype of type I deletions, including obesity, cognitive impairment, and developmental and speech delays.¹⁰ 

An individual with a translocation between chromosomes 15 and 19 demonstrated typical PWS features, such as hyperphagia and skin picking, along with cognitive delay, seizures, and attention-deficit/hyperactivity disorder (ADHD). Hypopigmentation and hypogonadism/hypogenitalism were not observed.¹²

Phenotypic characteristics or variations of the typical PWS phenotype were not well described in the studies reporting on translocations between chromosome 15 and chromosomes 11 and 14.^9,11

Read more about PWS signs and symptoms

References

1. Butler MG, Manzardo AM, Forster JL. Prader-Willi syndrome: clinical genetics and diagnostic aspects with treatment approaches. Curr Pediatr Rev. 2016;12(2):136-166. doi:10.2174/1573396312666151123115250
2. Zhang L, Liu X, Zhao Y, et al. Genetic subtypes and phenotypic characteristics of 110 patients with Prader-Willi syndrome. Ital J Pediatr. 2022;48:121. doi:10.1186/s13052-022-01319-1
3. Costa RA, Ferreira IR, Cintra HA, Gomes LHF, Guida L da C. Genotype-phenotype relationships and endocrine findings in Prader-Willi syndrome. Front Endocrinol (Lausanne). 2019;10:864. doi:10.3389/fendo.2019.00864
4. Torrado M, Araoz V, Baialardo E, et al. Clinical-etiologic correlation in children with Prader-Willi syndrome (PWS): an interdisciplinary study. Am J Med Genet A. 2007;143A:460-468. doi:10.1002/ajmg.a.31520
5. Butler MG, Bittel DC, Kibiryeva N, Talebizadeh Z, Thompson T. Behavioral differences among subjects with Prader-Willi syndrome and type I or type II deletion and maternal disomy. Pediatrics. 2004;113(3 Pt 1):565-573. doi:10.1542/peds.113.3.565
6. Ohta T, Gray TA, Rogan PK, et al. Imprinting-mutation mechanisms in Prader-Willi syndrome. Am J Hum Genet. 1999;64(2):397-413. doi:10.1086/302233
7. Cheon CK. Genetics of Prader-Willi syndrome and Prader-Willi-like syndrome. Ann Pediatr Endocrinol Metab. 2016;21(3):126-135. doi:10.6065/apem.2016.21.3.126
8. Smeets DFCM, Hamel BCJ, Nelen MR, et al. Prader-Willi syndrome and Angelman syndrome in cousins from a family with a translocation between chromosomes 6 and 15. N Engl J Med. 1992;326(12):807-811. doi:10.1056/NEJM199203193261206
9. Charrow J, Balkin N, Cohen MM. Translocations in Prader-Willi syndrome. Clin Genet. 1983;23(4):304-307. doi:10.1111/j.1399-0004.1983.tb01881.x
10. Sheth F, Liehr T, Shah K, Sheth J. Prader-Willi syndrome – type 1 deletion, a consequence of an unbalanced translocation of chromosomes 13 and 15, easily to be mixed up with a Robertsonian translocation. Mol Cytogenet. 2015;8:52. doi:10.1186/s13039-015-0163-2
11. Flori E, Biancalana V, Girard-Lemaire F, et al. Difficulties of genetic counseling and prenatal diagnosis in a consanguineous couple segregating for the same translocation (14;15) (q11;q13) and at risk for Prader–Willi and Angelman syndromes. Eur J Hum Genet. 2004;12(3):181-186. doi:10.1038/sj.ejhg.5201134
12. Dang V, Surampalli A, Manzardo AM, et al. Prader-Willi syndrome due to an unbalanced de novo translocation [t(15;19)(q12;p13.3)]. Cytogenet Genome Res. 2016;150(1):29-34. doi:10.1159/000452611

Reviewed by Harshi Dhingra, MD, on 7/19/2023.

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Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT

Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT is a freelance medical writer and Doctor of Physical Therapy from Maryland. She has expertise in the therapeutic areas of orthopedics, neurology, chronic pain, gastrointestinal dysfunctions, and rare diseases especially Ehlers Danlos Syndrome.