Thompson & Thompson Genetics in Medicine, 8th Edition

Case 38. Prader-Willi Syndrome (Absence of Paternally Derived 15q11-q13, MIM 176270)

Chromosomal Deletion, Uniparental Disomy


• Imprinting

• Uniparental disomy

• Microdeletion

• Recombination between repeated DNA sequences

Major Phenotypic Features

• Age at onset: Infancy

• Infantile feeding difficulties

• Childhood hyperphagia and obesity

• Hypotonia

• Cognitive impairment

• Short stature

• Dysmorphism

History and Physical Findings

J.T. was born at 38 weeks' gestation after an uncomplicated pregnancy and delivery. She was the second child of nonconsanguineous parents. Shortly after birth, her parents and the nurses noticed that she was hypotonic and feeding poorly. Her parents and older sister were in good health; she did not have a family history of neuromuscular, developmental, genetic, or feeding disorders. Review of the medical record did not reveal a history of overt seizures, hypoxic insults, infection, cardiac abnormalities, or blood glucose or electrolyte abnormalities. On examination, J.T. did not have respiratory distress or dysmorphism; her weight and length were appropriate for gestational age; she was severely hypotonic with lethargy, weak cry, decreased reflexes, and a poor suck. Subsequent evaluation included testing for congenital infections and congenital hypothyroidism; measurements of blood ammonium, plasma amino acids, and urine organic acids; chromosomal microarray; and methylation testing for the Prader-Willi/Angelman region on 15q11-13 (see Chapter 6). The results of the methylation testing showed an abnormal methylation pattern consistent with Prader-Willi syndrome (one hypermethylated copy of SNRPN), and the chromosomal microarray revealed a deletion on chromosome 15q11-q13. The geneticist explained to the parents that J.T. had Prader-Willi syndrome. After much discussion and thought, J.T.'s parents decided that they were unable to care for a disabled child and gave her up for adoption.


Disease Etiology and Incidence

Prader-Willi syndrome (PWS, MIM 176270) is a panethnic developmental disorder caused by loss of expression of genes on paternally derived chromosome 15q11-q13. Loss of paternally expressed genes can arise by several mechanisms; approximately 70% of patients have a deletion of 15q11-q13, 25% have maternal uniparental disomy, less than 5% have mutations within the imprinting control element, and less than 1% have another chromosomal abnormality (see Chapter 6). PWS has an incidence of 1 in 10,000 to 1 in 15,000 live births.


Many genes within 15q11-q13 are differentially expressed, depending on whether the region is inherited from the father or the mother. In other words, some genes expressed by paternal 15q11-q13 are not expressed by maternal 15q11-q13, and other genes expressed by maternal 15q11-q13 are not expressed by paternal 15q11-q13. This phenomenon of differential expression of a gene according to whether it is inherited from the father or mother is known as imprinting (see Chapters 3 and 6). Maintenance of correct expression of imprinted genes requires switching of the imprint on passage through the germline; all imprints are switched “off” in the gonadal cells, and maternal imprints are then activated in the egg cells, whereas paternal imprints are activated in the sperm cells. Switching of imprinting on passage through the germline is regulated by an imprinting control element and reflected by epigenetic changes in DNA methylation and chromatin that regulate gene expression.

Deletion of 15q11-q13 during male meiosis gives rise to children with PWS because children formed from a sperm carrying the deletion will be missing genes that are active only on the paternally derived 15q11-q13. The mechanism underlying this recurrent deletion is illegitimate recombination between low-copy repeat sequences flanking the deletion interval (see Chapter 6). Less commonly, inheritance of a deletion spanning this region occurs if a patient inherits an unbalanced karyotype from a parent who has a balanced translocation.

Failure to switch the maternal imprints to paternal imprints during male meiosis gives rise to children with PWS because children formed from a sperm with a maternally imprinted 15q11-q13 will not be able to express genes active only on the paternally imprinted 15q11-q13. Imprinting failure arises from mutations within the imprinting control element.

Maternal uniparental disomy also gives rise to PWS because the child has two maternal chromosomes 15 and no paternal chromosome 15. Maternal uniparental disomy is thought to develop secondary to trisomy rescue, that is, loss of the paternal chromosome 15 from a conceptus with chromosome 15 trisomy secondary to maternal nondisjunction.

Despite the observations that loss of a paternally imprinted 15q11-q13 gives rise to PWS, and despite the identification of many imprinted genes within this region, the precise cause of PWS is still unknown. PWS has not yet been shown definitively to result from a mutation in any one specific gene.

Phenotype and Natural History

In early infancy, PWS is characterized by severe hypotonia, feeding difficulties, and hypogonadism, with cryptorchidism in males. The hypotonia improves over time, although adults remain mildly hypotonic. The hypogonadism, which is of hypothalamic origin, does not improve with age and usually causes delayed and incomplete pubertal development as well as infertility. The feeding difficulties usually resolve within the first year of life, and between 1 and 6 years, patients develop extreme hyperphagia and food-seeking behavior (hoarding, foraging, and stealing). This behavior and a low metabolic rate cause marked obesity. The obesity is a major cause of morbidity due largely to cardiopulmonary disease and non–insulin-dependent (type 2) diabetes mellitus. Longevity can be nearly normal if obesity is avoided.

Most children with PWS have delayed motor and language development as well as mild intellectual disability (mean IQ, 60 to 80). They also have behavioral problems, including temper tantrums, obsessive-compulsive disorders, and poor adaptation to changes in routine. These behavioral problems continue into adulthood and remain disabling. Approximately 5% to 10% of patients also develop psychoses during early adulthood.

Other anomalies associated with PWS include short stature, scoliosis, osteoporosis, and dysmorphism. Dysmorphic features include a narrow bifrontal diameter, almond-shaped eyes, triangular mouth, and small hands and feet (Fig. C-38). Also, many patients have hypopigmentation of the hair, eyes, and skin.


FIGURE C-38 A 12-month-old girl with Prader-Willi syndrome. Note her fair coloring, narrow bifrontal diameter, almond-shaped eyes, and down-turned mouth. The hyperphagia, with resulting central obesity, generally does not begin until the age of 2 to 6 years. See Sources & Acknowledgments.


Although it is often suspected on the basis of history and physical features, a diagnosis of PWS is defined by the absence of a paternally imprinted 15q11-q13. Loss of the paternal imprint is detected by DNA analyses showing that the imprinted genes have only a maternal methylation pattern. If the DNA studies confirm PWS, genetic counseling requires a subsequent karyotype and FISH for 15q11-q13 to determine whether PWS arose from inheritance of a chromosomal translocation.

No medications are currently available to treat the hyperphagia; a very low-calorie and restrictive diet and exercise remain the mainstays for controlling the obesity. Growth hormone replacement can normalize height and improve lean body mass. Sex hormone replacement promotes secondary sexual features but frequently worsens behavioral problems in males and increases the risk for stroke in females. Behavioral management and serotonin reuptake inhibitors are the most effective therapies currently available for the behavioral disorder. Adult patients usually perform best in sheltered living (group homes) and employment environments.

Inheritance Risk

The risk for recurrence of PWS in future children of parents is related to the molecular cause. For imprinting defects, the risk can be as high as 50%, whereas for either deletion of 15q11-q13 or maternal uniparental disomy, the recurrence risk is less than 1%. The risk for recurrence if a parent carries a balanced translocation depends on the nature of the translocation but can be as high as 25%; in contrast, all PWS patients reported to date with an unbalanced translocation have had a de novo chromosomal rearrangement.

Questions for Small Group Discussion

1. Angelman syndrome also arises from imprinting defects of 15q11-q13. Compare and contrast the phenotypes and causative molecular mechanisms of Prader-Willi syndrome and Angelman syndrome.

2. How might imprinting explain the phenotypes associated with triploidy?

3. Beckwith-Wiedemann syndrome and Russell-Silver syndrome also appear to be caused by abnormal expression of imprinted genes. Explain.

4. J.T.'s parents gave her up for adoption. Should the genetic counseling have been done differently? What is nondirective genetic counseling?


Cassidy SB, Schwartz S, Miller JL, et al. Prader-Willi syndrome. Genet Med. 2012;14:10–26.

Driscoll DJ, Miller JL, Schwartz S, et al. Prader-Willi syndrome. [Available from]