Prader-Willi Syndrome

A number sign (#) is used with this entry because of evidence that Prader-Willi syndrome (PWS) is in effect a contiguous gene syndrome resulting from deletion of the paternal copies of the imprinted SNRPN gene (182279), the NDN gene (602117), and possibly other genes within the chromosome region 15q11-q13.

Description

Prader-Willi syndrome is characterized by diminished fetal activity, obesity, muscular hypotonia, mental retardation, short stature, hypogonadotropic hypogonadism, and small hands and feet. It can be considered to be an autosomal dominant disorder and is caused by deletion or disruption of a gene or several genes on the proximal long arm of the paternal chromosome 15 or maternal uniparental disomy 15, because the gene(s) on the maternal chromosome(s) 15 are virtually inactive through imprinting. Horsthemke and Wagstaff (2008) provided a detailed review of the mechanisms of imprinting of the Prader-Willi/Angelman syndrome (105830) region.

See also the chromosome 15q11-q13 duplication syndrome (608636), which shows overlapping clinical features.

Clinical Features

The original paper by Prader et al. (1956) described the full clinical picture.

Prenatal

Mothers with prior experience of normal pregnancies almost without exception report distinctly delayed onset and reduced fetal activity during the pregnancies involving Prader-Willi children. Obstetricians often fail to detect diminished fetal activity with ultrasound investigation. When reduced fetal activity is observed, prenatal cytogenetic examination produces normal results because cytogeneticists were not instructed to look for the characteristic chromosomal changes of PWS (Schinzel, 1986). Alert clinicians should refer CVS material from pregnancies with fetuses that demonstrate poor activity for molecular diagnosis of the syndrome (see below). Other candidates for prenatal diagnosis of PWS are fetuses of pregnancies in which trisomy 15 or mosaic trisomy 15 was determined from CVS, and in which subsequent amniocyte or fetal blood examinations disclosed a normal diploid karyotype. Theoretically, one-third of trisomy 15 fetuses initially with 2 maternal chromosomes 15 and 1 paternal chromosome 15 should give rise to Prader-Willi syndrome patients exhibiting maternal uniparental disomy (Cassidy et al., 1992; Purvis-Smith et al., 1992; Hall, 1992).

Perinatal

Neonates are profoundly hypotonic, which often causes asphyxia. In addition, there is mild prenatal growth retardation with a mean birth weight of about 6 lbs (2.8 kg) at term, hyporeflexia, poor feeding due to diminished swallowing and sucking reflexes, which in many cases necessitates gavage feeding for about 3 to 4 months. Cryptorchidism occurs with hypoplastic penis and scrotum in boys and hypoplastic labiae in girls (Stephenson, 1980). Chitayat et al. (1989) commented on the normal size of hands and feet at birth and in the first year of life.

Miller et al. (1999) described 6 newborns evaluated for hypotonia who were later diagnosed with Prader-Willi syndrome. These newborns lacked the classic neonatal features of the syndrome (peculiar cry, characteristic craniofacial features, and clinical evidence of hypogonadism). The authors suggested that specific genetic testing for PWS be considered for all neonates with undiagnosed central hypotonia even in the absence of the other major features of the syndrome.

Oiglane-Shlik et al. (2006) studied 5 newborns with hypotonia, poor arousal, weak or absent cry, and no interest in food, in whom PWS was confirmed by the abnormal methylation test. All had a distinctive facial appearance, with high prominent forehead, narrow bifrontal diameter, downturned corners of the mouth, micrognathia, and dysplastic ears. Three neonates had a high-arched palate, and 4 had arachnodactyly. In the first few days of life, 4 of the 5 patients demonstrated a peculiar position of the hands, with the thumb constantly adducted over the index and middle finger. All 5 patients had transient bradycardia, thermolability, and acrocyanosis; and 3 also showed marked skin mottling, as previously reported by Chitayat et al. (1989).

Infancy and Childhood

Feeding difficulties generally improve by the age of 6 months. From 12 to 18 months onward, uncontrollable hyperphagia causes major somatic as well as psychologic problems. Diminished growth is observed in the majority of infants (Butler and Meaney, 1987). Small hands with delicate and tapering fingers and small feet (acromicria) are seen in most infants and adolescents; hand and foot sizes correlate well with length, but not with age, and foot size tends to be lower than hand size. However, patients of normal height tend to have normally sized hands (Hudgins and Cassidy, 1991). The face is characterized by a narrow bifrontal diameter, almond-shaped eyes (often in mild upslanted position), strabismus, full cheeks, and diminished mimic activity due to muscular hypotonia. Plethoric obesity becomes the most striking feature. From the age of about 6 years onward, many children present scars from scratching due to itching, and later, almost all show abdominal striae.

Depigmentation relative to the familial background is a feature in about three-quarters of the patients. Butler (1989), Hittner et al. (1982), and several authors remarked that this sign is confined to cases with deletions and absent in those with maternal disomy 15. Phelan et al. (1988) presented a black female child with oculocutaneous albinism, PWS, and an interstitial deletion of 15q11.2. Patients with classic albinism (203100) have misrouting of optic fibers, with fibers from 20 degrees or more of the temporal retina crossing at the chiasm instead of projecting to the ipsilateral hemisphere. Misrouting can result in strabismus and nystagmus. Because patients with PWS have hypopigmentation and strabismus, Creel et al. (1986) studied 6 patients, selected for a history of strabismus, with pattern-onset visual evoked potentials on binocular and monocular stimulation. Of the 4 with hypopigmentation, 3 had abnormal evoked potentials indistinguishable from those recorded in albinos. The 2 with normal pigmentation had normal responses. Wiesner et al. (1987) found that 14 of 29 patients with PWS had ocular hypopigmentation. There was possible correlation between hypopigmentation and a deletion of 15q.

MacMillan et al. (1972) described 2 unrelated girls with the features of PWS who additionally showed precocious puberty. They suggested that this is a variant and that a hypothalamic disturbance is responsible for this disorder. Hall and Smith (1972) pointed out narrow bifrontal cranial diameter as a feature. Hall (1985) pointed to a possibly increased risk of leukemia in PWS.

A frequent feature generally overlooked is thick saliva at the edges of the mouth. Patients tend to be relatively insensitive to pain (including that caused by obtaining blood samples)(Prader, 1991).

Eiholzer et al. (1999) presented data on body composition and leptin (164160) levels of 13 young, still underweight children and 10 older overweight children with Prader-Willi syndrome. Both groups showed elevated skinfold standard deviation scores for body mass index and elevated body mass index-adjusted leptin levels, suggesting relatively increased body fat even in underweight children. Leptin production appeared to be intact. The authors concluded that body composition in PWS is already disturbed in infancy, long before the development of obesity.

Van Mil et al. (2001) compared body composition in 17 patients with PWS with 17 obese control patients matched for gender and bone age. In children with PWS, adiposity was associated with reduced fat-free mass, and extracellular-to-intracellular water ratio was increased. Both findings are related to growth hormone (GH; 139250) function and physical activity. Bone mineral density, especially in the limbs, tends to be reduced in patients with PWS and is related to growth hormone function.

Gunay-Aygun et al. (2001) reviewed the sensitivity of PWS diagnostic criteria and proposed revised criteria for DNA testing. From birth to 2 years any infant with hypotonia and poor suck should have DNA testing for the PWS deletion. From age 2 to 6 years any child with hypotonia and a history of poor suck and global developmental delay should have DNA testing. From 6 years to 12 years any child with history of hypotonia and poor suck, global developmental delay, and excessive eating with central obesity should be tested for PWS.

Adolescence and Adulthood

Greenswag (1987) reported on a survey of 232 adults with PWS, ranging in age from 16 to 64 years. Of 106 patients whose chromosomes were analyzed, 54 had an abnormality of chromosome 15, primarily a deletion. Physical characteristics, health problems, intelligence, psychosocial adjustment, and impact on the family were reviewed. Emotional lability, poor gross motor skills, cognitive impairment, and insatiable hunger were especially remarkable features.

Olander et al. (2000) pointed to the occurrence of 3 PWS phenotypes: patients with paternal deletions have the typical PWS phenotype; patients with maternal UPD have a slightly milder phenotype with better cognitive function; and patients with maternal UPD and mosaic trisomy 15 have the most severe phenotype with a high incidence of congenital heart disease. They described a patient with the severe phenotype with maternal isodisomy rather than the more common maternal heterodisomy. They concluded that the more severe PWS phenotype was due to trisomy 15 mosaicism rather than to homozygosity for deleterious chromosome 15 genes.

In contrast to infants, adults invariably are small compared to their family members (Butler and Meaney, 1987). Due to high caloric intake, alimentary diabetes frequently sets in during or soon after the period of puberty. Puberty itself is diminished in PWS patients of both sexes. Adolescents and young adults often require digitalization because of cardiac insufficiency; however, it has been shown that substantial weight reduction relieves the need of cardiac therapy. Any attempt to reduce food intake in these adolescents often leads to serious psychologic and behavioral problems, and in some children, the situation in their home environment becomes intolerable (Curfs et al., 1991). Patients rarely survive beyond 25 to 30 years of age, the cause of death being diabetes and cardiac failure. However, if strict weight control is achieved, both diabetes and cardiac failure are greatly reduced and survival is either not or only mildly reduced. Johnsen et al. (1967) studied 7 mentally retarded patients, aged 4 to 19 years. Studies showed that fat synthesis from acetate during fasting was 10 times greater in patients than in unaffected sibs, and that hormone-stimulated lipolysis was depressed. These workers suggested that the condition is comparable to the genetic obese-hyperglycemic mouse. Since during fasting substrate continues to be used for new fat and lipolysis is deficient, survival depends on a continuous supply of exogenous calories. The abundant fat, muscle hypotonia, and small feet and hands are exactly the opposite of the sparse fat, muscle hypertrophy, and large hands and feet in Seip syndrome (269700).

Hoybye et al. (2002) studied the clinical, genetic, endocrinologic, and metabolic findings in 10 male and 9 female adult PWS patients (mean age, 25 years). The PWS karyotype was demonstrated in 13 patients. The mean BMI was 35.6 kg/m2, and total body fat was increased. Two-thirds were biochemically hypogonadal. Fifty percent had severe GH deficiency. Four were hypertensive. One patient had heart failure and diabetes. Impaired glucose tolerance was seen in 4 patients, elevated homeostasis model assessment index in 9, and modest dyslipidemia in 7. IGF-binding protein-1 (146730) correlated negatively with insulin (176730) levels. Four patients had osteoporosis, and 11 had osteopenia. There was no significant difference between the group with the PWS karyotype and the group without the karyotype in age, BMI, waist-to-hip ratio, percent body fat, insulin values, homeostasis model assessment index, or lipid profile, except for lipoprotein(a) (152200), which was significantly higher in the group with the negative karyotype. Hoybye et al. (2002) concluded that the risk factors found predicting cardiovascular disease were secondary to GHD and emphasized the importance of evaluating treatment of GHD in adults with PWS.

Curfs et al. (1991) concluded that PWS patients score better on visual motor discrimination skills than on auditory verbal processing skills.

Wise et al. (1991) described 5 patients with PWS who experienced recurrent hyperthermia in infancy. On the basis of these patients and other reports of abnormal temperature regulation in PWS patients, particularly hypothermia with exposure to cold, they concluded that defects in temperature regulation may be a manifestation of hypothalamic dysfunction in PWS. On the other hand, Cassidy and McKillop (1991) concluded on the basis of a survey that clinically significant abnormal temperature control is not a common finding in this disorder. Similarly, Williams et al. (1994) concluded on the basis of a survey that the prevalence of febrile convulsions, fever-associated symptoms, and temperature less than 94 degrees F were not unique to PWS but can occur in any neurodevelopmentally handicapped individual and do not necessarily reflect syndrome-specific hypothalamic abnormalities.

Individuals with Prader-Willi syndrome manifest severe skin picking behavior. Bhargava et al. (1996) described 3 adolescent patients in whom an extension of this behavior to rectal picking resulted in significant lower gastrointestinal bleeding and anal rectal disease. Recognition of this behavior is important to avoid misdiagnosing inflammatory bowel disease in PWS patients.

Wharton et al. (1997) presented 6 patients with PWS with dramatic acute gastric distention. In 3 young adult women with vomiting and apparent gastroenteritis, clinical course progressed rapidly to massive gastric dilatation and gastric necrosis. One patient died of overwhelming sepsis and disseminated intravascular coagulation. In 2 children, gastric dilatation resolved spontaneously. Gastrectomy was performed in 2 cases; in 1, gastrectomy was subtotal and distal, whereas in the other, gastrectomy was combined with partial duodenectomy and pancreatectomy. All specimens showed ischemic gastroenteritis. There was diffuse mucosal infarction with multifocal transmural necrosis.

From a study of 10 African Americans with PWS, Hudgins et al. (1998) pointed out that the clinical features differ from those of white patients. Growth is less affected, hand and foot lengths usually are normal, and the facies are atypical; as a result, PWS may be underdiagnosed in this population.

Lindgren et al. (2000) studied the microstructure of eating behavior in patients with PWS and compared it with that of members of obese and normal weight control groups of the same age. PWS patients had a mean age of 10 +/- 4 years, while the control groups were 12 +/- 3 years (normal weight) and 12 +/- 4 years (obese). Subjects with PWS had a longer duration of eating rate compared with members of both obese and normal weight groups. In subjects with PWS, 56% of the eating curves were non-decelerating, compared with 10% of the normal weight group and 30% of the obese group. Lindgren et al. (2000) concluded that the eating behavior found in subjects with PWS might be due to decreased satiation rather than increased hunger.

Nagai et al. (2000) reported standard growth curves for height and weight among Japanese children with Prader-Willi syndrome. No difference in height was seen between those with and those without chromosome 15q deletion.

Cassidy et al. (1997) personally examined and studied using molecular techniques 54 individuals with PWS to determine whether there are phenotypic differences between patients with the syndrome due to deletion (present in 37) or uniparental disomy (present in 17) as the mechanism. Previously recognized increased maternal age in patients with UPD and increased frequency of hypopigmentation in those with deletion were confirmed. Although the frequency and severity of most other manifestations of PWS did not differ significantly between the 2 groups, those with UPD were less likely to have a 'typical' facial appearance. In addition, this group was less likely to show some of the minor manifestations such as skin picking, skill with jigsaw puzzles, and high pain threshold. Females and those with UPD were also older, on average.

Gunay-Aygun et al. (2001) proposed new revised criteria for DNA testing for individuals in adolescence and adulthood. Anyone with cognitive impairment (usually mild mental retardation), excessive eating with central obesity, and hypothalamic hypogonadism, and/or typical behaviors, including temper tantrums and obsessive-compulsive features, should be referred for DNA testing for PWS.

Among 25 patients with PWS aged 18 years or older, Boer et al. (2002) found that 7 (28%) had severe affective disorder with psychotic features, with a mean age of onset of 26 years. The 7 affected persons, all aged 28 years or older, included all 5 with disomies of chromosome 15, 1 with a deletion in this chromosome, and 1 with an imprinting center mutation in the same chromosome. They postulated that in PWS, an abnormal pattern of expression of a sex-specific imprinted gene on chromosome 15 is associated with psychotic illness in early adult life.

Vogels et al. (2004) detailed the psychopathologic manifestations of 6 adults with PWS and a history of psychotic episodes. Characteristics of the psychotic disorder included early and acute onset, polymorphous and shifting symptoms, psychiatric hospitalization along with precipitating stress factors, and a prodromal phase of physiologic symptoms.

To evaluate the risk of cancer in patients with PWS, Davies et al. (2003) conducted a retrospective questionnaire survey of its occurrence among patients registered with the PWS Association compared with cases in the general US population based on the SEER program. The median age of 1,024 PWS patients was 19.0 years (range, 0.1-63 years) with 2 older than age 50. The ratio of observed (8) to expected (4.8) cancers was 1.67 (p = 0.1610; 95% CI = 0.72-3.28). Three myeloid leukemias were confirmed, resulting in a ratio of observed to expected of 40.18 (p = 0.0001; 95% CI = 8.0-117). The authors speculated that a gene within the 15q11-q13 region may be involved in the biology of myeloid leukemia or that secondary manifestations of PWS, such as obesity, may be associated with an increased risk of certain cancers.

Wey et al. (2005) described a woman with features consistent with PWS due to a mosaic imprinting defect. Three independent assays revealed a reduced proportion of nonmethylated SNURF-SNRPN alleles in peripheral blood DNA. Microsatellite analysis and FISH revealed apparently normal chromosomes 15 of biparental origin. Wey et al. (2005) estimated that approximately 50% of the patient's blood cells had an imprinting defect. Apart from a rather normal facial appearance, the proband had typical features of PWS in terms of truncal obesity, small hands with tapered fingers, and small feet. Operation for strabismus had been performed. When evaluated at 21 years of age, she presented with the major signs of PWS, except for the relatively normal facial appearance. Wey et al. (2005) suggested that the patient, although presenting with atypical PWS features at birth and in infancy, had progressively acquired more pronounced PWS features during childhood and adolescence.

Sinnema et al. (2012) reported the clinical features of 12 patients over the age of 50 years with genetically confirmed PWS. Eleven patients lived in a facility, and 1 lived with his elderly mother. Half of the patients had diabetes mellitus with an average age at diagnosis of 41.6 years. Three patients had hypertension, 3 had a history of stroke, 6 had a history of fractures, 10 had foot problems, 5 had scoliosis, 9 had edema, and 6 had erysipelas. Older patients had significantly lower functioning, particularly in activities of daily living, compared to younger control patients, and the decline began around age 40. All 8 patients with maternal uniparental disomy used psychotropic medications, 7 of whom had a psychiatric disorder. None of the 4 patients with a paternal deletion had a psychiatric illness. Sinnema et al. (2012) suggested that age-associated medical problems may be exacerbated by temperature instability, decreased mobility, and high pain threshold in PWS. Overall, the constellation of features suggested premature aging in PWS, which may also result from abnormalities in sex hormone levels. Sinnema et al. (2012) noted that the life expectancy of individuals with PWS had increased in recent years, and that these individuals have specific medical and social needs as they age.

To examine survival trends and risk factors in PWS, Manzardo et al. (2018) performed a survival analysis of the Prader-Willi Syndrome Association's 40-year mortality syndrome-specific database of 486 deaths. They compared 331 deaths that occurred between the years 2000 and 2015 (Recent) with 94 deaths that occurred before 2000 (Early). The risk for all-cause mortality in PWS was 1.5 (95% CI = 1.2-1.9) times higher for the Early than for the Recent cohort, reflected in female cardiac failure (hazard ratio (HR) = 1.8; 95% CI = 1.3-2.6), pulmonary embolism (HR = 6.1; 95% CI = 1.7-22), and gastrointestinal-related (HR = 3.2; 95% CI = 1.1-7.4) causes. Accidental deaths in males increased in the Recent cohort (HR = 5.7; 95% CI = 1.2-27.1), possibly due to enhanced weight management and mobility. Risk of death from respiratory failure was unchanged.

Butler et al. (2017) reviewed causes of death in Prader-Willi syndrome using the US Prader-Willi Syndrome Association 40-year mortality survey ranging from 1973 to 2015. A total of 486 deaths were reported (263 males, 217 females, 6 unknown) between 1973 and 2015, with mean age of 29.5 +/- 16 years (2 months-67 years); 70% occurred in adulthood. Respiratory failure was the most common cause, accounting for 31% of all deaths. Males were at increased risk for presumed hyperphagia-related accidents/injuries and cardiopulmonary factors compared to females. PWS maternal disomy 15 genetic subtype showed an increased risk of death from cardiopulmonary factors compared to the deletion subtype.

Prader-Willi-like Syndrome Associated with Chromosome 6

Fryns et al. (1986) described an 8-month-old girl with a de novo 5q/6q autosomal translocation resulting in loss of the distal part of the long arm of chromosome 6 (6q23.3-qter). Clinical manifestations included abnormal facies with broad, flat nasal bridge, small nose with broad tip, bilateral epicanthus, narrow palpebral fissures, small anteverted ears, and small mouth. Other features included truncal obesity, short hands and feet, and delayed psychomotor development. Prader-Willi syndrome was suspected initially.

Villa et al. (1995) reported a 23-month-old boy with mental and psychomotor delay, minor craniofacial abnormalities, and obesity who had a de novo interstitial deletion of chromosome 6q16.2-q21. The authors noted the phenotypic similarities to Prader-Willi syndrome. In a boy with clinical features mimicking Prader-Willi syndrome, but with a normal chromosome 15, Stein et al. (1996) found a de novo interstitial deletion of 6q22.2-q23.1. The boy showed delayed development, hypotonia, seizures, hyperactive behavior, a bicuspid aortic valve with mild aortic stenosis, small hands and feet, hypogonadism, and obesity since about 4 years of age. In a 38-year-old man with moderate to severe intellectual delay, short stature, small hands and feet, small mouth, and obesity, Smith et al. (1999) found a duplication of 6q24.3-q27. The authors noted that the phenotype showed similarities to Prader-Willi syndrome.

As reviewed by Gilhuis et al. (2000), several obese patients with cytogenetic alterations in the same region of 6q had been reported; all had in common some clinical features, including obesity, hypotonia, and developmental delays, resembling Prader-Willi syndrome. However, their behavior, facial features, and additional neurologic abnormalities, as well as a lack of cytogenetic changes or imprinting mutations on chromosome 15, clearly distinguished this PWS-like phenotype from PWS patients.

Holder et al. (2000) studied a girl with early-onset obesity and a balanced translocation between 1p22.1 and 6q16.2. At 67 months of age she weighed 47.5 kg (+9.3 SD) and was 127.2 cm tall (+3.2 SD); her weight for height was +6.3 SD. The child displayed an aggressive, voracious appetite, and the obesity was thought to be due to high intake, since measured energy expenditure was normal. However, the authors noted that apart from her obesity, there were no features suggestive of PWS. Genetic analysis of the region on chromosome 6 showed that the translocation disrupted the SIM1 gene (603128). Holder et al. (2000) hypothesized that haploinsufficiency of the SIM1 gene may be responsible for the obesity. In a boy with a Prader-Willi-like phenotype, Faivre et al. (2002) identified a deletion of chromosome 6q16.1-q21. Intrauterine growth retardation, oligohydramnios, and a left clubfoot were noted during the third trimester of pregnancy. Later, generalized obesity, slightly dysmorphic facial features, small hands and feet, clumsiness, and mental retardation were observed. Molecular analysis showed that the deletion was paternal in origin and resulted in a deletion of the SIM1 gene.

Other Features

Miller et al. (2007) evaluated 3-dimensional brain MRI scans of 20 individuals with PWS aged 3 months to 39 years. Intracranial morphologic abnormalities included ventriculomegaly (100%), decreased volume of the parietal-occipital lobe (50%), sylvian fissure polymicrogyria (60%), and incomplete insular closure (65%).

Fan et al. (2009) found that 10 of 56 PWS patients had seizures, 9 of whom had generalized seizures attributable to PWS. The remaining patient was born with intraventricular hemorrhage and had focal epileptic discharges, which was thought to be responsible for the seizures. Eight of the 9 with PWS-related seizures had a 15q11-q13 deletion, suggesting that decreased inhibitory effects of the GABA receptor cluster in this region may play a role in epileptogenesis. Six additional patients of the 56 had paroxysmal events such as staring spells, tremor spells, and collapsing spells.

Inheritance

Familial inheritance of PWS has been described frequently. Gabilan (1962) reported a family with affected brother and sister, as well as a second in which the parents of the proband were first cousins, but his patients were not entirely typical.

Jancar (1971) reported familial incidence. Hall and Smith (1972) reported 2 affected male maternal first cousins. One was of normal stature and intelligence. DeFraites et al. (1975) observed 5 cases in 3 sibships of an inbred Louisiana Acadian kindred. Clarren and Smith (1977) reported affected sibs and affected first cousins. They found a recurrence risk of 1.6% in sibs of probands.

It is clear that chromosomal mechanisms are principally responsible for PWS and that the syndrome is caused by lack of the paternal segment 15q11.2-q12. Basically, there are 2 mechanisms by which such a loss can occur: either through deletion of just the paternal 'critical' segment or through loss of the entire paternal chromosome 15 with presence of 2 maternal homologs (uniparental maternal disomy). The opposite, i.e., maternal deletion or paternal uniparental disomy, causes another characteristic phenotype, the Angelman syndrome (AS; 105830). This indicates that both parental chromosomes are differentially imprinted, and that both are necessary for normal embryonic development.

Ming et al. (2000) described 2 cousins with Prader-Willi syndrome resulting from a submicroscopic deletion detected by fluorescence in situ hybridization. Although the karyotype was cytogenetically normal, FISH analysis showed a submicroscopic deletion of SNRPN (182279), but not the closely associated loci D15S10, D15S11, D15S63, and GABRB3 (137192). The affected female and male were offspring of brothers who carried the deletion but were clinically normal, as were also 2 paternal aunts of the probands who likewise had the deletion. The grandmother was deceased and not available for study; the grandfather did not show deletion of SNRPN. DNA methylation analysis of D15S63 was consistent with an abnormality of the imprinting center associated with PWS. Ming et al. (2000) referred to this as grandmatrilineal inheritance, which occurs when a woman with deletion of an imprinted, paternally expressed gene is at risk of having affected grandchildren through her sons. In such an instance, PWS does not become evident as long as the deletion is passed through the female line.

Occurrence of the Prader-Willi Syndrome

The vast majority of PWS cases occur sporadically. These instances include virtually all interstitial deletions, the large majority of de novo unbalanced translocations, all instances of maternal uniparental disomy with normal karyotype or with a de novo rearrangement involving chromosome 15, and almost all cases of maternal uniparental disomy with a familial rearrangement involving chromosome 15. There is no parental age effect whatsoever in the deletion cases.

For full discussion on the mode of inheritance, see Cytogenetics, below.

Recurrence Risk

Monozygotic twins are concordantly affected. However, affected sibs and cousins have repeatedly been reported, and even if a publication bias is considered, their incidence is obviously higher than the estimated incidence in the population of about 1 in 25,000 would suggest. Clarren and Smith (1977) reported affected sibs and first cousins. They found a recurrence risk of 1.6% in sibs of probands. Cassidy (1987) stated that the Prader-Willi Syndrome Association maintained a registry of PWS individuals which, as of December 1986, contained 1,595 names of affected persons in the United States and Canada. While in some of these cases the diagnosis had not been fully confirmed, in only 1 family, that reported by Lubinsky et al. (1987), was there a well-documented recurrence. Thus, it is reasonable to assume that the recurrence risk for PWS is less than 1 in 1,000 and that such recurrence is not likely to occur when a 15q interstitial deletion is identified in the proband. (As pointed out by Kennerknecht (1992), the membership of the PWS association is not limited to affected persons; 'two thirds are families and one third professionals'.)

Ledbetter et al. (1987) summarized a scientific conference on PWS. Of 195 cases studied by high resolution cytogenetic methods, deletion of chromosome 15 was detected in 116 (59.5%); other chromosome 15 abnormalities were found in 7 additional cases (3.6%). It was suggested that the recurrence risk may be as low as 1 in 1,000.

Kennerknecht (1992) used the diagnostic criteria given by Cassidy (1987) to evaluate reported cases of PWS with a view to estimating recurrence risk. Since a deletion at 15q has not been found in familial cases of PWS, except in those where del(15q) is due to familial structural chromosome rearrangement, the recurrence risk with de novo deletion should be nearly zero. In cases with familial translocation, risk estimates depend on the nature of the translocations concerned. If only 1 child is affected and the karyotype is apparently normal, Kennerknecht (1992) estimated an overall recurrence risk of 0.4%. However, if 2 or more sibs are affected, he estimated that the risk to the next sib would be 50%. If every proband were investigated cytogenetically (to ascertain unbalanced chromosome rearrangements), molecularly (with probes to detect invisible deletions and to determine the methylation pattern), and if in each instance of a paternal deletion an examination of the father was carried out, then the few instances with a high recurrence risk could be ascertained before a second child was born.

Mutagenic Factors

Strakowski and Butler (1987) found an increased incidence of paternal periconceptional employment in hydrocarbon-exposing occupations. Among 81 patients with PWS, Cassidy et al. (1989) compared the frequency of possible periconceptional occupational hydrocarbon exposure in those fathers who demonstrated a 15q deletion with the frequency in those who did not. There was no statistically significant difference between the cytogenetically different groups. In both groups, approximately half the fathers had been employed in hydrocarbon-exposing jobs. The data provided additional support for the possibility that hydrocarbon exposure is causally related to the disorder and further suggested lack of etiologic heterogeneity between the cytogenetically different groups.

Cytogenetics

Deletions account for 70 to 80% of cases; the majority are interstitial deletions, many of which can be visualized by prometaphase banding examination. A minority consist of unbalanced translocations, mostly de novo, which are easily detected by routine chromosome examination. The remainder of cases are the result of maternal uniparental disomy. In most of these latter cases, cytogenetic examinations yield normal results. However, in a few cases, either balanced translocations, familial or de novo, or supernumerary small marker chromosomes, are observed.

Deletions

Butler et al. (1986) found an interstitial deletion of chromosome 15 (breakpoints q11 and q13) in 21 of 39 cases and an apparently normal karyotype in the remainder. By studying chromosome 15 heteromorphisms, the del(15q) was demonstrably paternal in origin in all cases, although both parents were normal and all deletions were de novo events. Paternal age was not increased. The exclusively paternal origin of deletions was subsequently confirmed cytogenetically and by molecular marker analysis (Magenis et al., 1990; Zori et al., 1990; Robinson et al., 1991). Examination of other series of patients by different groups resulted in the figures that two-thirds to three-fourths of PWS patients have a deletion of 15q11-q13. In less than 10%, this is due to an unbalanced translocation while the remainder have interstitial deletions.

To analyze the mechanism underlying the interstitial de novo deletions at 15q11-q13 that underlie approximately 70% of PWS cases, Carrozzo et al. (1997) genotyped 10 3-generation families of PWS-deletion patients using microsatellite markers flanking the common deletion region. By FISH and/or other molecular techniques, each patient was known to be deleted for the interval from D15S11 to GABRB3. In 5 of 7 cases, a different grandparental origin was identified for the alleles flanking the deletion, a finding significantly different from the expected frequency in light of the close position of the markers. This finding was considered highly suggestive of an unequal crossover occurring in the paternal meiosis at the breakpoint as the mechanism leading to deletion. The authors noted that asymmetric exchanges between nonsister chromatids in meiosis I have previously been demonstrated and are the basis of a number of genetic diseases. When the related sequences are part of tandemly arrayed homologous genes, nonhomologous recombination may lead to the formation of chimeric genes, such as those of Lapore hemoglobin and of the red-green pigment genes involved in abnormalities of color vision. In other instances, the deletion/duplication event may arise from the unequal recombination between repetitive elements interspersed throughout a genomic region. A misalignment between Alu-repetitive sequences has been demonstrated in duplications of the LDL-receptor gene (606945; Lehrman et al., 1987) and the HPRT gene (308000; Marcus et al., 1993).

In 2 PWS families studied by Carrozzo et al. (1997), the data were consistent with an intrachromosomal mechanism being responsible for the deletion. One of the few precedents for intrachromosomal recombination leading to human disease is provided by the recombination that occurs between the small intronless gene within intron 22 of the factor VIII gene (300841), and a copy of gene A (FSA; 305423) located 500 kb telomeric to the F8 gene, a recombination that causes severe hemophilia (306700) (Lakich et al., 1993). This rearrangement arises almost exclusively in male meioses, indicating that it is intrachromosomal. Carrozzo et al. (1997) suggested that the in-cis mechanism leading to the deletions in PWS patients may be related either to an exchange of chromosomal material between sister chromatids or to the formation of an intrachromosomal loop, either during meiosis or as a somatic event, followed by an excision of the chromosomal material lying between the recombining regions.

Deletions in PWS and AS are subdivided into 2 main groups based on their proximal breakpoints: type 1 deletions encompass the region between BP1 and BP3 (about 6 Mb) and type 2 deletions encompass the region from BP2 to BP3 (about 5.3 Mb). However, some patients have atypical deletions. Using methylation-specific multiplex ligation-dependent probe amplification to analyze the type of deletion in 88 PWS patients, Kim et al. (2012) found that 32 (36.4%) had a type 1 deletion and 49 (55.7%) had a type 2 deletion. Seven patients (8%) had atypical larger (2) or smaller (5) de novo deletions that were associated with unique phenotypic features, although there were no unifying characteristics across the group. Variable atypical clinical features in these patients included macrocephaly, microcephaly, large hands, no hypopigmentation, lack of facial gestalt, and variable cognitive impairment. Kim et al. (2012) discussed the possible role of different genes in the manifestation of different features.

In a 23-year-old woman with Prader-Willi syndrome, Bieth et al. (2015) identified a paternally transmitted 118-kb deletion of the SNORD116 gene cluster. The authors stated that this was the smallest deletion described to that time. SNORD109A and IPW (601491) were also deleted in the patient. SNORD116 expression was absent in patient cells, but present in her unaffected father's cells.

Maternal Uniparental Disomy

Nicholls et al. (1989), studying cases of PWS in which no deletion was cytologically evident using RFLP analysis, were the first to demonstrate maternal uniparental disomy (UPD) in 2 families. Two different, apparently intact, maternal chromosomes were present ('heterodisomy'), and, as with deletion cases of PWS, there was an absence of paternal genes from the 15q11-q13 segment. Robinson et al. (1991) used cytogenetic and molecular techniques to examine 37 patients with features of PWS. Clinical features in 28 of the patients were thought to fulfill diagnostic criteria for typical PWS. In 21 of these, a deletion of the 15q11.2-q12 region could be identified molecularly, including several cases in which the cytogenetic results were inconclusive. Five cases of maternal heterodisomy and 2 of isodisomy for 15q11-q13 were observed. All 9 patients who did not fulfill clinical criteria for typical PWS showed normal maternal and paternal inheritance of chromosome 15 markers; however, one of these carried a ring-15 chromosome. Thus, all typical PWS cases showed either a deletion or maternal uniparental disomy of 15q11.2-q12. As the disomy patients did not show any additional or more severe features than did the typical deletion patients, it is likely that there is only one imprinted region on chromosome 15. A significantly increased mean maternal age was found in the disomy cases, suggesting an association between increased maternal age and nondisjunction.

Mascari et al. (1992) demonstrated maternal uniparental disomy for chromosome 15 in 18 of 30 patients (60%) without a cytogenetic deletion. Furthermore, they confirmed the observation of Robinson et al. (1991) that the phenomenon was associated with advanced maternal age. In another 8 patients (27%), they identified large molecular deletions. The remaining 4 patients (13%) had evidence of normal biparental inheritance for chromosome 15; 3 of these patients were the only ones in the study which had some atypical clinical features. All told, they estimated that about 20% of cases of PWS result from maternal uniparental disomy and that, by the combined use of cytogenetic and molecular techniques, the genetic basis of PWS can be identified in at least 95% of patients.

Mitchell et al. (1996) compared 79 cases of PWS with UPD and 43 cases with deletions. Although there were no major clinical differences between the 2 classes of patients analyzed as a whole, mean maternal and paternal age were significantly higher in the UPD patients. The UPD group had a predominance of males, yet a gender bias was not seen in the deletion group. Hypopigmentation was found in 77% of the deletion group compared to only 39% of the UPD children. When the groups were analyzed by gender, females with UPD tended to be less severely affected than female deletion patients.

Mutirangura et al. (1993) demonstrated maternal heterodisomy in 10 PWS patients. Since the markers used were 13 cM from the centromere, heterodisomy indicated that maternal meiosis I nondisjunction was primarily involved in the origin of UPD. In contrast, 2 paternal disomy cases of Angelman syndrome (AS) showed isodisomy for all markers tested along the length of chromosome 15. This suggested a paternal meiosis II nondisjunction event (without crossing over) or, more likely, monosomic conception (due to maternal nondisjunction) followed by chromosome duplication. The latter mechanism would indicate that at least some instances of uniparental disomy in PWS and AS initiate as reciprocal products of maternal nondisjunction events.

Robinson et al. (1993) reported data indicating that the majority (82%) of maternal nondisjunction events leading to UPD and causing PWS involve a meiosis I error, whereas most paternal UPD Angelman syndrome cases are meiosis II or, more likely, mitotic errors. Robinson et al. (1993) made the interesting statement that the proportion of UPD cases among all PWS patients in Switzerland is higher than in the United States, which could reflect the higher mean maternal age at birth in Switzerland versus the United States.

Gold et al. (2014) studied the frequency of Prader-Willi syndrome in births conceived via assisted reproductive technology (ART). The overall incidence in those who used ART was 1.1%; the population frequency for the United States was 1.0%. However, the proportion of individuals with maternal disomy 15/imprinting defects born after ART was higher than that in the total sample, 55.6% (10 of 18) and 34.5% (431 of 1,250), respectively. As compared with naturally conceived individuals with Prader-Willi syndrome, those who were ART-conceived were more likely to have uniparental disomy and imprinting defects than deletions. This study also demonstrated no association between twinning and Prader-Willi syndrome when ART-conceived pregnancies were excluded.

Rescuing of Trisomy 15

Maternal nondisjunction does not itself directly lead to uniparental disomy but must also involve a further nondisjunction event to produce a euploid embryo. Purvis-Smith et al. (1992) have confirmed such an origin of uniparental disomy 15 resulting from 'correction' of an initial trisomy 15. Routine chorionic villus sampling performed for advanced maternal age led to detection of placental mosaicism for trisomy 15. Follow-up studies on amniotic fluid indicated a normal 46,XY karyotype with no evidence of trisomy 15, and the pregnancy continued to term. At birth, the baby was found to have PWS. Molecular analysis indicated that the mother was the sole contributor of the chromosome 15 pair in the child. Centromere/short-arm heteromorphisms were different in the 2 chromosome 15 homologs, consistent with meiosis I error. Cassidy et al. (1992) reported a similar case that supported the idea that maternal disomy can result from a 'corrected' trisomy 15 and that maternal age was a predisposing factor to nondisjunction. Thus, in any case in which trisomy or mosaic trisomy 15 has been prenatally determined through CVS examination, a molecular study should follow to exclude uniparental (paternal or) maternal disomy. This type of examination should also be considered in case of pregnancies of translocation carrier parents involving chromosome 15.

Devriendt et al. (1997) proposed partial zygotic trisomy rescue as a mechanism for mosaicism for a de novo jumping translocation of distal chromosome 15q, resulting in partial trisomy for 15q24-qter in a patient with PWS. A maternal uniparental heterodisomy for chromosome 15 was present in all cells and was responsible for the PWS phenotype. The translocated 15q segment was of paternal origin and was present as a jumping translocation, involving chromosomes 14q, 4q, and 16p. The recipient chromosomes were cytogenetically intact. Devriendt et al. (1997) reported that mental retardation was more marked in their patient than is usually observed in PWS, and proposed that this was due to partial trisomy for distal 15q.

Multiple Affected Relatives

There are several mechanisms that explain the simultaneous occurrence of affected first- and second-degree relatives in PWS families. These include translocations that give rise to maternal nondisjunction and hence effective maternal uniparental disomy for the PWS region and translocations which give rise to paternally derived deletions.

The first report of involvement of a D group translocation in PWS (later identified as a 15-15 translocation) dates back to 1963 (Buehler et al., 1963). Additional translocations were found subsequently, and after the introduction of chromosome banding it became obvious that at least one chromosome 15 was involved in all instances (Zuffardi et al., 1978; Kucerova et al., 1979; Guanti, 1980). However, the situation was further complicated by cases in which not only the proband had a translocation involving chromosome 15, but the mother and 2 normal sibs showed the seemingly identical translocation as well (Smith and Noel, 1980). In addition, there were a few cases that did not show a translocation involving chromosome 15, but had a small supernumerary chromosome, presumably an isochromosome for the short arm of an acrocentric (Fleischer-Michaelsen et al., 1979; Fujita et al., 1980; Wisniewski et al., 1980).

Smith and Noel (1980) described a family in which a Prader-Willi girl had the same balanced 4;15 translocation as her mother and other phenotypically normal family members. A second such family was observed by Smith et al. (1983). Nicholls et al. (1989) reported a similar family and demonstrated that the Prader-Willi proband had inherited the maternal translocation chromosome plus the normal maternal homolog, but no paternal 15. Therefore, having a balanced translocation involving chromosome 15 predisposes to PWS offspring via nondisjunction, and this is a much more frequent cause than spontaneous nondisjunction, which may arise from chromosomally normal individuals. The opposite, i.e., Angelman syndrome, could also occur with paternal translocation carriers.

The simplest instance is that of a balanced rearrangement with a breakpoint in 15q13 in related male carriers. Fernandez et al. (1987) reported a family with a 15;22 translocation carrier father who had 2 children with PWS because of an unbalanced segregation. Hulten et al. (1991) described a family in which a balanced translocation involving 15q13 was segregating. Females with the translocation appeared to have an increased risk of having children with AS, whereas male carriers of the translocation had an increased risk of having children with PWS.

Ledbetter et al. (1980) pointed out that apparent balanced translocations involving chromosome 15 have been found. The defect may be an alteration in gene expression, i.e., a regulatory defect. Ledbetter et al. (1981), assuming a small deletion of proximal 15q as the cause of the clinical features in the translocated cases, studied 45 persons with the clinical diagnosis of PWS. Of the 45, 25 had an abnormality of chromosome 15 (which in 23 was an interstitial deletion affecting the q11-q12 region). No relatives of probands showed chromosomal changes.

Orstavik et al. (1992) described 3 sibs thought to have the Prader-Willi syndrome but with no abnormality in the 15q11-q13 region detectable by cytogenetic or molecular genetic methods. One of the sibs, a boy, was born at 32 weeks by cesarean section. He was extremely hypotonic and died at 7 days of age from respiratory distress. The other sibs, a 12-year-old brother and a 7-year-old sister, had an accessory nipple and seemingly typical PWS. A paternally inherited submicroscopic deletion was suggested as one possibility. A very small deletion was later molecularly detected in affected members of this family (Tommerup, 1993).

Ishikawa et al. (1987) described 2 sisters with PWS. No interstitial deletion of 15q was detected in either; 1 sister had a possibly unrelated partial deletion of one X chromosome. No molecular investigations were performed in this family.

Lubinsky et al. (1987) reported the cases of 2 brothers and 2 sisters in a single sibship with PWS but apparently normal chromosomes. Results of chromosome studies in the parents and surviving sibs were normal. The diagnosis was made clinically on the basis of history, behavior, and physical findings in 3 of the sibs. The fourth child had died at the age of 10 months with a history and clinical findings typical of the first phase of PWS. Again, no molecular or fluorescence in situ hybridization (FISH) studies were performed. It seems likely that an undetected structural chromosome rearrangement is the cause for this multiple occurrence of PWS.

McEntagart et al. (2000) described a brother and sister with PWS in whom there was no microscopically visible deletion in 15q11-q13 or maternal disomy. Methylation studies at D15S63 and at the SNRPN locus confirmed the diagnosis of PWS. Molecular studies revealed biparental inheritance in both sibs with the exception of 2 markers where no paternal contribution was present, indicating a deletion of the imprinting center. Family studies indicated that the father of the sibs carried the deletion which he had inherited from his mother. Recurrence risk of PWS in his offspring was 50%.

Co-Occurrence of Prader-Willi and Angelman Syndromes

Hasegawa et al. (1984) studied a family in which 2 cousins were claimed to have the Prader-Willi syndrome and found a reciprocal translocation t(14;15)(q11.2;q13) in a single parent of each cousin and in their common grandmother. The affected cousins had the same unbalanced translocation including monosomy of the 15pter-q13 segment. Schinzel et al. (1992) pointed out that the unbalanced karyotype with deletion of 15q11-q13 came from the mother in the case of the proband who had been described to have classic Prader-Willi syndrome and from the father in the case of the cousin; the mother of the proband and the father of the cousin were sister and brother. However, the proband was not hypotonic and had seizures. Schinzel et al. (1992) suggested that the diagnosis in the proband actually may have been Angelman syndrome, consistent with the finding that there has been no reported instance of a patient in which absence of the paternal segment 15q11-q13 does not cause PWS, while the absence of the maternal segment leads to AS.

Another mechanism by which the Prader-Willi syndrome and Angelman syndrome can occur in cousins was reported by Smeets et al. (1992). Two female first cousins were offspring of brothers, both of whom had a familial translocation between chromosome 6 and 15, t(6;15)(p25.3;q11.1). The cousin with the Prader-Willi syndrome had the karyotype 45,XX,-6,-15+t(6;15)(p25.3;q13); DNA studies indicated that there was a large paternally derived deletion of all loci from the Prader-Willi chromosomal region tested. The cousin with Angelman syndrome had the karyotype 45,XX,-6,-15,+t(6;15)(p25.3;q11.1) and DNA studies indicated that she had uniparental heterodisomy, having inherited both the (6;15) translocation and the normal chromosome 15 from her father, but no chromosome 15 from her mother. In an editorial, Hall (1992) suggested that the cousin with Angelman syndrome had started out life as a trisomy and survived only through the loss of extra chromosomal material.

Greenstein (1990) presented a kindred in which both the Prader-Willi and the Angelman syndromes were found; the inheritance pattern was consistent with genetic imprinting.

Marker Chromosomes

Finally, additional small marker chromosomes representing isochromosomes or isodicentric chromosomes from the short arms of acrocentrics have repeatedly been observed (Fleischer-Michaelsen et al., 1979; Fujita et al., 1980; Wisniewski et al., 1980) before Robinson et al. (1993) demonstrated maternal uniparental disomy 15 in a Prader-Willi child mosaic for such a marker and paternal UPD 15 in an Angelman patient also mosaic for a small metacentric marker chromosome.

Investigation of PWS and AS patients with a small inv dup(15) chromosome attributes the abnormal phenotype to uniparental disomy rather than to the extra chromosome (Robinson et al., 1993). The small chromosome may represent either the remnant of the missing parental chromosome 15 or could be associated with nondisjunction.

Park et al. (1998) described an example of maternal disomy and Prader-Willi syndrome consistent with gamete complementation. They considered that the probable event was adjacent-1 segregation of a paternal t(3;15)(p25;q11.2) with simultaneous maternal meiotic nondisjunction for chromosome 15. The patient, a 17-year-old white male with PWS, had 47 chromosomes with a supernumerary, paternal der(15) consisting of the short arm and the proximal long arm of chromosome 15 fused to distal 3p. The t(3;15) was present in the balanced state in the patient's father and a sister. Fluorescence in situ hybridization analysis demonstrated that the PWS critical region resided on the derivative chromosome 3 and that there was no deletion in the PWS region on the normal pair of 15s present in the patient. Maternal disomy was confirmed by 2 methods.

Mapping

Kirkilionis et al. (1991) constructed a long-range restriction map of the PWS region, 15q11.1-q12, using a combination of pulsed-field gel techniques and rare cutting restriction enzymes.

A preliminary YAC contig map was reported by Kuwano et al. (1992), which also localized many common proximal and distal deletion breakpoints to two YACs. Ozcelik et al. (1992) refined the localization of the small nuclear ribonucleoprotein N gene (SNRPN; 182279) within the minimum deletion region. FISH ordering of reference markers in this region was also reported by Knoll et al. (1993) who placed D15S63 in the minimum PWS deletion region between D15S13 and D15S10. Mutirangura et al. (1993) published a complete YAC contig of the PWS/AS critical region and discussed the potential role of uniparental disomy (UPD) in PWS and AS. Buiting et al. (1993) constructed a YAC restriction map of the entire minimum PWS critical region defined by the shortest region of overlap between two key PWS deletion patients. This region is 320 kb and includes D15S63 and SNRPN.

Molecular Genetics

Latt et al. (1987) isolated probes from the proximal region of the long arm of chromosome 15 that are useful in the study of PWS.

Buiting et al. (1992) isolated a putative gene family and candidate genes by microdissection and microcloning from the 15q11-q13 region. One microclone, designated MN7, detected multiple loci in 15q11-q13 and 16p11.2. There were 4 or 5 different MN7 copies spread over a large distance within 15q11-q13. The presence of multiple copies of the MN7 gene family in proximal 15q may be related to the instability of this region and thus to the etiology of PWS and Angelman syndrome.

Using restriction digests with the methyl-sensitive enzymes HpaII and HhaI and probing Southern blots with several genomic and cDNA probes, Driscoll et al. (1992) systematically scanned segments of 15q11-q13 for DNA methylation differences between patients with PWS (20 deletion cases and 20 cases of uniparental disomy) and those with AS (26 deletion cases and 1 case of uniparental disomy). They found that the sequences identified by the cDNA DN34, which is highly conserved in evolution, demonstrate distinct differences in DNA methylation of the parental alleles at the D15S9 locus. Clayton-Smith et al. (1993) used DN34 to perform methylation analysis of 2 first-cousin males, one with AS and the other with PWS. The methylation pattern varied according to the parent of origin, providing further evidence for the association of methylation with genomic imprinting. Thus, DNA methylation can be used as a reliable postnatal diagnostic tool. Dittrich et al. (1992) found that an MspI/HpaII restriction site at the D15S63 locus in 15q11-q13 is methylated on the maternally derived chromosome, but unmethylated on the paternally derived chromosome. Based on this difference, they devised a rapid diagnostic test for patients suspected of having PWS or AS.

The human homolog for the mouse pink-eyed dilution locus (p locus) was found to be equivalent to the D15S12 locus which maps within the PWS/AS deletion region (Rinchik et al., 1993). Mutations in both copies of the P gene were found in a patient with type II oculocutaneous albinism, and it is suggested that deletion of 1 copy of this gene is the cause of hypopigmentation in PWS and AS.

The SNRPN gene was shown by RT-PCR to be expressed in normal and AS individuals, but not in fibroblasts from either deletion or maternal UPD PWS patients who lack a paternal copy of this gene (Glenn et al., 1993). Parent-specific DNA methylation was also identified for the SNRPN gene. Reed and Leff (1994) showed that in the human, as in the mouse, there is maternal imprinting of SNRPN, thus supporting the hypothesis that paternal absence of SNRPN is responsible for the PWS phenotype. See SNRPN (182279) for discussion of evidence indicating that this is a candidate gene in PWS and suggesting that PWS may be caused, in part, by defects in mRNA processing. In 2 sibs with the typical phenotype of PWS but without a cytogenetically detectable deletion in 15q, Ishikawa et al. (1996) demonstrated deletion of SNRPN by FISH.

A DNA transcript, OP2, was identified just centromeric to D15S10 by Woodage et al. (1994). Multiple expressed genes were identified by Sutcliffe (1994) in the region between SNRPN and D15S10. They showed that at least 4 genes are expressed only on the paternal chromosome including SNRPN, PAR1 (600161), PAR5 (600162), and PAR7. A PWS patient with a small paternal deletion showed no expression of these genes, even though the deletion occurs proximal to but not including these maternally imprinted genes, implying a common element involved in regulation of these genes. Wevrick et al. (1994) identified another expressed gene in the region, designated IPW (601491) for 'imprinted gene in the Prader-Willi syndrome region,' that is expressed only from the paternal chromosome 15.

DNA replication was shown by FISH to be asynchronous between maternal and paternal alleles within 15q11-q13 (Knoll et al., 1993). Loci in the PWS-critical region were shown to be early replicating on the paternal chromosome, and alleles within the AS critical region were early replicating on the maternal chromosome. A mosaic replication pattern with maternal and paternal alleles alternatively expressed was noted at the P locus, and is consistent with the presence of hypopigmentation in both PWS and AS due to decreased product.

Schulze et al. (1996) reported a boy with PWS who had a rare translocation and a normal methylation pattern at SNRPN. Although the boy fulfilled the diagnostic criteria for PWS defined by Holm et al. (1993), he had a normal methylation pattern due to the position of the translocation breakpoint.

Cassidy (1997) provided a comprehensive review of the clinical and molecular aspects of Prader-Willi syndrome. Cassidy and Schwartz (1998) provided a similar review of both Prader-Willi syndrome and Angelman syndrome.

PWS and AS are caused by the loss of function of imprinted genes in proximal 15q. In approximately 2 to 4% of patients, this loss of function is the result of an imprinting defect. In some cases, the imprinting defect is the result of a parental imprint-switch failure caused by a microdeletion of the imprinting center (IC). Buiting et al. (1998) described the molecular analysis of 13 PWS patients and 17 AS patients who had an imprinting defect but no IC deletion. Furthermore, heteroduplex and partial sequence analyses did not reveal any point mutations in the known IC elements. All of these patients represented sporadic cases, and some shared the paternal PWS or maternal AS 15q11-q13 haplotype with an unaffected sib. In each of the 5 PWS patients informative for the grandparental origin of the incorrectly imprinted chromosome region and 4 cases described elsewhere, the maternally imprinted paternal chromosome region was inherited from the paternal grandmother. This suggested that the grandmaternal imprint was not erased in the father's germline. In 7 informative AS patients reported by Buiting et al. (1998) and in 3 previously reported patients, the paternally imprinted maternal chromosome region was inherited from either the maternal grandfather or the maternal grandmother. The latter finding was not compatible with an imprint-switch failure, but it suggested that a paternal imprint developed either in the maternal germline or postzygotically. Buiting et al. (1998) concluded that (1) the incorrect imprint in non-IC-deletion cases is the result of a spontaneous prezygotic or postzygotic error; (2) these cases have a low recurrence risk; and (3) the paternal imprint may be the default imprint.

Buiting et al. (2003) described a molecular analysis of 51 patients with PWS and 85 patients with AS. A deletion of an IC was found in 7 patients with PWS (14%) and 8 patients with AS (9%). Sequence analysis of 32 PWS patients and 66 AS patients, neither with an IC deletion, did not reveal any point mutation in the critical IC elements. The presence of a faint methylated band in 27% of patients with AS and no IC deletion suggested that these patients were mosaic for an imprinting defect that occurred after fertilization. In patients with AS, the imprinting defect occurred on the chromosome that was inherited from either the maternal grandfather or grandmother; however, in all informative patients with PWS and no IC deletion, the imprinting defect occurred on the chromosome inherited from the paternal grandmother. These data suggested that this imprinting defect resulted from a failure to erase the maternal imprint during spermatogenesis.

Microdeletions of the imprinting center in 15q11-q13 have been identified in several families with PWS or Angelman syndrome who show epigenetic inheritance for this region that is consistent with a mutation in the imprinting process. The IC controls resetting of parental imprints in this region of 15q during gametogenesis. Ohta et al. (1999) identified a large series of cases of familial PWS, including 1 case with a deletion of only 7.5 kb, that narrowed the PWS critical region to less than 4.3 kb spanning the SNRPN gene CpG island and exon 1. The identification of a strong DNase I hypersensitive site, specific for the paternal allele, and 6 evolutionarily conserved (human-mouse) sequences that are potential transcription factor binding sites is consistent with a conclusion that this region defines the SNRPN gene promoter. These findings suggested that promoter elements at SNRPN play a key role in the initiation of imprint switching during spermatogenesis. Ohta et al. (1999) also identified 3 patients with sporadic PWS who had an imprinting mutation (IM) and no known detectable mutation in the IC. An inherited 15q11-q13 mutation or a trans-factor gene mutation are unlikely; thus, the disease in these patients may arise from a developmental or stochastic failure to switch the maternal-to-paternal imprint during parental gametogenesis. These studies allowed a better understanding of the novel mechanism of human disease, since the epigenetic effect of an imprinting mutation in parental germline determines the phenotypic effect in the patient.

To elucidate the mechanism underlying the deletions that lead to PWS and Angelman syndrome, Amos-Landgraf et al. (1999) characterized the regions containing 2 proximal breakpoint clusters and a distal cluster. Analysis of rodent-human somatic cell hybrids, YAC contigs, and FISH of normal or rearranged chromosomes 15 identified duplicated sequences, termed 'END' repeats, at or near the breakpoints. END-repeat units are derived from large genomic duplications of the HERC2 gene (605837) (Ji et al., 1999). Many copies of the HERC2 gene are transcriptionally active in germline tissues. Amos-Landgraf et al. (1999) postulated that the END repeats flanking 15q11-q13 mediate homologous recombination resulting in deletion. Furthermore, they proposed that active transcription of these repeats in male and female germ cells may facilitate the homologous recombination process.

To identify additional imprinted genes that could contribute to the PWS phenotype and to understand the regional control of imprinting in 15q11-q13, Lee and Wevrick (2000) constructed an imprinted transcript map of the PWS-AS deletion interval. They found 7 new paternally expressed transcripts localized to a domain of approximately 1.5 Mb surrounding the SNRPN-associated imprinting center, which already included 4 imprinted, paternally expressed genes. All other tested new transcripts in the deletion region were expressed from both alleles. A domain of exclusive paternal expression surrounding the imprinting center suggested strong regional control of the imprinting process. Bielinska et al. (2000) reported a PWS family in which the father was mosaic for an imprinting center deletion on his paternal chromosome. The deletion chromosome had acquired a maternal methylation imprint in his somatic cells. Identical observations were made in chimeric mice generated from 2 independent embryonic stem cell lines harboring a similar deletion. Bielinska et al. (2000) concluded that the Prader-Willi syndrome imprinting center element is not only required for the establishment of the paternal imprint, but also for its postzygotic maintenance.

Boccaccio et al. (1999) and Lee et al. (2000) independently cloned and characterized MAGEL2 (605283), a gene within the PWS deletion region. They demonstrated that the MAGEL2 gene is transcribed only from the paternal allele.

Balanced translocations affecting the paternal copy of 15q11-q13 have been proven to be a rare cause of PWS or PWS-like features. Wirth et al. (2001) reported a de novo balanced reciprocal translocation t(X;15)(q28;q12) in a female patient with atypical PWS. The translocation breakpoints in this patient and 2 previously reported patients mapped 70 to 80 kb distal to the SNURF-SNRPN gene (182279) and defined a breakpoint cluster region. The breakpoints disrupted one of several previously unknown 3-prime exons of this gene. RT-PCR experiments demonstrated that sequences distal to the breakpoint, including the C/D box small nucleolar RNA (snoRNA) gene cluster HBII-85/PWCR1 (SNORD116-1; 605436), as well as IPW (601491) and PAR1 (600161), were not expressed in the patient. The authors suggested that lack of expression of these sequences may contribute to the PWS phenotype.

Meguro et al. (2001) determined the allelic expression profiles of 118 cDNA clones using monochromosomal hybrids retaining either a paternal or maternal human chromosome 15. There was a preponderance of unusual transcripts lacking protein-coding potential that were expressed exclusively from the paternal copy of the critical interval. This interval also encompassed a large direct repeat (DR) cluster displaying a potentially active chromatin conformation of paternal origin, as suggested by enhanced sensitivity to nuclease digestion. Database searches revealed an organization of tandemly repeated consensus elements, all of which possessed well-defined C/D box sequences characteristic of small nucleolar RNAs (snoRNAs). Southern blot analysis further demonstrated a considerable degree of phylogenetic conservation of the DR locus in the genomes of all mammalian species tested. The authors suggested that there may be a potential direct contribution of the DR locus, representing a cluster of multiple snoRNA genes, to certain phenotypic features of PWS.

Fulmer-Smentek and Francke (2001) explored whether differences in histone acetylation exist between the 2 parental alleles of SNRPN and other paternally expressed genes in the region by using a chromatin immunoprecipitation assay with antibodies against acetylated histones H3 (see 601058) and H4 (see 602822). SNRPN exon 1, which is methylated on the silent maternal allele, was associated with acetylated histones on the expressed paternal allele only. SNRPN intron 7, which is methylated on the paternal allele, was not associated with acetylated histones on either allele. The paternally expressed genes NDN, IPW, PWCR1/HBII-85, and MAGEL2 were not associated with acetylated histones on either allele. Treatment of the lymphoblastoid cells with trichostatin A, a histone deacetylase inhibitor, did not result in any changes to SNRPN expression or association of acetylated histones with exon 1. Treatment with 5-aza-deoxycytidine, which inhibits DNA methylation, resulted in activation of SNRPN expression from the maternal allele, but was not accompanied by acetylation of histones. The authors hypothesized that histone acetylation at this site may be important for regulation of SNRPN and of other paternally expressed genes in the region, and that histone acetylation may be a secondary event in the process of gene reactivation by CpG demethylation.

The Prader-Willi syndrome/Angelman syndrome region on chromosome 15q11-q13 exemplifies coordinate control of imprinted gene expression over a large chromosomal domain. Establishment of the paternal state of the region requires the PWS imprinting center (PWS-IC); establishment of the maternal state requires the AS-IC. Cytosine methylation of the PWS-IC, which occurs during oogenesis in mice, occurs only after fertilization in humans, so this modification cannot be the gametic imprint for the PWS/AS region in humans. Xin et al. (2001) demonstrated that the PWS-IC shows parent-specific complementary patterns of histone H3 (see 602810) lysine-9 (lys9) and H3 lysine-4 (lys4) methylation. H3 lys9 is methylated on the maternal copy of PWS-IC and H3 lys4 is methylated on the paternal copy. Xin et al. (2001) suggested that H3 lys9 methylation is a candidate maternal gametic imprint for this region, and they showed how changes in chromatin packaging during the life cycle of mammals provide a means of erasing such an imprint in the male germline.

Bittel et al. (2003) performed cDNA microarray analysis of 73 genes/transcripts from the 15q11-q13 region in actively growing lymphoblastoid cell lines established from 9 young adult males: 6 with PWS (3 with deletion and 3 with UPD) and 3 controls. They detected no difference in expression of genes with known biallelic expression located outside the 15q11-q13 region in all cell lines studied. When comparing UPD cell lines with controls, there was no difference in expression levels of biallelically expressed genes from within 15q11-q13 (e.g., OCA2; 611409). Two genes previously identified as maternally expressed, UBE3A (601623) and ATP10C (605855), showed a significant increase in expression in UPD cell lines compared with those from control and PWS deletion patients. The results suggested that differences in expression of candidate genes may contribute to phenotypic differences between the deletion and UPD types of PWS.

Horsthemke et al. (2003) described a girl with PWS who was mosaic for maternal uniparental disomy 15 [upd(15)mat] in blood and skin. The upd event occurred prior to X inactivation. DNA microarray experiments on cloned normal and upd fibroblasts detected several chromosome 15 genes known to be imprinted, but there was no evidence for novel 15q genes showing imprinted expression. Differentially expressed genes on other chromosomes were considered candidates for downstream genes regulated by an imprinted gene and may play a role in the pathogenesis of PWS. Upon finding strongly reduced mRNA levels in upd(15)mat cells of the gene encoding secretogranin II (SCG2; 118930), a precursor of the dopamine-releasing factor secretoneurin, the authors speculated that the hyperphagia in patients with PWS might be due to a defect in dopamine-modulated food reward circuits.

Kantor et al. (2004) constructed a transgene including both the 4.3-kb SNRPN promoter/exon 1 (PWS-SRO) sequence and the 880-bp sequence (AS-SRO) located 35 kb upstream of the SNRPN transcription start site and determined that the transgene carried out the entire imprinting process. The epigenetic features of this transgene resembled those previously observed on the endogenous locus, thus allowing analyses in mouse gametes and early embryos. In gametes, they identified a differentially methylated CpG cluster (DMR) on AS-SRO that was methylated in sperm and unmethylated in oocytes. This DMR specifically bound a maternal allele-discrimination protein that was involved in DMR maintenance through implantation when methylation of PWS-SRO on the maternal allele takes place. While the AS-SRO was required in gametes to confer methylation on PWS-SRO, it was dispensable later in development.

The Prader-Willi deleted region on chromosome 15q11 contains a small nucleolar RNA (snoRNA), HBII-52 (SNORD115-1; 609837), that exhibits sequence complementarity to the alternatively spliced exon Vb of the serotonin receptor HTR2C (312861). Kishore and Stamm (2006) found that HBII-52 regulates alternative splicing of HTR2C by binding to a silencing element in exon Vb. Prader-Willi syndrome patients do not express HBII-52. They have different HTR2C mRNA isoforms than healthy individuals. Kishore and Stamm (2006) concluded that a snoRNA regulates the processing of an mRNA expressed from a gene located on a different chromosome, and the results indicate that a defect in pre-mRNA processing contributes to the Prader-Willi syndrome.

Runte et al. (2005) found that individuals with complete deletion of all copies of HBII-52 had no obvious clinical phenotype, suggesting that HBII-52 does not play a major role in PWS.

Sahoo et al. (2008) reported a boy with all of 7 major clinical criteria for Prader-Willi syndrome, including neonatal hypotonia, feeding difficulties and failure to thrive during infancy, excessive weight gain after 18 months, hyperphagia, hypogonadism, and global developmental delay; facial features were considered equivocal, with bitemporal narrowing and almond-shaped eyes. Additional minor features included behavioral problems, sleep apnea, skin picking, speech delay, and small hands and feet relative to height. High-resolution chromosome and array comparative genomic hybridization showed an atypical deletion of the paternal chromosome within the snoRNA region at chromosome 15q11.2. The deletion encompassed HBII-438A, all 29 snoRNAs comprising the HBII-85 cluster, and the proximal 23 of the 42 snoRNAs comprising the HBII-52 cluster. The data suggested that paternal deficiency of the HBII-85 cluster may cause key manifestations of the PWS phenotype, although some atypical features suggested that other genes in the region may make lesser phenotypic contributions.

De Smith et al. (2009) reported a 19-year-old male with hyperphagia, severe obesity, mild learning difficulties, and hypogonadism, in whom diagnostic tests for PWS had been negative. The authors identified a 187-kb deletion at chromosome 15q11-q13 that encompassed several exons of SNURF-SNRPN, the HBII-85 cluster (SNORD116-1; 605436), and IPW but did not include the HBII-52 cluster. HBII-85 snoRNAs were not expressed in peripheral lymphocytes from the patient. Characterization of the clinical phenotype revealed increased ad libitum food intake, normal basal metabolic rate when adjusted for fat-free mass, partial hypogonadotropic hypogonadism, and growth failure. These findings provided direct evidence for the role of a particular family of noncoding RNAs, the HBII-85 snoRNA cluster, in human energy homeostasis, growth, and reproduction.

Using bioinformatic predictions and experimental verification, Kishore et al. (2010) identified 5 pre-mRNAs (DPM2, 603564; TAF1, 313650; RALGPS1, 614444; PBRM1, 606083; and CRHR1, 122561) containing alternative exons that are regulated by MBII-52, the mouse homolog of HBII-52. Analysis of a single member of the MBII-52 cluster of snoRNAs by RNase protection and Northern blot analysis showed that the MBII-52 expressing unit generated shorter RNAs that originate from the full-length MBII-52 snoRNA through additional processing steps. These novel RNAs associated with hnRNPs and not with proteins associated with canonical C/D box snoRNAs. Kishore et al. (2010) concluded that not a traditional C/D box snoRNA MBII-52, but a processed version lacking the snoRNA stem, is the predominant MBII-52 RNA missing in Prader-Willi syndrome. This processed snoRNA functions in alternative splice site selection.

Kaminsky et al. (2011) presented the largest copy number variant case-control study to that time, comprising 15,749 International Standards for Cytogenomic Arrays cases and 10,118 published controls, focusing on recurrent deletions and duplications involving 14 copy number variant regions. Compared with controls, 14 deletions and 7 duplications were significantly overrepresented in cases, providing a clinical diagnosis as pathogenic. The 15q11.2-q13 (BP2-BP3) deletion was identified in 41 cases and no controls for a p value of 2.77 x 10(-9) and a frequency of 1 in 384 cases.

Diagnosis

Seven clinicians experienced with PWS, in consultation with national and international experts, proposed 2 scoring systems as diagnostic criteria: one for children aged 0-36 months and another for children aged 3 years to adults (Holm et al., 1993).

The American Society of Human Genetics/American College of Medical Genetics Test and Technology Transfer Committee (1996) outlined approaches to the laboratory diagnosis of PWS and Angelman syndrome.

White et al. (1996) exploited the allele-specific replication differences that had been observed in imprinted chromosomal regions to obtain a diagnostic test for detecting uniparental disomy. They used FISH of D15S9 and SNRPN (182279) on interphase nuclei to distinguish between Angelman and Prader-Willi syndrome patient samples with uniparental disomy of 15q11-q13 and those with biparental inheritance. They found that the familial recurrence risks are low when the child has de novo uniparental disomy and may be as high as 50% when the child has biparental inheritance. The frequency of interphase cells with asynchronous replication was significantly lower in patients with uniparental disomy than in patients with biparental inheritance. Within the sample population of patients with biparental inheritance, those with altered methylation and presumably imprinting center mutations could not be distinguished from those with no currently detectable mutation. White et al. (1996) considered the test cost-effective because it could be performed on interphase cells from the same hybridized cytologic preparation in which a deletion was included, and additional specimens were not required to determine the parental origin of chromosome 15.

Kubota et al. (1996) noted that neither FISH nor uniparental disomy (UPD) analysis with microsatellite markers will detect rare PWS patients with imprinting mutations, including small deletions or point mutations in the imprinting center region. They reported that as an initial screening test, methylation analysis has the advantage of detecting all of the major classes of molecular defects involved in PWS (deletions, uniparental disomy, and imprinting mutations) without the need for parental blood. Kubota et al. (1996) reported that in 67 patients examined clinically, the methylation results for PW71 were consistent with the clinical diagnosis. They concluded that SNRPN methylation analysis, similar to PW71 methylation analysis, constitutes a reliable diagnostic test for PWS. They emphasized the importance of conventional cytogenetic analysis in parallel with DNA methylation analysis. They noted that a few patients with signs of PWS have balanced translocations within or distal to SNRPN and normal methylation patterns. They noted also that conventional cytogenetic analysis is important to rule out other cytogenetic anomalies in patients who may have similar clinical manifestations but who do not have PWS.

Since the SNRPN gene is not expressed in any patient with PWS regardless of the underlying cytogenetic or molecular cause, Wevrick and Francke (1996) tested for expression of the SNRPN gene and a control gene in 9 patients with PWS and 40 control individuals by PCR analysis of reverse transcribed mRNA from blood leukocytes. SNRPN expression could readily be detected in blood leukocytes by PCR analysis in all control samples but not in samples from known PWS patients. Four suspected PWS cases were negative for SNRPN expression and were found to have chromosome 15 rearrangements, while the diagnosis of PWS was excluded in 7 other patients with normal SNRPN expression based on clinical, molecular, and cytogenetic findings. Thus, Wevrick and Francke (1996) concluded that the SNRPN-expression test is rapid and reliable in the molecular diagnosis of PWS.

The diagnostic criteria arrived at by a consensus group (Holm et al., 1993) were presented in a table by Schulze et al. (1996). In a point system, 1 point each was allowed for each of 5 major criteria, such as feeding problems in infancy and failure to thrive, and one-half point each for 7 minor criteria, such as hypopigmentation. A minimum of 8.5 points was considered necessary for the diagnosis of PWS.

Hordijk et al. (1999) reported a boy with a PWS-like phenotype who was found to have maternal heterodisomy for chromosome 14. The authors noted that while previous reports of this phenotype had been associated with a Robertsonian translocation involving chromosome 14, in this case the karyotype was normal. Hordijk et al. (1999) concluded that patients with a PWS-like phenotype and normal results of DNA analysis for PWS should be reexamined for uniparental disomy for maternal chromosome 14.

Whittington et al. (2002) compared clinical and genetic laboratory diagnoses of PWS. The genetic diagnosis was established using the standard investigation of DNA methylation of SNRPN, supplemented with cytogenetic studies. The 5 clinical features of floppy at birth, weak cry or inactivity, poor suck, feeding difficulties, and hypogonadism were present in 100% of persons with positive genetic findings, the absence of any 1 predicting a negative genetic finding. The combination of poor suck at birth, weak cry or inactivity, decreased vomiting, and thick saliva correctly classified 92% of all cases. Whittington et al. (2002) hypothesized that these criteria ('core criteria') invariably present when genetic findings are positive and are necessary accompaniments of the genetics of PWS. No subset of clinical and behavioral criteria was sufficient to predict with certainty a positive genetic diagnosis, but the absence of any 1 of the core criteria predicted a negative genetic finding.

Clinical Management

The suggestion of a hypothalamic defect located in the ventromedial or ventrolateral nucleus is plausible, but no such lesion has been reported, nor was such found on careful search in a typical case (Warkany, 1970). Hamilton et al. (1972) showed that the hypogonadism is the hypogonadotropic type and the result of hypothalamic dysfunction. Treatment with clomiphene citrate raised plasma luteinizing hormone, testosterone, and urinary gonadotropin levels to normal and resulted in normal spermatogenesis and physical signs of puberty.

Vagotomy has been successful in correcting obesity in experimental obesity produced by hypothalamic lesions (Hirsch, 1984). Fonkalsrud and Bray (1981) performed truncal vagotomy without pyloroplasty in a 17-year-old boy who had maintained a weight of approximately 264 lb (120 kg) for several years. Initially, he lost weight satisfactorily but by 11 months postoperative he had regained most of the weight. Prader (1991) reported a 17-year-old boy weighing 264 lb (120 kg) who had developed diabetes, required digitalization for cardiac failure, and presented with intolerable behavior problems. Strict dietary control in combination with psychotherapy in a foster environment resulted in a weight reduction to 143 lb (65 kg), cessation of hyperglycemia and glucosuria, and cardiac normalization.

Carrel et al. (1999) presented the results of a randomized controlled study of growth hormone treatment in children with Prader-Willi syndrome. They showed that growth hormone treatment accelerated growth, decreased percent body fat, and increased fat oxidation, but did not significantly increase resting energy expenditure. Improvements in respiratory muscle strength, physical strength, and agility also were observed, leading the authors to suggest that growth hormone treatment may have value in reducing disability in children with PWS. Lindgren et al. (1999) measured resting ventilation, airway occlusion pressure, and respiratory response to CO(2) in 9 children, aged 7 to 14 years, before and 6 to 9 months after the start of growth hormone therapy. Treatment resulted in a significant increase in all 3 measurements.

Studies had shown that GH (139250) therapy with doses of GH typically used for childhood growth improves growth, body composition, physical strength and agility, and fat utilization in children with PWS. However, these measurements remained far from normal after up to 2 years of GH therapy. Carrel et al. (2002) assessed the effects of 24 additional months of GH treatment at varying doses on growth, body composition, strength and agility, pulmonary function, resting energy expenditure, and fat utilization in 46 children with PWS, who had previously been treated with GH therapy for 12 to 24 months. During months 24 to 48 of GH therapy, continued beneficial effects on body composition (decrease in fat mass and increase in lean body mass), growth velocity, and resting energy expenditure occurred with higher GH therapy doses, but not with the lowest dose. Bone mineral density continued to improve at all doses of GH (P less than 0.05). Prior improvements in strength and agility that occurred during the initial 24 months were sustained but did not improve further during the additional 24 months regardless of dose. They authors concluded that salutary and sustained GH-induced changes in growth, body composition, bone mineral density, and physical function in children with PWS can be achieved with daily administration of GH doses greater than or equal to 1 mg/m2.

Marzullo et al. (2007) evaluated the cardiovascular response to GH therapy in 13 adult PWS patients. GH therapy increased cardiac mass devoid of diastolic consequences. The observation of a slight deterioration of right heart function as well as the association between IGF-I and left ventricular function during GH therapy suggested the need for appropriate cardiac and hormonal monitoring.

With regard to genetic counseling, the type of cytogenetic aberration and molecular results determine the recurrence risk. Prenatal molecular investigation from chorionic villi should be recommended in every case despite very low recurrence risk. Prenatal ultrasonographic studies of fetal activity may be useful for a first screening since Prader-Willi fetuses will show diminished fetal movement during the second trimester (Schinzel, 1986). Furthermore, a molecular examination for uniparental disomy is indicated in any pregnancy in which a CVS examination disclosed (mosaic) trisomy 15 and a subsequent cytogenetic examination from amniocytes or fetal blood revealed a normal diploid karyotype.

Treatment with octreotide, a somatostatin (182450) agonist, decreases ghrelin (605353) concentrations in healthy and acromegalic adults and induces weight loss in children with hypothalamic obesity. To investigate whether the high fasting ghrelin concentrations of children with PWS could be suppressed by short-term octreotide administration, Haqq et al. (2003) treated 4 subjects with PWS with octreotide (5 microg/kg-d) for 5 to 7 days and studied ghrelin concentration, body composition, resting energy expenditure, and GH markers. Octreotide treatment decreased mean fasting plasma ghrelin concentration by 67% (P less than 0.05). Meal-related ghrelin suppression was still present after intervention but was blunted. Body weight, body composition, leptin, insulin (176730), resting energy expenditure, and GH parameters did not change. However, one subject's parent noted fewer tantrums over denial of food during octreotide intervention. The authors concluded that short-term octreotide treatment markedly decreased fasting ghrelin concentrations in children with PWS but did not fully ablate the normal meal-related suppression of ghrelin.

Festen et al. (2006) studied the effects of GH treatment on respiratory parameters in prepubertal children with PWS. At baseline, the median apnea hypopnea index (AHI) was 5.1 per hour, mainly due to central apneas. Six months of GH treatment did not aggravate the sleep-related breathing disorders in young PWS children. Festen et al. (2006) concluded that monitoring during upper respiratory tract infection in PWS children should be considered.

Because of the very high (3%) annual death rate of PWS patients, with most deaths occurring during moderate infections, and because PWS patients have hypothalamic dysregulations and show no or few signs of illness, de Lind van Wijngaarden et al. (2008) investigated whether PWS patients suffer from central adrenal insufficiency (CAI) during stressful conditions. They found that 15 (60%) of 25 randomly selected PWS patients had CAI. De Lind van Wijngaarden et al. (2008) concluded that the high percentage of CAI in PWS patients might explain the high rate of sudden death in these patients, particularly during infection-related stress; the authors suggested that treatment with hydrocortisone during acute illness should be considered in PWS patients unless CAI had been ruled out with a metyrapone test.

From a multicenter study of 38 diverse GH-deficient PWS adults, Mogul et al. (2008) concluded that GH improves body composition, normalizes triiodothyronine (T3), and is well tolerated without glucose impairment. Mildly progressive ankle edema in 5 patients was the most serious treatment-emergent adverse event.

Pathogenesis

Relationship of Ghrelin to Hyperphagia

To determine whether ghrelin, a GH (139250) secretagogue with orexigenic properties, is elevated in PWS, Delparigi et al. (2002) measured fasting plasma ghrelin concentration, body composition, and subjective ratings of hunger in 7 subjects with PWS and 30 healthy subjects who had fasted overnight. The mean plasma ghrelin concentration was higher in PWS than in the reference population and this difference remained significant after adjustment for percentage of body fat. A positive correlation was found between plasma ghrelin and subjective ratings of hunger. The authors concluded that ghrelin is elevated in subjects with PWS. They also suggested that ghrelin may be responsible, at least in part, for the hyperphagia observed in PWS.

Haqq et al. (2003) measured fasting serum ghrelin levels in 13 children with PWS with an average age of 9.5 years and body mass index (BMI) of 31.3 kilograms per square meter. The PWS group was compared with 4 control groups: normal weight controls, obese children, and children with melanocortin-4 receptor (155541) mutations and leptin (164160) deficiency. Ghrelin levels in children with PWS were significantly elevated (3-4 fold) compared with BMI-matched obese controls. The authors concluded that elevation of serum ghrelin levels to the degree documented in this study may play a role as an orexigenic factor driving the insatiable appetite and obesity found in PWS.

Feigerlova et al. (2008) studied total plasma ghrelin levels in 40 children with PWS and 84 controls from 2 months to 17 years. Plasma ghrelin levels were higher in children with PWS than controls, both in the youngest children below 3 years who were not receiving GH (771 vs 233 pg/ml, P less than 0.0001) and in the children older than 3 years, all of whom were treated with GH (428 vs 159 pg/ml, P less than 0.0001). The authors concluded that plasma ghrelin levels in children with PWS are elevated at any age, including during the first years of life, thus preceding the development of obesity.

Population Genetics

In a review, Butler (1990) estimated the frequency of PWS at about 1 in 25,000 and suggested that it is the most common syndromal cause of human obesity. In a comprehensive survey of PWS in North Dakota, Burd et al. (1990) identified 17 affected persons, from which they derived a prevalence rate of 1 per 16,062.

Whittington et al. (2001) identified all definite or possible PWS cases in the Anglia and Oxford Health Region of the U.K. (population approximately 5 million people). From a total of 167 people referred with possible PWS, 96 were classified as having PWS on genetic and/or clinical grounds. From this, Whittington et al. (2001) estimated a lower limit of population prevalence of 1 in 52,000 with a proposed true prevalence of 1 in 45,000; a lower limit of birth incidence of 1 in 29,000 was also estimated.

Animal Model

Nakatsu et al. (1992) found that the mouse homolog of a human gene within the PWCR is tightly linked to the p locus, which is the site of mutations affecting pigmentation and is often associated with neurologic abnormalities as well. The p locus is located on mouse chromosome 7 near a chromosomal region associated with imprinting effects. Nakatsu et al. (1992) suggested that the hypopigmentation in both PWS and Angelman syndrome may result from an imprinting effect on the human cognate of the mouse p locus.

Although representing only indirectly an animal model in the usual sense, studies focusing on the effects of imprinted genes on brain development by examining the fate of androgenetic (Ag; duplicated paternal genome) and parthenogenetic/gynogenetic (Pg/Gg; duplicated maternal genome) cells in chimeric mouse embryos (Keverne et al., 1996) sheds interesting light on the pathogenesis of the distinctive neuropsychologic features of PWS and Angelman syndrome. Keverne et al. (1996) observed striking cell-autonomous differences in the role of the 2 types of uniparental cells in brain development. Ag cells with a duplicated paternal genome contributed substantially to the hypothalamic structures and not the cerebral cortex. By contrast, Pg/Gg cells with a duplicated maternal genome contributed substantially to the cortex, striatum, and hippocampus but not to the hypothalamic structures. Furthermore, growth of the brain was enhanced by Pg/Gg and retarded by Ag cells. Keverne et al. (1996) proposed that genomic imprinting may represent a change in strategy controlling brain development in mammals. In particular, genomic imprinting may have facilitated a rapid nonlinear expansion of the brain, especially the cortex, during development over evolutionary time. It is noteworthy that Ag cells were seen predominantly in the medial preoptic area and hypothalamus, regions of the brain concerned with neuroendocrine function and primary motivated behavior, including feeding and sexual behavior, which are disturbed in PWS. Contrariwise, MRI shows that the sylvian fissures are anomalous in Angelman patients, who are severely mentally retarded with speech and movement disorders, findings not inconsistent with the distribution of Pg cells.

Yang et al. (1998) created 2 deletion mutations in mice to understand PWS and the mechanism of the 'imprinting center,' or IC, which maps in part to the promoter and first exon of the SNRPN gene (182279). Mice harboring an intragenic deletion of Snrpn were phenotypically normal, suggesting that mutations of SNRPN are not sufficient to induce PWS. Mice with a larger deletion involving both Snrpn and the putative PWS-IC lacked expression of the imprinted genes Zfp127 (mouse homolog of ZNF127; 176270), Ndn (602117), and lpw, and manifested several phenotypes common to PWS infants. Mice heterozygous for the paternally inherited IC-deletion died as neonates, 72% within 48 hours. At birth, the heterozygous mutant mice were present in the expected mendelian ratio. On the day of birth, the affected mice appeared normal but underweight. There was little hypotonia, but one consistently observed difference was that mutant mice were unable to support themselves on their hind feet, resting on their knees instead. No genital or gonadal hypoplasia was observed at the time of birth.

Gabriel et al. (1999) reported the characterization of a transgene insertion into mouse chromosome 7C, which resulted in mouse models for PWS and AS dependent on the sex of the transmitting parent. Epigenotype (allelic expression and DNA methylation) and fluorescence in situ hybridization analyses indicated that the transgene-induced mutation had generated a complete deletion of the PWS/AS homologous region but had not deleted flanking loci. Because the intact chromosome 7, opposite the deleted homolog, maintained the correct imprint in somatic cells of PWS and AS mice and established the correct imprint in male and female germ cells of AS mice, homologous association and replication asynchrony are not part of the imprinting mechanism. This heritable-deletion mouse model could be particularly useful for the identification of the etiologic genes and mechanisms, phenotypic basis, and therapeutic approaches for PWS.

Muscatelli et al. (2000) also produced mice deficient for necdin (602117), and suggested that postnatal lethality associated with loss of the paternal gene may vary dependent on the strain. Viable necdin mutants showed a reduction in both oxytocin (167050)-producing and luteinizing hormone-releasing hormone (LHRH; 152760)-producing neurons in hypothalamus, increased skin scraping activity, and improved spatial learning and memory. The authors proposed that underexpression of necdin is responsible for at least a subset of the multiple clinical manifestations of PWS.

Chamberlain et al. (2004) reported survival of PWS-IC deletion mice on a variety of strain backgrounds. Expression analysis of genes affected in the PWS region suggested that while there was low expression from both parental alleles in PWS-IC deletion pups, this expression did not explain their survival on certain strain backgrounds. Rather, the data provided evidence for strain-specific modifier genes that supported the survival of PWS-IC deletion mice.

Lee et al. (2005) demonstrated that morphologic abnormalities in axonal outgrowth and fasciculation manifested in several regions of the nervous system in Ndn (602117)-null mouse embryos, including axons of sympathetic, retinal ganglion cell, serotonergic, and catecholaminergic neurons. Lee et al. (2005) concluded that necdin mediates intracellular processes essential for neurite outgrowth and that loss of necdin may impinge on axonal outgrowth, and further suggested that loss of necdin may contribute to the neurologic phenotype of PWS. They speculated that codeletion of necdin and the related protein Magel2 (605283) may explain the lack of single gene mutations in PWS.

History

Langdon-Down (1828-1896), who described 'mongolism' (Down syndrome), also described PWS (Down, 1887) about 70 years before Prader et al. (1956), and called it polysarcia (see account by Brain, 1967). The patient was a mentally subnormal girl who, when 13 years old, was 4 feet 4 inches tall (1.32 m) and weighed 196 lbs (84 kg). At 25 years of age she weighed 210 lbs (95.4 kg). 'Her feet and hands remained small, and contrasted remarkably with the appendages they terminated. She had no hair in the axillae, and scarcely any on the pubis. She had never menstruated, nor did she exhibit the slightest sexual instinct.'