omim entry - # 176270 - prader-willi syndrome; pws.pdf

8/12/2019 OMIM Entry - # 176270 - PRADER-WILLI SYNDROME; PWS.pdf

1/27


2/27

27/5/2014 OMIM Entry - # 176270 - PRADER-WILLI SYNDROME; PWS

http://omim.org/entry/176270?search=prader-willi&highlight=praderwilli 2/27

neonatal features of the syndrome (peculiar cry, characteristic craniofacial features, and clinical evidence of hypogonadism). The authors suggested thatspecific genetic testing for PWS be considered for all neonates with undiagnosed central hypotonia even in the absence of the other major features of thesyndrome.

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 bythe abnormal methylation test. All had a distinctive facial appearance, with high prominent forehead, narrow bifrontal diameter, downturned corners of themouth, 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 5patients 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 aspsychologic problems. Diminished growth is observed in the majority of infants (Butler and Meaney, 1987). Small hands with delicate and tapering fingersand 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 bya narrow bifrontal diameter, almond-shaped eyes (often in mild upslanted position), strabismus, full cheeks, and diminished mimic activity due to muscularhypotonia. Plethoric obesity becomes the most striking feature. From the age of about 6 years onward, many children present scars from scratching due toitching, 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 severalauthors remarked that this sign is confined to cases with deletions and absent in those with maternal disomy 15. Phelan et al. (1988) presented a blackfemale child with oculocutaneous albinism, PWS, and an interstitial deletion of 15q11.2. Patients with classic albinism (203100) have misrouting of opticfibers, with fibers from 20 degrees or more of the temporal retina crossing at the chiasm instead of projecting to the ipsilateral hemisphere. Misrouting canresult in strabismus and nystagmus. Because patients with PWS have hypopigmentation and strabismus, Creel et al. (1986) studied 6 patients, selected for ahistory of strabismus, with pattern-onset visual evoked potentials on binocular and monocular stimulation. Of the 4 with hypopigmentation, 3 hadabnormal 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 avariant and that a hypothalamic disturbance is responsible for this disorder. Hall and Smith (1972) pointed out narrow bifrontal cranial diameter as afeature. 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 overweightchildren 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 authorsconcluded 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 childrenwith PWS, adiposity was associated with reduced fat-free mass, and extracellular-to-intracellular water ratio was increased. Both findings are related togrowth hormone (GH; 139250) function and physical activity. Bone mineral density, especially in the limbs, tends to be reduced in patients with PWS andis 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 anyinfant 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 poorsuck and global developmental delay should have DNA testing. From 6 years to 12 years any child with history of hypotonia and poor suck, globaldevelopmental 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 impacton 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 withmaternal 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 ratherthan the more common maternal heterodisomy. They concluded that the more severe PWS phenotype was due to trisomy 15 mosaicism rather than tohomozygosity 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, alimentarydiabetes frequently sets in during or soon after the period of puberty. Puberty itself is diminished in PWS patients of both sexes. Adolescents and young
http://omim.org/entry/139250http://omim.org/entry/164160http://omim.org/entry/203100


3/27


4/27



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 psychoticdisorder included early and acute onset, polymorphous and shifting symptoms, psychiatric hospitalization along with precipitating stress factors, and aprodromal 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 patientsregistered with the PWS Association compared with cases in the general US population based on the SEER program. The median age of 1,024 PWSpatients 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 authorsspeculated that a gene within the 15q11-q13 region may be involved in the biology of myeloid leukemia or that secondary manifestations of PWS, such asobesity, 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 reducedproportion of nonmethylated SNURF-SNRPN alleles in peripheral blood DNA. Microsatellite analysis and FISH revealed apparently normal chromosomes15 of biparental origin. Wey et al. (2005) estimated that approximately 50% of the patient's blood cells had an imprinting defect. Apart from a rathernormal facial appearance, the proband had typical features of PWS in terms of truncal obesity, small hands with tapered fingers, and small feet. Operationfor strabismus had been performed. When evaluated at 21 years of age, she presented with the major signs of PWS, except for the relatively normal facialappearance. Wey et al. (2005) suggested that the patient, although presenting with atypical PWS features at birth and in infancy, had progressivelyacquired 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 hadhypertension, 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 patientshad significantly lower functioning, particularly in activities of daily living, compared to younger control patients, and the decline began around age 40. All8 patients with maternal uniparental disomy used psychotropic medications, 7 of whom had a psychiatric disorder. None of the 4 patients with a paternaldeletion 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 fromabnormalities in sex hormone levels. Sinnema et al. (2012) noted that the life expectancy of individuals with PWS had increased in recent years, and thatthese individuals have specific medical and social needs as they age.

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 psychomotordevelopment. 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 novointerstitial deletion of chromosome 6q16.2-q21. The authors noted the phenotypic similarities to Prader-Willi syndrome. In a boy with clinical featuresmimicking 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 boyshowed 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-Willisyndrome.

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 someclinical features, including obesity, hypotonia, and developmental delays, resembling Prader-Willi syndrome. However, their behavior, facial features, andadditional 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 47.5kg (+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 wasthought to be due to high intake, since measured energy expenditure was normal. However, the authors noted that apart from her obesity, there were nofeatures 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 thirdtrimester of pregnancy. Later, generalized obesity, slightly dysmorphic facial features, small hands and feet, clumsiness, and mental retardation wereobserved. 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 abnormalitiesincluded ventriculomegaly (100%), decreased volume of the parietal-occipital lobe (50%), sylvian fissure polymicrogyria (60%), and incomplete insular
http://omim.org/entry/603128


5/27



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 bornwith intraventricular hemorrhage and had focal epileptic discharges, which was thought to be responsible for the seizures. Eight of the 9 with PWS-relatedseizures had a 15q11-q13 deletion, suggesting that decreased inhibitory effects of the GABA receptor cluster in this region may play a role inepileptogenesis. 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 affectedfirst 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 entirepaternal chromosome 15 with presence of 2 maternal homologs (uniparental maternal disomy). The opposite, i.e., maternal deletion or paternal uniparentaldisomy, causes another characteristic phenotype, the Angelman syndrome (AS; 105830). This indicates that both parental chromosomes are differentiallyimprinted, 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 associatedloci D15S10, D15S11, D15S63, and GABRB3 (137192). The affected female and male were offspring of brothers who carried the deletion but were clinicallynormal, as were also 2 paternal aunts of the probands who likewise had the deletion. The grandmother was deceased and not available for study; thegrandfather did not show deletion of SNRPN. DNA methylation analysis of D15S63 was consistent with an abnormality of the imprinting center associatedwith PWS. Ming et al. (2000) referred to this as grandmatrilineal inheritance, which occurs when a woman with deletion of an imprinted, paternallyexpressed 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 ispassed 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 unbalancedtranslocations, all instances of maternal uniparental disomy with normal karyotype or with a de novo rearrangement involving chromosome 15, and almostall cases of maternal uniparental disomy with a familial rearrangement involving chromosome 15. There is no parental age effect whatsoever in the deletioncases.

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 isconsidered, 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 SyndromeAssociation maintained a registry of PWS individuals which, as of December 1986, contained 1,595 names of affected persons in the United States andCanada. 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 tooccur when a 15q interstitial deletion is identified in the proband. (As pointed out by Kennerknecht (1992), the membership of the PWS association is notlimited 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 chromosome15 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. Sincea 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, therecurrence risk with de novo deletion should be nearly zero. In cases with familial translocation, risk estimates depend on the nature of the translocationsconcerned. 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 ascertainunbalanced chromosome rearrangements), molecularly (with probes to detect invisible deletions and to determine the methylation pattern), and if in eachinstance 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 asecond child was born.

Mutagenic Factors
http://omim.org/entry/137192http://omim.org/entry/182279http://omim.org/entry/105830


6/27



Strakowski and Butler (1987) found an increased incidence of paternal periconceptional employment in hydrocarbon-exposing occupations. Among 81patients with PWS, Cassidy et al. (1989) compared the frequency of possible periconceptional occupational hydrocarbon exposure in those fathers whodemonstrated a 15q deletion with the frequency in those who did not. There was no statistically significant difference between the cytogenetically differentgroups. In both groups, approximately half the fathers had been employed in hydrocarbon-exposing jobs. The data provided additional support for thepossibility that hydrocarbon exposure is causally related to the disorder and further suggested lack of etiologic heterogeneity between the cytogeneticallydifferent 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. Aminority consist of unbalanced translocations, mostly de novo, which are easily detected by routine chromosome examination. The remainder of cases arethe 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 theremainder. By studying chromosome 15 heteromorphisms, the del(15q) was demonstrably paternal in origin in all cases, although both parents werenormal and all deletions were de novo events. Paternal age was not increased. The exclusively paternal origin of deletions was subsequently confirmedcytogenetically and by molecular marker analysis (Magenis et al., 1990; Zori et al., 1990; Robinson et al., 1991). Examination of other series of patients bydifferent 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 othermolecular techniques, each patient was known to be deleted for the interval from D15S11 to GABRB3. In 5 of 7 cases, a different grandparental origin wasidentified for the alleles flanking the deletion, a finding significantly different from the expected frequency in light of the close position of the markers. Thisfinding 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 numberof genetic diseases. When the related sequences are part of tandemly arrayed homologous genes, nonhomologous recombination may lead to the formationof chimeric genes, such as those of Lapore hemoglobin and of the red-green pigment genes involved in abnormalities of color vision. In other instances, thedeletion/duplication event may arise from the unequal recombination between repetitive elements interspersed throughout a genomic region. Amisalignment between Alu-repetitive sequences has been demonstrated in duplications of the LDL-receptor gene (606945; Lehrman et al., 1987) and theHPRT 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. Oneof the few precedents for intrachromosomal recombination leading to human disease is provided by the recombination that occurs between the smallintronless 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, arecombination that causes severe hemophilia (306700) (Lakich et al., 1993). This rearrangement arises almost exclusively in male meioses, indicating that itis intrachromosomal. Carrozzo et al. (1997) suggested that the in-cis mechanism leading to the deletions in PWS patients may be related either to anexchange 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 andBP3 (about 6 Mb) and type 2 deletions encompass the region from BP2 to BP3 (about 5.3 Mb). However, some patients have atypical deletions. Usingmethylation-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 wereassociated with unique phenotypic features, although there were no unifying characteristics across the group. Variable atypical clinical features in thesepatients 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.

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 maternaluniparental disomy (UPD) in 2 families. Two different, apparently intact, maternal chromosomes were present ('heterodisomy'), and, as with deletion casesof PWS, there was an absence of paternal genes from the 15q11-q13 segment. Robinson et al. (1991) used cytogenetic and molecular techniques to examine37 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 ofthe 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 maternaland paternal inheritance of chromosome 15 markers; however, one of these carried a ring-15 chromosome. Thus, all typical PWS cases showed either adeletion or maternal uniparental disomy of 15q11.2-q12. As the disomy patients did not show any additional or more severe features than did the typicaldeletion patients, it is likely that there is only one imprinted region on chromosome 15. A significantly increased mean maternal age was found in thedisomy cases, suggesting an association between increased maternal age and nondisjunction.
http://omim.org/entry/306700http://omim.org/entry/305423http://omim.org/entry/300841http://omim.org/entry/308000http://omim.org/entry/606945


7/27


8/27



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 thanspontaneous nondisjunction, which may arise from chromosomally normal individuals. The opposite, i.e., Angelman syndrome, could also occur withpaternal 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 witha 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 ingene 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 thetranslocated cases, studied 45 persons with the clinical diagnosis of PWS. Of the 45, 25 had an abnormality of chromosome 15 (which in 23 was aninterstitial 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 bycytogenetic 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 7days 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. Apaternally inherited submicroscopic deletion was suggested as one possibility. A very small deletion was later molecularly detected in affected members ofthis 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 ofone 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 ofchromosome studies in the parents and surviving sibs were normal. The diagnosis was made clinically on the basis of history, behavior, and physicalfindings 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, nomolecular or fluorescence in situ hybridization (FISH) studies were performed. It seems likely that an undetected structural chromosome rearrangement isthe 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 sibswith the exception of 2 markers where no paternal contribution was present, indicating a deletion of the imprinting center. Family studies indicated that thefather 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 includingmonosomy of the 15pter-q13 segment. Schinzel et al. (1992) pointed out that the unbalanced karyotype with deletion of 15q11-q13 came from the motherin 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 theproband and the father of the cousin were sister and brother. However, the proband was not hypotonic and had seizures. Schinzel et al. (1992) suggestedthat the diagnosis in the proband actually may have been Angelman syndrome, consistent with the finding that there has been no reported instance of apatient 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 femalefirst 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 thePrader-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 allloci 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 DNAstudies indicated that she had uniparental heterodisomy, having inherited both the (6;15) translocation and the normal chromosome 15 from her father, butno chromosome 15 from her mother. In an editorial, Hall (1992) suggested that the cousin with Angelman syndrome had started out life as a trisomy andsurvived 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 withgenetic 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 maternaluniparental 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 metacentricmarker chromosome.

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


9/27



associated with nondisjunction.

Park et al. (1998) described an example of maternal disomy and Prader-Willi syndrome consistent with gamete complementation. They considered that theprobable event was adjacent-1 segregation of a paternal t(3;15)(p25;q11.2) with simultaneous maternal meiotic nondisjunction for chromosome 15. Thepatient, a 17-year-old white male with PWS, had 47 chromosomes with a supernumerary, paternal der(15) consisting of the short arm and the proximallong 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 situhybridization analysis demonstrated that the PWS critical region resided on the derivative chromosome 3 and that there was no deletion in the PWS regionon the normal pair of 15s present in the patient. Maternal disomy was confirmed by 2 methods.

MappingKirkilionis et al. (1991) constructed a long-range restriction map of the PWS region, 15q11.1-q12, using a combination of pulsed-field gel techniques andrare 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 twoYACs. 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 ofuniparental disomy (UPD) in PWS and AS. Buiting et al. (1993) constructed a YAC restriction map of the entire minimum PWS critical region defined bythe 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 andAngelman syndrome.

Using restriction digests with the methyl-sensitive enzymes HpaII and HhaI and probing Southern blots with several genomic and cDNA probes, Driscoll etal. (1992) systematically scanned segments of 15q11-q13 for DNA methylation differences between patients with PWS (20 deletion cases and 20 cases ofuniparental 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 areliable postnatal diagnostic tool. Dittrich et al. (1992) found that an MspI/HpaII restriction site at the D15S63 locus in 15q11-q13 is methylated on thematernally derived chromosome, but unmethylated on the paternally derived chromosome. Based on this difference, they devised a rapid diagnostic test forpatients 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/ASdeletion 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 issuggested 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 PWSpatients 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 ofSNRPN is responsible for the PWS phenotype. See SNRPN (182279) for discussion of evidence indicating that this is a candidate gene in PWS andsuggesting that PWS may be caused, in part, by defects in mRNA processing. In 2 sibs with the typical phenotype of PWS but without a cytogeneticallydetectable 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) inthe 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 occursproximal 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 onlyfrom 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 consistentwith 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 thediagnostic criteria for PWS defined by Holm et al. (1993), he had a normal methylation pattern due to the position of the translocation breakpoint.
http://omim.org/entry/601491http://omim.org/entry/600162http://omim.org/entry/600161http://omim.org/entry/182279http://omim.org/entry/182279


10/27



Cassidy (1997) provided a comprehensive review of the clinical and molecular aspects of Prader-Willi syndrome. Cassidy and Schwartz (1998) provided asimilar 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 ofan imprinting defect. In some cases, the imprinting defect is the result of a parental imprint-switch failure caused by a microdeletion of the imprintingcenter (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 representedsporadic cases, and some shared the paternal PWS or maternal AS 15q11-q13 haplotype with an unaffected sib. In each of the 5 PWS patients informativefor the grandparental origin of the incorrectly imprinted chromosome region and 4 cases described elsewhere, the maternally imprinted paternalchromosome 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 regionwas inherited from either the maternal grandfather or the maternal grandmother. The latter finding was not compatible with an imprint-switch failure, butit suggested that a paternal imprint developed either in the maternal germline or postzygotically. Buiting et al. (1998) concluded that (1) the incorrectimprint 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 paternalimprint 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 mutationin 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 mosaicfor an imprinting defect that occurred after fertilization. In patients with AS, the imprinting defect occurred on the chromosome that was inherited fromeither the maternal grandfather or grandmother; however, in all informative patients with PWS and no IC deletion, the imprinting defect occurred on thechromosome inherited from the paternal grandmother. These data suggested that this imprinting defect resulted from a failure to erase the maternalimprint during spermatogenesis.

Microdeletions of the imprinting center in 15q11-q13 have been identified in several families with PWS or Angelman syndrome who show epigeneticinheritance for this region that is consistent with a mutation in the imprinting process. The IC controls resetting of parental imprints in this region of 15qduring 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 thePWS 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, specificfor the paternal allele, and 6 evolutionarily conserved (human-mouse) sequences that are potential transcription factor binding sites is consistent with aconclusion that this region defines the SNRPN gene promoter. These findings suggested that promoter elements at SNRPN play a key role in the initiationof imprint switching during spermatogenesis. Ohta et al. (1999) also identified 3 patients with sporadic PWS who had an imprinting mutation (IM) and noknown detectable mutation in the IC. An inherited 15q11-q13 mutation or a trans-factor gene mutation are unlikely; thus, the disease in these patients mayarise from a developmental or stochastic failure to switch the maternal-to-paternal imprint during parental gametogenesis. These studies allowed a betterunderstanding 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 regionscontaining 2 proximal breakpoint clusters and a distal cluster. Analysis of rodent-human somatic cell hybrids, YAC contigs, and FISH of normal orrearranged chromosomes 15 identified duplicated sequences, termed 'END' repeats, at or near the breakpoints. END-repeat units are derived from largegenomic 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, theyproposed 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, Leeand Wevrick (2000) constructed an imprinted transcript map of the PWS-AS deletion interval. They found 7 new paternally expressed transcripts localizedto a domain of approximately 1.5 Mb surrounding the SNRPN-associated imprinting center, which already included 4 imprinted, paternally expressedgenes. All other tested new transcripts in the deletion region were expressed from both alleles. A domain of exclusive paternal expression surrounding theimprinting center suggested strong regional control of the imprinting process. Bielinska et al. (2000) reported a PWS family in which the father was mosaicfor 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 forits postzygotic maintenance.

Boccaccio et al. (1999) and Lee et al. (2000) independently cloned and characterized MAGEL2 (605283), a gene within the PWS deletion region. Theydemonstrated 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 patientand 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) andPAR1 (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 maternalhuman chromosome 15. There was a preponderance of unusual transcripts lacking protein-coding potential that were expressed exclusively from the
http://omim.org/entry/600161http://omim.org/entry/601491http://omim.org/entry/605436http://omim.org/entry/182279http://omim.org/entry/605283http://omim.org/entry/605837


11/27



paternal copy of the critical interval. This interval also encompassed a large direct repeat (DR) cluster displaying a potentially active chromatinconformation of paternal origin, as suggested by enhanced sensitivity to nuclease digestion. Database searches revealed an organization of tandemlyrepeated consensus elements, all of which possessed well-defined C/D box sequences characteristic of small nucleolar RNAs (snoRNAs). Southern blotanalysis further demonstrated a considerable degree of phylogenetic conservation of the DR locus in the genomes of all mammalian species tested. Theauthors suggested that there may be a potential direct contribution of the DR locus, representing a cluster of multiple snoRNA genes, to certain phenotypicfeatures of PWS.

Fulmer-Smentek and Francke (2001) explored whether differences in histone acetylation exist between the 2 parental alleles of SNRPN and other paternallyexpressed genes in the region by using a chromatin immunoprecipitation assay with antibodies against acetylated histones H3 (see 601058) and H4 (see602822). 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 genesNDN, IPW, PWCR1/HBII-85, and MAGEL2 were not associated with acetylated histones on either allele. Treatment of the lymphoblastoid cells withtrichostatin 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 notaccompanied by acetylation of histones. The authors hypothesized that histone acetylation at this site may be important for regulation of SNRPN and ofother paternally expressed genes in the region, and that histone acetylation may be a secondary event in the process of gene reactivation by CpGdemethylation.

The Prader-Willi syndrome/Angelman syndrome region on chromosome 15q11-q13 exemplifies coordinate control of imprinted gene expression over alarge chromosomal domain. Establishment of the paternal state of the region requires the PWS imprinting center (PWS-IC); establishment of the maternalstate requires the AS-IC. Cytosine methylation of the PWS-IC, which occurs during oogenesis in mice, occurs only after fertilization in humans, so thismodification cannot be the gametic imprint for the PWS/AS region in humans. Xin et al. (2001) demonstrated that the PWS-IC shows parent-specificcomplementary 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 thisregion, and they showed how changes in chromatin packaging during the life cycle of mammals provide a means of erasing such an imprint in the malegermline.

Bittel et al. (2003) performed cDNA microarray analysis of 73 genes/transcripts from the 15q11-q13 region in actively growing lymphoblastoid cell linesestablished 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 withknown biallelic expression located outside the 15q11-q13 region in all cell lines studied. When comparing UPD cell lines with controls, there was nodifference in expression levels of biallelically expressed genes from within 15q11-q13 (e.g., OCA2; 611409). Two genes previously identified as maternallyexpressed, UBE3A (601623) and ATP10C (605855), showed a significant increase in expression in UPD cell lines compared with those from control andPWS deletion patients. The results suggested that differences in expression of candidate genes may contribute to phenotypic differences between thedeletion 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 eventoccurred prior to X inactivation. DNA microarray experiments on cloned normal and upd fibroblasts detected several chromosome 15 genes known to beimprinted, but there was no evidence for novel 15q genes showing imprinted expression. Differentially expressed genes on other chromosomes wereconsidered candidates for downstream genes regulated by an imprinted gene and may play a role in the pathogenesis of PWS. Upon finding stronglyreduced 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 epigeneticfeatures of this transgene resembled those previously observed on the endogenous locus, thus allowing analyses in mouse gametes and early embryos. Ingametes, they identified a differentially methylated CpG cluster (DMR) on AS-SRO that was methylated in sperm and unmethylated in oocytes. This DMRspecifically bound a maternal allele-discrimination protein that was involved in DMR maintenance through implantation when methylation of PWS-SROon 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 sequencecomplementarity to the alternatively spliced exon Vb of the serotonin receptor HTR2C (312861). Kishore and Stamm (2006) found that HBII-52 regulatesalternative splicing of HTR2C by binding to a silencing element in exon Vb. Prader-Willi syndrome patients do not express HBII-52. They have differentHTR2C mRNA isoforms than healthy individuals. Kishore and Stamm (2006) concluded that a snoRNA regulates the processing of an mRNA expressedfrom 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 doesnot 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 wereconsidered equivocal, with bitemporal narrowing and almond-shaped eyes. Additional minor features included behavioral problems, sleep apnea, skinpicking, speech delay, and small hands and feet relative to height. High-resolution chromosome and array comparative genomic hybridization showed anatypical deletion of the paternal chromosome within the snoRNA region at chromosome 15q11.2. The deletion encompassed HBII-438A, all 29 snoRNAscomprising the HBII-85 cluster, and the proximal 23 of the 42 snoRNAs comprising the HBII-52 cluster. The data suggested that paternal deficiency of theHBII-85 cluster may cause key manifestations of the PWS phenotype, although some atypical features suggested that other genes in the region may make
http://omim.org/entry/312861http://omim.org/entry/609837http://omim.org/entry/118930http://omim.org/entry/605855http://omim.org/entry/601623http://omim.org/entry/611409http://omim.org/entry/602810http://omim.org/entry/602822http://omim.org/entry/601058


12/27



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 diagnostictests 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 peripherallymphocytes from the patient. Characterization of the clinical phenotype revealed increased ad libitum food intake, normal basal metabolic rate whenadjusted for fat-free mass, partial hypogonadotropic hypogonadism, and growth failure. These findings provided direct evidence for the role of a particularfamily 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 asingle member of the MBII-52 cluster of snoRNAs by RNase protection and Northern blot analysis showed that the MBII-52 expressing unit generatedshorter RNAs that originate from the full-length MBII-52 snoRNA through additional processing steps. These novel RNAs associated with hnRNPs and notwith 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 processedversion lacking the snoRNA stem, is the predominant MBII-52 RNA missing in Prader-Willi syndrome. This processed snoRNA functions in alternativesplice site selection.

Kaminsky et al. (2011) presented the largest copy number variant case-control study to that time, comprising 15,749 International Standards forCytogenomic 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. The15q11.2-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 forchildren 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 tothe 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 testfor detecting uniparental disomy. They used FISH of D15S9 and SNRPN (182279) on interphase nuclei to distinguish between Angelman and Prader-Willisyndrome patient samples with uniparental disomy of 15q11-q13 and those with biparental inheritance. They found that the familial recurrence risks arelow 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 cellswith asynchronous replication was significantly lower in patients with uniparental disomy than in patients with biparental inheritance. Within the samplepopulation of patients with biparental inheritance, those with altered methylation and presumably imprinting center mutations could not be distinguishedfrom those with no currently detectable mutation. White et al. (1996) considered the test cost-effective because it could be performed on interphase cellsfrom the same hybridized cytologic preparation in which a deletion was included, and additional specimens were not required to determine the parentalorigin of chromosome 15.

Kubota et al. (1996) noted that neither FISH nor uniparental disomy (UPD) analysis with microsatellite markers will detect rare PWS patients withimprinting 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, andimprinting mutations) without the need for parental blood. Kubota et al. (1996) reported that in 67 patients examined clinically, the methylation results forPW71 were consistent with the clinical diagnosis. They concluded that SNRPN methylation analysis, similar to PW71 methylation analysis, constitutes areliable diagnostic test for PWS. They emphasized the importance of conventional cytogenetic analysis in parallel with DNA methylation analysis. Theynoted 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 donot 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 transcribedmRNA from blood leukocytes. SNRPN expression could readily be detected in blood leukocytes by PCR analysis in all control samples but not in samplesfrom known PWS patients. Four suspected PWS cases were negative for SNRPN expression and were found to have chromosome 15 rearrangements, whilethe 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 eachwas 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 thatwhile previous reports of this phenotype had been associated with a Robertsonian translocation involving chromosome 14, in this case the karyotype wasnormal. Hordijk et al. (1999) concluded that patients with a PWS-like phenotype and normal results of DNA analysis for PWS should be reexamined foruniparental disomy for maternal chromosome 14.
http://omim.org/entry/182279http://omim.org/entry/122561http://omim.org/entry/606083http://omim.org/entry/614444http://omim.org/entry/313650http://omim.org/entry/603564http://omim.org/entry/605436


13/27



Whittington et al. (2002) compared clinical and genetic laboratory diagnoses of PWS. The genetic diagnosis was established using the standardinvestigation of DNA methylation of SNRPN, supplemented with cytogenetic studies. The 5 clinical features of floppy at birth, weak cry or inactivity, poorsuck, feeding difficulties, and hypogonadism were present in 100% of persons with positive genetic findings, the absence of any 1 predicting a negativegenetic 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 necessaryaccompaniments of the genetics of PWS. No subset of clinical and behavioral criteria was sufficient to predict with certainty a positive genetic diagnosis, butthe absence of any 1 of the core criteria predicted a negative genetic finding.

Clinical ManagementThe suggestion of a hypothalamic defect located in the ventromedial or ventrolateral nucleus is plausible, but no such lesion has been reported, nor was suchfound on careful search in a typical case (Warkany, 1970). Hamilton et al. (1972) showed that the hypogonadism is the hypogonadotropic type and theresult of hypothalamic dysfunction. Treatment with clomiphene citrate raised plasma luteinizing hormone, testosterone, and urinary gonadotropin levels tonormal 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 boyweighing 264 lb (120 kg) who had developed diabetes, required digitalization for cardiac failure, and presented with intolerable behavior problems. Strictdietary control in combination with psychotherapy in a foster environment resulted in a weight reduction to 143 lb (65 kg), cessation of hyperglycemia andglucosuria, 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. Theyshowed that growth hormone treatment accelerated growth, decreased percent body fat, and increased fat oxidation, but did not significantly increaseresting energy expenditure. Improvements in respiratory muscle strength, physical strength, and agility also were observed, leading the authors to suggestthat growth hormone treatment may have value in reducing disability in children with PWS. Lindgren et al. (1999) measured resting ventilation, airwayocclusion 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 strengthand agility, and fat utilization in children with PWS. However, these measurements remained far from normal after up to 2 years of GH therapy. Carrel etal. (2002) assessed the effects of 24 additional months of GH treatment at varying doses on growth, body composition, strength and agility, pulmonaryfunction, 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), growthvelocity, and resting energy expenditure occurred with higher GH therapy doses, but not with the lowest dose. Bone mineral density continued to improveat 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 notimprove 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 thanor 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 ofdiastolic consequences. The observation of a slight deterioration of right heart function as well as the association between IGF-I and left ventricular functionduring 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 investigationfrom 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 molecularexamination for uniparental disomy is indicated in any pregnancy in which a CVS examination disclosed (mosaic) trisomy 15 and a subsequent cytogeneticexamination 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 inducesweight 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 ghrelinconcentration, 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 foodduring octreotide intervention. The authors concluded that short-term octreotide treatment markedly decreased fasting ghrelin concentrations in childrenwith 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 apneahypopnea index (AHI) was 5.1 per hour, mainly due to central apneas. Six months of GH treatment did not aggravate the sleep-related breathing disordersin 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
http://omim.org/entry/176730http://omim.org/entry/605353http://omim.org/entry/182450http://omim.org/entry/139250


14/27



hypothalamic dysregulations and show no or few signs of illness, de Lind van Wijngaarden et al. (2008) investigated whether PWS patients suffer fromcentral adrenal insufficiency (CAI) during stressful conditions. They found that 15 (60%) of 25 randomly selected PWS patients had CAI. De Lind vanWijngaarden 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 PWSpatients 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, normalizestriiodothyronine (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 plasmaghrelin concentration, body composition, and subjective ratings of hunger in 7 subjects with PWS and 30 healthy subjects who had fasted overnight. Themean plasma ghrelin concentration was higher in PWS than in the reference population and this difference remained significant after adjustment forpercentage of body fat. A positive correlation was found between plasma ghrelin and subjective ratings of hunger. The authors concluded that ghrelin iselevated 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 31.3kilograms 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 anorexigenic 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 werehigher 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 ghrelinlevels 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 humanobesity. 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 5million 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 birthincidence 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 mutationsaffecting pigmentation and is often associated with neurologic abnormalities as well. The p locus is located on mouse chromosome 7 near a chromosomalregion associated with imprinting effects. Nakatsu et al. (1992) suggested that the hypopigmentation in both PWS and Angelman syndrome may resultfrom 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 byexamining the fate of androgenetic (Ag; duplicated paternal genome) and parthenogenetic/gynogenetic (Pg/Gg; duplicated maternal genome) cells inchimeric mouse embryos (Keverne et al., 1996) sheds interesting light on the pathogenesis of the distinctive neuropsychologic features of PWS andAngelman 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 cellswith 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 representa 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 areaand 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 thepromoter and first exon of the SNRPN gene (182279). Mice harboring an intragenic deletion of Snrpn were phenotypically normal, suggesting thatmutations of SNRPN are not sufficient to induce PWS. Mice with a larger deletion involving both Snrpn and the putative PWS-IC lacked expression of theimprinted genes Zfp127 (mouse homolog of ZNF127; 176270), Ndn (602117), and lpw, and manifested several phenotypes common to PWS infants. Mice
http://omim.org/entry/602117http://omim.org/entry/176270http://omim.org/entry/182279http://omim.org/entry/164160http://omim.org/entry/155541http://omim.org/entry/139250


15/27



heterozygous for the paternally inherited IC-deletion died as neonates, 72% within 48 hours. At birth, the heterozygous mutant mice were present in theexpected mendelian ratio. On the day of birth, the affected mice appeared normal but underweight. There was little hypotonia, but one consistentlyobserved difference was that mutant mice were unable to support themselves on their hind feet, resting on their knees instead. No genital or gonadalhypoplasia 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 ASdependent on the sex of the transmitting parent. Epigenotype (allelic expression and DNA methylation) and fluorescence in situ hybridization analysesindicated 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 thecorrect 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, andtherapeutic 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 mayvary 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 proposedthat 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 PWSregion suggested that while there was low expression from both parental alleles in PWS-IC deletion pups, this expression did not explain their survival oncertain 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 inNdn (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, andfurther suggested that loss of necdin may contribute to the neurologic phenotype of PWS. They speculated that codeletion of necdin and the related proteinMagel2 (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 theappendages 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.'

See Also:

Bray et al. (1983); Burke et al. (1987); Butler et al. (1982); Butler et al. (1982); Butler and Palmer (1983); Butler and Palmer (1983); Carpenter (1994); Cassidy(1987); Cassidy et al. (1984); Charrow et al. (1983); Donlon et al. (1986); Duckett et al. (1984); Dunn (1968); Fraccaro et al. (1983); Fryns (1988); Fuhrmann-Rieger et al. (1984); Futterweit et al. (1986); Gabilan and Royer (1968); Gregory et al. (1990); Gregory et al. (1991); Hawkley and Smithies (1976); Hoefnagelet al. (1967); Holm et al. (1981); Katcher et al. (1977); Kousseff (1982); Labidi and Cassidy (1986); Laurance (1967); Laurance et al. (1981); Ledbetter et al.(1982); Mattei et al. (1983); Mattei et al. (1984); Michaelsen et al. (1979); Nicholls et al. (1989); Orenstein et al. (1980); Qumsiyeh et al. (1992); Reed andButler (1984); Ridler et al. (1971); Rivera et al. (1990); Robinson et al. (1993); Robinson et al. (1993); Robinson et al. (1993); Seyler et al. (1979); Smith et al.(1991); Trent et al. (1991); Veenema et al. (1984); Zellweger and Schneider (1968)

REFERENCES

1. American Society of Human Genetics/American College of Medical Genetics Test and Technology Transfer Committee. Diagnostic testing forPrader-Willi and Angelman syndromes. Am. J. Hum. Genet. 58: 1085-1088, 1996. [PubMed: 8651269, related citations]

2. Amos-Landgraf, J. M., Ji, Y., Gottlieb, W., Depinet, T., Wandstrat, A. E., Cassidy, S. B., Driscoll, D. J., Rogan, P. K., Schwartz, S., Nicholls, R. D.Chromosome breakage in the Prader-Willi and Angelman syndromes involves recombination between large, transcribed repeats atproximal and distal breakpoints. Am. J. Hum. Genet. 65: 370-386, 1999. [PubMed: 10417280, related citations] [Full Text: Elsevier Science]

3. Bhargava, S. A., Putnam, P. E., Kocoshis, S. A., Rowe, M., Hanchett, J. M. Rectal bleeding in Prader-Willi syndrome. Pediatrics 97: 265-267, 1996.[PubMed: 8584392, related citations]

4. Bielinska, B., Blaydes, S. M., Buiting, K., Yang, T., Krajewska-Walasek, M., Horsthemke, B., Brannan, C. I. De novo deletions of SNRPN exon 1 inearly human and mouse embryos result in a paternal to maternal imprint switch. Nature Genet. 25: 74-78, 2000. Note: Erratum: NatureGenet. 25: 241 only, 2000. [PubMed: 10802660, related citations] [Full Text: Nature Publishing Group]

5. Bittel, D. C., Kibiryeva, N., Talebizadeh, Z., Butler, M. G. Microarray analysis of gene/transcript expression in Prader-Willi syndrome:deletion versus UPD. J. Med. Genet. 40: 568-574, 2003. [PubMed: 12920063, related citations] [Full Text: HighWire Press]
http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=12920063http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=link&linkname=pubmed_pubmed&uid=12920063http://www.ncbi.nlm.nih.gov/pubmed/12920063http://dx.doi.org/10.1038/75629http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=link&linkname=pubmed_pubmed&uid=10802660http://www.ncbi.nlm.nih.gov/pubmed/10802660http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=link&linkname=pubmed_pubmed&uid=8584392http://www.ncbi.nlm.nih.gov/pubmed/8584392http://linkinghub.elsevier.com/retrieve/pii/S0002-9297

omim entry - # 176270 - prader-willi syndrome; pws.pdf

Documents