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Prader-Willi syndrome: Clinical features and diagnosis

Prader-Willi syndrome: Clinical features and diagnosis
Literature review current through: May 2024.
This topic last updated: Feb 06, 2023.

INTRODUCTION — Prader-Willi syndrome (PWS), also known as Prader-Willi-Labhart syndrome, is the most common syndromic form of obesity. It is caused by absent expression of the paternally active genes on chromosome 15q11.2q13, either due to deletions from the paternal chromosome, maternal disomy, or an imprinting defect. The vast majority of cases occur sporadically.

In adults and children, the primary clinical features are hyperphagia, usually leading to early-onset obesity; hypogonadism; developmental delay; characteristic behaviors (eg, obsessive-compulsive tendencies, outbursts, perseveration, insistence on sameness, and rigidity); and characteristic facial features. In infants, the most prominent findings are hypotonia and feeding difficulties.

The clinical features and diagnosis of PWS will be reviewed here. The management of this disorder is discussed separately. (See "Prader-Willi syndrome: Management".)

EPIDEMIOLOGY — PWS is the most common syndromic form of obesity and affects between 350,000 and 400,000 individuals worldwide. Males and females are affected equally [1].

Although prevalence estimates differ, this is likely due to using different methods for case identification and there is no strong evidence for increased risk in specific countries or gene pools. Within the United States, the reported prevalence is between 1:10,000 to 1:30,000 [2]. Outside of the United States, reported prevalence rates for PWS range from 1:8000 in rural Sweden [3] to 1:16,000 in Western Japan [4], 1:16,000 in Australia [5], and 1:76,500 in Flanders [6]. Within the United Kingdom, the estimated population prevalence is somewhat lower, at approximately 1:45,000 [7]. In each of these populations, PWS represents a very small fraction of children with obesity or even severe obesity.

The prevalence of PWS is higher in cohorts referred for the key clinical features. One study reported PWS in 11 percent of infants referred for hypotonia [8]. The prevalence of PWS among individuals with intellectual disability is less than 1 percent [9].

GENETICS AND PATHOGENESIS

Overview — PWS (MIM #176270) was the first genetic disorder attributed to genomic imprinting, meaning that the expression of the gene depends on the sex of the parent donating the gene. PWS arises due to absent paternal expression of the PWS "critical region" on chromosome 15q11.2-q13, whereas loss of the maternal expression of 15q11.2-q13 results in Angelman syndrome. (See "Inheritance patterns of monogenic disorders (Mendelian and non-Mendelian)", section on 'Parent-of-origin effects (imprinting)' and "Microdeletion syndromes (chromosomes 12 to 22)", section on '15q11-13 paternal deletion syndrome (Prader-Willi syndrome)'.)

The majority of cases of PWS arise sporadically. Monozygotic twins are concordantly affected. PWS can be caused by several types of genetic defects involving the PWS critical region (table 1). Determining the type of mutation has implications for recurrence risk. (See 'Risk of recurrence in future pregnancies' below.)

Genotype-phenotype association — There appears to be some association between the type of genetic defect and the phenotypic features seen in an individual with PWS. Higher body mass index and scoliosis may be more associated with the deletion subtype [10]. Individuals with uniparental disomy generally have less distinct physical features, higher intelligence quotients (IQs), and milder behavioral problems than individuals with PWS caused by deletions. However, patients with uniparental disomy are also more likely to exhibit autistic behaviors and psychosis [2,11,12].

PWS-like phenotypes, especially during infancy, have been reported with maternal uniparental disomy of chromosome 14 (Temple syndrome) or microdeletions of the 14q32.2 imprinted region [13,14]. Interstitial 6q deletions and 1q36 deletions are associated with a PWS-like phenotype [15,16]. Schaaf-Yang syndrome (MIM #615547) is characterized by PWS-like features (intellectual disability, infantile hypotonia, and early-onset obesity), as well autistic behaviors and contractures; it is caused by truncating variants of the MAGEL2 gene in the PWS-critical region [17-20].

Risk of recurrence in future pregnancies — The risk of PWS in siblings of an affected child depends on the type of molecular defect in that individual. Thus, genetic testing is important not only to establish the diagnosis of PWS but to determine the risk of recurrence in future pregnancies, which is important for genetic counseling (table 1). (See 'Mutation identification' below.)

Low recurrence risk – In the vast majority of cases, the affected child has a deletion or maternal disomy, or an imprinting defect without a deletion (an epimutation). For these families, the risk of recurrence in subsequent pregnancies with the same parents is less than 1 percent.

High recurrence risk – Two rare molecular defects that cause PWS are associated with a higher recurrence risk:

If the affected child has an inherited deletion of the imprinting control center (representing a small fraction of those with imprinting defects and less than 0.5 percent of all PWS cases), the recurrence risk for siblings is up to 50 percent.

If the affected child has a parental chromosomal rearrangement (representing less than 1 percent of all PWS cases), the recurrence risk for siblings is up to 25 percent [2,21].

Molecular pathogenesis — Several genes have been mapped to the 15q11.2-13 region. Genetic analysis of many different individuals with PWS progressively narrowed the candidate region, and it now appears that the major manifestations of PWS are caused by paternal deficiency for SNORD116-1 (HBII-85) "small nucleolar ribonucleic acid" (snoRNA) cluster [22,23]. SnoRNAs are noncoding molecules that guide post-transcriptional modification of ribosomal RNA and other small nuclear RNAs. The modifications include methylation, which is the mechanism for sex-specific imprinting. The precise mechanisms through which SNORD116-1 deletions cause the clinical features of PWS have not been established.

SNORD116-1 and several other snoRNA clusters are located just downstream of the SNURF-SNRPN, NDN, MAGEL2, and MKRN3 genes, explaining the apparent association of PWS with these candidate genes in previous studies [2,21]. These genes, or others in the PWS critical region, may account for some associated features but are unlikely to be exclusive causes. As an example, truncating mutations in MAGEL2 cause Schaaf-Yang syndrome, which shares several phenotypic features of PWS (see 'Genotype-phenotype association' above). Also, the P gene encodes for tyrosinase-positive albinism, is associated with OCA2, and is likely responsible for the hypopigmentation observed in 30 percent of individuals with PWS.

CLINICAL MANIFESTATIONS

Prenatal — Prenatal characteristics of PWS often include [24]:

Reduced fetal activity – Later perception of movement ("quickening"); overall reduction in the vigor of the movement.

Small size for gestational age.

Polyhydramnios.

Breech positioning.

Asymmetrical intrauterine growth – Increased ratio of head:abdomen circumference.

Hands and feet – Third-trimester ultrasounds may show unusual positioning of the fetal hands and feet, with flexed wrists and dorsi-extended feet with flexed toes [25]. These abnormalities of limb positioning are supported only by case reports but are probably more specific than other ultrasound findings for PWS.

Cytogenetic examination is revealing only if specific molecular diagnosis for PWS is requested. (See 'Molecular diagnosis' below.)

Infancy — In infancy, common features of PWS include:

Neonatal hypotonia – This is one of the hallmark features of this disorder and is a valuable clue to initiate diagnostic testing. The profound hypotonia can lead to asphyxia.

Feeding difficulties – Poor suck, lack of interest in feeding, or poor weight gain.

Weak cry.

Genital hypoplasia – Cryptorchidism, scrotal hypoplasia, hypoplasia or absence of the labia minora, or clitoral hypoplasia [26].

Hypopigmentation – Hypopigmentation of the skin, eyes (iris), and hair relative to the familial background is present in 30 to 50 percent of patients [2,27].

Early childhood — Notable features that develop during childhood are:

Delayed development – Toddlers with PWS demonstrate late acquisition of major motor milestones (eg, average age for walking 27 months and for talking 39 months) [28].

Growth hormone deficiency – Most children with PWS have growth hormone deficiency, manifested by slow linear growth and short stature. Treatment with recombinant growth hormone has benefits on linear growth, body composition, and neuromotor development. (See "Prader-Willi syndrome: Management", section on 'Recombinant growth hormone treatment'.)

Hyperphagia – Nutritional stages of PWS have been described, with excessive weight gain beginning at approximately two years of age, followed by frank hyperphagia with onset between 5 and 13 years (figure 1) [29].

Obesity – Obesity rapidly develops if environmental controls are not in place to restrict access to food. Body composition is abnormal, with reduced lean body mass and increased fat mass as compared with healthy children with and without obesity [30,31]. Perhaps as a result of the reduced lean body mass, resting energy expenditure is also reduced [32].

Late childhood and adolescence — Key issues during childhood and adolescence are (table 2):

Hyperphagia and obesity – Hyperphagia is universal, and management of feeding and obesity is the central focus of care. (See "Prader-Willi syndrome: Management", section on 'Feeding and obesity'.)

Complications of obesity – Including sleep apnea, obesity hypoventilation syndrome, cor pulmonale, diabetes mellitus, and atherosclerosis. (See "Prader-Willi syndrome: Management", section on 'Other obesity-related comorbidities'.)

Behavioral issues – Behavior problems and learning disabilities are common. Up to 25 percent of patients with PWS have epilepsy, which is usually focal (eg, staring spells) [33]. (See 'Behavior characteristics' below.)

Endocrine disorders:

Growth hormone deficiency – Growth hormone deficiency continues; recombinant human growth hormone treatment improves but does not normalize body composition and linear growth. (See "Prader-Willi syndrome: Management", section on 'Growth hormone deficiency'.)

Premature adrenarche – Pubic and axillary hair may arise prematurely in children with PWS due to adrenarche.

Hypogonadism – The appearance of other secondary sexual characteristics generally is delayed or incomplete and may be related to hypogonadotropic hypogonadism, hypergonadotropic hypogonadism, or both [34]. If cryptorchidism is present and untreated, testicular descent has occurred as late as adolescence. Without intervention, menarche is usually absent or severely delayed. This may be, in part, due to concurrent obesity, as suggested by the appearance of menarche as late as age 30 years in response to significant weight loss [35].

Other endocrine disorders that may be associated with PWS are hypothyroidism and, possibly, central adrenal insufficiency. (See "Prader-Willi syndrome: Management", section on 'Hypothyroidism' and "Prader-Willi syndrome: Management", section on 'Central adrenal insufficiency'.)

Sleep-disordered breathing – Over 80 percent of individuals with PWS have sleep-disordered breathing, with obstructive and central sleep apnea widely reported from infancy [36]. Excessive daytime sleepiness is pervasive in PWS. Individuals with PWS may have features of narcolepsy with or without cataplexy. All individuals with PWS are at risk for obstructive sleep apnea, regardless of body weight, but those with rapid weight gain or obesity are at particularly high risk.

Orthopedic problems – Includes scoliosis, hip dysplasia, lower limb alignment abnormalities, as well as osteopenia and osteoporosis, which is mitigated by treatment with estrogen or growth hormone. Gait abnormalities are increasingly recognized in PWS, although the impact on quality of life and clinical significance remain to be elucidated [37]. (See "Prader-Willi syndrome: Management", section on 'Orthopedic problems'.)

Adulthood — Key issues during adulthood are:

Obesity and hyperphagia – The prevalence of obesity is very high in adults with PWS, with concomitant increases in obesity-related complications over time, including cardiovascular problems, nonalcoholic fatty liver disease, hypercholesterolemia, diabetes mellitus, and sleep apnea [38]. Complications of hyperphagia include choking and gastric rupture, which are important causes of sudden death [39]. (See "Prader-Willi syndrome: Management", section on 'Other obesity-related comorbidities' and "Prader-Willi syndrome: Management", section on 'Acute complications of hyperphagia'.)

Cognitive and functional decline – One case series describes 12 individuals older than 50 years of age [40]. Most of these individuals had experienced decline in physical and psychological function with advancing age. A separate case series of 26 individuals older than 40 years of age found evidence of dementia in four (15 percent) [41]. All four patients with early-onset dementia were female, had a long history of psychotic illness, and had maternal uniparental disomy. One study found that young adults with PWS had brain imaging features similar to those of healthy adults more than eight years older, indicating accelerated brain senescence [42]. One study described shorter telomere length in adults with PWS, suggesting that this may be a mechanism for this pattern of accelerated biologic aging [43]; this association may be mediated by sleep apnea [44,45].

Causes of death — People with PWS have substantially shorter lifespans compared with the general population, with an average age of death in the third decade of life [39,46]. In a systematic review of almost 500 deaths among people with PWS in the United States, the main causes of death were [46]:

Respiratory failure (almost always associated with obesity) – 30 percent

Cardiac – 16 percent

Gastrointestinal (perforation, distention, or obstruction) – 10 percent

Infection – 9 percent

Obesity – 7 percent

Pulmonary embolism – 7 percent

Choking – 6 percent

Accident – 6 percent

Deaths related to food seeking (choking and some accidents) were responsible for one-half of the deaths in children and adolescents, while cardiac disease and pulmonary embolism primarily occurred during adulthood [46]. Of note, this study spanned four decades and most patients had severe obesity; it is likely that survival improves with optimal management of weight, hyperphagia, and other comorbidities and with lifelong growth hormone treatment.

BEHAVIOR CHARACTERISTICS — Behavioral problems and learning difficulties are commonly seen in PWS. Common manifestations are temper tantrums, stubbornness, and obsessive-compulsive behaviors that can impede school performance [47]. Specific issues are:

Food seeking – Food-seeking behaviors may include eating garbage, nonfood-related items, and frozen food and stealing resources to obtain food. Decreased ability to vomit and increased tolerance of pain can promote binging on spoiled foods and delay treatment for gastrointestinal disease. After episodes of binge eating (eg, at holidays), individuals with PWS (with and without obesity) have developed abdominal discomfort with acute gastric dilation seen on radiography [48]. Choking episodes, typically associated with voracious eating habits, have been reported as the cause of death among 8 percent of patients in one series of sudden death cases [49]. (See "Prader-Willi syndrome: Management", section on 'Acute complications of hyperphagia'.)

The mechanism that causes impaired satiety in individuals with PWS is unknown. However, levels of ghrelin, an orexigenic peptide, are persistently elevated in individuals with PWS as compared with weight-matched controls, providing a possible mechanism for the increased appetite [50,51]. Because infants have a high level of unacylated ghrelin (which promotes satiety) and children/adults with PWS have a higher proportion of acylated ghrelin (which is orexigenic) [52,53], some authors have proposed that a change in the ratio of acylated to unacylated ghrelin might mediate the hyperphagia and obesity observed in older children [54,55]. To date, the role of ghrelin as a primary or secondary factor in the satiety defect is unclear, but results of interventions to modify this ratio have been disappointing [56,57]. Brain-derived neurotropic factor is another potential mediator of hyperphagia in PWS; this neurohormone is decreased among individuals with PWS [58]. Other possible mediators include pancreatic polypeptide [59,60].

Autistic behaviors – Some of these behaviors are similar to those found in autism spectrum disorder. In a systematic review, behaviors meeting criteria for autism spectrum disorder were found in 27 percent of individuals with PWS [61]. One publication has linked autistic-type behaviors to variants of the MAGEL2 gene located within the PWS locus [17]. Other studies suggest that these behaviors are particularly common in PWS caused by uniparental disomy [61-64]. (See 'Mutation identification' below.)

Skin picking – Skin picking and rectal-gouging behavior are common and may respond to treatment with N-acetylcysteine [65-68]. In some cases, the rectal picking leads to rectal bleeding and ulceration sufficient to cause anemia or mimic colitis [69].

Psychiatric disorders – A variety of psychiatric symptoms and disorders have been reported among adults, including mood disorders and florid psychotic states [35,67,70].

Cognition – A mild to moderate degree of cognitive impairment is a commonly associated characteristic. In one study, the mean intelligence quotient (IQ) of individuals with PWS was 40 points below the population mean [71]. The range of IQs is normally distributed; thus, approximately 5 percent of individuals with PWS will have IQs in the low-normal range (>85) and 5 percent will have severe intellectual disability [72]. Adults tend to experience cognitive decline with age. (See 'Adulthood' above.)

DIAGNOSIS

Indications for genetic testing — The diagnosis of PWS is suspected in patients who have characteristic clinical features and is confirmed by genetic testing. Based on a retrospective review of the clinical characteristics of 90 patients with genetically confirmed PWS, molecular testing should be performed in patients who have all of the following clinical features for their age if they are otherwise unexplained [73,74]:

Birth to 2 years:

Hypotonia with poor suck, poor weight gain, and lack of interest in feeding

Excessive sleepiness

Sleep disorders

Cryptorchidism in males

2 to 6 years:

Hypotonia with history of poor suck

Global developmental delay

Short stature and/or growth failure associated with accelerated weight gain

Sleep disorders

6 to 12 years:

Hypotonia with history of poor suck (hypotonia often persists)

Global developmental delay

Hyperphagia (obsession with food), with obesity if food intake is uncontrolled

Behavioral rigidity

Sleep disorders

13 years through adulthood:

Cognitive impairment (usually mild intellectual disability)

Hyperphagia (obsession with food), with central obesity if uncontrolled

Hypogonadotropic or hypergonadotropic hypogonadism (eg, delayed puberty)

Behavior concerns (including temper tantrums and obsessive-compulsive features)

Sleep disorders

Occasionally, prenatal genetic testing may be performed as part of an investigation for abnormal findings on prenatal ultrasound [24] (see 'Prenatal' above) or for pregnancies in a family with a child who has PWS caused by a known paternal history of balanced translocation or a deletion at the imprinting center. (See 'Risk of recurrence in future pregnancies' above.)

Molecular diagnosis — Molecular testing for PWS should include identification of the individual's specific molecular subtype. Initial testing may start with methylation analysis to detect over 99 percent of PWS cases, followed by more specific testing to determine whether there is a deletion, maternal disomy, or an imprinting defect present. If clinical suspicion persists and a diagnosis remains elusive, it may be prudent to perform high-resolution chromosomal analysis to detect a translocation (approximately 1 percent of cases). Next-generation sequencing panels may perform a stepwise approach to diagnostic evaluation [75].

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

Mutation identification — If abnormal methylation is detected, further studies are performed to determine the type of mutation, which is important for the purposes of genetic counseling (table 1) [2,75]:

Deletion (65 to 75 percent of PWS cases) – Deletions of the PWS-critical region are detected by fluorescence in situ hybridization (FISH) using the probe SNRPN, or by chromosomal microarray (CMA). If FISH or CMA are positive, additional investigation may be indicated to determine if a translocation is present.

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

Imprinting center defects (2 percent of PWS cases) – If microsatellite markers detect no uniparental disomy, a defect affecting the imprinting center is suspected. Further diagnostic studies such as whole-exome sequencing, high-resolution CMA, or droplet digital PCR may be required to distinguish between these types of imprinting center defects [76]:

The majority of imprinting defects are "epimutations," in which the imprint, but not the underlying DNA sequence, is abnormal. In these cases, the recurrence risk for future pregnancies is low [2,77].

A minority of imprinting defects (<1 percent of PWS cases) are caused by deletions in the imprinting center, which carry a higher risk of recurrence (up to 50 percent recurrence in siblings of the proband).

Balanced translocation (<1 percent of cases) – Translocations are rare but important because the recurrence risk for siblings is up to 25 percent [78]. (See 'Risk of recurrence in future pregnancies' above.)

Genetic counseling is essential for families with a parental chromosome translocation or a mutation affecting the imprinting center. While these mutations are rare, they are associated with a risk of recurrence in future pregnancies. (See 'Risk of recurrence in future pregnancies' above.)

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

SUMMARY AND RECOMMENDATIONS

Epidemiology – Prader-Willi syndrome (PWS) is the most common syndromic form of obesity but is still rare compared with nonsyndromic obesity. The prevalence of PWS is approximately 1 in 15,000 live births, and males and females are equally affected. The vast majority of cases are sporadic rather than familial. (See 'Epidemiology' above.)

Genetics – PWS is caused by the absence of expression of the paternally active genes in the "PWS-critical" region of chromosome 15q11.2-13, either due to deletions from the paternal chromosome, maternal disomy, or (rarely) defects in the imprinting center (table 1). The dependence of the phenotype on the sex of the parent of origin is known as "genomic imprinting." (See 'Genotype-phenotype association' above.)

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

Clinical presentation – PWS is associated with key clinical characteristics that help to distinguish this disorder from simple obesity and guide selection of candidates for genetic testing:

Prominent clinical features in infants and toddlers are hypotonia and feeding problems, sometimes leading to failure to thrive. Hypotonic infants with PWS are also at risk for asphyxia. (See 'Infancy' above and 'Early childhood' above.)

Common clinical features in older children, adolescents, and adults are hyperphagia, intellectual disability, sleep disorders, behavioral concerns, and hypogonadism. Short stature relative to genetic background usually becomes apparent during childhood or puberty. (See 'Late childhood and adolescence' above and 'Adulthood' above.)

Molecular diagnosis – The diagnosis of PWS is made by genetic testing of individuals that exhibit typical clinical features. A standard diagnostic panel for PWS begins with a single-nucleotide polymorphism microarray and methylation studies, if needed, and microsatellite probes to detect maternal uniparental disomy followed by additional testing including sequencing of the SNRPN gene to detect a potential deletion at the imprinting center (algorithm 1). Molecular testing for PWS is highly sensitive, and standard panels with a methylation analysis will detect more than 99 percent of cases. (See 'Molecular diagnosis' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Jessica Duis, MD, MS, who contributed to earlier versions of this topic review.

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Topic 5875 Version 29.0

References

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