Pediatrics

Prader-Willi syndrome

OVERVIEW: What every practitioner needs to know

Are you sure your patient has Prader-Willi syndrome? What are the typical findings for this disease?

What are the typical findings for Prader-Willi syndrome in the neonatal period?

  1. Neonatal hypotonia - significant, often with decreased fetal movement

  2. Difficulty feeding due to poor suck and excessive sleepiness - the baby frequently must be awakened to feed

  3. Cryptorchidism in boys, very small labia in girls - evidence of hypogonadism

What clinical clues distinguish PWS from other causes of hypotonia?

The hypotonia in PWS is profound. Infants with PWS are generally quiet and placid, but alert when awake. This distinguishes them from infants with hypotonia due to encephalopathies (for example, from an inborn error of metabolism or sepsis). In many cases, parents and nurses will comment on the "easy" nature of the baby, although poor suck and feeding difficulty is prominent.

Deep tendon reflexes may be faint, but are present, and tongue fasciculations are not seen (distinguishes from spinal muscular atrophy type I).

Infants with PWS typically do not have significantly dysmorphic appearance or other birth defects (except for cryptorchidism). This distinguishes them from most infants with aneuploidies and most large chromosomal rearrangements.

Hypoplasia of the external genitalia is almost universal in PWS, due to hypogonadotropic hypogonadism. In males, this presents as undescended testes and frank cryptorchidism. The phallus is also small, less than 3 cm stretched, and the scrotum under-developed. In females, hypogonadism manifests as absence of the typical clitoral and labial hypertrophy seen in the newborn. This is most obvious in the first weeks of life when the clitoris may be difficult to identify in the infant girl with PWS. This finding can be easily overlooked in newborn females if not specifically sought out.

Hypopigmentation of skin and hair is often apparent in infants with PWS due to deletions (see below).

What other disease/condition shares some of these symptoms?

Many congenital and acquired conditions of the neonate can present with profound hypotonia. Sepsis, intoxication due to maternal drug use, and inborn errors of metabolism (especially hyperammonemia or significant acidosis) should be evaluated.

Most chromosomal rearrangements (aneuploidy, deletions or duplications) cause abnormal central nervous system development and present with neonatal hypotonia. Many other single gene disorders can share this presentation, although most of these will be associated with other birth defects or clinical findings.

Several genetic disorders that present with few findings other than neonatal hypotonia include spinal muscular atrophy type I (also called Werdnig-Hoffman disease or SMA I) and congenital myotonic dystrophy. A wide variety of rare congenital myopathies can present in the neonatal period, but these are typically not considered until after the more common conditions, such as PWS, are ruled out, unless there is a specific family history.

Zellweger syndrome, a defect of peroxisomal biogenesis, presents with profound hypotonia, although these infants often develop hepatic and renal disease early on. Congenital disorders of glycosylation should also be considered in the differential diagnosis.

What caused this disease to develop at this time?

  • PWS is a genetic disorder caused by lack of expression of genes in the proximal (near the centromere) end of the long (q) arm of chromosome 15. There are several genes in the PWS critical region that are only expressed on the chromosome 15 inherited from the father. The mechanism by which this occurs, referred to as imprinting, is due to differential methylation of the promoter regions of these genes, which is specifically determined by the sex of the parent. The role of the specific imprinted genes involved, SNRPN, NDN, MAGEL2 and MKRN3, has not been clearly determined.

  • In PWS, the imprinted genes on the chromosome 15 inherited from the mother (hereafter referred to as maternal 15) have hypermethylation of the promoter region that inhibits expression of the genes noted above. The paternal 15 does not have this hypermethylation, so the genes are normally expressed. Thus, there are several mechanisms that cause PWS:

    • Deletion of the paternally inherited chromosome 15. This is the most common mechanism, accounting for ~70% of cases. This deletion occurs recurrently because there are long stretches of highly similar duplicated DNA flanking the region that predispose to misalignment and rearrangement during meiosis.

    • Maternal uniparental disomy. Maternal uniparental disomy for chromosome 15 accounts for ~20%-25% of PWS individuals. In this case, most often the pregnancy starts as trisomy 15, which is the most common aneuploidy identified in spontaneous early abortions but not seen in live born infants. Most often, failure of the chromosomes to separate during maternal meiosis leads to an ovum with 2 copies of chromosome 15, which may be associated with increased maternal age. The trisomic conceptus will miscarry unless a second error, loss of one of the three copies of chromosome 15, occurs as a mitotic error, generating a new pluripotent cell line with the correct number of copies of chromosome 15. If the chromosome lost is the single copy contributed by the father, the fetus will develop, but will have maternal uniparental disomy for chromosome 15, and thus have PWS.

    • Imprinting error. Rarely, the defect arises because the father is unable to erase the imprint (the methylation) of the chromosome 15 he inherited from his mother. As a result, the fetus inherits one chromosome 15 from the mother and one from the father, but the chromosome 15 from the father still carries a "maternal" methylation pattern, resulting in absence of expression of the genes in the PWS critical region. Imprinting errors account for less than 5%, perhaps as few as 1%, of cases of PWS. The specific cause of the imprinting defect is often not identified.

  • Recently, a few cases with most of the findings of PWS were described with the only apparent genetic defect being deletion of a small part of a "non-coding" intron in the SNRPN gene. There are several clusters of microRNAs located in these distal introns. Because microRNAs appear to control the regulation of expression of other genes, possibly at distant locations in the genome, it is conceivable that the findings of PWS may be significantly impacted by the expression, or altered expression, of genes outside the PWS region of chromosome 15. The possible role of small mutations or deletions that only affect the microRNA clusters is unknown, but there is currently little evidence to suggest that these types of defects are common in classic PWS.

  • There are no known environmental risk factors for PWS. The recurrence risk for PWS is low, less than 1%, for both deletion and maternal uniparental disomy. Risk of uniparental disomy may increase with advanced maternal age, due to the increased risk of trisomic pregnancy. Imprinting errors can be inherited or can arise de novo; thus, there may be as high as a 50% recurrence risk for the rare man whose child has PWS due to this mechanism. \

  • The major findings of PWS are associated with abnormal function of the hypothalamus of the brain, or inadequate connection between the hypothalamus and other parts of the brain. The specific mechanism for this failure of normal CNS development is not clear at this time.

  • Absence of expression of a maternally active gene in the region, UBE3A, causes a completely different disorder, Angelman syndrome (AS). Thus, laboratory analysis of the methylation pattern in the PWS/AS region of chromosome 15 is critical to making the correct diagnosis in infants with a deletion or uniparental disomy identified by chromosome analysis, or microarray.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Although the genetic mechanisms leading to PWS are complex, the testing strategy for suspected PWS is relatively straightforward, as shown in the accompanying flow diagram (Figure 1). It is often helpful to consult a clinical geneticist to assist with the molecular diagnosis as they will be most familiar with assays that are most readily available in a particular institution.

  • The first test evaluates the methylation pattern of the genes in the PWS region of chromosome 15. In PWS, only the maternal methylation pattern is present. This test identifies essentially all cases of PWS. There are several methods available for this testing, including Southern blot, methylation sensitive polymerase chain reaction (PCR) (using bisulfite modification of the template DNA), or multiplex ligation probe analysis (MLPA). The MLPA test, not yet widely available in the United States, is also able to determine deletion status.

  • It is not unreasonable to evaluate the chromosomes at the same time that the methylation test is ordered. If the methylation confirms PWS, the next step will be to look for a deletion of chromosome 15. If the methylation test rules out PWS, the chromosome analysis will be an important next step in the diagnostic process.

  • If the methylation test confirms the diagnosis of PWS, the specific cause must be identified so that the appropriate recurrence risk can be assigned. The next step is to look for deletion, the most common mechanism. This can be accomplished by fluorescence in-situ hybridization (FISH) using probes in the PWS region, or by comparative genomic hybridization microarray. It is common to obtain G-banded chromosome analysis at the same time, if not done already, to rule out a translocation associated with the deletion.

  • If no deletion is found, the next step should be to test for uniparental disomy by evaluating multiple polymorphic markers in the region and comparing the pattern in the child to that of both parents. This test is best interpreted in relation to samples from both of the parents, although if one parent is not available it may be performed using only one parent's sample.

    • If a single-nucleotide polymorphism (SNP) microarray is used to detect the deletion, one may also, in some cases, identify uniparental disomy by the presence of apparent homozygosity for SNPs on chromosome 15 without evidence of deletion, suggesting that the two chromosome 15s are identical. This is not a reliable test for all cases of uniparental disomy, though, because it only detects isodisomy, not heterodisomy.

  • In situations were there is abnormal methylation consistent with PWS, no deletion is found, and there is not uniparental disomy, the diagnosis of exclusion is an imprinting defect. Molecular analysis of the sequence around the imprinting center (IC) identifies a mutation in a minority of cases. If an IC mutation is found, the father can be tested to determine his recurrence risk more accurately. When no mutation is found, one must presume that the recurrence risk is as high as 50% for the father with each future pregnancy.

Figure 1.

Flow diagram showing laboratory diagnostic approach to the patient suspected of having Prader-Willi syndrome.

Would imaging studies be helpful? If so, which ones?

Imaging studies generally are not particularly useful in PWS. The brain MRI does not show specific findings, although generalized atrophy and minor changes in measurements in pituitary height have been reported. These findings do not provide diagnostic or management insight at this time.

If the testes cannot be palpated, ultrasound evaluation may be helpful to identify their location.

Confirming the diagnosis

Clinical diagnostic criteria for PWS have been elucidated before molecular testing was widely available. These criteria are now most useful to help determine whether molecular testing is appropriate.

The most helpful clinical finding to raise suspicion for PWS is the presence of significant neonatal hypotonia with feeding difficulty and poor weight gain. In the absence of this finding, PWS is highly unlikely. In older children, the characteristic phenotype of hyperphagia and obesity, mild mental retardation, and behavioral problems can occur with many conditions. Eliciting the typical neonatal history for PWS is helpful in determining the value of molecular testing.

A detailed discussion of diagnostic approaches can be found at GeneReviews.org.

If you are able to confirm that the patient has Prader-Willi syndrome, what treatment should be initiated?

Neonatal Period

After the diagnosis is considered and confirmed in the neonate, the major issues in management center on feeding and motor development. The neonate with PWS is usually very sleepy, does not wake spontaneously for feeds, and has a weak suck. It is valuable to point out to the parents at this time that the there are two major clinical phases in PWS, neonatal hypotonia with poor feeding and poor weight gain, followed several years later by the childhood onset of hyperphagia and potential for excessive weight gain. While somewhat ironic, it can be reassuring to parents to know that the neonatal feeding issues will definitely resolve. It is also useful at this time to remind them that there will be a period, possibly lasting several years, between the resolution of the first phase and the onset of the latter phase.

  • Caloric intake should be individualized to maintain appropriate weight gain for an infant. Caloric need for weight gain may be somewhat reduced because of low muscle mass, but this may be offset by the calories wasted because of prolonged and inefficient feeding. Infants with PWS often require tube feeding to supplement oral feeding for as long as 4 to 6 months, although most take all feedings by mouth by 3 months. Nasogastric tubes are well tolerated and can be used to complete feedings after 15 to 20 minutes of sucking.

  • Breast feeding is occasionally successful, but more often frustrating because of difficulty with attaching, weak suck, and falling asleep. It is worth trying with early assistance from a lactation consultant experienced with infants with low muscle tone. Supplemental tube feedings are also helpful.

  • For bottle feeding, use of soft sided bottles or special nipples with one-way valves (i.e., those used for infants with cleft palate) may be useful to support sucking.

  • Surgically placed gastric tubes are best avoided because the need is transient, but the placement leaves a significant scar. Because the typical body habitus in PWS includes truncal obesity, even in patients managed with aggressive weight control and growth hormone, this scar can be cosmetically displeasing. Some families refer to the G-tube scar as a "second belly-button", an aptly descriptive term.

  • Urological evaluation for cryptorchidism is appropriate in the newborn; however, there may be less urgency for surgical intervention because protecting fertility is not typically an issue for males with PWS. The increased risk of anesthesia associated with the hypotonia and resultant airway problems means that risks and benefits of early vs. later surgical intervention must be considered.

Recombinant human growth hormone (rhGH). There is some controversy about the use of rhGH in infants with PWS. A variety of studies have shown benefit from treatment of growth hormone deficiency in linear growth, lean mass, adiposity, and global development in children with PWS. Several prospective studies in the United States and in Europe have shown benefit in children as young as 3 to 4 months of age, particularly in improved lean mass and reduced fat mass, but also in cognitive development, and to a lesser degree, motor development. Similar effects on growth have been shown when rhGH was started at an older age, but at least one study suggests that early treatment leads to improved linear growth and lean mass relative to later onset treatment. It appears that the benefits persist when rhGH is continued through childhood, which is not surprising since children with PWS typically have GH deficiency when tested provocatively, or by physiological evaluation of downstream growth mediators, such as insulin-like growth factor 1 (IGF-1).

Several reports of unexpected death after starting rhGH raised concern about its safety; however, later work revealed that the risk of unexpected death appears to be increased in PWS regardless of the use of rhGH. Whether rhGH may contribute to the modest increase in mortality rates compared with typically developing children remains unclear, although there are no firm data to suggest that this is true. There may be an increased risk of respiratory compromise related to hyperplasia of nasopharyngeal lymphoid tissue, which may potentiate underlying respiratory disease or acute infection during use of rhGH. For this reason, many experts recommend polysomnographic evaluation (sleep study) to diagnose any underlying obstructive sleep apnea in infants and children with PWS prior to initiation of rhGH therapy, with treatment of any problems prior to starting. Management of obesity should be part of the treatment of obstructive sleep apnea. It is worth noting that children with PWS often have a variety of ventilatory issues, including mildly reduced responsiveness to hypoxia and to hypercapnia, along with modest central sleep apnea. Some of these issues may improve during rhGH therapy.

Some centers that care for infants with PWS are comfortable initiating therapy earlier in infancy, which, in most cases, means starting at 3 to 4 months of age, or later, after confirming the diagnosis, obtaining appropriate baseline information, and obtaining approval for insurance coverage. Those centers have not reported significant complications or deaths. At this time there is no clear recommendation on when to begin rhGH therapy for PWS, and providers should work closely with their local Pediatric Endocrinology colleagues and the families to make the best decision for the patient and family.

Possible side effects of rhGH therapy in infants with PWS include the lymphoid hyperplasia noted above, which, along with low airway muscle tone, may contribute to worsening obstructive sleep apnea. In the days and weeks following initiation of rhGH, there may be fluid shifts that can lead to modest increases in intracranial pressure, although this is generally not a significant problem in infants with open cranial sutures. It may lead to symptomatic changes in older children, so parents should be counseled regarding signs and symptoms of pseudotumor cerebri, including headache, nausea and vomiting, vision disturbance, and other complications of increased intracranial pressure. In younger children, parents should be asked to report changes in sleep patterns, irritability, or behavior changes, as well. In general, this rare complication of rhGH responds to lowering the dosage, or a temporary interruption of therapy, restarting later at a lower dose.

Worsening of scoliosis may be seen, especially in the first year of therapy. There may also be a modest decrease in bone density in older children beginning therapy with rhGH, which resolves later, with long-term therapy being associated with improved bone density compared with untreated PWS individuals. There is no clear evidence that rhGH therapy increases the risk of scoliosis progressing to need for surgical intervention, and it has been suggested that the long-term outcome of therapy may actually be a stabilization of the scoliosis.

Prior to initiating therapy with rhGH, consideration should be given to measuring baseline metabolic function (electrolytes and renal function parameters), calcium, phosphorus, thyroid function, CBC, and growth factors, including insulin-like growth factor 1 (IGF1) and IGF binding protein 3 (IGFBP3). Most treating physicians confirm the absence of clinically significant sleep-disordered breathing prior to starting therapy, and again a few months after initiation of therapy. Recently, the trend has been to repeat polysomnographic (PSG) studies when there is a change in symptoms of snoring, excessive daytime sleepiness, or behavioral changes that are not otherwise explained. Some providers routinely repeat the PSG every few years.

The general starting dose for rhGH in infants and children with PWS is 0.24 mg/kg/week, divided into daily subcutaneous injections. There is evidence that excessive doses of rhGH, which are reflected in supraphysiological blood concentrations of IGF1, may be associated with increased risk of respiratory complication; therefore, it is reasonable to make dosage adjustments based on growth parameters, followed by measurement of IGF1 after increasing the dose to confirm that the new dose is achieving the target IGF1 in the physiological range.

Cryptorchidism and use of human chorionic gonadotrophin (hCG). Traditionally, hCG injections were used to attempt medical treatment of undescended testes. This therapy is rarely, if ever, successful by itself in boys with PWS; however, there are several salutary effects of the treatment. First, the associated transient increase in locally produced testosterone may help to increase the size of the scrotum, making later surgical correction somewhat easier. Also, there may be a modest increase in the penile length toward normal making it easier for the male child to be successful at standing micturition. The urgency to treat cryptorchidism in typically developing boys at an early age, preferably by 6 months, is based on the dual goals of preserving fertility and minimizing risk of testicular cancer. Males with PWS have significant underdevelopment of the testes, however, and the risk of cancer is not clearly understood. Recent evidence suggests that hCG therapy may lead to increased apoptosis of germ cells in the testes of boys with cryptorchidism, although there are no data reported as to the long-term effect of this finding on fertility. Further, male fertility may not be a compelling goal of therapy for a boy with PWS, whereas avoiding or postponing general anesthesia and surgery may be more important because of the respiratory complications. Again, the final decision regarding use of hCG is best made with careful consultation of the family, the endocrinologist, and the urologist carefully weighing the risks and benefits of early surgical intervention.

Childhood, Adolescence and Adulthood

Management of PWS occurs primarily in the outpatient setting. Several resources are available to guide the practitioner. In early childhood, attention focuses on maintaining adequate nutrition and supporting development through the provision of early intervention services. Because the goal of therapy with rhGH is to increase muscle bulk and maintain normal growth, children treated with rhGH should be monitored according to growth curves for the normal population, especially with regard to weight for height and body mass index. There are PWS specific growth curves available in the literature for individuals not treated with rhGH.

Appetite and growth. Whereas in early life the challenge is to provide adequate calories for normal growth, at some point in the 2nd to 6th year of life for most children with PWS, the family will observe the onset of reduced satiety when eating, often manifest as hyperphagia. In general, older children and adults with PWS will eat longer and take in more food before feeling full, and the sense of satiety does not last as long as in typically developing individuals. Further, basal caloric need is typically low in individuals with PWS, so that they do not need the expected number of calories for appropriate weight gain. Therefore, strict control of access to food, and limitation of the daily caloric intake to that required for normal growth for the individual, are absolutely essential. This usually means that kitchens, or food cabinets, are locked, and that care is taken to avoid prolonged exposure to uncontrolled sources of food (e.g., grocery stores).

To date, no medication has been shown to have a significant effect on food consumption in individuals with PWS, in spite of clear evidence of dysregulation of the satiety pathway as evidenced by measurements of a variety of intermediates, including ghrelin.

Children with PWS may eat items not intended for human consumption, or food that is spoiled and generally not edible, including eating food found in garbage cans. Older children and adults may steal and horde food. In the inpatient setting, constant supervision is required to avoid access to food trays from roommates, in serving trays in hallways, and in common areas and nursing stations. The resourcefulness of individuals with PWS in obtaining access to food is often surprising relative to their general cognitive disability.

It is not surprising that individuals with PWS appear to be at increased risk of ingesting potentially toxic compounds, including medications. Care should be taken to ensure that non-food items that may be attractive to the PWS individual (e.g., brightly colored automobile coolant) must also be kept in locked storage. In general, passive protections, such as not having toxins in the home, or keeping them in locked cabinets, are most effective.

Endocrine Issues. Most Pediatric Endocrinologists are comfortable initiating growth hormone therapy by the age of 2 to 4 years. The complications and approach, as well as the dose, are the same as reviewed above in the discussion of neonatal management.

There is a suggestion in the literature that some individuals with PWS may be predisposed to partial central adrenal insufficiency as a manifestation of their abnormal hypothalamic-pituitary axis. This combination has been suggested to partly explain the recognized increase in mortality among people with PWS at any given age when compared with their typically developing peers. Low-dose ACTH stimulation testing may not be adequate to identify all cases, and the value of other forms of provocative testing is not clear. Metyrapone stimulation testing is used in Europe, but the drug is not easily available in the United States. There are no evidence-based guidelines for care at this time, but it seems prudent to keep the possibility in mind when individuals with PWS present with acute illness, and consider treatment with stress-dose steroids pending results of cortisol and ACTH measurements in blood.

Children with PWS tend to be quite healthy, and, although they have a tendency toward abnormal thermoregulation, it is unusual for them to be hospitalized with illness. It is worth remembering that the typical child with PWS has significantly increased tolerance to pain, so that it is well recognized that they can have significant intra-abdominal pathology (e.g., appendicitis), or even broken bones, with relatively little complaint. Finally, children with PWS rarely vomit. Therefore, when the child with PWS presents with abdominal pain, especially if vomiting, care should be taken to rule out significant intra-abdominal disease.

Cardiac issues. Congenital heart defects do not appear to be more common in PWS than in the general population. Right-sided hypertrophic cardiomyopathy is a common complication in young adults with marked obesity, and has been one of the more common causes of mortality in the past. Management in the acute setting is best achieved by careful fluid management, use of standard interventions and, somewhat paradoxically, exercise. Aggressive weight loss measures and regular walking may lead to marked improvements in heart failure over days to weeks. Long-term treatment involves correction of any underlying obstructive sleep apnea, which is a major contributor to the heart failure. Atherosclerosis may also be found in adults with poor weight control, although the prevalence is not well described.

Anesthesia considerations. Anesthesia is generally well-tolerated by individuals with PWS, although several common findings of the condition may predispose to complications. First, the hypotonia and tendency to central obesity both contribute to airway collapse that can complicate ventilation during anesthesia and can make extubation more difficult. Oral hygiene may be poor because of thick saliva and behavioral complications; therefore, integrity of dentition should be carefully evaluated prior to anesthesia. Difficulty with thermoregulation should be considered during and after anesthesia to prevent complications as well as unnecessary diagnostic adventures.

Response to standard doses of drugs may also be difficult to predict, in part because of the altered lean-to fat-ratio in PWS individuals. Volume of distribution for some drugs may be different than expected, leading to both increased or reduced responsiveness. Likewise, drugs that are compartmentalized to lipids may accumulate in the increased adipose tissue, leading to prolonged effect of fat-soluble drugs.

Behavioral and psychiatric issues. Several common behavioral manifestations of PWS may impact the inpatient care of individuals with PWS. These individuals tend to be intolerant to changes in schedule or routine, which can often lead to refusal to cooperate, or even severe tantrums. Advance warning and preparation by child-life specialists may improve outcomes for simple procedures (e.g., IV insertion, sleep study, etc.). Often, food and attempts to limit food, are the instigating events in significant behavioral "meltdowns," characterized by rapid escalation of temper tantrums. Occasionally, older children may exhibit aggressive behaviors as well. Generally, these issues are most easily dealt with prospectively, by having the family work with a behavioral specialist to develop avoidance approaches and interventions that will work for their specific situation well before the unacceptable behaviors become firmly established and self-perpetuating.

Skin-picking in a compulsive manner, often beginning with small lesions such as insect bites, can lead to serious infection or permanent injury to superficial and deep tissues. Like most behaviors associated with PWS, this is best addressed early, before the behavior becomes well established. In adult life, rectal picking can become a difficult problem to treat. Topiramate has shown some efficacy for the more severe forms of skin-picking.

Psychiatric manifestations of PWS include anxiety, depression, obsessive-compulsive disorder (OCD) and psychosis. Many, if not most, children and adults with PWS have some degree of excessive anxiety that complicates daily life and medical care. Attentiveness to the possibility, with simple behavioral interventions including cognitive approaches, is often the only treatment needed, although in some cases medication may be helpful. Depression often accompanies anxiety, and may be manifest by loss of interest in activities (although rarely loss of interest in eating). Obsessive-compulsive tendencies seen in most people with PWS can progress to the point where they preclude normal activities. Typical-appearing psychosis may present in young adults, and is typically responsive to standard therapy. Psychosis and OCD may be more common in individuals with uniparental disomy (UPD) as the genetic basis for the PWS, although they appear to be seen in all genetic forms of PWS.

Risk of unexpected death. Children with PWS tend to be quite healthy, and, although they have a tendency to abnormal thermoregulation, it is unusual for them to be hospitalized with illness. It is worth remembering that the typical child with PWS has significantly increased tolerance to pain, so that it is well recognized that they can have significant intra-abdominal pathology (e.g., appendicitis), or even broken bones, with relatively little complaint. Finally, children with PWS rarely vomit. Therefore, when the child with PWS presents with abdominal pain, especially if vomiting, care should be taken to rule out significant intra-abdominal disease. Particularly concerning in older adolescents and adults are multiple case reports of gastric rupture following episodes of binge eating, which is usually fatal.

What is the prognosis for an individual with PWS?

The long-term prognosis for PWS appears to correlate with the age of diagnosis and the ability of family and caretakers to limit access to food and to maintain reasonable weight control.

Outcome with good weight control. There have been no long-term outcome studies in individuals with early diagnosis, life-long avoidance of excessive obesity, or use of rhGH. Clinical experience suggests that weight control is the primary factor in long-term survival, with a number of individuals in the 5th and 6th decades of life now being recognized. The weight control does not necessarily have to be lifelong, in that there are many individuals who were once quite obese who through diligent management have reduced to a desired weight as adults, avoiding the typical complications that lead to premature death.

Outcome with significant obesity. In the past, without aggressive weight management, obesity led to poor perfusion in the extremities, right-sided cardiac failure, and diabetes mellitus. The mean lifespan of a poorly controlled patient is reported to be into the 3rd to 4th decade of life, with what appears to be an increased risk of death from a variety of metabolic and respiratory complications earlier.

Clearly, careful management of the natural consequences of PWS can lead to markedly improved clinical outcomes.

What causes this disease and how frequent is it?

The genetic basis of PWS is described above. The incidence is estimated to be as high as 1 in 15,000 births, or higher, with population prevalence estimates varying markedly from 1 in 15,000 to 1 in 52,000. There are no ethnic or geographic predispositions to PWS, and it occurs in all populations in both males and females.

There are no known risk factors for PWS, although advanced maternal age appears to be more common in patients with UPD, presumably due to increased risk for trisomic pregnancy in older mothers. The recurrence risk is generally low, except for rare families with inherited defects of imprint switching.

Other clinical manifestations that might help with diagnosis and management

Several other clinical issues in PWS merit mention here.

Ocular manifestations. The most common issues are strabismus, in early life, myopia and hyperopia. Strabismus occurs in the majority of PWS individuals and commonly requires surgical correction. Myopia and hyperopia tend to be recognized earlier than in typically developing populations but respond to standard correction. Other findings are reported but are individually rare.

Orthopedic concerns. Scoliosis and reduced bone density are both extremely common in older children and adults with PWS. Scoliosis may be partly related to hypotonia and tends to progress throughout childhood. The effect of treatment with rhGH may be to initially increase the rate of progression, but later there may be stabilization with increased bone density. There does not appear to be a large increase in need for surgery related to use of rhGH, and the majority of individuals with scoliosis do not require surgical intervention.

Seizures. There appears to be a 3- to 4-fold risk of generalized seizures in PWS, with a variety of seizure types seen, including staring spells, with many seizures fitting into the category of generalized epilepsy with febrile seizures. The seizures are generally uncomplicated and respond to standard monotherapy in most cases when any treatment is required.

Are additional laboratory studies available; even some that are not widely available?

Polysomnography is a critical tool for the management of PWS. The sleep lab used should be familiar with the special behavioral needs of the PWS individual, and the interpreting physician should be familiar with both the central respiratory complications of PWS and the potential for obstructive symptoms. Further multiple sleep latency testing may be indicated for those individuals with excessive daytime sleepiness without significant sleep-disordered breathing.

What is the evidence?

In general, management recommendations for this relatively rare genetic disorder are based on experience, reason, and expert opinion. The one exception is the use of growth hormone, which has been studied in randomized, placebo-controlled, double-blinded clinical trials.

Additional resources for more in-depth understanding of PWS include:

General references:

Butler, MG, Lee, PDK, Whitman, BY. "Management of Prader-Willi syndrome". Springer. 2006.

Cassidy, SB, Schwartz, S. "(updated 3 September 2009) Prader-Willi Syndrome". GeneReviewsTM at GeneTests: Medical Genetics Information Resource (database online). University of Washington. 1 October 2011. http://www.genetests.org..

McCandless, SE, Cassidy, SB, Epstein, CJ, Erickson, RP, Wynshaw-Boris, AW. "15q11-13 and the Prader-Willi syndrome". Inborn errors of development: the molecular basis of clinical disorders of morphogenesis. Oxford University Press. 2008. pp. 766-75.

Diagnostic considerations:

Gunay-Aygun, M, Schwartz, S, Heeger, S. "The changing purpose of Prader-Willi syndrome clinical diagnostic criteria and proposed revised criteria". Pediatrics. vol. 108. 2001. pp. E92.

Clinical management:

Cassidy, SB, McCandless, SE, Cassidy, SB, Allanson, JE. "Prader-Willi syndrome". Management of genetic syndromes. John Wiley and Sons. 2010. pp. 625-50.

McCandless, SE. "Clinical Report--health supervision for children with Prader-Willi syndrome". Pediatrics. vol. 127. 2011. pp. 195-204.

Growth hormone therapy:

Carrel, AL, Moerchen, V, Myers, SE. "Growth hormone improves mobility and body composition in infants and toddlers with Prader-Willi syndrome". J Pediatr. vol. 145. 2004. pp. 744-9.

Eiholzer, U, Meinhardt, U, Rousson, V. "Developmental profiles in young children with Prader-Labhart-Willi syndrome: effects of weight and therapy with growth hormone or coenzyme Q10". Am J Med Genet A. vol. 146. 2008. pp. 873-80.

Festen, DA, de Lind van Wijngaarden, R, van Eekelen, M. "Randomized controlled GH trial: effects on anthropometry, body composition and body proportions in a large group of children with Prader-Willi syndrome". Clin Endocrinol (Oxf). vol. 69. 2008. pp. 443-51.

Festen, DA, Wevers, M, Lindgren, AC. "C. Mental and motor development before and during growth hormone treatment in infants and toddlers with Prader-Willi syndrome". Clin Endocrinol (Oxf). vol. 68. 2008. pp. 919-25.

Haqq, AM, Stadler, DD, Jackson, RH. "Effects of growth hormone on pulmonary function, sleep quality, behavior, cognition, growth velocity, body composition, and resting energy expenditure in Prader-Willi syndrome". J Clin Endocrinol Metab. vol. 88. 2003. pp. 2206-12.

Myers, SE, Carrel, AL, Whitman, BY, Allen, DB. "Sustained benefit after 2 years of growth hormone on body composition, fat utilization, physical strength and agility, and growth in Prader- Willi syndrome". J Pediatr. vol. 137. 2000. pp. 42-9.

Sode-Carlsen, R, Farholt, S, Rabben, KF. "Growth hormone treatment for two years is safe and effective in adults with Prader-Willi syndrome". Growth Horm IGF Res. vol. 21. 2011. pp. 185-90.

Whitman, BY, Myers, S, Carrel, A, Allen, D. "The behavioral impact of growth hormone treatment for children and adolescents with Prader-Willi syndrome: a 2-year, controlled study". Pediatrics. vol. 109. 2002. pp. E35.

Causes of mortality:

Grugni, G, Crinò, A, Bosio, L. "The Italian National Survey for Prader-Willi syndrome: an epidemiologic study". Am J Med Genet A. vol. 146. 2008. pp. 861-72.

Stevenson, DA, Anaya, TM, Clayton-Smith, J. "Unexpected death and critical illness in Prader-Willi syndrome: report of ten individuals". Am J Med Genet A. vol. 124. 2004. pp. 158-64.

Stevenson, DA, Heinemann, J, Angulo, M. "Gastric rupture and necrosis in Prader-Willi syndrome". J Pediatr Gastroenterol Nutr. vol. 45. 2007. pp. 272-4.

Tauber, M, Diene, G, Molinas, C, Hébert, M. "Review of 64 cases of death in children with Prader-Willi syndrome (PWS)". Am J Med Genet A. vol. 146. 2008. pp. 881-7.

Central adrenal insufficiency:

de Lind van Wijngaarden, RF, Otten, BJ, Festen, DA. "High prevalence of central adrenal insufficiency in patients with Prader-Willi syndrome". J Clin Endocrinol Metab. vol. 93. 2008. pp. 1649-54.

Role of microRNA in PWS:

Sahoo, T, del Gaudio, D, German, JR. "Prader-Willi phenotype caused by paternal deficiency for the HBII-85 C/D box small nucleolar RNA cluster". Nat Genet. vol. 40. 2008. pp. 719-21.

Ongoing controversies regarding etiology, diagnosis, treatment

It is not clear which genes in the PWS region of chromosome 15q11-13 account for which parts of the phenotype. Animal models have not clarified the issue, in that no model, including deletion of the whole region in a mouse, fully recapitulates the entire phenotype. Some authors believe that this is a true contiguous gene syndrome, with more than one of the genes contributing to the overall phenotype. However, the discovery that most of the findings can be associated with loss of a microRNA from the PWS region of chromosome 15 suggests that PWS may not be a truly contiguous gene syndrome.

When to begin treatment with rhGH remains controversial. Although several controlled trials support efficacy in early infancy, many experts question whether the long-term value of the therapy has been well-established, and whether the benefits outweigh potential risks. It is not at all clear how to resolve such questions for rare diseases like PWS due to the size, complexity, and expense of the trials that would be needed.

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