Abstract
Background:
Prader-Willi syndrome (PWS) is a neuro-developmental genetic disorder due to lack of expression of genes inherited from the paternal chromosome 15q11-q13 region with three main genetic subtypes. These include paternal 15q11-q13 deletion (about 70% of cases), maternal uniparental disomy 15 or both 15s from the mother (20–30% of cases), and defects in the imprinting center (1–3%) which controls the expression of imprinted genes in this chromosome region. Clinical manifestations include infantile hypotonia with a poor suck resulting in failure to thrive, short stature, small hands/feet and hypogonadism/hypogenitalism due to growth and other hormone deficiencies, hyperphagia and excessive weight gain with obesity and cognitive and behavioral problems including obsessive compulsions, tantrums and self-injury. The phenotype is likely related to hypothalamic dysfunction.
Objective:
Hyperphagia and obesity with related complications are major causes of morbidity and mortality in PWS requiring accurate diagnosis, appropriate medical management and treatment; the major objective of our report.
Methods and Results:
An extensive review of the literature was undertaken including genetics, clinical and behavioral aspects, and updated health-related information addressing the importance of early diagnosis and treatment of individuals with Prader-Willi syndrome. A searchable, bulleted and formatted list of topics related to this obesity syndrome was provided utilizing a Table of Contents approach for the clinical practitioner.
Conclusions:
Physicians and other health care providers can use this review with clinical, genetic and treatment summaries divided into sections that are pertinent in the context of clinical practice. Finally, frequently asked questions by clinicians, families and other interested participants will be addressed.
Keywords: Diagnostic and treatment approaches, genetic testing, genetics clinical description of Prader-Willi syndrome, genomic imprinting, medical management, obesity, Prader-Willi syndrome
INTRODUCTION
Prader-Willi syndrome (PWS) is a rare complex multi-system genetic disorder leading to the most commonly known genetic cause of life-threatening obesity in humans [1]. PWS arises from errors of genomic imprinting due to lack of expression of paternally inherited imprinted genes in the chromosome 15q11-q13 region. The cardinal features of this syndrome include severe infantile hypotonia, hyperphagia with onset of obesity during early childhood, if not controlled, developmental delay with learning and behavioral problems, short stature with small hands/feet and hypogonadism/hypogenitalism due to growth and other hormone deficiencies with mild dysmorphism. Psychiatric phenotypes, behavioral and autism features correlate with specific PWS genetic subtypes. The collections of findings pose difficult management care issues for patients, families and care-givers. PWS occurs in about 1 in 15,000 individuals [e.g., 2–5].
The objective of this review is to provide a searchable bulleted format of terms related to clinical and genetic background information and topics about Prader-Willi syndrome and recommendations for diagnosis, management, treatment and care to guide clinical practice throughout the natural history and life span of affected individuals. The shared information is supported by evidence-based medical knowledge obtained from experienced clinicians, cited peer-reviewed published reports and syndrome-specific health care guidelines. The importance of early diagnosis and use of a multidisciplinary team will be described and information shared and divided into sections in a bulleted format throughout. Each section represents the clinical presentation and list of features, genetic causation and counseling, diagnostic testing with therapeutic and management approaches including diet intervention, medication and hormone use and treatment options for behavioral and psychiatric problems that are most commonly seen in this disorder. These suggested recommendations are intended for health care providers and those assisting in the care and treatment of infants, children and adults with PWS. The clinical and laboratory testing recommendations are based on current medical practice and knowledge, supported by medical evidence reported by clinicians with expertise in PWS and geneticists, essential for smooth and effective provisions of care at all ages for those affected with this classical but rare obesity-related genetic disorder. A searchable bulleted format can be accessed by the clinician utilizing the following Table of Contents (See Table 1) to quickly identify pertinent information about clinical presentation, genetics, diagnostic aspects and treatment approaches.
Table 1.
Table of Contents
| INTRODUCTION | 1 |
| Key Points | 2 |
| Background | 2 |
| MATERIAL AND METHODS | 4 |
| RESULTS AND DISCUSSION | 4 |
| Epidemiology | 4 |
| Causes and Risk Factors | 4 |
| Associated Disorders Ordered by Importance | 5 |
| Complications Related to Prader-Willi Syndrome | 5 |
| Population at Risk or Screening Modalities | 6 |
| Preventive Measures | 6 |
| Clinical Presentation | 6 |
| Clinical Consensus Diagnostic Criteria | 8 |
| Laboratory Evaluation | 8 |
| Specific Tests | 9 |
| Other Obesity-related Disorders | 13 |
| Consultation for Diagnosis | 15 |
| Treatment and Medications | 15 |
| Vitamins and Other Supplements | 22 |
| Non-drug Treatments | 22 |
| CONCLUSION | 25 |
| Patient Satisfaction/Lifestyle Priorities | 25 |
| Consultation | 26 |
| Monitoring | 25 |
| Prognosis | 26 |
| Complications | 26 |
| Secondary Prevention/Patient Education | 27 |
| Practice Performance Measures/Summary of Evidence | 27 |
| Guidelines | 28 |
| Diagnostic Codes (ICD9–759.81 and ICD10-Q87.1) for Prader-Willi Syndrome | 28 |
| Clinical and Parent Questions | 28 |
| CONFLICT OF INTEREST STATEMENT | 29 |
| ACKNOWLEDGEMENTS | 29 |
| REFERENCES | 30 |
Key Points
Section Content and Questions to Answer
Bulleted list of clinically important features and genetic aspects of Prader-Willi syndrome are provided based on clinical application, genetic testing options with diagnostic and therapeutic approaches to care.
Prader-Willi syndrome (PWS) is a complex neurodevelopmental disorder characterized by infantile hypotonia and feeding difficulty, short stature, small hands and feet due to growth hormone deficiency, hypogonadism, mental deficiency, behavioral problems and hyperphagia leading to obesity in early childhood [2–4].
Individuals with PWS, early in life, display characteristic dysmorphic craniofacial features, among which include dolichocephaly, a narrow bifrontal diameter, strabismus, a small upturned nose with a thin upper lip and down-turned corners of the mouth, sticky salvia, and a dry mouth with enamel hypoplasia.
Cognitive impairment reduced for family background, behavior problems (temper tantrums, stubbornness, outbursts, self-injury) and psychiatric illness (obsessive compulsive disorder, schizophrenia, autism) are observed and correlated with genetic subtypes [2, 3,7–13].
Initial clinical consensus diagnostic criteria have been revised and updated; however, confirmation of the diagnosis requires molecular genetic testing [14, 15].
PWS results from errors in genomic imprinting, most often due to a de novo paternal deletion of the chromosome 15q11-q13 region (about 70% of cases) leading to a lack of expression of paternally derived genes. Maternal disomy 15 or both chromosome 15s inherited from the mother is seen in about 25% of cases. Defects within an imprinting center (microdeletions, epimutations) in the chromosome 15q11-q13 region or from other chromosome 15q abnormalities do account for the disorder in the remaining individuals [3, 5, 16–22].
Management is most effectively directed by multidisciplinary teams including clinical geneticists, endocrinologists, dietitians, primary care physicians and mental health experts with the goal to control weight gain, monitor and treat associated comorbid conditions, manage behavioral problems and replace growth and sex hormones [2, 9, 23, 24].
Rigorous control of the diet and securing the food environment with regular exercise plans are strategies to manage hyperphagia and obesity, complications of which represent the major causes of morbidity and mortality in this disorder [2, 24–26].
Background
Section Content and Questions to Answer
Case definition with abbreviations, alternative names and references will be provided with cardinal features listed for Prader-Willi syndrome in a bulleted format including distinctive characteristics or a constellation of findings that define this syndrome.
Description
Genetics and Genetic Subtypes
Genetics
Prader-Willi syndrome (PWS) is a complex genetic condition that arises due to the lack of expression of genes classified as imprinted on chromosome 15 and are paternally inherited [e.g., 18].
In the case of PWS, most of the genes from chromo-some 15q11-q13 region are subject to genomic imprinting, and only the alleles from the paternally derived chromosome are active. These same alleles from the maternally derived chromosome 15 are silenced by epigenetic factors, primarily through methylation.
The absence of paternally inherited gene expression from the chromosome.
15q11-q13 region gives rise to the PWS phenotype and syndrome.
Most PWS cases are sporadic, but familial cases can occur in situations where the father contributes a microdeletion of the imprinting center received from his mother but is uncommon. Imprinting center defects (microdeletion or epimutation) occur in less than 3% of PWS families. Under these circumstances, additional children with PWS may result with the risk of recurrence at 50% [e.g., 3, 21].
Genetic Subtypes
Chromosome 15q11-q13 Deletions in Prader-Willi Syndrome
About 70% of PWS individuals will show a de novo typical paternal deletion of the 15q11-q13 region consisting of two types, type I and type II [e.g., 1, 11].
The type I deletion is larger and involves chromo-some 15q proximal breakpoint, BP1 and distal breakpoint, BP3 [e.g., 21].
The type II deletion is smaller and involves chromo-some 15q proximal breakpoint, BP2 and distal breakpoint BP3.
In about 5% of PWS individuals, an unusual or atypical deletion is seen which is greater or smaller in size than the typical type I or type II deletion [3, 5, 27–29].
Maternal Disomy 15 in Prader-Willi Syndrome
-
The second most common genetic cause of PWS is found in about 25% of individuals and referred to as maternal disomy 15 where both chromosome15s come from the mother. Genes on chromosome 15 inherited from the mother are normally silenced by epigenetic factors, primarily through methylation and consists of three recognized disomic types:
Maternal heterodisomy 15 with two different chromosome 15s from the mother due to errors in meiosis I from homologous chromosome nondisjunction and no crossover events.
Maternal isodisomy 15 with two identical chromosome 15s from the mother due to errors in meiosis II from nondisjunction.
Maternal segmental isodisomy 15 with two partially different chromosome 15s from the mother due to errors in meiosis I from nondisjunction and crossover events leading to segments of isodisomy or loss of heterozygosity [3–5, 30].
Cardinal Clinical Features and Presentation
Cardinal Clinical Features
Craniofacial anomalies.
Intellectual disability.
Infantile hypotonia.
Growth hormone deficiency.
Hypogonadism.
Behavioral problems.
Hyperphagia leading to obesity in early childhood.
Clinical Course Development and Presentation
The course of PWS is historically divided into two clinical stages with failure to thrive representing the first stage and hyperphagia with onset of obesity representing the second stage. Recent studies have shown more gradual and complex progression of the nutritional phases, as outlined below.
Prenatal features include reduced fetal activity, breech presentation and non-term delivery. Other characteristics of the fetal phenotype include small for gestational age and increased head/abdomen circumference ratio.
Features of PWS often become evident at birth or during early infancy as illustrated by infantile hypotonia, feeding problems with a poor suck reflex and decreased muscle mass and strength, developmental delay, temperature instability, hypopigmentation, hypogonadism/hypogenitalism with a small penis and cryptorchidism in males, absent labia minora in females, and growth hormone deficiency with short stature and small hands and feet [e.g., 1].
Reduced fetal activity, breech presentation and non-term delivery are often observed but as the patient enters early childhood (about 2 to 6 years of age) additional features develop including food seeking behavior and hyperphagia leading to obesity, if not controlled. Mental deficiency and other behavioral problems including temper tantrums, emotional outbursts compulsivity, and self-injury with high pain threshold are commonly seen [e.g., 5].
Craniofacial findings seen in PWS include dolichocephaly, a narrow minimal frontal diameter, strabismus, almond-shaped eyes, short upturned nose with thin upper lip and downturned corners of the mouth with sticky salvia and enamel hypoplasia [1, 2, 31].
Nutritional Phases in PWS
Historically, PWS is described as having two clinical stages (i.e., failure to thrive then followed by hyperphagia leading to obesity), but recent classification schemes based on natural history studies, have proposed five main nutritional phases highlighted by gradual and complex progression of this disorder. Progression through the nutritional phases may be altered by the use of growth hormone treatment beginning at a young age.
Phase 0: Occurs in utero with decreased fetal movement and growth restriction.
- Phase 1: Hypotonic, non-obese infant (birth to 15 months of age).
- Subphase 1a: Difficulty feeding with or without failure to thrive.
- Subphase 1b: Steady infant growth and weight gain along a representative growth curve.
- Phase 2: Weight gain begins (~2 years of age).
- Subphase 2a: Weight increases without change in appetite or caloric intake.
- Subphase 2b: Weight gain occurs with increased interest in food.
Phase 3: Hyperphagia and lack of satiety accompanied by food seeking (~8 years of age).
Phase 4: Appetite is no longer insatiable [25].
MATERIAL AND METHODS
A searchable bulleted formatted list of clinically important features and genetic aspects of Prader-Willi syndrome is provided along with diagnostic approaches and treatment/medical care plans for the practicing physician or health care provider using a Table of Contents approach. An extensive review was undertaken searching published reports from the literature, textbooks and medical practice guidelines with recommendations generated by clinicians and established organizations/groups experienced with screening prevention, diagnosis and treatment options for patients with this rare obesity-related genetic disorder. This pertinent information was collated and arranged in sections that can be searchable and needed at the time of patient care in the clinical setting to address specific questions/issues such as key points, causes and risk factors, clinical presentation, diagnosis/laboratory evaluation, specific tests, consultation, treatment and medications, patient satisfaction/lifestyle priorities, prognosis, complications and guidelines.
RESULTS AND DISCUSSION
Epidemiology
Section Content and Questions to Answer
Gender, age group and ethnicity will be identified with quantitative data on incidence/prevalence in a bulleted format.
Introduction and Background
The estimated prevalence of PWS is 1 in 10,000 to 20,000 individuals with a reported range of 1 in 8,000 to 1 in 30,000. The number of individuals worldwide with PWS is estimated at 400,000 and about 20,000 individuals in the USA [1, 32].
Most cases of PWS are sporadic with an approximate 1:1 gender ratio. All ethnic groups are represented, but PWS is reported disproportionately more in Caucasians [33]. Based on population studies, the death rate in PWS is estimated at 3% per year [34].
Prader-Willi syndrome is the most common known genetic cause of life threatening obesity in humans [1, 2].
Causes and Risk Factors
Section Content and Questions to Answer
Specific causes and comorbidities of PWS will be listed in order of importance and specific risk factors or predisposing circumstances discussed. Causes will be considered when a direct etiologic role and risk or predisposing factors are known and described using a bulleted format.
Causes
Prader-Willi syndrome is due to errors in genomic imprinting involving the long arm of chromosome 15 leading to the loss of expression of paternally derived genes. These imprinted genes are present on the maternal chromosome 15 but are normally inactivated [21].
The most common event is a due to de novo paternal deletions of 5–6 Mb in size from the chromosome 15q11-q13 region and occurs in 70% of PWS cases [35].
Maternal disomy 15 (both chromosome 15s are contributed by the mother) occurs in about 25% of the cases [5, 21].
An imprinting center defect (microdeletion or epimutation) or other chromosome 15q abnormality (e.g., translocation or inversion) accounts for the minority of cases (3% or fewer) [21].
PWS individuals with maternal disomy 15 having the isodisomy or segmental isodisomy forms are at risk for secondary genetic conditions involving recessive genes on chromosome 15 if the mother is a recessive gene carrier. Several hundred recessive genes are known to be present on chromosome 15 causing different types of health problems such as hearing loss, cardiac abnormalities, seizures or metabolic defects. In addition, PWS females with maternal disomy 15, due to trisomy 15 rescue in early pregnancy may develop X-linked genetic conditions. This results from non-random X chromosome inactivation skewness in which the X chromosome carrying the abnormal X-linked gene is active in the majority of cells (e.g., >80%). [3, 30, 36]
Studies are underway using animal models [e.g., 37], measures of neuropeptides (e.g., oxytocin, substance P, neurotensin) [38–41], development of pluripotent stem cells [42], functional MRI scans to examine eating and aberrant behavior in PWS [43] and clinical trials.
Risk Factors
As with other numerical chromosome syndromes (e.g., Down syndrome due to trisomy 21), there is a correlation with advanced maternal age and trisomic 15 fertilized eggs (zygotes) due to maternal meiosis errors (nondisjunction) and trisomy rescue in early pregnancy. Trisomy 15 rescue event leads to maternal disomy 15 and PWS by reducing the 47 chromosome count to a normal 46 but with two chromosome 15s from the mother with loss of the chromosome 15 from the father in subsequent cells in the developing fetus [30, 44].
Hydrocarbons are known to cause chromosomal damage in human cell cultures. Early reports of over-representation of fathers with occupations associated with exposure to hydrocarbons were noted among children who develop PWS.
Recent evidence has shown a correlation with assisted reproductive technology (ART) and imprinting disorders such as Beckwith-Weidemann syndrome due to interference with the methylation DNA pattern required to control normal gene activity and may impact PWS, as well [45, 46].
Associated Disorders Ordered by Importance
Section Content and Questions to Answer
Comorbid conditions are included that tend to occur in the same patient as the index disease such as PWS and may be linked to the index disease by etiology or by common risk factors but not linked in a cause/effect relationship. Conditions that predispose to Prader-Willi syndrome or develop from it or other conditions that frequently accompany PWS will be addressed.
Introduction and Background
Osteoporosis, scoliosis and bone fractures due to osteoporosis are seen in PWS and possibly relate to growth and sex steroid hormone deficiencies which are commonly seen in this disorder. Hip subluxation is also seen during infancy. Monitoring for scoliosis is required, and if present then bracing or surgical intervention may be needed. Orthopedic complications should be monitored closely particularly during growth hormone (GH) treatment commonly in use in PWS infants, children and adolescents [e.g., 2].
Other endocrine disturbances, besides insulin resistance and diabetes, include hypothyroidism and central adrenal insufficiency, which are seen in about 10% of PWS individuals [2, 47, 48].
An increased risk of seizures is noted along with temperature instability, which is common during infancy and childhood, and possibly related to hypothalamic abnormalities and autonomic nervous system dysfunction. The disturbance in the autonomic nervous system may also contribute to dry mucosal membranes and decreased salivary flow common in individuals with PWS at all ages [e.g., 2].
Periodic breathing with central apneas is increased in frequency in infants with PWS with desaturations worse in rapid eye movement (REM) sleep along with narcolepsy-like symptoms [e.g., 2].
Adenotonsillar hypertrophy, obesity, craniofacial abnormalities and neuromuscular weakness are risk factors for obstructive sleep apnea (OSA). Sleep studies are indicated to determine the presence and severity of OSA, prior to initiating GH treatment and spinal fusion/instrumentation for scoliosis or as part of an evaluation to identify the cause of excessive daytime sleepiness [e.g., 2].
Adults with PWS have been reported with body temperatures below 90° F. Infection or hypothyroidism should be ruled out, but the most common cause is iatrogenic due to medications (atypical antipsychotics or beta blockers). Serious medical sequelae include prolonged bleeding time, myocardial abnormalities (bradycardia, dysrhythmia, conduction defects), decreased metabolism of medications, decreased kidney function with disturbed acid/base balance and altered mental status. Idiopathic hyper- or hypothermia may occur during minor illnesses and during anesthesia [49]. PWS individuals may not respond normally to infection regarding bodily temperatures [e.g., 2].
GABA receptor gene subunits which are not imprinted but located in the chromosome 15q11-q13 region are commonly deleted in PWS; therefore, neurotransmitter disturbances may be present. In addition, reduced expression of GABA receptor subunits could alter the response to anesthesia or sedative agents such as propofol. PWS patients should be monitored closely before, during and after surgery to avoid complications from anesthesia [21, 49].
PWS individuals with maternal disomy 15 are at risk for secondary genetic conditions involving recessive genes on chromosome 15 if the mother is a carrier. In addition, PWS females with maternal disomy 15 due to trisomy 15 rescue in early pregnancy may develop X-linked genetic conditions due to non-random X chromosome inactivation skewness. If the father is a carrier of an imprinting defect such as a microdeletion then genetic testing and counseling can be offered to rule out the presence of the defect in a newborn sibling or for prenatal diagnosis. Fathers carrying the genetic imprinting defect due to a microdeletion would be at a 50% risk of passing on the defect to his offspring leading to PWS [3–5].
Complications Related to Prader-Willi Syndrome
PWS is associated with findings related to obesity and hyperphagia if weight is not adequately controlled. These include:
Diabetes mellitus.
Osteoporosis.
Right-sided heart failure.
Fatty liver.
Hypoventilation.
Obstructive sleep apnea and narrow airway.
Stasis ulcers and cellulites.
Gastroparesis and gastric necrosis with rupture may occur secondary to excessive food intake even in those individuals with PWS without morbid obesity. Gastroparesis may also occur with gastroenteritis or constipation. PWS individuals have a high pain threshold and lack of vomiting, therefore they may not respond normally to abdominal distention or pain from life-threatening gastric inflammation or necrosis [2, 50].
Water intoxication and electrolyte imbalances (e.g., dilutional hyponatremia) can occur due to excessive fluid intake or low vasopressin levels with fluid retention, or medications such as diuretics and anti-depressants, interfering with electrolyte levels [2].
Population at Risk or Screening Modalities
Section Content and Questions to Answer
Briefly, an outline is given for whom and how to screen and guideline-based recommendations cited for screening when appropriate using a bulleted format. Specific group(s) are identified for screening and why to screen including a list of screening measures and their description.
Introduction and Background
No specific groups are at risk or should be screened but an over-representation of Caucasian patients with PWS has been reported.
No screening for PWS among the general population is currently available but newborn screening approaches have been raised using both methylation testing and chromosome deletion assays.
Preventive Measures
Section Content and Questions to Answer
Briefly, an outline with measures for prevention and to whom they apply will be cited in bulleted format.
There is no recognized approach to prevent the risk of lowering the chance of having a child with Prader-Willi syndrome. PWS occurs at random but an association is found with advanced maternal age in those PWS children with maternal disomy 15.
Clinical Presentation
Section Content and Questions to Answer
Short and succinct summary of entire diagnostic approach mentioning clinical presentation (symptoms and signs) and testing strategy will be produced and discussion of test results impacting on disease management in bulleted format. Standard criteria for diagnosis, diagnostic guidelines, and severity classifications will be provided including an approach for diagnostic evaluation and syndromic features with specialized tests and their descriptions.
Introduction and Background
The clinical presentation of PWS has historically been divided into two distinct clinical stages with failure-to-thrive and feeding problems representing the first stage and onset of obesity representing the second stage [e.g., 1].
During the perinatal period, reduced fetal activity, breech presentation and non-term delivery are often observed.
During infancy, PWS is characterized by infantile hypotonia, feeding problems with a poor suck reflex, and decreased muscle mass and strength.
Developmental delay, temperature instability, hypopigmentation, hypogonadism/hypogenitalism (with a small penis and cryptorchidism in males) and growth hormone deficiency with short stature and small hands and feet are recognizable features of the syndrome early in development.
PWS craniofacial findings include dolichocephaly or a narrow headshape, a narrow minimal frontal diameter, strabismus, almond-shaped eyes, short upturned nose with thin upper lip and downturned corners of the mouth with sticky salvia and enamel hypoplasia.
During early childhood (about 2 to 6 years of age), additional features appear including food seeking behavior and hyperphagia leading to obesity, if not controlled.
Mental deficiency and behavioral problems including compulsions, outbursts and self-injury, due to a high pain threshold, also develop during childhood [e.g., 2–4, 9, 10, 51].
Testing Strategy
Consensus diagnostic criteria have been established for PWS based on clinical findings and presentation, and should be fulfilled to support a diagnosis of PWS [14].
Genetic testing by an appropriately licensed laboratory is mandatory to confirm the diagnosis of PWS when suspected on clinical grounds. Early diagnosis in infancy using accredited genetic testing should be sought and allows early intervention.
Molecular testing should include DNA methylation analysis and detection of the chromosome 15 deletion (or other chromosome 15 anomalies).
- Findings that should prompt genetic testing for PWS, classified by age, include:
- Birth to age 2: Hypotonia with a poor suck and feeding problems with inadequate weight gain should trigger testing for PWS using current molecular genetic testing assays for PWS.
- Ages 2–6: History of congenital central hypotonia, a poor suck and global developmental delay.
- Ages 6–12: History of hypotonia with a poor suck, global developmental delay, food foraging with hyperphagia and central obesity.
- Ages 13 years through adulthood: Cognitive impairment, preoccupation with food, hyperphagia with central obesity, behavioral problems (e.g., temper tantrums, self-injury) and hypogonadotropic hypogonadism.
Molecular Analysis
Molecular testing for PWS should begin with DNA methylation analysis of a blood specimen, but will not identify the specific genetic subtype. If the DNA methylation test is normal, then other clinical disorders should be considered.
A chromosome analysis with fluorescence in situ hybridization (FISH) will identify the typical 15q11-q13 deletion but preferably a DNA chromosomal microarray analysis should be performed using both copy number variant (CNV) and single nucleotide polymorphism (SNP) probes to identify not only the size of the 15q11-q13 deletion (typical and atypical) but helpful for determining the maternal disomy 15 sub-type status by identification of loss of heterozygosity (LOH) of chromosome 15 gene alleles [35, 52].
If methylation testing shows a PWS methylation pattern and no recognizable 15q11-q13 deletion, then genotyping with polymorphic chromosome 15 DNA markers may be needed to identify biparental (normal) inheritance of chromosome 15 indicating an imprinting defect, if DNA chromosomal microarray analysis with CNV and SNP probes did not identify a deletion or extensive LOH (e.g., ≥10Mb in size) on chromosome 15 indicating maternal disomy 15 status [52].
Clinical Symptoms
Hyperphagia-Begins in early childhood or later.
Lack of satiety.
Clinical Signs
Mild prenatal growth retardation-Birth weight, length, and body mass index (BMI) are reduced by 15% compared to unaffected siblings.
Hypotonia-Prenatal hypotonia is evident by reduced fetal movement. Infantile hypotonia (central origin) is evident by reduced movement, hypoarousal and a weak cry with poor suck and feeding problems.
Poor suck and lethargy result in failure to thrive.
Global developmental delay and mental deficiency (average IQ=65) occur in nearly all children with PWS in relationship to family background.
Dysmorphic craniofacial findings-dolichocephaly, a narrow minimal frontal diameter, strabismus, almond-shaped eyes, short upturned nose with thin upper lip and downturned corners of the mouth, and enamel hypoplasia.
Hip subluxation in infants.
Thick viscous saliva.
Food foraging, hoarding and stealing.
Excessive and rapid weight gain leading to obesity.
Short stature.
Small hands and feet.
Narrow hands with straight ulnar border.
Kyphosis, lordosis, and anterior head tilt (adolescence and adulthood).
Hypopigmentation.
Genital hypoplasia.
Esotropia/myopia.
Enamel hypoplasia, dental caries, and dry mucosal membranes.
Skin picking can be problematic particularly at a surgical site or in a covered area (e.g., perianal abscess).
Clinical Findings
Behavioral and psychiatric disturbances.
Impulsivity, aggression, food theft, property destruction and self-injury.
Rigidity leading to outbursts, tantrums and oppositional behavior.
Repetitive and compulsive behaviors with cognitive rigidity becoming more problematic in adolescence and young adulthood along with depression, anxiety and in some cases psychosis.
Food-related activities such as food seeking, stealing and hoarding, eating non-food items (e.g., dog food), searching in garbage cans, stealing money to buy food and running away from home to access food.
Scoliosis.
Speech articulation defects.
Dysphagia, choking and silent aspiration.
Sleep disturbances, including central and obstructive sleep apnea.
Osteoporosis.
Decreased vomiting.
High pain threshold.
Temperature instability.
Growth hormone deficiency.
Adrenal insufficiency – In about 10% of individuals with PWS.
Early adrenarche.
Hypogonadism-Mixed primary and central (hypothalamic) components, but the latter predominate.
Incomplete and/or delayed pubertal development.
Infertility-Pregnancies and livebirths have been reported but rarely in females with PWS.
Academic difficulties beyond that expected for level of ability, often reflecting additional learning disabilities in focused areas.
Clinical Consensus Diagnostic Criteria
Consensus diagnostic criteria for PWS have been reported and revised with updates based on clinical findings and presentation [14, 15].
For children under 3 years of age, five of the clinical diagnostic criteria points are required, three of which must come from the major criteria category. For those older than 3 years of age, eight of the clinical diagnostic criteria points are required, four of which must come from the major criteria category. Supportive criteria do not contribute to the point total will require 8 points (with 4 from the major criteria category).
The Major Criteria Include
Neonatal and infantile hypotonia.
Feeding problems and failure to thrive in infancy.
Excessive or rapid weight gain with onset between 12 months and 6 years of age.
Characteristic facial features.
Hypogonadism.
Global development delay and mild to moderate mental retardation.
Hyperphagia.
The Minor Criteria Include
Decreased fetal movement.
Characteristic behavior problems.
Sleep disturbances/sleep apnea.
Short stature.
Hypopigmentation.
Small hands and feet.
Narrow hands with straight ulnar border.
Eye abnormalities.
Thick viscous saliva.
Speech articulation defects and skin picking.
Supportive Findings Include
High pain threshold.
Decreased vomiting.
Temperature instability.
Scoliosis and/or kyphosis.
Early adrenarche.
Osteoporosis.
Unusual skill with jigsaw puzzles.
Normal neuromuscular studies.
Formal genetic testing for confirmation of the clinical diagnosis of PWS is still required, and this should include (1) DNA methylation analysis; and (2) detection of the chromosome 15 deletion or other chromosome 15 anomaly.
Laboratory Evaluation
Section Content and Questions to Answer
A summary approach is provided for diagnostic evaluation, outlining of tests and imaging. Specific tests are followed by subsections on each test to include: Description, normal results and comments with evidence based medicine (EBM) entries at the end of each test subsection, if indicated. EBM entries are summarized with relevant results and most important statistical values. The sensitivity and specificity for the most important tests are given along with supportive evidence. Other tests that might important for designing a management strategy are discussed.
Summary of Test
Several laboratory tests are necessary for the molecular diagnosis and subtyping of PWS. A stepwise approach to utilizing these tests is recommended with the first step to confirm the clinical suspicion for PWS using DNA methylation analysis. The second step is to determine the cytogenetic or molecular class (i.e., the specific genetic lesion involving chromosome 15).
Options for DNA methylation analysis now include polymerase chain reaction (PCR) along with Southern blotting of the SNRPN probe for the chromosome 15q11-q13 region or methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) approaches utilizing several imprinted probes from this chromosome region. If the methylation result is abnormal (as found in 99% of PWS individuals), then historically FISH (fluorescence in situ hybridization) analysis would be ordered to identify the deletion status and to rule out a translocation or other chromo-some 15 anomaly. Currently, DNA microarrays with SNP and CNV probes or MS-MLPA kits can determine the deletion status [presence (and size) or absence] performed at any age for the patient [3–5, 53, 54].
Molecular analysis for maternal disomy 15 (the second most common genetic cause of PWS) should be undertaken if the deletion status is normal and methylation is abnormal (PWS pattern). DNA microarrays with SNP and CNV probes can assist in determining the maternal disomy 15 subtype status (heterodisomy, isodisomy or segmental isodisomy) in a significant number of those with maternal disomy 15. Genotyping DNA markers located throughout the long arm of chromosome 15 will allow for determination of the parental source of the chromosome 15s (normal bi-parental inheritance or maternal disomy 15) if DNA microarrays are not informative and paternity status is established [e.g., 3].
If necessary, additional testing may be required to identify the type of imprinting defects (microdeletion or epimutation), which represents the third genetic subtype seen in PWS (~3% of patients). This type of testing is typically conducted in research settings.
DNA methylation analysis is the initial molecular test to confirm the diagnosis of PWS.
Methylation-specific multiplex-ligation probe analysis (MS-MLPA) is performed to determine the molecular class (i.e., the specific genetic lesion involving chromosome 15) [54].
Fluorescence in-situ hybridization (FISH) with high resolution karyotype may be ordered to identify the deletion status and to rule out a translocation or other chromosome 15 anomaly.
Chromosomal microarray (CMA) probes utilized in high resolution and single nucleotide polymorphism (SNP) or copy number variant (CNV) probes utilized in high resolution microarrays can be ordered to determine the presence and size of a chromosome deletion as well as to determine the presence of maternal disomy 15 subtype status (heterodisomy, isodisomy or segmental isodisomy) depending on level or size of loss of heterozygosity.
DNA polymorphism or genotype analysis using chromosome 15 DNA markers can be performed to determine whether the inheritance pattern is biparental, (normal) or maternal-only (maternal disomy).
DNA sequence analysis is reserved for rare situations after DNA methylation analysis (maternally methylated allele only), FISH (no deletion), quantitative microsphere hybridization [22] and DNA polymorphism analysis (biparental inheritance) have been performed [55].
Adrenal reserve assessment is performed to assess for central adrenal insufficiency in PWS.
Thyroid function tests are performed to assess for hypothyroidism, particularly prior to initiating GH therapy even in the presence of normal thyroid screening at birth.
Liver function testing and serum insulin-like growth factor-1 (IGF-1) levels are used to assess for growth hormone deficiency and to monitor GH replacement therapy on a regular basis (e.g., every 3 months with IGF-1 levels) [56].
Fasting blood glucose and oral glucose tolerance tests are used to assess for diabetes.
Dual X-ray absorptiometry (DXA) scan is used to evaluate bone mineral density and body composition.
Polysomnography is performed to assess for sleep apnea prior to growth hormone treatment and after 3 months treatment in infancy [e.g., 2].
Baseline spine radiographs are obtained to assess for scoliosis beginning at about 18 months of age and for periodic evaluation subsequently depending on onset of GH treatment, skeletal findings and growth rate which may depend on family history and growth hormone receptor (GHR) gene polymorphism status which has been shown to impact growth rate on PWS and control individuals while treated with GH [e.g., 2, 57].
Specific Tests
Single Probe DNA Methylation Analysis
DNA methylation for PWS can be done utilizing three methods: historically. Southern blotting with chromosome15 methylated DNA probes; methylation specific PCR (mPCR) using single chromosome 15 methylated DNA probes (i.e., SNRPN) and MS-MLPA kits provided with multiple methylation sensitive DNA probes from the 15q11-q13 region.
Description
A venous blood sample from the proband must be collected for DNA extraction and isolation.
Genetic testing technique that uses the principle of epigenetics or the differential DNA methylation of imprinted loci to assess for paternal-only, maternal-only and biparental (normal) inheritance.
Southern blot or methylation-specific polymerase chain reaction (mPCR) utilizing single methylation-related probes [55].
The most robust, latest generation assays available target the carboxy-terminal CpG island of the SNRPN locus.
Normal Results
DNA from normal individuals will have both a methylated (maternally inherited) and an unmethylated (paternally inherited) allele.
Comments
Most efficient test to start the genetic work up if PWS is suspected as it will identify PWS in > 99% of cases [e.g., 3].
Test cannot distinguish the molecular class (i.e., deletion, uniparental disomy, or imprinting defect); therefore additional tests are needed if the methylation pattern is maternal-only inherited (a result that is indicative of PWS) [e.g., 2].
Methylation-specific Multiplex-ligation Probe Analysis (MS-MLPA)
Description
Normal results
DNA from normal individuals will have both a methylated (maternally inherited) and an unmethylated (paternally inherited) allele.
Comments
MS-MLPA is a genetic test technique that is used to determine methylation status of the PWS region and can also detect genomic deletions or duplications. It combines the technique of DNA methylation analysis and gene dosage analysis using multiple specific probes across the PWS region at one time.
Test will identify PWS in > 99% of cases and is used in some centers as a first line test for the molecular diagnosis of PWS. The advantage of MS-MLPA analysis over single locus DNA methylation analysis is that the MS-MLPA interrogates 5 separate differentially methylated sites. It can also estimate the size and distinguish the deletion type (typical type I and II or atypical-larger or smaller than usual deletions in the 15q11-q13 region) [e.g., 2, 6].
Test can distinguish chromosomal deletion from uni-parental disomy, but cannot generally distinguish uni-parental disomy from an imprinting defect, unless in rare individuals, a microdeletion of the imprinting center is seen.
Test will not identify chromosomal rearrangements involving the proximal region of chromosome 15.
Fluorescence in-situ Hybridization (FISH) with High Resolution Karyotype
Description
A venous blood sample from the proband must be collected for DNA extraction and isolation.
Normal results
A chromosomal analysis technique that permits cytogenetic localization of a DNA sequence to determine whether a chromosomal region, or gene, has been deleted or rearranged.
Fluorescently generated probe hybridizes, and therefore generates a single fluorescent signal, at the PWS/AS region of chromosome 15q11-q13, indicating no deletions or rearrangements.
Note that if prior DNA methylation analysis is positive and a “normal” FISH result is found, further testing to distinguish between uniparental disomy and an imprinting center defect is indicated.
Comments
FISH tests are historically ordered as a follow up to positive results from DNA methylation analysis in order to further determine the PWS genetic subtype. It is done in conjunction with a karyotype but current practice includes chromosomal or high resolution microarrays with SNP and CNV probes to determine the PWS genetic subtype.
In the evaluation of PWS, a specific fluorescently labeled probe corresponding to the PWS/AS region (e.g., SNRPN locus) may be utilized to identify deletions of the chromosome 15q11-q13 region.
The combination of FISH with karyotype has historically distinguished chromosomal deletions from chromosomal rearrangements (translocations and inversions) involving the 15q11-q13 region.
FISH tests are not sensitive enough to be used as the first line molecular test to identify PWS, and a negative FISH analysis does not exclude the diagnosis of PWS. Furthermore, FISH analysis alone will not identify the source (maternal or paternal) of the deletion in 15q11-q13 region (a paternal 15q11-q13 deletion is consistent with PWS while a maternal deletion is consistent with Angelman syndrome). Microarray testing is now considered to be an optimal test for determining PWS genetic subtypes.
FISH test not discern among normal, uniparental disomy and imprinting center defects and requires living cells and chromosome testing for interpretation of results.
Chromosomal Microarray (CMA) or High Resolution Microarray Using Single Nucleotide Polymorphism (SNP) or Copy Number Variant (CNV) Probes
Description
Genetic testing technique utilizing chromosomal microarrays to detect deletion status [presence (and size) or absence] at the PWS critical chromosome region using copy number variant probes.
Normal results
Normal; High resolution microarrays using SNP probes can be used to identify regions of homozygosity (ROH) or areas within the genome having identical DNA patterns on chromosomes indicating consanguinity or large areas (e.g., ≥ 10Mb in size) with loss of heterozygosity (LOH) on specific chromosomes indicating uniparental disomy (e.g., maternal disomy 15 in PWS) [35, 52].
Comments
Advantage of CMA or high resolution microarray as compared to FISH includes query of the entire genome, and therefore can provide information regarding deletions and duplications in the rest of the genome. Therefore, this test is useful when testing for PWS is negative.
Disadvantage as compared to FISH is that microarrays will not identify chromosomal rearrangements (balanced translocations and inversions).
SNP and CNV probes in the high resolution microarray can assist in determining the maternal disomy subtype status (heterodisomy, isodisomy, or segmental isodisomy).
CMA or high resolution microarrays are more expensive than using FISH analysis.
In the maternal isodisomy 15 subtype, the entire length to the chromosome 15 shows loss of heterozygosity with no evidence of DNA polymorphism. This indicates that the two maternal 15s are identical due to nondisjunction in gametogenesis or meiosis.
In the maternal segmental isodisomy subtype, only segments of chromosome 15 show loss of heterozygosity (e.g., ≥ 10Mb in size). This indicates that both maternal 15s contain areas where crossing over occurred and genetic maternal was exchanged during the first stage of gametogenesis (in meiosis I) [3, 52].
In the maternal heterodisomy 15 subtype, there is no evidence of loss of heterozygosity or crossing over in meiosis I. High resolution microarrays will not determine the PWS genetic subtype in this situation and additional genetic testing is needed such as genotyping with chromosome 15 DNA markers from the parents and PWS child.
Polymorphism Analysis of DNA Markers
Description
A venous blood sample from the proband and both parents must be collected for DNA extraction and isolation.
Normal results
“Normal” result would indicate a pattern of polymorphisms in the proband indicating biparental or normal inheritance. In the context of a prior abnormal DNA methylation analysis, the molecular class would be an imprinting defect in the presence of proven paternity. A maternal-only inheritance pattern indicates maternal uniparental disomy.
Comments
Genetic testing technique that compares the pattern of DNA marker polymorphisms of chromosome 15 loci among the proband and both parents to determine whether the inheritance pattern is biparental or maternal-only (maternal disomy).
Test is typically ordered after DNA methylation test is consistent with PWS [55], but negative results are obtained from FISH analysis (e.g., no deletion). DNA polymorphism analysis aims to distinguish between maternal unipartental disomy and an imprinting center defect.
Chromosome 15 DNA marker polymorphism analysis is not performed as a first line test, but is considered the “gold standard” test for defining uniparental disomy as the molecular class responsible for PWS but current studies indicate the value of identifying maternal disomy 15 by the use of high resolution microarrays with CNV and SNP probes [3, 5].
If biparental (normal) inheritance is demonstrated, then further testing in a specialized laboratory is necessary to determine whether the imprinting defect is due to an epimutation or micro-deletion in the imprinting center.
DNA Sequence Analysis
Description
A venous blood sample from the proband must be collected for DNA extraction and isolation.
Normal results
“Normal” result would demonstrate a normal nucleotide sequence, with no mutations or deletions.
Comments
Genetic testing technique that defines the smallest region of overlap (SRO) for the PWS imprinting center.
Test is reserved for rare situations after DNA methylation analysis (maternally methylated allele only), FISH (no deletion), and DNA polymorphism analysis (biparental inheritance) have been performed.
DNA sequence analysis is performed in research laboratories.
It is important to identify imprinting center microdeletions for genetic counselling purposes. The recurrence risk for additional children with PWS is impacted by whether the defect is due to a microdeletion or epimutation. If the father carries a microdeletion of the imprinting center on the maternally inherited chromosome 15, recurrence risk approaches 50%; if the defect is due to an epimutation, the recurrence risk is less than 1% [e.g., 3].
Adrenal Reserve Assessment
Description
Initial testing consists of measurement of the morning (8 AM) cortisol and ACTH level from a venous blood sample.
Normal results
8 AM serum cortisol level ≥ 18 mcg/dl indicates normal adrenal glucocorticoid production and secretion.
Comments
Thyroid Function Tests
Description
Measurement of serum thyroid stimulating hormone (TSH) and free thyroxine level (free T4) from a randomly obtained venous blood sample.
Normal results
TSH: 0.5–4.5 mIU/L (age specific ranges may apply).
Free T4: 0.7–2.0 ng/dL (age specific ranges may apply).
Comments
When interpreting test results, the reference interval supplied by the laboratory performing the test should always be used; these intervals are instrument- and/or method-dependent.
A TSH level > 10 mIU/L combined with a free T4 level below the lower limit of the reference range is usually indicative of primary hypothyroidism.
A TSH that is below the lower limit of the reference range or within the reference range combined with a low free T4 level may indicate central hypothyroidism.
Borderline abnormal results should prompt repeat testing for confirmation.
Assessment of thyroid function is advisable prior to initiating GH therapy.
Serum Insulin like Growth Factor 1 (IGF-1)
Description
Randomly obtained venous blood sample.
IGF-1 is a hormone product synthesized and secreted by the liver in a non-pulsatile manner, in response to GH receptor stimulation.
Serum IGF-1 levels therefore reflect GH action.
Normal results
Normative ranges for age and sex are laboratory and assay dependent.
Comments
Serum Fasting Glucose
Description
Venous blood sample obtained following an 8-hour fast (no consumption of food or beverages other than water; usually overnight).
If the result is abnormal, the test must be repeated to establish the diagnosis.
Normal results
70–100 mg/dl (3.9–5.6 mmol/L).
Comments
Current criteria for diagnosis of diabetes mellitus from the ADA include fasting plasma glucose level greater than or equal to 126 mg/dL (7 mmol/L).
Current criteria for diagnosis of impaired fasting glucose from the ADA include fasting plasma glucose level greater than or equal to 100 mg/dL.
Fasting glucose should be measured prior to commencing GH replacement therapy then every 6–12 months after maintenance doses are achieved [5].
Oral Glucose Tolerance Test
Description
In the morning after a 10-hour fast the fasting plasma glucose level is obtained and a 75-g oral glucose load is then administered; periodic serum glucose measurement is then compared to an established nomo-gram for normal glucose metabolism, generally over a 2-hour period.
Normal results
Fasting serum glucose: 70–100 mg/dL.
Serum glucose after 1 hour: < 200 mg/dL.
Serum glucose after 2 hours: < 140 mg/dL.
Comments
During the test, the patient should remain seated and should not smoke.
Should be done only in patients whose diet and physical activity have been unrestricted for 3 days before testing.
A plasma glucose level between 140 and 200 mg/dL at 2 hours after glucose load is considered due to impaired glucose tolerance (sometimes called “prediabetes”); this group is at increased risk for developing diabetes. A level greater than 200 mg/dL at 2 hours after glucose load is a sign of diabetes mellitus [e.g., 2, 5, 23, 24].
In the absence of unequivocal hyperglycemia, where the index of suspicion is high, repeat testing should be done.
Dual X-ray Absorptiometry (DXA) Scan
Description
Imaging technique that measures bone mineral density (BMD) (g/cm2) and can be used to measure body composition (fat and lean mass) [57].
In pediatric and adolescents, measurement of BMD should occur at two sites-lumbar spine and total body BMD.
Normal results
Pediatric and adolescent BMD results are reported as Z-scores (mean values as compared to age-matched controls).
Normal: A Z-score ranging from −2 to +2.
Comments
DXA scans should be performed and interpreted by radiologists familiar with technical aspects of DXA scanning in pediatric and adolescent populations.
Normative pediatric DXA datasets should be consulted, which take into account age, sex, ethnicity, weight, and Tanner stage [e.g., 2].
Polysomnography
Description
Nocturnal laboratory-based diagnostic study used to assess for the presence of sleep apnea.
Study quantifies the total time spent in sleep, time spent in sleep according to sleep stage, the number of arousals, and hypoxemic events.
Normal results
The number (frequency) of apneic and hypopneic episodes per hour is used to determine the apnea/hypopnea index (AHI) or respiratory disturbance index (RDI) which includes respiratory-effort related arousals (RERA) from sleep but does not meet the definition of apneas or hypopneas although sleep is disrupted but do disrupt sleep. They are characterized by increasing respiratory effort for 10 seconds or more leading to an arousal from sleep. A high RDI is significantly correlated with excessive daytime sleepiness. A normal result is an AHI or RDI of < 5 events hourly.
Minimal oxygen desaturations should occur.
Comments
Spine Radiographs
Description
Posteroanterior and lateral radiographs of the spine, including the iliac crest and cervical spine, used to assess for scoliosis.
Normal results
No kyphosis, lordosis, or deformities.
Proper alignment of the vertebral bodies.
Cobb angle (coronal plane angle measurement) < 10 degrees.
Comments
Adolescent scoliosis is identified by three-dimensional deformity of the spine with lateral curvature plus rotation of the vertebral bodies.
Standing radiographs are usually sufficient for the initial evaluation of scoliosis. Right and left bending films usually are obtained only if the patient is being considered for bracing or surgery.
Radiographs should be read and interpreted by radiologists or orthopedists with expertise in evaluating conditions of spinal curvature [2, 5, 23, 24].
Other Obesity-related Disorders
Section Content and Questions to Answer
The components are ordered by importance in bulleted format with common and key features that differ from PWS are described. How a disorder in the differential diagnosis can be differentiated from PWS will be discussed. Disorders in the differential diagnosis that present similarly to PWS but not linked by etiology, cause or effect, will be discussed. Names of diseases in the differential diagnosis will be discussed along with consultation advice for diagnostic dilemmas and procedures.
There are several imprinting disorders in humans that impact growth size and development due to errors in genomic imprinting besides PWS [45, 58]. These include:
Angelman Syndrome
Complex imprinted disorder generally due to deletions of maternal chromosome 15q11-q13 region with loss of the UBE3A gene which is maternally expressed and under the control of a separate imprinting center within the region.
Characterized by intellectual disability, microcephaly, gait ataxia, seizures, and behavioral disorder.
Distinguished from Prader-Willi syndrome on the basis of molecular genetic testing, starting with DNA methylation testing showing the presence of only the paternal set of alleles.
Albright Hereditary Osteodystrophy
Autosomal dominantly inherited condition of resistance to parathyroid hormone (PTH), resulting in hypocalcemia and hyperphosphatemia.
Caused by inactivating mutations in the GNAS1 gene located on chromosome 20 [45].
Characterized by developmental delay, round facies, short stature, obesity, and short fourth metacarpal bones.
Distinguished from Prader-Willi syndrome on the basis of molecular genetic testing and serum biochemistry (calcium, phosphorus, intact PTH levels).
Beckwith-Wiedemann Syndrome
Overgrowth disorder caused by abnormally imprinted gene expression in the chromosome 11p15.5 region.
The presentation is highly variable, characterized by macrosomia, visceromegaly, omphalocele and macroglossia.
Distinguished from Prader-Willi syndrome on the basis of molecular genetic testing (Methylation specific - multiplex ligation probe analysis or MS-MLPA) [53, 54].
Silver-Russell Syndrome
Inherited disorder due to epigenetic alterations involving the imprinting control region that regulates expression of the insulin-like growth factor 2 (IGF2) gene or other genes located in the region of chromo-some 11p15.5.
Characterized by intrauterine or postnatal growth retardation, and abnormal facies.
Distinguished from Prader-Willi syndrome on the basis of molecular genetic testing.
Maternal Disomy 14
Complex imprinted disorder with features similar to Prader-Willi syndrome, caused by maternal uniparental disomy of chromosome 14 or microdeletions of the 14q32.2 imprinted region.
Distinguished from Prader-Willi syndrome on the basis of molecular genetic testing.
Spinal Muscular Atrophy
Neonatal neuromuscular disorder caused by degeneration of the anterior horn cells in the spinal cord and motor nuclei in the lower brainstem.
Characterized clinically by hypotonia and weakness.
Children usually die before the age of 1 year due to respiratory failure.
Distinguished from Prader-Willi syndrome on the basis of molecular genetic testing.
Myotonic Dystrophy
Autosomal dominantly inherited multisystem disorder caused by trinucleotide (DM1) or tetranucleotide (DM2) repeats.
Numerous manifestations include skeletal muscle weakness, myotonia, muscle pain, cardiac conduction abnormalities, respiratory dysfunction, and hypogonadism.
Distinguished from Prader-Willi syndrome on the basis of molecular genetic testing.
Cohen Syndrome
Autosomal dominant disorder caused by inactivating mutations in VPS13B gene.
Characterized by developmental delay, intellectual disability, microcephaly, and hypotonia.
Abnormal facies are evident, with long eyelashes, down-slanting eyes, bulbous nasal tip, a smooth or shortened area between the nose and the upper lip (philtrum), and prominent upper central teeth.
Distinguished from Prader-Willi syndrome on the basis of molecular genetic testing.
Alström Syndrome
Multisystem disorder that presents in infancy caused by mutations in ALMS1 gene on chromosome 2, possibly involved in cilia proteins.
Characterized by dilated cardiomyopathy, obesity, type 2 diabetes mellitus, short stature and fibrosis of organs with shortened life expectancy.
Progressive loss of vision and hearing with multiple organ involvement.
Distinguished from Prader-Willi syndrome on the basis of molecular genetic testing.
Bardet-Biedl Syndrome
Multisystem disorder that presents in childhood, caused by mutations of one of several genes encoding cilia proteins.
Characterized by childhood obesity, retinitis pigmentosa, polydactyly, intellectual disability or learning problems, and abnormal genitalia.
Distinguished from Prader-Willi syndrome on the basis of molecular genetic testing.
Fragile X Syndrome
Form of inherited intellectual disability caused by inactivating mutations in the fragile X mental retardation 1 (FMR1) gene, located on chromosome Xq27.3 and usually affects males.
Characterized clinically by global developmental delay, intellectual disability, and learning disabilities.
Physical features include relative macrocephaly, blue irises, arched palate, joint laxity.
Distinguished from Prader-Willi syndrome on the basis of molecular genetic testing.
Single Gene Mutations (SIM1, POMC, MC4R)
Monogenic disorders characterized by extreme obesity beginning in childhood.
Distinguished from Prader-Willi syndrome on the basis of molecular genetic testing.
Leptin Deficiency
Congenital leptin deficiency is caused by mutations in the gene encoding leptin (LEP), whereas mutations in the leptin receptor (LEPR) causes leptin resistance.
Massive obesity in early childhood, hyperphagia, and delayed puberty due to hypogonadotropic hypogonadism are characteristic findings.
Distinguished from Prader-Willi syndrome on the basis of molecular genetic testing.
Cytogenetic Abnormalities, Including Chromosomal Deletions of 1p36 or 16p11.2
Microdeletions of either 1p36 or 16p11.2 cause intellectual disabilities and craniofacial abnormalities.
The 1p36 deletion syndrome has multisystem effects, including congenital heart disease, renal, skeletal, and ophthalmologic anomalies. Microcephaly, low set ears, flat nasal bridge are common.
The 16p11.2 deletion syndrome is characterized by developmental delay/learning problems, dysmorphic features with digital anomalies, short stature and severe early-onset obesity.
Distinguished from Prader-Willi syndrome on the basis of molecular genetic testing.
Wilms’ Tumor, Aniridia, Genitourinary Anomalies, and Mental Retardation (WAGR) Syndrome
Haploinsufficiency of the WT1 and PAX6 genes on ch11p13 to BDNF (11p14.1);
size of deletion determines degree of BDNF deficiency that in turn relates to obesity;
Low birth weight; 100 % obese by age 10 years; Wilm’s tumor, aniridia, genitourinary anomalies, intellectual deficiency.
Distinguished from Prader-Willi syndrome on the basis of molecular genetic testing.
Craniopharyngioma
Craniopharyngioma and/or the consequences of treatment causing brain/hypothalamic damage can lead to features similar to those seen in Prader-Willi syndrome, particularly at an early age.
This non-genetic condition is often referred to as “acquired Prader-Willi syndrome.”
Diagnosis is established through brain imaging and medical history of brain/hypothalamic tumor or damage.
Syndrome Summaries
Several of these disorders can resemble PWS, specifically obesity and learning/behavioral problems. If the DNA methylation test is normal (not indicative of PWS), then these clinical disorders may be considered to account for the clinical presentation.
During infancy, other chromosome rearrangements, infections, metabolic derangements (e.g., mitochondrial defects), spinal muscular atrophy, myotonic dystrophy or brain insults or anomalies should be considered. Later, other obesity-related conditions (e.g., Cohen, Alström, Bardet-Biedl, fragile X) should be considered as well as single gene mutations (e.g., SIM1, POMC, MC4R) [59, 60], leptin deficiency or other cytogenetic abnormalities (e.g., 1p36 or 16p11.2 deletions) [e.g., 61].
Additional cytogenetic abnormalities reported in individuals with obesity and learning/behavioral problems resembling PWS are duplications (3p25.3-p26.2 and Xq27.2-qter), but more commonly deletions of chromosome regions 1p36, 2q37.3, 6q16.2, 10q26, 11p12-p14, 16p11.2, 20q13.13-q13.32 or Xq26.3 [62]. Besides obesity, many of these cytogenetic or single gene disorders will present with birth defects or other clinical information that are not commonly seen in PWS and should help distinguish them from PWS. These include overgrowth and an omphalocele in Beckwith-Weidemann syndrome, a family history of male mental retardation in fragile X syndrome or retinitis pigmentosa in Bardet-Biedl syndrome.
Genome-wide and sequencing studies and microarray analysis have identified at least 60 gene loci or defects associated with an obesity phenotype including FTO, POMC, SH2B1, MC4R, TUB and BDNF genes. Several of these genes are known to contribute individually or collectively to extreme childhood obesity, increased body mass index, waist circumference or waist-to-hip ratios, and if recognized early, can be treated to avoid the health related complications in individuals carrying these genetic defects. At least 370 genes have currently been recognized in playing a role in human obesity [63].
Craniopharygioma and/or the consequences of treatment causing brain/hypothalamic damage can lead to features similar to those seen in PWS, particularly at an early age. This non-genetic condition is often referred to as “acquired Prader-Willi syndrome” [e.g., 2].
Consultation for Diagnosis
Section Content and Questions to Answer
Consultation for diagnostic dilemmas and procedures are described in bulleted format and outlined.
Introduction and Background
A trained medical geneticist, usually a board certified clinical geneticist will be involved with the diagnosis and care throughout the patient’s life time specifically to order appropriate genetic testing to confirm the diagnosis of PWS and interpret results. They will supply information about the syndrome and treatment options including providing genetic counseling services for family members.
Treatment and Medications
Section Content and Questions to Answer
The overall treatment approach will be summarized including medication and non-drug modalities that are concordant with their coverage in sections below followed in bulleted format.
Introduction and Background
There is a paucity of evidence-based data supporting the use of medical approaches documented for PWS; however, standard recommendations for treatment have been published by professional societies and published reviews or textbooks [e.g., 2, 5, 6, 23, 24, 56].
Treatment of PWS involves the management of several disorders that constitute the syndrome, and the ongoing assessment for the emergence of associated conditions and complications that evolve over the lifespan of an individual with PWS.
Medication Use
No single medication is available to treat or cure this genetic disorder.
Replacement for growth hormone, sex steroids, thyroid hormone, and glucocorticoids are indicated if and when deficiencies arise.
Medications are also used to treat behavioral problems, if behavioral management therapy is unsuccessful. The use of pharmacogenetics testing is becoming more common in clinical practice to check the status of the p450 hepatic enzyme system encoded by specific genes required for normal drug metabolism. Alternations in these genes can significantly affect selection of medication types and dosage [e.g., 64].
Medications can be helpful to manage the obesity-related complications associated with PWS, but to date, there is no medication that has successfully managed the drive for food acquisition.
Failure to Thrive
Assisted feeding techniques are often required for infants with poor suck.
During infancy, the goal is to maintain weight between the 25th through 75th percentile using established syndrome specific growth charts for PWS [65]. A recommended diet consists of the following macronutrient percentages: 25–30% protein, 40–50% carbohydrate and 25–30% fat. Increased dietary protein allows for increased muscle mass to occur when growth hormone is prescribed for PWS infants and children as well as to improve stature. Overall, the caloric intake needs should be monitored closely to avoid obesity in childhood and to avoid the failure to thrive in PWS infants [2, 5, 25, 66, 67].
Obesity
Weight management is one of the most important aspects of treatment along with endocrine disturbances for individuals with PWS. Specific dietary guidelines and development of clinical trials are underway or have been established with the goal of appetite treatment preventing obesity and its complications [e.g., 2, 5, 26, 66, 68].
Endocrine
Endocrine problems due to dysregulation of the hypothalamic-pituitary axis are common in PWS. A recommended initial consultation is warranted with a pediatric endocrinologist at an early age including for thyroid and adrenal function (particularly during times of stress) and for growth and sex hormone release. These endocrine concerns should be also be monitored with periodic hormone surveillance (e.g., every 6 months during infancy and yearly at later ages) [5, 23, 24, 56, 68].
Growth hormone insufficiency is considered a nearly universal finding in PWS; therefore, provocative testing is generally not required before growth hormone therapy. Growth hormone is used successfully for treating infants as early as 2 months of age once the diagnosis of PWS is genetically confirmed.
Hypogonadism is present in both males and females and has both a primary and central (hypothalamic) etiology, with the latter believed to be more influential. Although individuals with PWS do enter puberty, the progress is arrested and puberty is not complete. Testosterone (in males) and estrogen (in females) treatment should be considered as recommended by the endocrinologist in discussion with the parents, depending on the age of the patient [e.g., 2, 5, 68].
Scoliosis, Risk for Fractures and Other Orthopedic Problems
Scoliosis is seen in 20–60% of individuals with PWS ranging from mild to severe and may worsen during growth hormone treatment. It should be monitored closely with scoliosis x-ray series, bone density and bone age studies along with orthopedic consultations, if scoliosis is suspected [1]. Bracing and scoliosis surgery may be required.
Osteoporosis and osteopenia commonly develop in PWS and bone mineral density should be monitored with by DXA scans [e.g., 57].
Calcium and vitamin D supplements should be considered to optimize attainment of peak bone mass. The use of weight bearing exercises is often advised [e.g., 2, 5, 23, 24].
Behavioral Problems
Description
Many behavioral problems in PWS can be attributed to food insecurity. Food insecurity increases anxiety and preoccupation with potential food sources, which in turn triggers food seeking. The fundamental approach to behavioral management in PWS is the establishment of an environment that provides controlled food access, psychological food security, and a daily plan that includes mandatory exercise and leisure activities. A linear schedule that alternates preferred with non-preferred activities works well to improve transitions.
Behavioral counseling and management programs are an important component of treatment for individuals with PWS. Active partnership of the parents, teachers, primary care provider, pediatrician and psychologist are required. Behavior management works best by rewarding desired behaviors, discouraging or ignoring undesirable behaviors, providing incentives, and outlining consequences of inappropriate behavior [e.g., 2].
A safe environment should be established for the person with anger management problems. Modified cognitive behavioral therapy a and social skills training should be Implemented by building adaptive coping strategies (scripted, rehearsed, and cued) through coaching.
Medications that have been used occasionally to treat behavior problems include stimulants, alpha-adrenergic agonists, beta blockers, mood stabilizers (lithium, valproate, lamotrigine) and typical and atypical antipsychotics, and antidepressants, specifically selective serotonin reuptake inhibitors (SSRIs,). These classes of medications have been used to treat the emotional disturbances, depression, impulsivity, aggression, obsessive-compulsive tendencies and psychosis occurring in Prader-Willi syndrome patients, but no selection or order of medications have been approved specifically for treating behavioral problems in PWS as the response may vary from patient to patient [e.g., 2].
Individuals with PWS are stress sensitive and susceptible to anxiety and depression. The uniparental disomy form of PWS has been associated with cyclic psychosis that appears to increase with age. Psycho-tropic medications are used to treat co-morbid psychiatric disorders that occur in PWS or to help in the management of phenotypic behaviors.
Although haloperidol was used extensively in the past for management of the behavioral as well as psychotic symptoms in PWS, the atypical antipsychotic agents are now used almost exclusively. These include risperidone, aripiprazole, quetiapine, and ziprasidone.
Antipsychotic medications maybe prescribed in PWS for psychotic findings including delusions and hallucinations but can have side effects. The typical extrapyramidal side effects of tremors, stiffness, may not be as evident in PWS due to hypotonia. Weight gain may be managed by controlled food access. Loss of facial expression and associated arm swing are the best indicators of extrapyramidal side effects and need to be monitored closely in PWS. Individuals with PWS are at the same risk as the general population for neuroleptic malignant syndrome and tardive dyskinesia but may also be at-risk for iatrogenic hypothermia [e.g., 2].
The antianxiety agents, such as benzodiazepines and buspirone, may help with anxiety, cognitive rigidity, and insomnia but can produce sedation and decreased mental alertness [e.g., 2].
Some medications can produce iatrogenic mood and behavioral activation in PWS. These include SSRI’s, NSRI’s, aripiprazole, modafanil, gonadal steroids and rarely, stimulants and alpha-adrenergic agonists. Symptoms include increased intensity of phenotypic behaviors, followed by increased impulsivity, mood lability, and possibly psychosis [e.g., 2].
Medications and Hormone Replacement
Description
For each medication, subsections on indications, dose and related information (e.g., route and frequency and duration of administration), major contraindications and comments will be presented and limited to those of greatest clinical relevance. Evidence based medicine (EBM) entries and appropriate information will be summarized and effectiveness of various regimens discussed in bulleted format and described accordingly.
Hormone Replacement
Recombinant human growth hormone (rhGH).
Indications
Treatment of growth hormone deficiency (as manifested by growth failure and/or short stature) in PWS [e.g., 56].
Dose and related information
Starting dose: 0.5 mg/m2 /d administered SQ once daily beginning at or before age 2 years; alternative dosage of 0.24 mg/kg/wk.
Only available in subcutaneous formulation.
Major contraindications: active malignancy; severe obesity (weight >225 percent of ideal body weight; severe respiratory impairment.
Comments
Children with PWS and clinically significant obstructive airway disease or apnea, gastroesophageal reflux with poor airway protection, morbid obesity, or uncontrolled weight gain should receive attention to and/or treatment of these medical issues prior to commencement of GH therapy.
Provocative testing to demonstrate GH deficiency is usually unnecessary for patients with genetically confirmed PWS who demonstrate growth failure.
Titrate dose (usually about 1.0 mg/m2/d) but may require less initially in PWS infants to achieve insulin like growth factor 1 (IGF-1) levels in the upper one-half of the normative range for age for infants and children.
Monitor for clinical effects that would indicate over-replacement, such as sleep apnea, edema, worsening/new snoring, headache, excessive long bone growth, worsening of scoliosis.
rhGH is FDA-approved for use in PWS beginning at age 2 years, but now commonly used at an early age (by 2–3 months) and has shown beneficial effects on motor development, muscle, and cognition. It is in common use in this patient population. Head circumference increases can be related to skull bone thickening [5].
Continuation of treatment into adulthood after epiphyseal closure to sustain the beneficial effects of rhGH on body composition and bone mass is controversial. If used, the transition from pediatric to adult use of rhGH should be guided by endocrinologists.
Evidence
A meta-analysis studying the effect of rhGH therapy on body composition in adults with PWS identified 8 studies that included 134 individuals treated with rhGH for 12 months. Treatment of individuals with PWS with rhGH led to [weighted mean difference (MD) 95% confidence interval (CI)] reduced body fat (MD: −2.9%; CI: −3.90 to −1.910), visceral fat (MD: −32.97 cm2; CI: −55.67 to −10.26), subcutaneous adiposity (MD: −55.24 cm2; CI: −89.05 to −21.22), and increased lean body mass (MD: 2.41 kg; CI: 1.32 to 3.49). Studies of longer duration confirmed the findings for change in body fat (MD: −2.89%, CI: −4.69 to −1.07) and lean body mass (MD: 2.82 kg; CI: 1.31 to 4.33). Individuals treated with rhGH for 12 months did exhibit small increases in fasting glucose (MD: 0.27 mmol/L; 95% CI: 0.05 to 0.49) [69].
A multicenter prospective trial studied the effects of long-term continuous rhGH treatment on body composition, growth, bone maturation, and safety parameters in children with PWS. 55 prepubertal children (mean age of 5.9 ± 3.2 years) were followed over 4 years while treated with rhGH (1.0 mg/m2). Body fat percentage (SDS) was significantly lower after 4 years of rhGH treatment (P < 0.0001). Lean body mass SDS significantly increased during the first year of treatment (P = 0.02) but returned to baseline values the second year and remained unchanged thereafter. Mean ± SD height normalized from −2.27 ± 1.2 SDS to −0.24 ± 1.2 SDS (P < 0.0001) after treatment with rhGH. Body mass index SDS significantly decreased. Thus, body composition and height were significantly improved in children with PWS after long-term treatment with rhGH. No adverse effects were noted on bone maturation, blood pressure, glucose homeostasis, and serum lipids [70].
A randomized controlled trial (RCT) studied the effects of rhGH treatment on cognitive functioning in 50 prepubertal children (ages 3.5 to 14 yr) with PWS. Cognitive functioning was measured biennially by validated intelligence tests [the Wechsler Preschool and Primary Scale of Intelligence-Revised, Dutch version (WPPSI-R) or the Wechsler Intelligence Scale for Children-Revised, Dutch version (WISC-R)]. Total intelligence quotient (IQ) score was estimated based on two subtest scores. After 4 years of GH treatment, mean standard deviation scores (SDS) on the Similarities and Block design subtests were significantly higher than at baseline [mean difference (MD); 95% confidence interval (CI)] for Similarities test- MD: +0.4; 95% CI: −0.1 to 0.7; P = 0.01 for Block Design- MD: +0.3; CI: 0.07 to 0.6, P = 0.01. These results indicate that long-term GH treatment significantly improves abstract verbal reasoning and visuospatial skills, and reduces the gap between children with PWS and healthy controls on these skills. Thus, during long-term GH treatment, children with PWS developed their vocabulary at the same pace as healthy references. The mean estimated total IQ score improved 4 points during 4 years of GH treatment, but this result did not reach significance (P = 0.2) [71]. A more recent review of growth hormone treatment protocols in PWS was summarized by Deal, C., Tony, M., Hoybye, C., and the 2011 GH in PWS Clinical Care Guidelines Workshop Participants. Growth Hormone Research Society workshop summary: Consensus guidelines for recombinant human growth hormone therapy in Prader-Willi syndrome [56]. This reference is important for health care providers treating PWS infants, children and adults with GH.
Testosterone enanthate
Indications
Treatment of hypogonadism and induction of puberty in males with PWS; prevention of osteoporosis [e.g., 5].
Dose and related information
Starting dose in early adolescence: 50 mg IM once a month, beginning around age 14; may increase by 25–50 mg every 6 months as needed.
FDA approved as an intramuscular injection for children and adults, but available in transdermal and gel preparations for adults.
Major contraindications: prostate or male breast cancer (adults).
Comments
Establish a baseline on mood and behavior before starting medication.
Initiate low dose therapy and titrate cautiously, assessing mood and behavior before each dose change to avert any undesirable effects on mood or behavior.
Establish minimal effective dose that will achieve clinical and biochemical eugonadism.
Systematic studies evaluating the benefits and safety of sex hormone replacement in adolescents or adults with PWS are not available.
Monitor testosterone level annually to target dosing (once eugonadism is achieved) and monitor hemoglobin periodically for development of polycythemia.
Monitor for new or worsening glucose intolerance and/or worsening of scoliosis.
Protects against osteopenia/osteoporosis.
Estradiol
Indications
Treatment of hypogonadism and induction of puberty in females with PWS; prevention of osteoporosis [e.g., 5].
Dose and related information
Starting dose: 0.25 mg micronized PO daily beginning at around age 12 years.
Transdermal starting dose: 14 mcg transdermal daily but usually applied twice weekly.
Major contraindications: Vaginal cancer, cervical cancer, uterine cancer, or other estrogen-responsive tumors; undiagnosed vaginal bleeding; pregnancy; mood and behavior problems.
Comments
Often females with PWS never develop menses due to sex hormone deficiency throughout life.
Starting dose of estradiol is not sufficient to induce menstruation. After initiation, increase the dose of estradiol gradually over a two year time span to achieve the adult dose of 2–4 mg micronized PO daily (or 100–200 mcg transdermal daily)
After two years, or once breakthrough bleeding occurs on unopposed estradiol, add cyclic progestin (or replace estradiol with a low dose oral contraceptive that contains both estrogen and progesterone).
Systematic studies evaluating the benefits and safety of sex hormone replacement in adolescents or adults with PWS are not available.
Longitudinal studies on continuation of sex hormone replacement in females with PWS throughout life are not available. Due to central gonadotropin failure, there is no puberty or menopause, so the endpoint to sex hormone replacement therapy has not been established.
Protects against osteopenia/osteoporosis.
Micronized progestin
Indications
Treatment of hypogonadism in females with PWS (in combination with estradiol).
Dose and related information
Starting dose: 200 mg PO days 1 to 12 of the calendar month.
Major contraindications
Vaginal cancer, cervical cancer, or uterine cancer; undiagnosed vaginal bleeding; history of thrombophlebitis or thromboembolic disease.
Comments
The addition of a progestin to the sex steroid replacement regimen is advisable after estradiol therapy has begun to prevent endometrial hyperplasia, usually 2 years after estradiol treatment begins.
Psychotropic Medications
Description
Psychotropic medications may be used to treat behavior disturbances and psychiatric problems in individuals with PWS following unsuccessful behavioral management therapies. A common practice in PWS is to begin the medication dosage at a low level and adjust upward when indicated. Pharmacogenetics and genetic testing of the p450 hepatic enzyme gene networks is a new field in medical practice which is related to personalized medicine. The study of polymorphisms or variants impacting function of genes involved with drug metabolism will impact drug selection and dosage per individual. This should be considered prior to prescribing psychotropic medications and /or in those individuals not successfully treated with routine medication and dosage protocols. The level of obesity, gastric function and intestinal absorption may also impact on medication use.
Stimulant Medications
Indications
Treatment of symptoms of Attention Deficit Hyperactive Disorder (ADHD) and excessive daytime sleepiness. Baseline behavioral assessments are usually obtained from the school or work place. Standardized tools include the Connors Rating Scales, the Vanderbilt Assessment Scales and the Clinical Attention Problem Scale (CAP) rating scale. These tools are also used to monitor treatment response. Affected children with PWS are more likely to have attention problems without hyperactivity.
Dose and related information
It is best to start with short acting medications, such as:
Methylphenidate (Ritalin) (0.3–1.5 mg/kg); lasts 4 hours.
Dextroamphetamine (Dexedrine) or (0.3–1.5 mg/kg); lasts 6 hours.
Mixed amphetamine salts (Adderall) (5mg-30mg).
Establish optimal dose response and efficacy, and then try a sustained or continuous release agent, such as:
Concerta (18mg-72mg).
Metadate CD (10mg-60mg).
Dexedrine spansule (5mg-15mg).
Mixed amphetamine salts extended release (Adderall XR) (5mg-30mg).
Lisdexamfetamine (Vyvanse) (20mg-70mg).
Major contraindications
Cardiac abnormalities or abnormal rhythm may require cardiology evaluation before initiating treatment.
Comments
Monitor for increased heart rate and blood pressure. Stimulants are controlled medications that carry a risk for abuse.
Non-stimulant Medications
Indications
Treatment of symptoms of Attention Deficit Hyperactive Disorder (ADHD), disruptive behavior associated with hyperarousal, and anxiety.
Dose and related information
Atomoxetine (Strattera) norepinephrine reuptake inhibitor (0.5mg/kg/d-1.2mg/kg/d).
Alpha adrenergic agonists (short acting).
Guanfacine 0.5mg-1mg TID.
Clonidine 0.05mg-0.1mg TID.
Comments
May produce sedation. A decrease in hyperarousal and hyperactivity may be seen soon after initiating therapy, but it may take weeks to months to decrease achieve anxiolytic effects.
Non-stimulant Medications
Indications
Treatment of excessive daytime sleepiness.
Dose and related information
Modafanil (Provigil) 100 mg q am; may increase as needed.
Comments
Watch for mood and behavioral activation.
Selective Serotonin Reuptake Inhibitors (SSRIs)
Indications
Dose and related information
Because mood and behavioral activation have occurred at typical starting doses of SSRI medications, it is recommended to start at half dose and titrate slowly.
Fluoxetine: initially, 5 mg/d orally; increase at intervals of no shorter than 4 weeks.
Paroxetine: initially 5 mg/d orally; increase at intervals of no shorter than 2 weeks.
Sertraline: initially 12.5 mg/d orally; increase at intervals of no shorter than 2 weeks.
Fluvoxamine: initially 12.5mg/d orally; increase at intervals of no shorter than 2 weeks.
Citalopram: initially 5 mg/d orally; increase at intervals of no shorter than 2 weeks.
Escitalopram: initially 2.5mg/d orally; increase at intervals of no shorter than 2 weeks.
Major contraindications
Concurrent use of monoamine oxidase inhibitors (MAOIs).
Comments
FDA reports increased awareness (FDA black box warning) of the risk of suicidal ideation and behavior within this population after starting SSRI medications. The risk of increased self-harm is outweighed by the efficacy in reducing depressive symptoms.
Use caution in patients with hepatic or renal impairment; a dose reduction may be necessary.
Systematic studies evaluating the benefits and safety of SSRIs in adolescents or adults with PWS are not available.
FDA reports a warning related to Celexa (citalopram) because of the risk of QT prolongation. ECG monitoring and/or electrolyte monitoring should be performed if citalopram is used.
Antipsychotics
Indications
Treatment of psychosis, agitation and impulsive aggression in PWS [e.g., 2].
Dose related information
Due to increased sensitivity to drug dosage in PWS from an abnormal body composition, a lower drug dose (e.g., about one-half usual dosage) may initially be administered and then a higher dosage prescribed depending on clinical response.
Risperidone: 0.25 mg/day orally; increase at intervals of no shorter than 1 week, titrated to address target symptoms; not to exceed 6 mg/day.
Aripiprazole: 2 mg/day (or every other day in young children); titrate slowly, but be aware of the possibility of mood and behavioral activation; not to exceed 20 mg/day.
Ziprazidone: 20 mg twice daily with food, may increase based on clinical response to 80 mg twice daily.
Olanzepine: 2.5 mg/day and increase by 2.5 mg/day weekly until target symptoms resolve or dose reaches 20 mg/day.
Quetiapine: 25 mg/day and increase by 25mg/day in multiple doses to 400 mg/day (Quetiapine SR is the long acting form and can be started at 100mg at hs, but not all medical insurance covers this on formulary).
Haloperidol: 0.5 mg/day; titrate as tolerated. Not to exceed 10 mg/day.
Major contraindications
Atypical antipsychotics are noted to increase appetite and weight gain in typical persons. Although there may be an increase in weight in PWS, it is unlikely to occur in situations where food access is controlled, which is the standard of care for PWS. Aripiprazole can cause mood and behavioral activation even at low doses.
Ziprasidone has been noted to increase QT interval on electrocardiogram (ECG), so baseline ECG should be obtained and monitored during increases in dose.
Olanzepine has been noted to contribute to the occur-rence of metabolic syndrome. It also causes sedation and is therefore best administered at hour of sleep.
Comments
Monitor weight, fasting glucose and fasting lipids.
Monitor for extrapyramidal symptoms (EPS) and tardive dyskinesia. Muscle rigidity may not be appreciated in PWS due to hypotonia, but loss of emotional expression and loss of associated arm swing while walking are more reliable indicators of EPS. Occurrence of tremor is variable. The risk of tardive dyskinesia and neuroleptic malignant syndrome appears to be the same in PWS compared to typical persons. Assessment of neuroleptic malignant syndrome is complicated by hypotonia and unreliability of fever in PWS.
The incidence of dementia in PWS is not known, but atypical neuroleptics are not approved for the treatment of dementia-related psychosis.
Long before atypical antipsychotics were available, haloperidol was used with some success to manage the behavioral outbursts in PWS. It is still used in individuals who do not respond to atypical antipsychotics.
The class of atypical antipsychotics has been helpful for treating behavioral problems as well as mood instability. However, because some of the newer agents, such as aripiprazole, activate serotonin receptors, they carry the same risk of producing a syndrome of mood and behavioral activation.
Mood Stabilizers
Indications
Treatment of bipolar disorder, and also, treatment of intermittent explosive disorder and picking behaviors in PWS.
Dose and related information
Lithium: Begin at a dose of 300 mg/d orally and titrate to a dose of 300 mg three times daily, increasing at intervals of no shorter than 1 week. Follow trough serum lithium levels until the desired mood and behavioral response is achieved, or until dose–related side effects of tremor or polyuria prohibit higher dosing. Levels of up to 1 meq/L may be required for impulsive aggression, and up to 1.5 mEq/L may be required for mania. If polyuria becomes a significant clinical symptom while mood and behavior are improved at steady state lithium levels, reduce the total daily dose by one-third, and administer it at hour of sleep; this reduces the renal side effects.
Carbamazepine/oxcarbazepine: Begin at a dose of 100 mg twice daily orally; increase at intervals of no shorter than 1 week. Obtain serum electrolytes at a dose of 300 mg bid to rule out hyponatremia (see below). Between doses of 600–900 mg/d, there is a high likelihood that hyponatremia will prohibit the titration to optimal doses to obtain the necessary mood and behavioral benefit.
Valproic acid: Begin at a dose of 250 mg daily and increase to 250 mg twice daily after one week and then to three times daily, titrating the dose to a trough serum level of between 50–100 mcg/L. Monitor liver function, platelet count and serum ammonia levels. Non-hepatic hyperammonia is linearly related to total daily dose, duration of treatment and increases with age in PWS; it responds to dose reduction or discontinuation. Fine tremor is seen at higher doses. Higher doses are required for management of manic mood.
Topiramate: Begin at a dose of 25 mg/d orally; increase at intervals of no shorter than 1 week, not to exceed 200 mg daily. Doses of 25 mg three times daily have shown some benefit with skin picking in PWS. Monitor serum electrolytes for increasing chloride and decreasing bicarbonate indicative of hyper-chloremic acidosis (see contraindications below).
Lamotrigine: Begin at a dose of 25 mg/d and titrate very slowly by 25 mg every 2 weeks due to risk of Steven’s Johnson rash. Doses up to 200 mg/d may be tolerated without difficulty.
Major contraindications
Carbamazepine/oxcarbazepine should not be used in patients with a history of previous bone marrow depression, hypersensitivity to the drug, or known sensitivity to any of the tricyclic compounds or concurrent use of monoamine oxidase inhibitors. There is a dose related incidence of hyponatremia in PWS; serum sodium levels ofless than 130 mEq/L have been associated with seizures. There is an additive risk of hyponatremia when these agents are used in combination with other psychotropic agents, such as SSRIs or atypical neuroleptics. CBC and differential must be obtained due to the risk of neutropenia and thrombocytopenia. There is also a risk of Steven’s Johnson rash.
Topiramate is a carbonic anhydrase inhibitor. It can cause renal tubular acidosis, resulting in a hyper-chloremic metabolic acidosis that leaches calcium from bone, worsening risk of osteoporosis in PWS. It is for this reason that topiramate has been associated with the development of kidney stones. Also, it has been reported to cause cognitive blunting and irritability at higher doses.
Valproic acid should not be used in patients with impaired liver function or impaired bleeding time. It should not be used in individuals with mitochondrial disorder, as this increases the risk of hyperammonemia.
Comments
Lithium: Obtain baseline values of thyroid, serum electrolytes and renal function.
Monitor kidney function and lithium levels at regular intervals, as there is a narrow therapeutic index. Obtain thyroid function at 6 weeks after maximum dose is achieved and monitored every 6 months thereafter.
Carbamazepine/oxcarbazepine: monitor CBC and differential for agranulocytosis and thrombocytopenia; monitor serum electrolyes for hyponatremia.
Topiramate: Can increase the risk of kidney stones by 2–4 times. Use caution in patients with hepatic or renal impairment; a dose reduction may be necessary. Monitor serum electrolytes for decreasing bicarbonate and rising chloride, indicators of metabolic acidosis. Although topiramate has been used for weight reduction in individuals with binge eating disorder and to reduce cravings in individuals with addictions, there is no evidence that topiramate has any effect on the food related behaviors in PWS.
Valproic acid: monitor liver function, platelet count and serum ammonia (specimen must be placed on ice immediately, so levels should be obtained at a hospital laboratory).
Systematic studies evaluating the benefits and safety of anticonvulsant mood stabilizers in adolescents or adults with PWS are not available.
Lamotrigine has both antidepressant and mood stabilizing properties.
Vitamins and Other Supplements
Calcium
Indications:
prevention of osteopenia/osteoporosis in PWS.
Recommended daily intake:
Ages 1–3: 700 mg/d orally.
Ages 4–8: 1000 mg/d orally.
Ages 9–83: 1300 mg/d orally.
Ages 19–70: 1000 mg/d orally.
Ages > 70: 1200 mg/d orally.
Comments:
Daily recommended intakes are based upon values determined by the Institute of Medicine.
Vitamin D
Indications:
prevention of osteopenia/osteoporosis in PWS.
Recommended daily intake:
Ages 1–70: 600 IU/d orally.
Ages > 70: 800 IU/d orally.
Comments:
Vitamin D should be taken in conjunction with calcium supplementation.
Daily recommended intakes are based upon values determined by the Institute of Medicine.
Omega-3 Fish Oils
Indications:
fatty acid supplementation; mood and behavior stability; prevention of seasonal affective disorder.
Recommended daily intake.
1000 mg three times daily with meals.
Comments:
The calorie restriction in the PWS diet may sacrifice fats, including healthy fat sources from meat and fish. Fatty acids are essential for maintenance of neuronal membranes, essential to neuronal function and may also reduce inflammation.
N-acetyl Cysteine
Indications:
NAC has been shown to be effective in treating the skin picking associated with PWS. It is available as a capsule and a dissolvable fizzy (PharmNac).
Recommended starting dose:
600mg once daily. Increase to 600 mg twice daily after 6 weeks, and increase by 600 mg every 6 weeks up to 1200mg twice daily.
Comments:
NAC is a powerful peripheral antioxidant and modulator of the interaction between glutamate and GABA neurotransmitters in the brain. It has been used extensively for the treatment of Tylenol overdoses in children and frequently used during radiographic procedures that require contrast media. Recently, it has been found to be effective in treating refractory trichotillomania at doses up to 2400 mg/d. It has also been effective in managing ritualistic and repetitive behavior in autistic spectrum children at doses of 900 mg TID [72].
Non-drug Treatments
Section Content and Questions to Answer
Surgical and other procedural interventions including radiation therapy and other non-surgical modalities and ancillary medical care such as respiratory care, nutritional support, physical therapy and lifestyle measures will be discussed using bulleted format. Such modalities will be listed in an order that reflects acuity of care and the usual progression of applicability provided in subsections on: Description, indications, complications and comments. EBM entries will be provided at the end of each subsection, if indicated and summarized with effectiveness provided.
Assisted Feeding (infancy)
Description
Techniques used to feed infants with inability to suck.
Manual assistance with sucking may be tried with the use of special nipples, but in some cases, nasogastric or gastrostomy tubes may need to be placed in order to ensure adequate delivery of nutrients.
Indications
Failure to thrive in infants with PWS.
Tube feedings are usually reserved as a final resort after intensive efforts at nursing have failed.
Complications
Potential deleterious metabolic or cardiovascular effects of excessive weight gain, if infants are over-fed with this method.
Comments
There are no data addressing the optimal method for assisted feeding techniques in infants with PWS but observe closely for aspiration and aspiration-related pneumonia.
Weight Management
Description
Dietary and physical activity counseling and strategies implemented to prevent obesity.
Indications
All children with PWS should begin a weight management program at the onset of hyperphagia.
Comments
When hyperphagia develops, caloric restriction at 60% of the recommendations for non-PWS children or about 8 to 11 kilocalories per centimeter of height per day to maintain weight and 7 kilocalories per centimeter of height per day to lose weight should be established. In adulthood, 800–1000 kilocalories per day is often needed to lose weight and 1200 kilocalories per day to maintain weight for non-GH treated individuals with PWS. GH therapy and exercise plans now commonly in use in PWS at all ages may require different calorie intake per individual [e.g., 2, 25, 66].
Increased physical activity (e.g., 30 minutes per day of using an exercise bike) is recommended to assist in preventing and treating obesity. In some individuals with PWS, an increased caloric intake (e.g., 1800 kcal/day) can be utilized if exercise sessions last for extended periods of time (such as 45–60 minutes) [e.g., 66].
Other weight management strategies include: locks on the refrigerator and pantry, limited amounts/types of food available in the home, non-food related rewards, reduced portion size at meal time using smaller dishes, encouraging participation in meal planning.
Bariatric surgery to decrease gastric size, and thus lower caloric intake, has been explored as an option to reduce appetite and treat obesity, but is not recommended due to complications of gastric necrosis, increased risk for gastric rupture, and skin excoriation of the suture site in PWS.
Orthopedic Bracing or Surgery
Description
Procedures to correct spinal curvature in younger children or adolescents with scoliosis.
Indications
Bracing is recommended for curves of 20 to 40 degrees to prevent progression.
Surgery is indicated for severe, early onset scoliosis in adolescents near skeletal maturity.
Complications
There is an apparent increased risk for paraplegia associated with orthopedic surgery for scoliosis in PWS but with improved complication rates noted with newer spinal instrumentation.
Deep infections and pneumonia may occur in up to 30% of cases.
Comments
Orthopedic assessment is recommended prior to initiating rhGH therapy.
Orchidopexy
Description
Surgical treatment of an undescended testicle by freeing and implanting it into the scrotum.
Indications
Male infants with cryptorchidism (undescended testes).
Complications
Mis-positioning of the relocated testis or testes.
Devascularization of the testis cord leading to testis atrophy.
Division of the vas deferens.
Comments
Orchidopexy should be performed within the first year of life because scrotal hypoplasia and/or obesity can make surgery difficult to perform. The likelihood of success for orchidopexy in males with PWS and hypogonadism is lower than in other males with un-descended testicles without PWS.
Tonsillectomy and Adenoidectomy
Description
Surgical removal of tonsils and adenoids.
Indications
Obstructive sleep apnea (OSA) in the presence of enlarged tonsils and adenoids and as the first line of treatment. CPAP is recommended if adenotonsillectomy is not performed or if OSA persists postoperatively and with pulmonary edema.
Complications
Post-operative hemorrhage
Pain, potentially leading to dehydration
Airway obstruction due to local edema or hemorrhage.
Comments
Tonsillectomy and adenoidectomy may be advisable to treat obstructive sleep apnea in children prior to commencing rhGH therapy. Weight loss is recommended in addition to other therapy in children who are overweight or obese.
Individuals with PWS are prone to having a small or narrow airway which requires special attention when intubating.
Ophthalmologic Surgery
Description
Surgical procedure to correct strabismus, performed with purpose of either restoring single binocular vision or eliminating anomalous head position.
Indications
Performed on patients with intermittent esotropia if deviation is poorly controlled. Signs of poor control include presence of manifest deviation more than 50% of individual observations, failure to recover normal alignment after a blink during testing, decrease in stereo acuity, and overall impression of surgeon that control is worse.
Complications
Ocular perforation with suture needle as tendon is re-attached to globe.
Diplopia in patients who cannot suppress image from one eye and whose visual axes are misaligned after surgery.
Comments
Bilateral surgery may be necessary to correct strabismus.
Behavioral Therapy
Description
Form of counseling that focuses on modifying behavior patterns to manage maladaptive conduct.
Indications
Children with PWS who display behavioral problems including excessive repetitive behavior. Impulsivity, aggression, property theft or destruction, self-injury, angry outbursts, temper tantrums, and oppositional defiance.
Comments
Behavior management works best by rewarding desired behaviors and ignoring, when possible, undesirable behaviors particularly in early childhood.
Behavior management should include incentives besides rewards and also consequences which are explained to the individual.
Skin picking can be lessened by diversion or reducing boredom and providing sensory rich alternatives to behavior (popping bubble pack, playing with yarn, etc.).
For behavioral issues such as impulsivity, aggression, food theft, property destruction and self-injury, therapeutic approaches should include a provision of a controlled environment with a daily schedule, exercise programs and supervision.
Reinforcement, food security, regular monitoring, provision of a safe environment, anger management, and social skills training should all ideally be included in the therapy plan.
Data are limited in addressing optimal behavioral treatment plans for all ages of persons with PWS and specific behavioral problems.
Speech Therapy
Description
A set of counseling techniques used to improve speech and verbal skills.
Indications
Language delay and articulation abnormalities in infancy and childhood.
Comments
Data on effectiveness? There are no data on effectiveness but yet used commonly in clinical practice.
Special Circumstances
Comorbidities
Ordered by importance. Identify special populations, comorbid conditions, medications or treatments that influence management strategies. Explain how management would be adjusted for these populations (e.g. how pregnancy alters the approach to treating tuberculosis). Use bulleted format. How do other patient characteristics or concomitant diseases affect management?
Endocrine disturbances may include hypothyroidism and central adrenal insufficiency which is seen in about 10% of PWS individuals [e.g., 48].
Increased risk of seizures (less than 5%) and temperature instability in PWS particularly during infancy, childhood and adulthood. Adults with PWS have been reported with body temperatures below 90° F but without a known cause. Idiopathic hyper- or hypothermia may occur during minor illnesses, anesthesia and psychotropic use. PWS individuals may not respond normally to infection, i.e., fever may not be present despite extensive infection [e.g., 2].
Gastroparesis, gastric necrosis and gastric rupture, a high pain threshold and lack of vomiting may occur. PWS individuals may not respond normally to abdominal distention or pain from life-threatening gastric inflammation or necrosis. These life-threatening complications should be monitored under close supervision and to avoid hyperphagia leading to these problems [e.g., 50].
Osteoporosis, scoliosis and fractures are common in PWS along with hip subluxation. Monitoring for scoliosis, which may require bracing and surgical intervention is mandatory. Growth hormone treatment commonly prescribed in PWS infants, children and adolescents may worsen scoliosis but growth hormone can improve bone density, muscle mass and strength which would improve surgical outcomes [e.g., 57].
Neurotransmitter levels may be disturbed in PWS due to a decrease in GABA receptor subunits from the presence of three GABA receptor subunit genes in the 15q11-q13 region deleted in the majority of PWS patients. This could alter the response to anesthesia or sedative agents such as propofol and in recovery time following surgery. Other medical concerns in PWS include unusual reactions to standard dosages of medication and anesthesia during infancy or later due to metabolic differences from a decreased muscle mass and increased obesity. A narrow airway may be present and certain agents (eg, GABA receptor agonist agents for sedation) could lead to uncommon anesthesia and medication reactions with prolonged recovery time following surgery [e.g., 49].
Enamel hypoplasia, dental caries, dry mucosal membranes, and decreased salivary secretion are common in PWS. Poor oral hygiene, bruxism and rumination can also negatively impact on the soft tooth enamel. Special tooth brushes can improve hygiene and products to increase salivary flow are encouraged. Dental examinations should begin at or before two years of age [e.g., 2].
Because hypopigmentation is due to a deletion of the P gene seen in most PWS patients, they are at risk of developing melanoma and skin carcinoma. Protection against ultraviolent exposure with sunscreen and clothing to inhibit sun exposure are recommended to lessen the malignancy risks. The decreased pigment may also affect retinal pigment and visual acuity. Hence, an ophthalmology evaluation is indicated in infancy or early childhood to address vision problems and to monitor for myopia and strabismus [e.g., 2].
Learning disabilities are very common among children with PWS. Although psychoeducational testing is performed by school districts, neuropsychological testing may provide a more informed blueprint upon which IEP recommendations can be made. Every child should have a 504 plan for PWS related to hyperphagia.
Stress sensitivity in PWS predisposes to mood disorders. Comorbid anxiety, depression and bipolar disorder increase with age. Incidence of bipolar disorder reaches 85% by age 30 among UPD subtype. Cyclic psychosis can occur in either subtype.
CONCLUSION
Patient Satisfaction/Lifestyle Priorities
Section Content and Questions to Answer
Disease and treatment that affects lives and activities of people with PWS including different lifestyles will be discussed using bulleted format describing the impact on disease and treatment for patients and their families.
The quality of life in PWS is directly related to hyperphagia and adverse outcomes associated with obesity. Many will ask for restrictive management of food.
Consultation
Section Content and Questions to Answer
Consultation for treatment decisions and therapeutic procedures will be discussed in a bulleted format and outlined with advice needed from experienced consultants in treating the patient with PWS. Situations requiring specialists input for management and what specialties to be consulted will be addressed.
A multidisciplinary team of consultants is required for the care of infants, children, adolescents and adults with PWS with the care coordinator being a specialist, depending on the age and individual needs of the patient, in the field of pediatrics, clinical genetics, endocrinology or neurology with support from learning/behavioral experts and dietitians. A neonatologist may be involved for medical care and intervention due to the feeding difficulties, hypotonia, and diagnostic issues while genetic counseling will be important for family members, and for delivery of syndrome-specific information. Other consultants may include developmental pediatrics, speech and language specialists, orthopedics, physical therapy, dentist, sleep disorder specialists, ENT specialists, ophthalmology, gastroenterology, pulmonary, urology, gynecology, cardiology, psychiatry and psychology may eventually become involved. A key member of the team will be a registered dietitian for input on caloric intake with macro- and micro-nutrient surveys is required thoughout the life of a person with PWS.
Monitoring
Section Content and Questions to Answer
In bulleted format, outlined appropriate plans for monitoring disease and treatment with specific metrics and time-lines will be discussed including recommendations for PWS.
Monitoring of body weight or body mass index should be an ongoing process throughout the lifespan of an individual with PWS. In infants to 18 years of age, the weight should be maintained between the 25th through 75th percentile according to established syndrome-specific PWS growth charts [e.g., 65, 73]. Growth charts for those PWS subjects treated with growth hormone between 0 to 18 years of age have also been reported [74]. In adults, the goal is to prevent overweight and obesity. Weight management strategies are discussed under “Non drug treatments.”
A pediatric endocrinologist should be involved to assess for the presence and monitor the evolution of endocrine disorders, including thyroid, adrenal, and growth hormone deficiencies. Occur at diagnosis and periodically thereafter (e.g., every 6 months during infancy and yearly at later ages). Growth hormone therapy may be continued into adulthood in some individuals.
Basal morning cortisol levels should be measured to monitor for central adrenal insufficiency and stimulation testing performed specifically before initiation of growth hormone treatment or planned surgery. Stress doses of glucocorticoids should be administered empirically during episodes of critical illness or prior to surgery unless adrenal insufficiency has been ruled out by recent prior provocative testing.
Insulin resistance and Type 2 diabetes mellitus, often develop secondary to obesity in PWS, do occur but respond to weight loss as seen in the general population. Medications to mitigate insulin resistance may also be considered in consultation with an endocrinologist on an individual patient basis. Fasting glucose and lipid levels are often monitored at ~6-month intervals.
Hypogonadism is present in both males and females with puberty being arrested and incomplete. Testosterone (in males) and estrogen (in females) treatment should be considered depending on the age of the patient at the time of pubertal onset and during adulthood. Males are thought to be infertile but a few PWS females have established pregnancies. About one-third of appropriately aged PWS females develop menstruation but with irregular cycles.
Osteoporosis and osteopenia should be monitored with bone density measurements by DXA. Consultation with an orthopedic expert specializing in bone metabolism is recommended. The use of calcium and vitamin D supplements and weight bearing exercises is often advised. Scoliosis may worsen during growth hormone treatment and growth acceleration should be monitored closely with skeletal x-ray series and bone age studies (e.g., yearly).
Enamel hypoplasia, dental caries and dry mucosal membranes with decreased salivary secretion are common in PWS which can lead to choking on food. Poor oral hygiene, bruxism and rumination can also negatively impact on the soft tooth enamel. Special tooth brushes can improve hygiene and products to increase salivary flow are also encouraged. Annual or biannual dental examinations should begin at or before two years of age.
Recent studies suggest that individuals with PWS of all ages may suffer from dysphagia due to abnormal esophageal motility. Increasing fluids during and after a meal while pacing the food bolus may lessen the risk of choking, improve mastication, and facilitate an efficient swallow.
Individuals with PWS carry an elevated risk for melanoma and other skin cancers, in association with skin hypopigmentation. Protection against ultraviolent exposure with sunscreen and clothing to inhibit sun exposure are recommended to lessen the malignancy risks. The decreased pigment may also affect retinal pigment and visual acuity. Hence, an ophthalmology evaluation is indicated at an early age to address vision problems and to monitor annually for myopia and strabismus in infancy or early childhood.
Prognosis
Section Content and Questions to Answer
In a bulleted format, the usual course of disease is outlined, both short- and long-term with treatment or without is discussed. Information will include morbidity and mortality, potential for relapse and recurrence and possible disease outcomes.
Introduction and Background
Prognosis depends on transition from stage 1 (failure to thrive) to stage 2 (hyperphagia and obesity) of clinical course development; monitoring the obesity status; determining mental capacity and identifying and treating neurological/psychiatric findings (e.g., seizures, autism, aberrant behavior, mental illness and psychosis); monitoring the endocrine, orthopedic, cardiopulmonary and gastrointestinal systems to avoid health related complications (e.g., diabetes, scoliosis, hypertension and heart failure, apnea, gastric necrosis) and death. [e.g., 2].
Many complications are common in PWS and will adversely impact morbidity and mortality, such as obesity, heart failure, apnea and diabetes. If left untreated or unresolved, these complications will shorten the life expectancy.
Death typically occurs in the fourth decade of life but if weight control is successful then PWS adults may live into their seventh decade or beyond. Unfortunately, choking-related deaths do occur [e.g., 2, 75].
Complications
Section Content and Questions to Answer
A list and discussion of the most common complications of both disease and treatment for PWS and how complications can affect further management and outcomes will be discussed including common complications of the disease listed with treatments related to PWS.
Complications Seen in Prader-Willi Syndrome
PWS is associated with findings related to obesity (if weight is not adequately controlled). The associated complications and co-morbidities of obesity include:
Diabetes mellitus.
Hypertension.
Orthopedic problems.
Osteoporosis.
Right-sided heart failure.
Fatty liver.
Hypoventilation.
Obstructive sleep apnea and narrow airway.
Stasis ulcers and cellulites.
Variable degree of mental deficiency and illness (delayed cognitive development, learning problems, psychiatric co-morbidity).
Behavioral problems such as outbursts, self-injury, tantrums, food stealing and hoarding.
Endocrine disturbances such as obesity, diabetes, short stature and growth hormone deficiency, adrenal insufficiency, hypothyroidism, sex hormone and reproductive problems.
Neurological disorders such as seizures, temperature instability, hypotonia, autonomic nervous system dysfunction, hyperphagia.
Musculoskeletal disorders, such as scoliosis, hip subluxation, kyphosis, osteoporosis, fractures, decreased muscle mass.
Disturbed energy balance and metabolism (decreased physical activity and strength, lower metabolic rate).
Gastrointestinal problems [gastroparesis, gastric inflammation, necrosis and rupture, delayed gastric emptying, rumination, decreased salivary secretions and swallowing difficulty including choking on food, increased ghrelin production, leading to enhanced reward from eating].
Water intoxication from excessive drinking, altered vasopressin secretion, and/or use of diuretic medication can lead to abnormal electrolyte levels.
Respiratory issues, including a narrow airway passage, low muscle tone and strength, and sleep apnea, collectively lead to an increased chance of aspiration pneumonia.
Secondary Prevention/Patient Education
Section Content and Questions to Answer
Measures to prevent recurrent disease or its complications in treated patients with PWS will be listed in a bulleted format and measures advised to prevent relapse or recurrence will be presented, if applicable. Elements of essential information for patients about diagnosis, treatment, and follow-up will be provided including web resources appropriate for patient use to know about the disease, treatment, prognosis, and other implications.
Introduction and Background
Family caretakers for patients with PWS should be informed of the following:
Infants with PWS should be handled carefully due to their poor muscle tone.
Individuals with PWS must be monitored carefully for weight gain and due to hyperphagia, access to food in the house must be restricted at a later age in early childhood. To avoid complications from obesity, monitoring caloric intake will be a lifelong activity in PWS.
In addition to controlled food access, individuals with PWS benefit from psychological food security, best described by the paradigm no doubt, no hope, no disappointment. This means that the person knows with certainty and accepts the conditions surrounding their diet plan, including menu, portion control and meal schedule. This assures that the behavioral manifestations of disappointment will not occur.
Exercise is an essential part of the daily plan for a person with PWS. It provides energy expenditure, sensory motor stimulation, deep breathing increased alertness and stress relief.
Children with PWS must be monitored with testing for numerous complications of PWS and caretakers must keep up with scheduled testing and outcome results measured.
Individuals with Prader-Willi syndrome require specialized care and supervision throughout adulthood, and most live in residential care facilities for safety, to avoid complications of obesity, and to provide supervised access to appropriate work, leisure skills, and socialization with peers.
The following websites are recommended to educate family caring for a patient with PWS.
www.pwsausa.org - Prader-Willi Syndrome Association (USA) is an organization of families and professionals working together to raise awareness, offer support, provide education and advocacy, and promote and fund research to enhance the quality of life of those affected by Prader-Willi syndrome.
Utah Medical Home Portal - www.medicalhomeportal.org - Review and information about providing care on Prader-Willi syndrome by primary care physicians, other health care providers and parents to address health care needs.
Practice Performance Measures/Summary of Evidence
Section Content and Questions to Answer
Standard performance indicators and a brief statement of the rule by which each is applied, as defined by Centers for Medicare and Medicaid Services (CMS), Joint Commission and others as appropriate will be provided and discussed on measured standards for quality of care. A summary of the EBM entries will be given.
Introduction and Background
A meta-analysis studying the effect of rhGH therapy on body composition in adults with PWS identified 8 studies that included 134 individuals treated with rhGH for 12 months. Treatment of individuals with PWS with rhGH led to [weighted mean difference (MD) 95% confidence interval (CI)] reduced body fat (MD: −2.9%; CI: −3.90 to −1.910), visceral fat (MD: −32.97 cm2; CI: −55.67 to −10.26), subcutaneous adiposity (MD: −55.24 cm2; CI: −89.05 to −21.22), and increased lean body mass (MD: 2.41 kg; CI: 1.32 to 3.49). Studies of longer duration confirmed the findings for change in body fat (MD: −2.89%, CI: −4.69 to −1.07) and lean body mass (MD: 2.82 kg; CI: 1.31 to 4.33). Individuals treated with rhGH for 12 months did exhibit small increases in fasting glucose (MD: 0.27 mmol/L; 95% CI: 0.05 to 0.49) [69].
A multicenter prospective trial studied the effects of long-term continuous rhGH treatment on body composition, growth, bone maturation, and safety parameters in children with PWS. 55 prepubertal children (mean age of 5.9 ± 3.2 years) were followed over 4 years while treated with rhGH (1.0 mg/m2). Body fat percentage (SDS) was significantly lower after 4 years of rhGH treatment (P < 0.0001). Lean body mass SDS significantly increased during the first year of treatment (P = 0.02) but returned to baseline values the second year and remained unchanged thereafter. Mean ± SD height normalized from −2.27 ± 1.2 SDS to −0.24 ± 1.2 SDS (P < 0.0001) after treatment with rhGH. Body mass index SDS significantly decreased. Thus, body composition and height were significantly improved in children with PWS after long-term treatment with rhGH. No adverse effects were noted on bone maturation, blood pressure, glucose homeostasis, and serum lipids [70].
A randomized controlled trial (RCT) studied the effects of rhGH treatment on cognitive functioning in 50 prepubertal children (ages 3.5 to 14 yr) with PWS. Cognitive functioning was measured biennially by validated intelligence tests [the Wechsler Preschool and Primary Scale of Intelligence-Revised, Dutch version (WPPSI-R) or the Wechsler Intelligence Scale for Children-Revised, Dutch version (WISC-R)]. Total intelligence quotient (IQ) score was estimated based on two subtest scores. After 4 years of GH treatment, mean standard deviation scores (SDS) on the Similarities and Block design subtests were significantly higher than at baseline [mean difference (MD); 95% confidence interval (CI)] for Similarities test- MD: +0.4; 95% CI: −0.1 to 0.7; P = 0.01 for Block Design- MD: +0.3; CI: 0.07 to 0.6, P = 0.01. These results indicate that long-term GH treatment significantly improves abstract verbal reasoning and visuospatial skills, and reduces the gap between children with PWS and healthy controls on these skills. Thus, during long-term GH treatment, children with PWS developed their vocabulary at the same pace as healthy references. The mean estimated total IQ score improved 4 points during 4 years of GH treatment, but this result did not reach significance (P = 0.2) [71].
Guidelines
Section Content and Questions to Answer
Relevant current guideline(s) identified from established organizations/groups will be provided and concordant with screening, prevention, diagnosis and treatment sections. There are at least five established peer-reviewed and textbook sources of information on the treatment of individuals with Prader-Willi syndrome with cited references for recommendations on diagnosis and management and portal home disease specific websites (e.g., medicalhomeportal.org). The reader is referred to the following published works for more in depth assessment of care, diagnosis and treatment of Prader-Willi syndrome:
The Endocrine Society has published the following and cited in this review:
Goldstone AP, Holland AJ, Hauffa BP, Hokken-Koelega AC, Tauber M. Recommendations for the diagnosis and management of Prader-Willi syndrome. J Clin Endocrinol Metab 2008; 93: 4183–97.
The American Academy of Pediatrics has published the following and cited in this review:
McCandless SE. Clinical report-health supervision for children with Prader-Willi syndrome. Pediatrics 2011; 127: 195–204.
The International Prader Willi Syndrome Organization has published the following and cited in this review:
Best Practice Guidleines for Standard of Care in PWS (2010) JL Forster (Ed), N Hoedebeck-Stuntebeck and H Soyer (Publishers) www.ipwso.org
Additional resources and websites related to care, diagnosis and treatment in Prader-Willi Syndrome:
Cataletto M, Angulo M, Hertz G, Whitman B. Prader-Willi syndrome: A primer for clinicians. Int J Pediatr Endocrinol 2011; 18, 12.
Online Mendelian Inheritance in Man (OMIM) [http://www.omim.org/].
Hoybye C (eds.): Prader-Willi Syndrome. Nova Science Publisher, Inc., Hauppauge, New York 2013: p.1–294.
Butler MG, Welch J, Riske M, Vogel R, Troxell R, Rope A. Prader-Willi Syndrome Website Module, www.medicalhomeportal.org:9090/diagnoses-and-conditions/prader-willi-syndrome/.
Butler MG, Roberts J, Hayes J, Tan X, Manzardo AM. Growth hormone receptor (GHR) gene polymorphism and Prader-Willi syndrome. Am J Med Genet A 2013; 161A(7): 1647–1653.
Buiting K, Cassidy SB, Driscoll DJ, et al. Clinical utility gene card for: Prader-Willi syndrome. Eur J Hum Genet 2014; 22(9). doi: 10.1038/ejhg.2014.66.
Prader-Willi Syndrome Association [PWSA (USA)] [http://pwsausa.org/].
Marcus CL, Brooks LJ, Draper KA, Gozal D, Hal-bower AC, Jones J. Diagnosis and management of childhood obstructive sleep apnea syndrome. Pediatrics 2012: 130, e714–55.
Vogels A, De Hert M, Descheemaeker MJ, et al. Psychotic disorders in Prader-Willi syndrome. Am J Med Genet A 2004; 127A: 238–243.
Diagnostic Codes (ICD9–759.81 and ICD10-Q87.1) for Prader-Willi Syndrome
Clinical and Parent Questions
Section Content and Questions to Answer
Five of the most important clinical questions (with answers that can be found in the text) will be provided by a clinician treating a patient with PWS and five questions that patients are most likely to ask will be presented.
Clinical Questions
What causes Prader-Willi syndrome?
PWS is a genomic imprinting disorder caused by loss of expression of genes from the chromosome 15q11-q13 region that are expressed only on the father’s chromosome 15 usually due to a deletion of the chromosome region from the father.
What are the most common features seen in patients with Prader-Willi syndrome?
The cardinal features are infantile hypotonia, a poor suck with feeding problems and failure to thrive, growth hormone deficiency with short stature and small hands and feet, hypogonadism/hypogenitalism, hyperphagia and onset of obesity in early childhood if not controlled and learning/behavioral problems.
What tests should be ordered to confirm the clinical suspicion of PWS?
DNA methylation testing of the chromosome 15q11-q13 region is usually ordered along with cytogenetic studies including FISH, MS-MLPA or chromosomal/DNA microarray analysis to identify the presence or absence of the DNA methylation pattern for PWS and the 15q11-q13 deletion which is seen in the majority of PWS patients. If the deletion is not identified then genotyping DNA markers from chromosome 15 is performed on the PWS patient and parents. Furthermore, microarray analysis is requested using polymorphic DNA probes to help identify maternal disomy 15 (both 15s from the mother) or an imprinting defect if biparental (normal) inheritance of chromosome 15 is found.
What is the suggested treatment once the diagnosis is confirmed?
Although there is no cure, growth hormone therapy is indicated to treat the growth hormone deficiency and to improve stature, decrease fat mass and increase muscle and strength. Diet intervention with reduced caloric intake and exercise programs to avoid obesity are recommended throughout the lifespan of an individual with PWS.
What is the prognosis for a patient with PWS?
Prognosis depends on early diagnosis and treatment with growth hormone and other therapies including stimulation programs to maximize learning, potential and diet intervention to control caloric intake and to lessen obesity and its complications thereby improving the quality of life and lifespan.
Parent Questions
What causes Prader-Willi syndrome?
PWS is a genomic imprinting disorder caused by loss of expression of genes from the chromosome 15q11-q13 region that are expressed only on the father’s chromosome 15 usually due to a deletion of the chromosome region from the father.
Was there something that I did that caused Prader-Willi syndrome to occur in my child?
PWS is due to errors in genomic imprinting usually due to a deletion of the chromosome 15q11-q13 region which is not from anything that the mother or father did or did not do to cause the condition. PWS is due to a genetic event that occurred at or around the time of conception.
Is there a cure or treatment for Prader-Willi syndrome?
There is no cure but treatment with growth and other hormones, diet and exercise plans to lessen the likelihood of obesity and gaining access to therapies (physical, occupation, speech) are warranted. Educational and behavioral treatment plans are helpful to improve the quality of life and to increase life expectancy. Consultation with a clinical geneticist and genetic counselor would be encouraged to answer questions and to provide information useful to the family (and patient) would be encouraged.
What are the chances that it will occur in future children?
The recurrence risk is generally less than 1% but in rare cases (e.g., imprinting center defect) the risk may be as high as 50%. Therefore, genetic evaluation and counseling are indicated to determine and discuss the chance for recurrence depending on the genetic sub-type which should be determined as it may impact not only on the recurrence risk but also for treatment and prognosis.
What can I expect from my child with Prader-Willi syndrome (will my child die early, attend school, live independently, have children)?
For newly diagnosed infants and children with PWS, the prognosis is improved with better care and treatment with growth and other hormones. Avoidance of obesity and its complications to improve life expectancy is a life long goal and if successful the live expectancy approaches normal. Hyperphagia remains a constant problem which lowers the likelihood for independent living. Children with PWS do attend school in regular classroom settings but may require individual educational programs to maximize their learning ability and progress but close supervision (and access) to food sources is required. PWS males are thought to be sterile although there have been a few PWS females who have established and maintained pregnancies giving birth to live born unaffected children. Those PWS females with the 15q11-q13 deletion are at risk (i.e., 50%) of having offspring with Angelman syndrome.
ACKNOWLEDGEMENTS
I acknowledge Tiffany Embry for assistance in manuscript preparation and the National Institute of Child Health and Human Development (NICHD) grant HD02528.
Biography
Footnotes
CONFLICT OF INTEREST
The authors confirm that this article content has no conflict of interest.
REFERENCES
- [1].Butler MG. Prader-Willi syndrome: Current understanding of cause and diagnosis. Am J Med Genet 1990; 35: 319–32. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [2].Butler MG, Lee PDK, Whitman BY. Management of Prader-Willi Syndrome. 3rd ed New York, NY: Springer Verlag Inc; 2006. [Google Scholar]
- [3].Butler MG. Prader-Willi syndrome: Obesity due to genomic imprinting. Curr Genomics 2011; 12(3): 204–15. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [4].Cassidy SB, Schwartz S, Miller JL, Driscoll DJ. Prader-Willi syndrome. Genet Med 2012; 14: 10–26. [DOI] [PubMed] [Google Scholar]
- [5].Angulo M, Butler MG, Cataletto M. Prader-Willi syndrome: A review of clinical, genetic and endocrine findings. J Endocrinol Invest, 2015. December; 38(12):1249–63. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [6].Butler MG, Cassidy SB. Genetic basis, genetic testing and genetic counseling for Prader-Willi syndrome In: Prader-Willi Syndrome. Hoybye C (ed.) Nova Science Publishers Inc; Hauppauge NY: 2013. [Google Scholar]
- [7].Dykens EM. Are jigsaw puzzle skills ‘spared’ in persons with Prader-Willi syndrome? J Child Psychol Psychiatry. 2002. March;43(3):343–52. [DOI] [PubMed] [Google Scholar]
- [8].Roof E, Stone W, MacLean W, Feurer ID, Thompson T, Butler MG. Intellectual characteristics of Prader-Willi syndrome: comparison of genetic subtypes. J Intellect Disabil Res. 2000. February; 44 (Pt 1):25–30. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [9].Soni S, Whittington J, Holland AJ, et al. The course and outcome of psychiatric illness in people with Prader-Willi syndrome: implications for management and treatment. J Intellect Disabil Res. 2007. January;51(Pt 1):32–42. [DOI] [PubMed] [Google Scholar]
- [10].Soni S, Whittington J, Holland AJ, et al. The phenomenology and diagnosis of psychiatric illness in people with Prader-Willi syndrome. Psychol Med. 2008. October; 38(10):1505–14. [DOI] [PubMed] [Google Scholar]
- [11].Butler MG, Bittel DC, Kibiryeva N, Talebizadeh Z, Thompson T. Behavioral differences among subjects with Prader-Willi syndrome and type I or type II deletion and maternal disomy. Pediatrics 2004; 113: 565–73. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [12].Zarcone J, Napolitano D, Peterson C, et al. The relationship between compulsive behavior and academic achievement across the three genetic subtypes of Prader-Willi syndrome. J Intellect Disabil Res 2007; 51: 478–87. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [13].Boer H, Holland A, Whittington J, Butler J, Webb T, Clarke D. Psychotic illness in people with Prader-Willi syndrome due to chromosome 15 maternal uniparental disomy. Lancet. 2002. January; 359(9301):135–6. [DOI] [PubMed] [Google Scholar]
- [14].Holm VA, Cassidy SB, Butler MG, et al. Prader-Willi syndrome: Consensus diagnostic criteria. Pediatrics 1993; 91: 398–402. [PMC free article] [PubMed] [Google Scholar]
- [15].Gunay-Aygun M, Schwartz S, Heeger S, O’Riordan MA, Cassidy SB. The changing purpose of Prader-Willi syndrome clinical diagnostic criteria and proposed revised criteria. Pediatrics. 2001. November;108(5):E92. [DOI] [PubMed] [Google Scholar]
- [16].Ledbetter DH, Riccardi VM, Airhart SD, Strobel RJ, Keenan BS, Crawford JD. Deletions of chromosome 15 as a cause of the Prader-Willi syndrome. N Engl J Med. 1981. February; 304(6):325–9. [DOI] [PubMed] [Google Scholar]
- [17].Butler MG, Palmer CG.Parental origin of chromosome 15 deletion in Prader-Willi syndrome. Lancet. 1983. June; 1(8336):1285–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [18].Nicholls RD, Knoll JH, Butler MG, Karam S, Lalande M. Genetic imprinting suggested by maternal heterodisomy in nondeletion Prader-Willi syndrome. Nature 1989; 342: 281–5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [19].Ohta T, Gray TA, Rogan PK, et al. Imprinting-mutation mechanisms in Prader-Willi syndrome. Am J Hum Genet 1999; 64: 397–413. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [20].Buiting K, Gross S, Lich C, Gillessen-Kaesbach G, el-Maarri O, Horsthemke B. Epimutations in Prader-Willi and Angelman syndromes: a molecular study of 136 patients with an imprinting defect. Am J Hum Genet. 2003. March; 72(3):571–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [21].Bittel DC, Butler MG. Prader-Willi syndrome: Clinical genetics, cytogenetics and molecular biology. Expert Rev Mol Med 2005; 7: 1–20. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [22].Newkirk HL, Bittel DC, Butler MG. Analysis of the Prader-Willi syndrome chromosome region using quantitative microsphere hybridization (QMH) array. Am J Med Genet A. 2008. September 15;146A(18):2346–54. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [23].Goldstone AP, Holland AJ, Hauffa BP, et al. Recommendations for the diagnosis and management of Prader-Willi syndrome. J Clin Endocrinol Metab. 2008. November; 93(11):4183–97. [DOI] [PubMed] [Google Scholar]
- [24].McCandless SE, Saal HM, Braddock SR, et al. Clinical report—health supervision for children with Prader-Willi syndrome. Pediatrics. 2011. January; 127(1):195–204. [DOI] [PubMed] [Google Scholar]
- [25].Miller JL, Lynn CH, Driscoll DC, et al. Nutritional phases in Prader-Willi syndrome. Am J Med Genet 2011; 155A: 1040–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [26].Griggs J, Sinnayah P, Mathai ML. Prader-Willi syndrome: From genetics to behaviour, with special focus on appetite treatments. Neurosci Biobehav Rev. 2015. October 16 pii: S0149–7634(15)00263–8. [DOI] [PubMed] [Google Scholar]
- [27].Butler MG, Christian SL, Kubota T, Ledbetter DH. A 5-year-old white girl with Prader-Willi syndrome and a submicroscopic deletion of chromosome 15q11q13. Am J Med Genet. 1996. October;65(2):137–41. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [28].Sahoo T, del Gaudio D, German JR, et al. Prader-Willi phenotype caused by paternal deficiency for the HBII-85 C/D box small nucleolar RNA cluster. Nat Genet. 2008. June; 40(6):719–21. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [29].Kim SJ, Miller JL, Kuipers PJ, et al. Unique and atypical deletions in Prader-Willi syndrome reveal distinct phenotypes. Eur J Hum Genet. 2012. March;20(3):283–90. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [30].Butler MG, Sturich J, Myers SE, Gold JA, Kimonis V, Driscoll DJ. Is gestation in Prader-Willi syndrome affected by the genetic sub-type? J Assist Reprod Genet. 2009. August;26(8):461–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [31].Butler MG, Meaney FJ, Palmer CG. Clinical and cytogenetic survey of 39 individuals with Prader-Labhart-Willi syndrome. Am J Med Genet. 1986. March; 23(3):793–809. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [32].Butler MG, Thompson T. Prader-Willi syndrome: Clinical and genetic findings. Endocrinology 2000; 10:2S–16S. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [33].Butler MG, Weaver DD, Meaney FJ. Prader-Willi syndrome: Are there population differences? Clin Genet. 1982. November; 22(5):292–4 [DOI] [PMC free article] [PubMed] [Google Scholar]
- [34].Whittington J, Holland A, Webb T, Butler J, Clarke D, Boer H. Cognitive abilities and genotype in a population-based sample of people with Prader-Willi syndrome. J Intellect Disabil Res 2004; 48: 172–87. [DOI] [PubMed] [Google Scholar]
- [35].Butler MG, Fischer W, Kibiryeva N, Bittel DC. Array comparative genomic hybridization (aCGH) analysis in Prader-Willi syndrome. Am J Med Genet A. 2008. April 1;146A(7):854–60. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [36].Butler MG, Theodoro MF, Bittel DC, Kuipers PJ, Driscoll DJ, Talebizadeh Z. X-chromosome inactivation patterns in females with Prader-Willi syndrome. Am J Med Genet A. 2007. March;143A(5):469–75. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [37].Yang T, Adamson TE, Resnick JL, et al. A mouse model for Prader-Willi syndrome imprinting-centre mutations. Nat Genet. 1998. May;19(1):25–31. [DOI] [PubMed] [Google Scholar]
- [38].Francis SM, Sagar A, Levin-Decanini T, Liu W, Carter CS, Jacob S. Oxytocin and vasopressin systems in genetic syndromes and neurodevelopmental disorders. Brain Res. 2014. September;1580: 199–218. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [39].Johnson L, Manzardo AM, Miller JL, Driscoll DJ, Butler MG. Elevated plasma oxytocin levels in children with Prader-Willi syndrome compared with healthy unrelated siblings. Am J Med Genet A. 2015. November 30. doi: 10.1002/ajmg.a.37488. [Epub ahead of print]. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [40].Butler MG, Nelson TA, Driscoll DJ, Manzardo AM. Evaluation of plasma substance P and beta-endorphin levels in children with Prader-Willi syndrome. J Rare Disease, 2015; 3(2): 1–10. [PMC free article] [PubMed] [Google Scholar]
- [41].Butler MG, Nelson TA, Driscoll DJ, Manzardo AM. High plasma neurotensin levels in children with Prader-Willi syndrome. Am J Med Genet A. 2015. August; 167A(8): 1773–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [42].Cruvinel E, Budinetz T, Germain N, Chamberlain S, Lalande M, Martins-Taylor K. Reactivation of maternal SNORD116 cluster via SETDB1 knockdown in Prader-Willi syndrome iPSCs. Hum Mol Genet. 2014. September;23(17):4674–85. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [43].Holsen LM, Zarcone JR, Brooks WM, et al. Neural mechanisms underlying hyperphagia in Prader-Willi syndrome. Obesity (Silver Spring) 2006; 14: 1028–37. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [44].Cassidy SB, Lai LW, Erickson RP, et al. Trisomy 15 with loss of the paternal 15 as a cause of Prader-Willi syndrome due to maternal disomy. Am J Hum Genet. 1992. October; 51(4): 701–8. [PMC free article] [PubMed] [Google Scholar]
- [45].Butler MG. Genomic imprinting disorders in humans: A mini-review. J Assist Reprod Genet. 2009. Sep-Oct; 26(9–10): 477–86. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [46].Gold JA, Ruth C, Osann K, et al. Frequency of Prader-Willi syndrome in births conceived via assisted reproductive technology. Genet Med. 2014. February;16(2):164–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [47].Irizarry KA, Bain J, Butler MG, et al. Metabolic profiling in Prader-Willi syndrome and nonsyndromic obesity: sex differences and the role of growth hormone. Clin Endocrinol (Oxf). 2015. March 4. doi: 10.1111/cen.12766. [Epub ahead of print] [DOI] [PMC free article] [PubMed] [Google Scholar]
- [48].Butler MG, Theodoro M, Skouse JD. Thyroid function studies in Prader-Willi syndrome. Am J Med Genet A. 2007. March; 143A(5): 488–92. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [49].Butler MG, Hayes BG, Hathaway MM, Begleiter ML. Specific genetic diseases at risk for sedation/anesthesia complications. Anesth Analg. 2000. October; 91(4):837–55. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [50].Stevenson DA, Heinemann J, Angulo M, et al. Gastric rupture and necrosis in Prader-Willi syndrome. J Pediatr Gastroenterol Nutr 2007; 45: 272–4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [51].Lo ST, Collin PJ, Hokken-Koelega AC. Psychiatric disorders in children with Prader-Willi syndrome-Results of a 2-year longitudinal study. Am J Med Genet A. 2015. May;167A(5):983–91. [DOI] [PubMed] [Google Scholar]
- [52].Papenhausen P, Schwartz S, Risheg H, et al. UPD detection using homozygosity profiling with a SNP genotyping microarray. Am J Med Genet A. 2011. April; 155A(4):757–68. [DOI] [PubMed] [Google Scholar]
- [53].Bittel DC, Kibiryeva N, Butler MG. Methylation-specific multiplex ligation-dependent probe amplification analysis of subjects with chromosome 15 abnormalities. Genet Test. 2007. Winter;11(4):467–75. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [54].Henkhaus RS, Kim SJ, Kimonis VE, et al. Methylation-specific multiplex ligation-dependent probe amplification and identification of deletion genetic subtypes in Prader-Willi syndrome. Genet Test Mol Biomarkers. 2012. March;16(3):178–86. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [55].Butler MG. Molecular diagnosis of Prader-Willi syndrome: comparison of cytogenetic and molecular genetic data including parent of origin dependent methylation DNA patterns. Am J Med Genet. 1996. January; 61(2):188–90. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [56].Deal CL, Tony M, Hoybye C, Allen DB, Tauber M, Christiansen JS. Growth Hormone Research Society workshop summary: Consensus guidelines for recombinant human growth hormone therapy in Prader-Willi syndrome. J Clin Endocrinol Metab 2013; 98: E1072–87. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [57].Butler MG, Haber L, Mernaugh R, Carlson MG, Price R, Feurer ID. Decreased bone mineral density in Prader-Willi syndrome: comparison with obese subjects. Am J Med Genet. 2001. October;103(3):216–22. [PMC free article] [PubMed] [Google Scholar]
- [58].Jones KL, ed. Smith’s Recognizable Patterns of Human Malformation. 6th ed Philadelphia: W.B. Saunders Company; 2006. p. 1–954. [Google Scholar]
- [59].Choquet H, Meyre D. Genetics of obesity: What have we learned? Curr Genomics. 2011. May;12(3):169–79. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [60].Choquet H, Meyre D. Molecular basis of obesity: Current status and future prospects. Curr Genomics. 2011. May;12(3):154–68. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [61].Butler MG, Wang K, Marshall JD et al. Coding and noncoding expression patterns associated with rare obesity-related disorders: Prader-Willi and Alström syndromes. Adv Genomics Genet. 2015; 2015(5):53–75. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [62].Dasouki MJ, Youngs EL, Hovanes K. Structural chromosome abnormalities associated with obesity: report of four new subjects and review of literature. Curr Genomics. 2011. May; 12(3): 190–203. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [63].Butler MG, McGuire A, Manzardo AM. Clinically relevant known and candidate genes for obesity and their overlap with human infertility and reproduction. J Assist Reprod Genet. 2015. April; 32(4): 495–508. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [64].Smith T, Sharp S, Manzardo AM, Butler MG. Pharmacogenetics informed decision making in adolescent psychiatric treatment: a clinical case report. Int J Mol Sci. 2015. February 20; 16(3):4416–28. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [65].Butler MG, Sturich J, Lee J, et al. Growth standards in infants with Prader-Willi syndrome. Pediatrics 2011; 127(4): 687–95. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [66].Butler MG. Management of obesity in Prader-Willi syndrome. Nat Clin Pract Endocrinol Metab. 2006. November; 2(11): 592–3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [67].Salehi P, Leavitt A, Beck AE, Chen ML, Roth CL. Obesity management in Prader-Willi syndrome. Pediatr Endocrinol Rev. 2015. March; 12(3):297–307. [PubMed] [Google Scholar]
- [68].Emerick JE, Vogt KS. Endocrine manifestations and management of Prader-Willi syndrome. Int J Pediatr Endocrinol. 2013. August 21;2013(1):14. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [69].Sanchez-Ortiga R, Klibanski A, Tritos NA. Effects of recombinant human growth hormone therapy in adults with Prader-Willi syndrome: a meta-analysis. Clin Endocrinol. 2012; 77:86–93 [DOI] [PubMed] [Google Scholar]
- [70].de Lind van Wijngaarden RF, Siemensma EP, Festen DA et al. Efficacy and safety of long-term continuous growth hormone treatment in children with Prader-Willi syndrome. J Clin Endocrinol Metab. 2009; 94: 4205–15 [DOI] [PubMed] [Google Scholar]
- [71].Siemensma EP, Tummers-de Lind van Wijngaarden RF, Festen DA et al. Beneficial effects of growth hormone treatment on cognition in children with Prader-Willi syndrome: A randomized controlled trial and longitudinal study. J Clin Endocrinol Metab. 2012; 97:2307–14 [DOI] [PubMed] [Google Scholar]
- [72].Miller JL, Angulo M. An open-label pilot study of N-acetylcysteine for skin-picking in Prader-Willi syndrome. Am J Med Genet A. 2014; 164A(2): 421–4. [DOI] [PubMed] [Google Scholar]
- [73].Butler MG, Lee J, Manzardo AM, et al. Growth charts for non-growth hormone treated Prader-Willi syndrome. Pediatrics 2015; 135: e126–135. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [74].Butler MG, Lee J, Cox DM, et al. Growth charts for Prader-Willi syndrome during growth hormone treatment, Clin Pediatri, in press. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [75].Stevenson DA, Heinemann J, Angulo M, et al. Deaths due to choking in Prader-Willi syndrome. Am J Med Genet A 1 2007; 143: 484–7. [DOI] [PMC free article] [PubMed] [Google Scholar]