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prader_willi_syndrome

Prader Willi Syndrome

An uncommon disorder that can effect the lymphatics and there are a number of reported cases of Prader Willi patients with severe leg lymphedema.

Related Terms: lymphedema, echocardiography, Prader–Willi syndrome, Ultrasound, Two-dimensional strain echocardiography, PWS, hyperphagia, neuroanatomy, chromosome 15q deletion, Magel2, candidate gene

History

Prader-Willi Syndrome first appeared in the medical literature when endocrinologists Prader, Labhart, and Willi published a report describing an unusual pattern of abnormalities. These abnormalities included diminished fetal activity, profound poor muscle tone, feeding problems in infancy, underdeveloped not allowed organs, short stature and retarded bone age, small hands and feet, delayed developmental milestones, characteristic faces, cognitive impairment, onset of gross obesity in early childhood due to insatiable hunger, and a tendency to develop diabetes in adolescence and adulthood when weight was not controlled. Further studies in the late 1960’s followed up on these cases, and added more. Orthopedic, dental and developmental characteristics that could assist in differential diagnosis of PWS were identified, and two clearly identifiable phases of the disorder were described (Phase I, the prenatal, neonatal, and early infancy period, in which the child shows diminished fetal activity, poor muscle tone, and failure to thrive after birth, and Phase II, in which the uncontrollable hunger drive emerges between ages 2 and 3).. Behavioral, personality and medical problems associated with PWS were described in literature in the 1970’s and 80’s. A study published by Greenswag in 1987of 232 individuals with PWS, age 16 and over, indicated that with appropriate nutritional control, the life expectancy of this population could be extended. The study also showed that emotional liability increases with age and is independent of the presence of adult obesity, that psychosocial adaptation to adulthood requires special management, and that the presence of PWS has a profound impact on family life.

The Genetics of Prader-Willi Syndrome:

An Explanation for the Rest of Us

Chromosome 15

Originally published in PWSA’s The Gathered View by Linda Keder, former editor, March-May 2000. Revised and updated in July 2004 with the assistance of Merlin G. Butler, M.D. Ph.D., Chair, PWSA-USA Scientific Advisory Board.)

When the medical world first learned about Prader-Willi syndrome in 1956, doctors had no idea what caused people to have this collection of features and problems that we now know as PWS. In 1981, Dr. David Ledbetter and his colleagues reported a first breakthrough discovery: Many people with PWS that they studied had the same segment of genes missing from one of their chromosomes. They had discovered the deletion on chromosome 15 that accounts for about 70 percent of the cases of PWS. Since then, researchers have made a series of other important discoveries about the genes involved in Prader-Willi syndrome. Thanks to their perseverance, we now know much more about the several genetic forms of this complex disorder, and we have genetic tests that can confirm nearly every case.

Originally published in PWSA’s The Gathered View by Linda Keder, former editor, March-May 2000. Revised and updated in July 2004 with the assistance of Merlin G. Butler, M.D. Ph.D., Chair, PWSA-USA Scientific Advisory Board.)

When the medical world first learned about Prader-Willi syndrome in 1956, doctors had no idea what caused people to have this collection of features and problems that we now know as PWS. In 1981, Dr. David Ledbetter and his colleagues reported a first breakthrough discovery: Many people with PWS that they studied had the same segment of genes missing from one of their chromosomes. They had discovered the deletion on chromosome 15 that accounts for about 70 percent of the cases of PWS. Since then, researchers have made a series of other important discoveries about the genes involved in Prader-Willi syndrome. Thanks to their perseverance, we now know much more about the several genetic forms of this complex disorder, and we have genetic tests that can confirm nearly every case.

Chromosomes and Genes: The Basics

To understand the genetics of PWS, it helps to have a basic understanding of chromosomes and genes. Chromosomes are tiny structures that are present in nearly every cell of our bodies. They are the packages of genes we inherit from our parents. Genes contain all the detailed instructions our bodies need to grow, develop, and function properly—our DNA. Specific genes direct our cells to produce proteins, enzymes, and other essential substances. Each of our many genes is located on a specific chromosome. Most of our body’s cells contain 46 chromosomes—23 inherited from our mother and 23 from our father. (Egg and sperm cells normally contain just 23 chromosomes, because those are the cells that join in conception and provide the baby the right number of chromosomes.) Twenty-two of the chromosome pairs are labeled with a number based on their size (chromosome 1 is the largest pair, and chromosome 22 is nearly the smallest), and the two chromosomes in each numbered pair contain the same genes (one set from mother and one from father). The changes that cause Prader-Willi syndrome occur on the pair known as chromosome 15. The 23rd chromosome pair is designated as the not allowed chromosome pair This pair determines the baby’s not allowed: XX for a girl, XY for a boy.

Changes or errors in genes and chromosomes are common in the formation of egg and sperm cells. Some of these genetic changes will have no effect when a baby is conceived; some will cause a miscarriage; and some, like those in Prader-Willi syndrome, will cause significant differences in how the baby develops and functions. While many genetic disorders are caused by a change in a single gene and can be passed down from parent to child, PWS is more complicated.

Some of the important genetic characteristics of PWS identified through research are:

More than one gene is involved in PWS, and these genes are near each other in a small area of what is called the “long arm” of chromosome 15—in a region labeled 15q11-q13. Scientists still don’t know exactly how many genes and which specific ones are involved.

The critical genes must come from the baby’s father in order to function properly; the mother’s genes in this area are “turned off” through a rare phenomenon called “genomic imprinting.”

There are at least three different chromosome errors that can keep these key genes from working normally, and all result in the child having Prader-Willi syndrome.

The two most common errors that cause PWS can occur in any conception—in other words, PWS is not usually an inherited condition; it just happens. In very rare cases, however, parents may have a 50-percent chance of having another child with PWS.

The Role of Genomic Imprinting

During the early 1980s, scientists puzzled over why some people who seemed to have PWS did not have the chromosome 15 deletion, and why some people with the chromosome 15 deletion seemed to have a different condition from PWS. Dr. Merlin Butler and colleagues began unraveling the puzzle when they reported in 1983 that the chromosome 15 deletion in PWS was on the father’s chromosome.

The next breakthrough came in 1989, when Dr. Robert Nicholls and fellow researchers announced their discovery that PWS is an example of genetic or genomic imprinting, a process well known in plant genetics but not previously identified in humans. This means that some of our genes have to come from a particular parent to work normally. These rare genes are said to be “imprinted,” or have the ability to be turned off or on, depending on which parent contributed the gene. In what scientists call the “Prader-Willi region” of chromosome 15 (the area where the deletion occurs), there are genes that must come from the baby’s father that are active, or “expressed,” in order to work. These genes are not active or expressed on the chromosome 15 inherited from the mother because the mother’s imprint turns them off. In Prader-Willi syndrome, these critical genes are either missing (deleted) from the father’s chromosome 15, functioning improperly because of an imprinting defect, or the entire chromosome 15 from the father is missing and both chromosome 15s come from the mother. (See The Three Genetic Forms of PWS for more detail on each of these errors.)

When a deletion of chromosome 15q11-q13 region is found on the mother’s chromosome 15, the result is an entirely different syndrome called Angelman syndrome (AS). That is because there is also one gene in the Prader-Willi region that is imprinted, or turned off, on the father’s chromosome 15; people who lack this gene from their mother have AS rather than PWS. This discovery explained the mysterious cases of people who had a chromosome 15 deletion but did not have the characteristics of PWS—their deletion was on the chromosome 15 that came from the mother. Because the genetic errors happen in the same section of chromosome 15, PWS and AS are sometimes called “sister” syndromes even though the disorders have few features in common.

The Three Genetic Forms of PWS

Although every case of Prader-Willi syndrome is due to the baby failing to receive active genes from a specific section of the father’s chromosome 15, there are three different ways that this can happen:

Paternal deletion — about 70% of all cases of PWS

In the most common form of PWS, part of the chromosome 15 inherited from the child’s father—the part containing the PWS critical genes—is missing. In some cases, the section that has disappeared (called a “deletion” or sometimes a “microdeletion”) is large enough to be identified with high resolution chromosome studies done with a microscope; in other cases, it is too small but it can be detected with another chromosome test called FISH (see Tests Used To Diagnose Prader-Willi Syndrome). Typical or common deletions are now classified as Class/Type 1 or Class/Type 2, based on the size of the deletion. Usually a deletion happens for no known reason, and it is not likely to happen again in another pregnancy (less than 1% chance of recurrence). There is nothing the father did (or did not do) to cause it and no way to prevent it.

Note: In rare cases of atypical deletions, imprinting defects (see below), or when a chromosome change such as a “translocation” caused the PWS genes to not function normally , the family could have another child with the same condition. (In a translocation, part of one chromosome is broken off and attached to a different chromosome.) It is especially important for these families to have further testing and genetic counseling.

Maternal uniparental disomy (UPD) — about 25% of cases

In this less common form of PWS, the baby inherits both copies of chromosome 15 from one parent—the mother. (Maternal means mother; uniparental means one parent; and disomy means two chromosome bodies). In these cases, the developing baby usually starts out with three copies of chromosome 15 (a condition called trisomy 15) because there was an extra chromosome 15 in the mother’s egg. Later, one of the three is lost—the chromosome 15 that came from the father’s sperm. The result has the same effect as a deletion. The child does not have active genes on chromosome 15 that must come from the father in order to be expressed (to function). Even though there are two complete copies of the mother’s chromosome 15, the key genes in the PWS region are imprinted, or turned off, in the mother’s copies. Because the error in this form of PWS starts with an extra chromosome in the mother’s egg, and older eggs are more likely to have errors of this type, older mothers are more likely than younger mothers to have a baby with this form of PWS. Even so, it is not likely to happen (and hasn’t yet) to a second child in the same family. When a baby inherits two identical chromosome 15s from the mother (isodisomy, or two copies of the same one rather than one of each of the mother’s own chromosomes), there is a chance of having additional genetic problems or conditions.

Imprinting defect — less than 5% of cases In very rare cases, the PWS genes on the father’s chromosome are present but do not work because the imprinting process is faulty. The activity of the genes is controlled by a tiny imprinting center on chromosome 15 in the same area as the PWS critical genes. Normally, when genes are passed down to a child, the prior imprints are cleared away, and new imprints are made according to the not allowed of the parent. When there is a microdeletion or other defect in the imprinting control center, gene function on the father’s chromosome 15 may not be set to work normally. An imprinting defect can appear suddenly, or it can be present in the father’s chromosome that he received from his mother. If he received the defect from his mother, the father would not have PWS himself (because it’s on his maternal chromosome 15), but he could pass it on to his child (it would be the child’s paternal chromosome 15). There is a 50-50 chance that any child he has will receive the chromosome with the defect instead of the one that’s working correctly. Likewise, the father’s siblings could carry and pass on the mutation to their children. Further testing and genetic counseling are especially important for families who have a child with an imprinting defect.

Which genetic tests should be done and in what order?

The approach to testing for PWS in any given case will depend on a number of considerations—what tests have already been done, what expertise and laboratories are available, whether both parents are available for blood samples, and so forth. Chromosome studies are typically done in any case, but the order of the other tests—and their results—will determine how many need to be done. In 1996, two national genetics groups worked together to develop guidelines on testing for Prader-Willi and Angelman syndromes. Their recommendations have been published and are available on the Internet at www.faseb.org/genetics/acmg/pol-22htm. In most cases, they recommend continued testing until the genetic cause of PWS is known.

Some testing scenarios:

If an experienced diagnostician suspects Prader-Willi syndrome in an older child or adult who meets the Diagnostic Criteria for PWS, the FISH test might be the first test of choice because it is widely available and will detect the majority of cases of PWS. If the FISH test is positive (a deletion is found), the diagnosis of PWS is confirmed and no further testing is needed. If the FISH test comes back negative (detecting no deletion), the next step would be the DNA methylation test. A relatively new test, DNA methylation can diagnose more than 99 percent of people with PWS, but it does not tell whether the cause of PWS is deletion, uniparental disomy (UPD), or an imprinting defect. If, after the negative FISH test, the methylation test confirms that the person has PWS, more testing is needed to find out whether the cause is UPD or an imprinting defect. If the UPD test is negative in this case, the cause must be an imprinting defect. At this time, imprinting defects are diagnosed by process of elimination—positive methylation test, but negative FISH and UPD tests–However, to confirm a suspected defect may require testing in genetics laboratories specializing in PWS research.

In cases where the suspicion of PWS is not as strong, or where the diagnosing physician is not as familiar with PWS, the DNA methylation test might be the best place to start. The test is becoming more widely available and can confirm or rule out PWS at the first step. If the methylation test is positive, then additional testing can be done at the same lab to determine the specific form of PWS. Even experienced diagnosticians have sometimes misdiagnosed infants as having PWS when in fact they had Angelman syndrome. (Both syndromes can cause hypotonia in the newborn baby, and both will show a chromosome 15 deletion on the FISH test.) Starting with the methylation test avoids this problem.

In cases of an imprinting defect or other rare test findings, families may need further testing through a research laboratory, both to get an accurate diagnosis and to learn about their risks of having another child with PWS.

What about prenatal testing?

Prenatal testing for PWS is now available. An expectant family might wonder whether to have testing done if they have had a child with PWS previously. Although the risk of having a second baby with PWS is very low in most cases, prenatal testing can provide important reassurance to the family that the new baby will not be affected. Counseling by a genetics professional can help a family understand their specific risks and whether testing of the fetus is important in their situation.

Prenatal testing for PWS might also be done in cases where a genetic study of the fetus (through chorionic villus sampling—CVS—or amniocentesis) shows abnormalities that raise suspicion of PWS. In one case, for example, a routine chromosome test done through CVS early in a woman’s pregnancy found that some of the baby’s cells had three chromosome 15s (called mosaic trisomy 15). This led the doctor to order a molecular test for maternal uniparental disomy (UPD) in the remaining cells. The test results showed that the baby would have PWS due to UPD.

Who should do the testing? Families who are seeking a diagnosis or who have concerns about their risks should work with a genetics specialist who is knowledgeable about PWS and the latest in testing. The geneticist will arrange to have blood samples sent to an appropriate laboratory for testing.

There is available on the Internet a free, searchable database of genetics laboratories and the tests they offer for specific conditions such as PWS. GeneTests Laboratory Directory (formerly called Helix) is sponsored by the Children’s Health Care System, Seattle, Washington, and can be found on the Internet at www.genetests.org . Note, however, that not every laboratory that performs these tests is included in the database.

Those who need help in locating a geneticist or a testing center may contact the PWSA (USA) national office at 1-800-926-4797 or through its Website, www.pwsausa.org .

References

ASHG/ACMG Report. Diagnostic Testing for Prader-Willi and Angelman Syndromes: Report of the ASHG/ACMG Test and Technology Transfer Committee. American Journal of Human Genetics 58:1085-1088. www.faseb.org/genetics/acmg/pol-22htm Cassidy, S.B. and Schwartz, S. (1998) Prader-Willi and Angelman Syndromes: Disorders of Genomic Imprinting. Medicine 77: 140-151. Butler, M.G. and Thompson, T. (2000) Prader-Willi Syndrome: Clinical and Genetic Findings. The Endocrinologist 10 (4) Suppl 1:3S-16S. Cassidy, S.B. (1998) Prader-Willi Syndrome. GeneClinics. http://www.geneclinics.org/profiles/pws/

The author wishes to thank Drs. Suzanne Cassidy, Dan Driscoll, and David Ledbetter for editing the original article, and Dr. Merlin Butler for assisting with this latest revision, so that families and other non-geneticists might better understand this complex and evolving subject.

What is Prader-Willi Syndrome?

A disorder of chromosome 15 Prevalence: 1:12,000- 15,000 (both sexes, all races) Major characteristics: hypotonia, hypogonadism, hyperphagia, cognitive impairment, difficult behaviors Major medical concern: morbid obesity

Cause and Diagnosis of PWS

The genetic cause is loss of yet unidentified genes normally contributed by the father. Occurs from three main genetic errors: Approximately 70% of cases have a non-inherited deletion in the paternally contributed chromosome 15; approximately 25% have maternal uniparental disomy (UPD)—two maternal 15s and no paternal chromosome 15; and 2–5 % have an error in the “imprinting” process that renders the paternal contribution nonfunctional.

Diagnostic testing: Individuals who have a number of the clinical findings should be referred for genetic testing. DNA methylation analysis confirms diagnosis of PWS. FISH and DNA techniques can identify the specific genetic cause and associated recurrence risk. (See ASHG/ACMG

Report, Am J Hum Genet 58: 1085, 1996.) Patients who had negative or inconclusive tests with older techniques should be retested.

Recurrence risk: Significant only for rare cases with imprinting mutations, translocations, or inversions. All families should receive genetic counseling.

Major Clinical Findings

The following common characteristics of individuals with PWS raise suspicion of the diagnosis. Published diagnostic criteria include supportive findings and a scoring system (Holm et al, Pediatrics 91, 2, 1993).

Neonatal and infantile central hypotonia, improving with age Feeding problems and poor weight gain in infancy Excessive or rapid weight gain between 1 and 6 years of age; central obesity in the absence of intervention Distinctive facial features—dolichocephaly in infants, narrow face/bifrontal diameter, almond-shaped eyes, small-appearing mouth with thin upper lip and down-turned corners of mouth Hypogonadism—genital hypoplasia, including undescended testes and small penis in males; delayed or incomplete gonadal maturation and delayed pubertal signs after age 16, including scant or no menses in women.

Global developmental delay before age 6; mild to moderate mental retardation or learning problems in older children Hyperphagia/food foraging/obsession with food

Minor Clinical Findings:

Decreased fetal movement, infantile lethargy, weak cry Characteristic behavior problems—temper tantrums, violent outbursts, obsessive/compulsive behavior; tendency to be argumentative, oppositional, rigid, manipulative, possessive, and stubborn; perseverating, stealing, lying Sleep disturbance or sleep apnea Short stature for genetic background by age 15 Hypopigmentation—fair skin and hair compared with family Small hands and/or feet for height age Narrow hands with straight ulnar border Eye abnormalities (esotropia, myopia) Thick, viscous saliva with crusting at corners of the mouth Speech articulation defects Skin picking

Weight and Behavior

Appetite Disorder

Hypothalamic dysfunction is thought to be the cause of the disordered appetite/satiety function characteristic of PWS. Compulsive eating and obsession with food usually begin before age 6. The urge to eat is physiological and overwhelming; it is difficult to control and requires constant vigilance.

Weight Management Challenge

Compounding the pressure of excessive appetite is a decreased calorie utilization in those with PWS (typically 1,000-1,200 kcal per day for adults), due to low muscle mass and inactivity. A balanced, low-calorie diet with vitamin and calcium supplementation is recommended. Regular weigh-ins and periodic diet review are needed. The best meal and snack plan is one the family or caregiver is able to apply routinely and consistently. Weight control depends on external food restriction and may require locking the kitchen and food storage areas. Daily exercise (at least 30 minutes) also is essential for weight control and health.

To date, no medication or surgical intervention has been found that would eliminate the need for strict dieting and supervision around food. GH treatment, because it increases muscle mass and function, may allow a higher daily calorie level.

Behavior Issues

Infants and young children with PWS are typically happy and loving, and exhibit few behavior problems. Most older children and adults with PWS, however, do have difficulties with behavior regulation, manifested as difficulties with transitions and unanticipated changes. Onset of behavioral symptoms usually coincides with onset of hyperphagia (although not all problem behaviors are food-related), and difficulties peak in adolescence or early adulthood. Daily routines and structure, firm rules and limits, “time out,” and positive rewards work best for behavior management. Psychotropic medications—particularly serotonin reuptake inhibitors, such as fluoxetine and sertroline—are beneficial in treating obsessive-compulsive (OCD) symptoms, perseveration, and mood swings. Depression in adults is not uncommon. Psychotic episodes occur rarely.

Developmental Concerns

Motor Skills

Motor milestones are typically delayed one to two years; although hypotonia improves, deficits in strength, coordination, balance, and motor planning may continue. Physical and occupational therapies help promote skill development and proper function. Foot orthoses may be needed. Growth hormone treatment, by increasing muscle mass, may improve motor skills. Exercise and sports activities should be encouraged and adaptations made, as needed. Proficiency with jigsaw puzzles is frequently reported, reflecting strong visual-perceptual skills.

Oral Motor and Speech

Hypotonia may create feeding problems, poor oral-motor skills, and delayed speech. The need for speech therapy should be assessed in infancy. Sign language and picture communication boards can be used to reduce frustration and aid communication. Products to increase saliva may help articulation problems. Social skills training can improve pragmatic language use. Even with delays, verbal ability often becomes an area of strength for children with PWS. In rare cases, speech is severely affected.

Cognition

IQs range from 40 to 105, with an average of 70. Those with normal IQs typically have learning disabilities. Problem areas may include attention, short-term auditory memory, and abstract thinking. Common strengths include long-term memory, reading ability, and receptive language. Early infant stimulation should be encouraged and the need for special education services and supports assessed in preschool and beyond.

Growth

Failure to thrive in infancy may necessitate tube feeding. Infants should be closely monitored for adequate calorie intake and appropriate weight gain. Growth hormone is typically deficient, causing short stature, lack of pubertal growth spurt, and a high body fat ratio, even in those with normal weight. The need for GH therapy should be assessed in both children and adults.

Sexual Development

not allowed hormone levels (testosterone and estrogen) are typically low. Cryptorchidism in male infants may require surgery. Both sexes have good response to treatment for hormone deficiencies, although side effects have been reported. Early pubic hair is common, but puberty is usually late in onset and incomplete.

Although it is often assumed that individuals with PWS are infertile, several pregnancies have been confirmed. Sexually active individuals should be counseled regarding risk of pregnancy and of genetic error in offspring (50%, except for those with PWS due to UPD). Basic not allowed education is important in all cases to promote good health and protect against abuse

Other Common Concerns

Strabismus—esotropia is common; requires early intervention, possibly surgery Scoliosis—can occur unusually early; may be difficult to detect without X-ray; curve may progress with GH treatment. Kyphosis is also common in teens and adults Osteoporosis—can occur much earlier than usual and may cause fractures; ensure adequate calcium, vitamin D, and weight-bearing exercise; bone density test recommended Diabetes mellitus, type II—secondary to obesity; responds well to weight loss; screen obese patients regularly Other obesity-related problems—include hypoventilation, hypertension, right-sided heart failure, stasis ulcers, cellulitis, and skin problems in fat folds Sleep disturbances—hypoventilation and desaturation during sleep are common, as is daytime sleepiness; sleep apnea may develop with or without obesity; sleep studies may be needed Nighttime enuresis—common at all ages; desmopressin acetate should be used in lower than normal doses Skin picking—a common, sometimes severe habit; usually in response to an existing lesion or itch on face, arms, legs, or rectum. Best managed by ignoring behavior, treating and bandaging sores, and providing substitute activities for the hands. Dental problems—may include soft tooth enamel, thick sticky saliva, poor oral hygiene, teeth grinding, and infrequently rumination. Special toothbrushes can improve hygiene. Products to increase saliva flow are helpful.

Quality of Life Issues

General health is usually good in individuals with PWS. If weight is controlled, life expectancy may be normal, and the individual’s health and functioning can be maximized.

The constant need for food restriction and behavior management may be stressful for family members. PWSA (USA) can provide information and support. Family counseling may also be needed.

Adolescents and adults with PWS can function well in group and supported living programs, if the necessary diet control and structured environment are provided. Employment in sheltered workshops and other highly structured and supervised settings is successful for many. Residential and vocational providers must be fully informed regarding management of PWS.

Abstracts and Studies

The neuroanatomy of genetic subtype differences in Prader-Willi syndrome.

March 2012

Honea RA, Holsen LM, Lepping RJ, Perea R, Butler MG, Brooks WM, Savage CR.

Source

Department of Neurology, University of Kansas School of Medicine, Kansas City, Kansas.

Keywords: chromosome 15q; hyperphagia; obesity; voxel-based morphometry; MRI

Abstract

Despite behavioral differences between genetic subtypes of Prader-Willi syndrome (PWS), no studies have been published characterizing brain structure in these subgroups. Our goal was to examine differences in the brain structure phenotype of common subtypes of PWS [chromosome 15q deletions and maternal uniparental disomy 15 (UPD)]. Fifteen individuals with PWS due to a typical deletion [(DEL) type I; n = 5, type II; n = 10], eight with PWS due to UPD, and 25 age-matched healthy-weight individuals (HWC) participated in structural magnetic resonance imaging (MRI) scans. A custom voxel-based morphometry processing stream was used to examine regional differences in gray and white matter volume (WMV) between groups, covarying for age, sex, and body mass index (BMI). Overall, compared to HWC, PWS individuals had lower gray matter volumes (GMV) that encompassed the prefrontal, orbitofrontal and temporal cortices, hippocampus and parahippocampal gyrus, and lower WMVs in the brain stem, cerebellum, medial temporal, and frontal cortex. Compared to UPD, the DEL subtypes had lower GMV primarily in the prefrontal and temporal cortices, and lower white matter in the parietal cortex. The UPD subtype had more extensive lower gray and WMVs in the orbitofrontal and limbic cortices compared to HWC. These preliminary findings are the first structural neuroimaging findings to support potentially separate neural mechanisms mediating the behavioral differences seen in these genetic subtypes.

Wiley Online Library

Appetite hormones and the transition to hyperphagia in children with Prader-Willi syndrome. Jan. 24, 2012

Goldstone AP, Holland AJ, Butler JV, Whittington JE.

Source

Metabolic and Molecular Imaging Group, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, London, UK.

Abstract

Objective: Prader-Willi syndrome (PWS) is a genetic neurodevelopmental disorder with several nutritional phases during childhood proceeding from poor feeding, through normal eating without and with obesity, to hyperphagia and life-threatening obesity, with variable ages of onset. We investigated whether differences in appetite hormones may explain the development of abnormal eating behaviour in young children with PWS.

Subjects: In this cross-sectional study, children with PWS (n=42) and controls (n=9) aged 7 months-5 years were recruited. Mothers were interviewed regarding eating behaviour, and body mass index (BMI) was calculated. Fasting plasma samples were assayed for insulin, leptin, glucose, peptide YY (PYY), ghrelin and pancreatic polypeptide (PP).

Results: There was no significant relationship between eating behaviour in PWS subjects and the levels of any hormones or insulin resistance, independent of age. Fasting plasma leptin levels were significantly higher (mean±s.d.: 22.6±12.5 vs 1.97±0.79 ng ml(-1), P=0.005), and PP levels were significantly lower (22.6±12.5 vs 69.8±43.8 pmol l(-1), P<0.001) in the PWS group compared with the controls, and this was independent of age, BMI, insulin resistance or IGF-1 levels. However, there was no significant difference in plasma insulin, insulin resistance or ghrelin levels between groups, though PYY declined more rapidly with age but not BMI in PWS subjects.

Conclusion: Even under the age of 5 years, PWS is associated with low levels of anorexigenic PP, as in older children and adults. Hyperghrelinaemia or hypoinsulinaemia was not seen in these young children with PWS. Change in these appetite hormones was not associated with the timing of the transition to the characteristic hyperphagic phase. However, abnormal and/or delayed development or sensitivity of the effector pathways of these appetitive hormones (for example, parasympathetic and central nervous system) may interact with low PP levels, and later hyperghrelinaemia or hypoinsulinaemia, to contribute to hyperphagia in PWS.International Journal of Obesity advance online publication, 24 January 2012; doi:10.1038/ijo.2011.274.

Journal of Obesity

Chromosome 15q24 microdeletion syndrome. Jan. 2012

Magoulas PL, El-Hattab AW.

Abstract

ABSTRACT: Chromosome 15q24 microdeletion syndrome is a recently described rare microdeletion syndrome that has been reported in 19 individuals. It is characterized by growth retardation, intellectual disability, and distinct facial features including long face with high anterior hairline, hypertelorism, epicanthal folds, downslanting palpebral fissures, sparse and broad medial eyebrows, broad and/or depressed nasal bridge, small mouth, long smooth philtrum, and full lower lip. Other common findings include skeletal and digital abnormalities, genital abnormalities in males, hypotonia, behavior problems, recurrent infections, and eye problems. Other less frequent findings include hearing loss, growth hormone deficiency, hernias, and obesity. Congenital malformations, while rare, can be severe and include structural brain anomalies, cardiovascular malformations, congenital diaphragmatic hernia, intestinal atresia, imperforate anus, and myelomeningocele.

Karyotypes are typically normal, and the deletions were detected in these individuals by array comparative genomic hybridization (aCGH). The deletions range in size from 1.7-6.1 Mb and usually result from nonallelic homologous recombination (NAHR) between paralogous low-copy repeats (LCRs). The majority of 15q24 deletions have breakpoints that localize to one of five LCR clusters labeled LCR15q24A, -B, -C, -D, and -E. The smallest region of overlap (SRO) spans a 1.2 Mb region between LCR15q24B to LCR15q24C. There are several candidate genes within the SRO, including CYP11A1, SEMA7A, CPLX3, ARID3B, STRA6, SIN3A and CSK, that may predispose to many of the clinical features observed in individuals with 15q24 deletion syndrome. The deletion occurred as a de novo event in all of the individuals when parents were available for testing. Parental aCGH and/or FISH studies are recommended to provide accurate genetic counseling and guidance regarding prognosis, recurrence risk, and reproductive options.

Management involves a multi-disciplinary approach to care with the primary care physician and clinical geneticist playing a crucial role in providing appropriate screening, surveillance, and care for individuals with this syndrome. At the time of diagnosis, individuals should receive baseline echocardiograms, audiologic, ophthalmologic, and developmental assessments. Growth and feeding should be closely monitored. Other specialists that may be involved in the care of individuals with 15q24 deletion syndrome include immunology, endocrine, orthopedics, neurology, and urology. Chromosome 15q24 microdeletion syndrome should be differentiated from other genetic syndromes, particularly velo-cardio-facial syndrome (22q11.2 deletion syndrome), Prader-Willi syndrome, and Noonan syndrome. These conditions share some phenotypic similarity to 15q24 deletion syndrome yet have characteristic features specific to each of them that allows the clinician to distinguish between them. Molecular genetic testing and/or aCGH will be able to diagnose these conditions in the majority of individuals.

Orphanet Journals of Rare Diseases

Prader-Willi syndrome. Jan. 2012

Cassidy SB, Schwartz S, Miller JL, Driscoll DJ.

Source

Division of Medical Genetics, Department of Pediatrics, University of California, San Francisco, San Francisco, California, USA.

Abstract

Prader-Willi syndrome is characterized by severe infantile hypotonia with poor suck and failure to thrive; hypogonadism causing genital hypoplasia and pubertal insufficiency; characteristic facial features; early-childhood onset obesity and hyperphagia; developmental delay/mild intellectual disability; short stature; and a distinctive behavioral phenotype. Sleep abnormalities and scoliosis are common. Growth hormone insufficiency is frequent, and replacement therapy provides improvement in growth, body composition, and physical attributes. Management is otherwise largely supportive. Consensus clinical diagnostic criteria exist, but diagnosis should be confirmed through genetic testing. Prader-Willi syndrome is due to absence of paternally expressed imprinted genes at 15q11.2-q13 through paternal deletion of this region (65-75% of individuals), maternal uniparental disomy 15 (20-30%), or an imprinting defect (1-3%). Parent-specific DNA methylation analysis will detect >99% of individuals. However, additional genetic studies are necessary to identify the molecular class. There are multiple imprinted genes in this region, the loss of which contribute to the complete phenotype of Prader-Willi syndrome. However, absence of a small nucleolar organizing RNA gene, SNORD116, seems to reproduce many of the clinical features. Sibling recurrence risk is typically <1%, but higher risks may pertain in certain cases. Prenatal diagnosis is available.Genet Med 2012:14(1):10-26.

PubMed

Transcription is required to establish maternal imprinting at the prader-willi syndrome and angelman syndrome locus.

Dec. 2011

Smith EY, Futtner CR, Chamberlain SJ, Johnstone KA, Resnick JL.

Source

Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville, Florida, United States of America. E-mail: resnick@mgm.ufl.edu

Abstract

The Prader-Willi syndrome (PWS [MIM 17620]) and Angelman syndrome (AS [MIM 105830]) locus is controlled by a bipartite imprinting center (IC) consisting of the PWS-IC and the AS-IC. The most widely accepted model of IC function proposes that the PWS-IC activates gene expression from the paternal allele, while the AS-IC acts to epigenetically inactivate the PWS-IC on the maternal allele, thus silencing the paternally expressed genes. Gene order and imprinting patterns at the PWS/AS locus are well conserved from human to mouse; however, a murine AS-IC has yet to be identified. We investigated a potential regulatory role for transcription from the Snrpn alternative upstream exons in silencing the maternal allele using a murine transgene containing Snrpn and three upstream exons. This transgene displayed appropriate imprinted expression and epigenetic marks, demonstrating the presence of a functional AS-IC. Transcription of the upstream exons from the endogenous locus correlates with imprint establishment in oocytes, and this upstream exon expression pattern was conserved on the transgene. A transgene bearing targeted deletions of each of the three upstream exons exhibited loss of imprinting upon maternal transmission. These results support a model in which transcription from the Snrpn upstream exons directs the maternal imprint at the PWS-IC.

Full text article

PLOS Genetics

Resources for Health Care Providers

“Health Care Guidelines for Individuals with PWS” and the book Management of Prader-Willi Syndrome are available from PWSA (USA), as are other publications for professionals and parents.

For a more comprehensive medical description of PWS, see the University of Washington School of Medicine, Seattle, GeneClinics: Medical Genetics Knowledge Base

Health Care Guidelines for Individuals with PWS

and the book

Management of Prader-Willi Syndrome

are available from PWSA (USA), as are other publications for professionals and parents.

For a more comprehensive medical description of PWS, see the University of Washington School of Medicine, Seattle,

GeneClinics: Medical Genetics Knowledge Base

This information is from the Prader Willi Syndrome Association

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Analysis of Endothelial Protein C Receptor Gene and Metabolic Profile in Prader-Willi Syndrome and Obese Subjects. Dec 2011

Testicular Failure in Boys with Prader-Willi Syndrome: Longitudinal Studies of Reproductive Hormones. Dec 11 (or) PubMed

Cardiac evaluation in children with Prader-Willi syndrome. Dec 2011

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Body composition, endocrine and metabolic profiles in adults with Prader-Willi syndrome.

Growth hormone treatment in adults with Prader-Willi syndrome: the Scandinavian study. Nov 2011

Severe neonatal-onset panniculitis in a female infant with Prader-Willi syndrome. Nov 2011

A polymorphism in the growth hormone receptor is associated with height in children with Prader-Willi syndrome. Nov 2011

Unique and atypical deletions in Prader-Willi syndrome reveal distinct phenotypes. Nov 2011

Importance of reward and prefrontal circuitry in hunger and satiety: Prader-Willi syndrome vs simple obesity. Oct 2011

Prader-Willi syndrome: A primer for clinicians Oct 2011

Prader-Willi Syndrome: Obesity due to Genomic Imprinting. May 2011

Long-Term Growth Hormone Therapy Changes the Natural History of Body Composition and Motor Function in Children with Prader-Willi Syndrome

The transition between the phenotypes of Prader-Willi syndrome during infancy and early childhood.

Perceptions of body image by persons with Prader-Willi syndrome and their parents.

A survey on Prader-Willi syndrome in the Italian population: prevalence of historical and clinical signs.

The C15orf2 gene in the Prader-Willi syndrome region is subject to genomic imprinting and positive selection.

Children with Prader-Willi syndrome exhibit more evident meal-induced responses in plasma ghrelin and peptide YY levels than obese and lean children.

Excessive appetitive arousal in Prader-Willi syndrome.

Sleep disordered breathing in infants with Prader-Willi syndrome during the first 6 weeks of growth hormone therapy: a pilot study.

Hypogonadism in females with Prader-Willi syndrome from infancy to adulthood: variable combinations of a primary gonadal defect and hypothalamic dysfunction

Plasma adiponectin level and sleep structures in children with Prader-Willi syndrome.

Physical health problems in adults with Prader-Willi syndrome.

Classification and Description

ICD-10 Q87.1

ICD-9 759.81

OMIM 176270

DiseasesDB 10481

eMedicine ped/1880

MeSH D011218

Patient Resources and Support

Prader-Willi Syndrome Association

PWSA (USA) offers support for families after the initial diagnosis of Prader-Willi syndrome. Upon diagnosis of a young child, we offer the Package of Hope as well as other helpful information. Older individuals diagnosed with PWS will also receive information from our office. Please call 800-926-4797

International Prader-Willi Syndrome Organisation (IPWSO)

Foundation for Prader-Willi Research

Prader-Willi California Foundation

Georgia Association for Prader-Willi Syndrome

562 Lakeland Plaza #327 Cumming, Georgia 30040

Tel: (770)-886-2334 Fax: (770)-886-2335 Toll Free: (877) 886-2334

Prader-Willi Syndrome Association of New England

Prader-Willi Alliance of New York, Inc.

includes listing of support groups in New York

Regional Support Groups

Prader-Willi Syndrome Association of Ohio

Utah Prader-Willi Syndrome Association

includes a list of Online support groups

Prader-Willi Syndrome Association of Wisconsin, Inc.

Angelman, Rett & Prader-Willi Syndromes Consortium

Please visit and support their associations and endeavors

Lymphedema People Internal Links

Lymphedema People Resources

prader_willi_syndrome.txt · Last modified: 2012/10/16 14:40 (external edit)