Quality of Life for Adults with Prader-Willi Syndrome in Residential Group Homes.

Background: Strict regimens of restricted caloric intake and daily physical exercise are life-saving in Prader-Willi syndrome (PWS) but are extremely challenging in home environments. PWS-specialized hostels (SH) succeed in preventing morbid obesity and in coping with behavioral disorders; however, effects of restricted living environments on quality of life (QOL) have not been described. Evidence on QOL is critical for clinicians involved in placement decisions. Methods: We examined the impact of living in SH versus at home or in non-specialized hostels (H and NSH) on QOL, behavior, and health parameters. All 58 adults (26 males) followed-up in the National Multidisciplinary Clinic for PWS were included: 33 resided in SH, 18 lived at home, and 7 lived in NSH. Questionnaires were administered to primary caregivers to measure QOL, and data were obtained from the medical records. Results: The H and NSH group were compared with those for adults in SH. Despite strict diet and exercise regimens, QOL was similar for both groups. Eight-year follow-up showed that food-seeking behavior decreased in SH but increased in H and NSH. BMI, cholesterol, and triglyceride levels were lower in SH. Conclusion: Our results suggest that living in SH is associated with benefits for physical health and behavior without negatively affecting QOL.

Glucose levels are not the same for everyone: a real-world big data study evaluating fasting serum glucose levels by sex and age among children.

OBJECTIVES: Understanding the normal range of laboratory values as pertained to different age groups and males or females is paramount in health care delivery. We aimed to assess the distribution of morning fasting serum glucose levels by age and sex in the general population of children using a large-scale population-based cohort. METHODS: A retrospective study with real-world de-identified data from a large, state mandated health fund in Israel among children aged 2-18 years old between 2006 and 2019. Age, sex, and BMI differences in mean glucose levels were evaluated. RESULTS: Study included 130,170 venous blood samples from 117,411 children, 53.3 % were female. After adjusting for age boys had higher fasting serum glucose levels than girls, with a mean of 89.21 ± 8.66 mg/dL vs. 87.59 ± 8.35 (p<0.001) [4.95 ± 0.48 mmol/L vs. 4.86 ± 0.46]. Compared to the 15 to 18 year-olds (88.49 ± 7.63 mg/dL) [4.92 ± 0.42 mmol/L], 2 to 5 year-olds had lower glucose levels (84.19 ± 10.65, [4.68 ± 0.59] (p<0.001)), 11 to 14 year-olds had higher glucose (90.40 ± 7.42 [5.02 ± 0.41], (p<0.001)) and 6 to 10 year-olds showed no difference (88.45 ± 8.25) [4.91 ± 0.46]. 33.0 % (n=42,991) had a BMI percentile record the same year as their glucose test result. There was a weak yet significant positive association between blood glucose levels and BMI. CONCLUSIONS: Our large cohort indicates that boys have slightly higher fasting serum glucose levels than girls, as do adolescents compared to younger children. This finding is important for the delivery of adequate health care, screening for illness and avoiding unnecessary investigations and tests.

The importance of gynecological examination in adolescent girls and adult women with Prader-Willi syndrome.

Current published guidelines for routine care of women with Prader-Willi syndrome (PWS) do not include recommendations for gynecologic examinations. We describe our experience with gynecological examinations in women with PWS and offer recommendations for routine health care for these patients. Data were collected on all 41 PWS females ages ≥12 year, followed in our national Israeli multidisciplinary clinic between the years 2011 and 2022. Menstrual data and findings on external gynecological examination, including evaluation of the vulva and hymen were recorded at yearly visits. During the gynecological evaluation the topic of sexual education was discussed. Pelvic ultrasound, specifically for antral follicular count, was performed for those visiting the clinic during 2020-2022. Blood samples for luteinizing hormone (LH), follicular stimulating hormone (FSH), and estradiol were obtained routinely and DEXA scans for bone density were done when indicated. Of the 41 women, (median age at start of follow-up 17 years, range [12.3-39], BMI 30.4 kg/m2 [IQR 23.5-37.1]), 39 women agreed to external gynecological examination. Eleven women (27%) had spontaneous menses, with menarche at the age of 14 to as late as 31 years. The hymen was intact in all except one. Poor hygiene was observed in eight women, three women with vulvovaginitis, and five with irritated vulva related to poor hygiene. Gynecological ultrasound was performed in 27 women. In 22, endometrial thickness was less than 5 mm. The median antral follicular count (AFC) was 6 (<10th percentile for age). No correlation between AFC and menstruation or BMI was found. Mean FSH level was 5.7 ± 3.6 IU, LH was 2.29 ± 2.23, and estradiol was 128 ± 76 pmol/L. Data on DEXA measurements were available in 25 women aged 16-39. Median spine T score was -1.3 (range between 0.5 and -3.7), and hip T score was -1.2 (range between 0.8 and -3.3). A negative correlation was found between endometrial thickness and the presence of osteopenia or osteoporosis (r = -0.5, p = 0.013). Despite our recommendations, only eight of 14 women agreed to hormonal treatment or contraception. One woman who received treatment had a thromboembolic event. Routine health care for women with PWS should include gynecological examinations. The gynecological evaluation should include external genital examination, assessment of hygiene, obtaining a blood sample for hormone levels, and documenting a history of sexual experience or sexual abuse. Hormonal treatment or contraception should be offered when appropriate.

Hypogonadism in Women with Prader-Willi Syndrome-Clinical Recommendations Based on a Dutch Cohort Study, Review of the Literature and an International Expert Panel Discussion.

Prader-Willi syndrome (PWS) is a rare neuroendocrine genetic syndrome. Characteristics of PWS include hyperphagia, hypotonia, and intellectual disability. Pituitary hormone deficiencies, caused by hypothalamic dysfunction, are common and hypogonadism is the most prevalent. Untreated hypogonadism can cause osteoporosis, which is already an important issue in PWS. Therefore, timely detection and treatment of hypogonadism is crucial. To increase understanding and prevent undertreatment, we (1) performed a cohort study in the Dutch PWS population, (2) thoroughly reviewed the literature on female hypogonadism in PWS and (3) provide clinical recommendations on behalf of an international expert panel. For the cohort study, we retrospectively collected results of a systematic health screening in 64 female adults with PWS, which included a medical questionnaire, medical file search, medical interview, physical examination and biochemical measurements. Our data show that hypogonadism is frequent in females with PWS (94%), but is often undiagnosed and untreated. This could be related to unfamiliarity with the syndrome, fear of behavioral changes, hygienic concerns, or drug interactions. To prevent underdiagnosis and undertreatment, we provide practical recommendations for the screening and treatment of hypogonadism in females with PWS.

Hypogonadism in Adult Males with Prader-Willi Syndrome-Clinical Recommendations Based on a Dutch Cohort Study, Review of the Literature and an International Expert Panel Discussion.

Prader-Willi syndrome (PWS) is a complex genetic syndrome characterized by hyperphagia, intellectual disability, hypotonia and hypothalamic dysfunction. Adults with PWS often have hormone deficiencies, hypogonadism being the most common. Untreated male hypogonadism can aggravate PWS-related health issues including muscle weakness, obesity, osteoporosis, and fatigue. Therefore, timely diagnosis and treatment of male hypogonadism is important. In this article, we share our experience with hypogonadism and its treatment in adult males with PWS and present a review of the literature. In order to report the prevalence and type of hypogonadism, treatment regimen and behavioral issues, we retrospectively collected data on medical interviews, physical examinations, biochemical measurements and testosterone replacement therapy (TRT) in 57 Dutch men with PWS. Fifty-six (98%) of the patients had either primary, central or combined hypogonadism. Untreated hypogonadism was associated with higher body mass index and lower hemoglobin concentrations. TRT was complicated by behavioral challenges in one third of the patients. Undertreatment was common and normal serum testosterone levels were achieved in only 30% of the patients. Based on the Dutch cohort data, review of the literature and an international expert panel discussion, we provide a practical algorithm for TRT in adult males with PWS in order to prevent undertreatment and related adverse health outcomes.

Growth hormone treatment for adults with Prader-Willi syndrome: another point of view.

Growth hormone treatment for children with Prader Willi syndrome (PWS) has shown proven benefits not only in increasing final height but also with positive effects on body composition and motor development. In a recent letter to the editor, Hoybye and colleagues recommend growth hormone treatment for adults with PWS based exclusively on the genetic diagnosis and without regard for growth hormone secretory status. We question whether the benefits of growth hormone treatment in PWS adults, mainly improvement in body composition, are significant enough to justify the as yet unkown consequences of long-term treatment in an adult population. Morbidity and mortality in PWS are mainly due to complications of obesity, and growth hormone treatment does not result in a decrease in BMI or waist circumference. Increases in insulin-like factor-1 as a result of growth hormone treatment over the course of several decades in PWS adults raises concern over possible increase risk of cancer. Compliance with daily injections is likely to be poor. We suggest that efforts to provide appropriate dietary and exercise regimens may be more beneficial and cost-effective than advocating for growth hormone treatment for adults with PWS.

Syndrome-Related Risk Factors for Sexual Abuse: The Example of Prader-Willi Syndrome.

Many genetic disorders associated with intellectual disability are characterized by unique behavioral phenotypes which may have serious psychological consequences such as increasing the risk for sexual abuse (SA). Prader-Willi Syndrome (PWS), a severe neurogenetic syndrome with uncontrollable hyperphagia and high threshold for pain, is an excellent example of this issue. The absence of reports on SA in PWS highlights the lack of awareness to the topic. Our aim was to report on SA in individuals with PWS, describe its unique characteristics, and offer recommendations for its prevention. Caregivers of all individuals with genetically confirmed PWS living in the only two residential facilities designated for PWS in Israel were interviewed for a history of sexual behavior and abuse, and medical data were collected from their files. SA was reported in a quarter of the sample. In most of the cases (78%), food reward was used by the perpetrators to attract their victims. Age at SA ranged from 11 to 29 years. Most of the individuals did not disclose the event and some continued to initiate inappropriate sexual activity to obtain food. Characteristics unique to PWS, such as food-seeking behaviors and high threshold for pain, likely contribute to the risk for SA. These findings suggest that syndrome-specific programs for SA prevention should be considered for individuals with any genetic syndrome with behavioral problems that may increase SA risk.

Long-term weight control in adults with Prader-Willi syndrome living in residential hostels.

Hyperphagia leading to severe obesity with increased morbidity and mortality is the major manifestation of Prader-Willi syndrome. Caring for these individuals in a home environment is challenging and stressful for caregivers and families. Residential hostels specifically for PWS adults offer programs of diet, exercise, and vocational opportunities, but long-term effects of PWS hostel living have not been reported. We studied long-term changes in body mass index (BMI) for PWS adults living in residential hostels compared with age-matched controls living with families at home. The study included all 34 individuals (18 men) aged >17 years with genetically confirmed PWS living in residential hostels. BMI was recorded at the time of yearly clinic visits and compared to 23 PWS adults (10 men) living at home. BMI on entering the hostel was 36.3 ± 11.0 kg/m2 and decreased to 27.0 ± 5.6 kg/m2 (p < 0.001) after 6.9 ± 3.9 years. For 21 residents, a slight rise of BMI to 28.8 kg/m2 was observed 5.1 ± 2.5 years after the lowest value was achieved. BMI of 23 PWS adults at home was 36.8 ± 12.7 kg/m2 versus 27.9 ± 7.1 kg/m2 for hostel residents in the same age range (p = 0.008). From 2008 to 2019, there were five deaths among PWS individuals aged 18-40 years living at home, compared with one death (a 43-year-old man) among hostel residents. Adults with PWS living in hostels lose weight, maintain BMI values in a normal to mildly overweight range, and have lower mortality in contrast to individuals in a family home environment.

Recognizing the unique prenatal phenotype of Prader-Willi Syndrome (PWS) indicates the need for a diagnostic methylation test.

OBJECTIVES: Prader-Willi syndrome (PWS) is a neurogenetic disorder characterized by mental retardation, morbid obesity, and endocrine and behavior disorders. We previously showed in a small group of patients that PWS may have a unique prenatal phenotype. We aimed to characterize clinical and ultrasonic features in a larger series of pregnancies with a PWS fetus. METHODS: We retrospectively interviewed all mothers of children with PWS followed in the Israel national multidisciplinary PWS clinic. We compared details of the PWS pregnancy with the pregnancies of healthy siblings and with data from the general population. Medical records including ultrasound reports, obstetric records, and genetic results were analyzed. RESULTS: Distinct prenatal features of PWS pregnancies included abnormal fetal growth [fetal growth restriction (FGR) (37.3%), increased head to abdominal circumference ratio (44.8%), decreased abdominal circumference (49.2%)], markedly decreased fetal movements (DFM) (80.4%), and polyhydramnios (42.0%) (P < 0.001 for all). The combination of abnormal growth accompanied by polyhydramnios or DFM was highly suggestive for PWS. CONCLUSIONS: Recognition of the unique PWS phenotype should alert obstetricians to consider the possibility of PWS, perform the diagnostic methylation test, provide appropriate counseling, and plan optimal management of the affected pregnancy.

Myokine levels after resistance exercise in young adults with Prader-Willi syndrome (PWS).

Individuals with PWS require marked caloric restriction and daily exercise to prevent morbid obesity. Lower energy expenditure, hypotonia, decreased muscle mass, and cognitive impairment make exercise challenging for this population. Exercise guidelines include resistance training as an important component. Myokine responses to resistance exercise may mediate beneficial metabolic effects. We aimed to determine if young PWS adults can perform a resistance exercise program and to measure myokine responses in PWS versus age- and BMI-matched controls. Each group included 11 participants (7M/4F). Ages and BMI for PWS and controls were 30.7 ± 4.6 versus 30.1 ± 4.3 years and 28.3 ± 4.3 versus 28.2 ± 4.2 kg/m2 , respectively. Glucose, creatine kinase (CK), lactate, and myokines were measured before, after, 30, and 60 min after completing eight resistance exercises. Myokines were assayed using a multiplex myokine panel (Merck Millipore). CK was lower in PWS versus controls (62 ± 16 vs.322 ± 100 U/L, p < .04). Peak lactate was 3.7 ± 0.7 in PWS versus 7.3 ± 0.7 mmol/Lin controls (p < .001). The increase in interleukin-6 was similar in PWS and controls (41 ± 16% and 35 ± 10%, respectively). Pre- and post-exercise levels of the six myokines assayed showed no consistent differences between the PWS and control participants. PWS young adults are capable of performing resistance/strength-building exercise. The lower CK and peak lactate levels in PWS may reflect decreased muscle mass in this population. Further studies are needed to determine optimal exercise regimens and assess the role of myokines incontributing to the metabolic phenotype of PWS.

Early puberty in end stage renal failure and renal transplant recipients.

Background Delayed puberty and hypogonadism are common in children with chronic kidney disease and in renal transplant recipients, but precocious puberty has rarely been reported in these populations. We describe six girls with precocious and/or early-onset, rapidly progressive puberty before and following renal transplantation. Methods Of 112 children under the age of 18 years (67 boys, 45 girls) who received renal transplants between 2010 and 2018, six girls presented with precocious or rapidly progressive early puberty at ages 6-7/12, 7-2/12, 7-4/12, 8, 8-8/12 and 8-11/12 years. Clinical evaluation included measurements of height, weight, body mass index (BMI), Tanner staging and bone age assessment. Gonadotropin responses to intravenous gonadotropin releasing hormone (GnRH) or intramuscular triptorelin acetate were determined. Results Tanner breast stage 3 was noted at 2-6 years following renal transplantation in five girls, four with preserved kidney function. One girl began puberty before renal transplantation. Peak luteinizing hormone (LH) and follicular stimulating hormone (FSH) levels were 6.5, 20.2, 7.83, 19.1, 9 and 2.2 mIU/mL and 13, 8.3, 8.01, 7.5, 8.1 and 7.7 mIU/mL, respectively. Treatment with an intramuscular slow-release formulation of triptorelin acetate every 4 weeks slowed progression of breast development. Conclusions Although delayed puberty is more common in children with renal disease, precocious puberty can also be seen. Evaluation of growth and puberty by a pediatric endocrinologist should be part of the routine care for all children following kidney transplantation.

Incomplete methylation of a germ cell tumor (Seminoma) in a Prader-Willi male.

BACKGROUND: Prader-Willi syndrome (PWS) is a multisystem genetic disorder characterized by lack of satiety leading to morbid obesity, variable degrees of mental retardation, behavior disorders, short stature, and hypogonadism. The underlying genetic cause for PWS is an imprinting defect resulting from a lack of expression of several paternally inherited genes embedded within the 15q11.2-q13 region. Although the clinical expression of hypogonadism in PWS is variable, there are no known cases of fertility in PWS men. In this paper, we described a pure, nearly diploid seminoma in an apparently 32 year-old infertile man with PWS due to maternal uniparental disomy (UPD) on chromosome 15. The development of a germ cell tumor in this subject was an unanticipated result. The aim of this study was to explore the origin of the germ cell tumor in this PWS male patient. METHODS: To explain the origin of the germ cell tumor (seminoma) in our PWS patient we have characterized the tumor for cell morphology and tumor type by pathological examination (H&E and immuno-stainings), evaluated its karyotype by chromosomal microarray analysis and confirmed its UPD origin by haplotype analysis. In addition, DNA methylation status of the PWS- and H19- imprinting centers in wild-type and affected fibroblasts, patient derived induced pluripotent stem cells (iPSCs), and PWS seminoma were determined by bisulfite DNA colony sequencing. RESULTS: To explain the apparent contradiction between the existence of a germ cell tumor and hypogonadism we first confirmed the germ cell origin of the tumor. Next, we determined the tumor chromosomal composition, and validated the presence of a maternal UPD in all examined cell types from this patient. Finally, we characterized the maternal imprints in the PWS and H19 imprinting centers in the tumor and compared them with patient's fibroblasts and iPSCs derived from them. Unpredictably, methylation was reduced to 50% in the tumor, while preserved in the other cell types. CONCLUSION: We infer from this assay that the loss of methylation in the PWS-IC specifically in the tumor of our patient is most likely a locus-specific event resulting from imprint relaxation rather than from general resetting of the imprints throughout the genome during germ line specification.

Physical activity and maximal oxygen uptake in adults with Prader-Willi syndrome.

BACKGROUND: Prader-Willi Syndrome (PWS) is the most common genetic syndrome causing life-threatening obesity. Strict adherence to a low-calorie diet and regular physical activity are needed to prevent weight gain. Direct measurement of maximal oxygen uptake (VO2 max), the "gold standard" for assessing aerobic exercise capacity, has not been previously described in PWS. OBJECTIVES: Assess aerobic capacity by direct measurement of VO2 max in adults with PWS, and in age and BMI-matched controls (OC), and compare the results with values obtained by indirect prediction methods. METHODS AND PATIENTS: Seventeen individuals (12 males) age: 19-35 (28.6 ± 4.9) years, BMI: 19.4-38.1 (27.8 ± 5) kg/m2 with genetically confirmed PWS who exercise daily, and 32 matched OC (22 males) age: 19-36 (29.3 ± 5.2) years, BMI: 21.1-48.1 (26.3 ± 4.9) kg/m2. All completed a medical questionnaire and performed strength and flexibility tests. VO2 max was determined by measuring oxygen consumption during a graded exercise test on a treadmill. RESULTS: VO2 max (24.6 ± 3.4 vs 46.5 ± 12.2 ml/kg/min, p < 0.001) and ventilatory threshold (20 ± 2 and 36.2 ± 10.5 ml/kg/min, p < 0.001), maximal strength of both hands (36 ± 4 vs 91.4 ± 21.2 kg, p < 0.001), and flexibility (15.2 ± 9.5 vs 26 ± 11.1 cm, p = 0.001) were all significantly lower for PWS compared to OC. Predicted estimates and direct measurements of VO2 max were almost identical for the OC group (p = 0.995), for the PWS group, both methods for estimating VO2 max gave values which were significantly greater (p < 0.001) than results obtained by direct measurements. CONCLUSIONS: Aerobic capacity, assessed by direct measurement of VO2 max, is significantly lower in PWS adults, even in those who exercise daily, compared to OCs. Indirect estimates of VO2 max are accurate for OC, but unreliable in PWS. Direct measurement of VO2 should be used for designing personal training programs and in clinical studies of exercise in PWS.

Attitudes toward prenatal genetic testing and therapeutic termination of pregnancy among parents of offspring with Prader-Willi syndrome.

INTRODUCTION: Prenatal diagnosis (PND) raises ethical dilemmas such as the option of termination of pregnancy (TOP) in cases with severe outcome. Prader-Willi Syndrome (PWS), a complex neurogenetic syndrome with high morbidity and mortality throughout life. Recently, a unique prenatal phenotype was reported and TOP becomes a possibility. OBJECTIVE: To explore factors influencing the attitudes of parents of PWS children toward PND and TOP concerning a hypothetical pregnancy with a PWS fetus. METHODS: All 85 parents of individuals with PWS were interviewed regarding their attitudes towards PND and TOP using semi-structured questionnaire. RESULTS: Fifty-seven parents were supportive of invasive PND and 28 of non-invasive tests only; none opposed PND. Thirty eight favored TOP, additional 31 supported TOP under certain conditions such as spiritual advice, 15 were categorically against TOP. Attitudes correlated with religiosity (p < 0.025), mother's education (p < 0.001), mother's work status (p < 0.001), current age of the child with PWS (p < 0.008). Couples had similar attitudes regarding PND and TOP. No correlation was found with gender, genetic subtype and parental age. CONCLUSIONS: Most parents of individuals with PWS support PND, however less than half support TOP. Religiosity was the most influential factor. Familial worldview should be taken into account during prenatal counseling.

Targeting the endocannabinoid/CB1 receptor system for treating obesity in Prader-Willi syndrome.

OBJECTIVE: Extreme obesity is a core phenotypic feature of Prader-Willi syndrome (PWS). Among numerous metabolic regulators, the endocannabinoid (eCB) system is critically involved in controlling feeding, body weight, and energy metabolism, and a globally acting cannabinoid-1 receptor (CB1R) blockade reverses obesity both in animals and humans. The first-in-class CB1R antagonist rimonabant proved effective in inducing weight loss in adults with PWS. However, it is no longer available for clinical use because of its centrally mediated, neuropsychiatric, adverse effects. METHODS: We studied eCB 'tone' in individuals with PWS and in the Magel2-null mouse model that recapitulates the major metabolic phenotypes of PWS and determined the efficacy of a peripherally restricted CB1R antagonist, JD5037 in treating obesity in these mice. RESULTS: Individuals with PWS had elevated circulating levels of 2-arachidonoylglycerol and its endogenous precursor and breakdown ligand, arachidonic acid. Increased hypothalamic eCB 'tone', manifested by increased eCBs and upregulated CB1R, was associated with increased fat mass, reduced energy expenditure, and decreased voluntary activity in Magel2-null mice. Daily chronic treatment of obese Magel2-null mice and their littermate wild-type controls with JD5037 (3 mg/kg/d for 28 days) reduced body weight, reversed hyperphagia, and improved metabolic parameters related to their obese phenotype. CONCLUSIONS: Dysregulation of the eCB/CB1R system may contribute to hyperphagia and obesity in Magel2-null mice and in individuals with PWS. Our results demonstrate that treatment with peripherally restricted CB1R antagonists may be an effective strategy for the management of severe obesity in PWS.

Case report: severe asymptomatic hyponatremia in Prader-Willi Syndrome.

BACKGROUND: Prader-Willi syndrome is a complex neurogenetic, multisystem disorder. Despite the variable endocrine abnormalities and hypothalamic-pituitary axis dysfunction, hyponatremia has been reported in only a few PWS patients. In previously reported PWS individuals, hyponatremia was associated with abnormal fluid intake or during desmopressin treatment. CASE PRESENTATION: We describe an infant with Prader-Willi syndrome who had severe, prolonged asymptomatic hyponatremia without a history of excessive fluid intake or desmopressin treatment. We compare the findings with those of the few other reported cases and describe, for the first time, results of a hypertonic saline infusion test and studies of adrenal cortical function. CONCLUSION: Hyponatremia should be suspected in children with Prader-Willi syndrome, especially in infants with severe failure to thrive. Further studies are needed to determine the pathophysiology of hyponatremia in this syndrome.

Irisin and the Metabolic Phenotype of Adults with Prader-Willi Syndrome.

CONTEXT: Hyperphagia, low resting energy expenditure, and abnormal body composition contribute to severe obesity in Prader Willi syndrome (PWS). Irisin, a circulating myokine, stimulates "browning" of white adipose tissue resulting in increased energy expenditure and improved insulin sensitivity. Irisin has not been previously studied in PWS. OBJECTIVES: Compare plasma and salivary irisin in PWS adults and normal controls. Examine the relationship of irisin to insulin sensitivity and plasma lipids. DESIGN AND STUDY PARTICIPANTS: A fasting blood sample for glucose, lipids, insulin, leptin, adinopectin, and irisin was obtained from 22 PWS adults and 54 healthy BMI-matched volunteers. Saliva was collected for irisin assay in PWS and controls. RESULTS: Fasting glucose (77 ± 9 vs 83 ± 7 mg/dl, p = 0.004), insulin (4.1 ± 2.0 vs 7.9 ± 4.7 µU/ml, p<0.001), and triglycerides (74 ± 34 vs 109 ± 71 mg/dl, p = 0.007) were lower in PWS than in controls. Insulin resistance (HOMA-IR) was lower (0.79 ± 0.041 vs 1.63 ± 1.02, p<0.001) and insulin sensitivity (QUICKI) was higher (0.41 ± 0.04 vs 0.36 ± 0.03, p<0.001) in PWS. Plasma irisin was similar in both groups, but salivary irisin (64.5 ± 52.0 vs 33.0 ± 12.1ng/ml), plasma leptin (33.5 ± 24.2 vs 19.7 ± 19.3 ng/ml) and plasma adinopectin (13.0 ± 10.8 vs 7.6 ± 4.5µg/ml) were significantly greater in PWS (p<0.001). In PWS, plasma irisin showed positive Pearson correlations with total cholesterol (r = 0.58, p = 0.005), LDL-cholesterol (r = 0.59, p = 0.004), and leptin (r = 0.43, p = 0.045). Salivary irisin correlated negatively with HDL-cholesterol (r = -0.50, p = 0.043) and positively with LDL-cholesterol (r = 0.51, p = 0.037) and triglycerides (r = 0.50, p = 0.041). CONCLUSIONS: Salivary irisin was markedly elevated in PWS although plasma irisin was similar to levels in controls. Significant associations with plasma lipids suggest that irisin may contribute to the metabolic phenotype of PWS.

[The reproductive system in Prader-Willi syndrome].

Prader-Willi syndrome (PWS) is a genetic syndrome caused by the lack of expression of imprinted genes located on paternal chromosome 15q11-q13, characterized by endocrine defects, an insatiable appetite, short stature, cognitive and behavioral difficulties and dysmorphic features. Nearly all PWS males and most PWS women show clinical and/or laboratory evidence of hypogonadism, affecting their habitus, health and quality of life. Until recently, hypogonadism in PWS was generally considered to be of centrall, hypothalamic origin. However, recent studies have shown that primary gonadal dysfunction is the major contributor to hypogonadism in this condition, while severe gonadotropin deficiency is rare. Despite clinical and laboratory evidence of hypogonadism, young adult PWS men and women have sexual and romantic interests and aspirations. Pregnancies have been reported in a few women with genetically documented PWS. Fertility has not been reported in PWS men. Recognition of these interests is essential for physicians and caregivers in order to offer proper anticipatory guidance, psychological and sex education and counseling. Individual variations in pubertal development, reproductive hormone profiles, bone-mineral density and individual appeal need to be considered when recommending sex hormone replacement in this population. Testosterone should be considered in most hypogonadal PWS males, considering possible side effects. Hormone replacement may be indicated in PWS women with decreasing bone mineral density or in PWS women who wish to have regular menses. Contraception should be considered in women with normal inhibin B levels. Hormone replacement is likely to improve bone density, quality of life and body image.

A disease specific questionnaire for assessing behavior in individuals with Prader-Willi syndrome.

OBJECTIVE: Prader-Willi syndrome (PWS) is a genetic multisystem disorder with various medical, cognitive, behavioral and psychiatric problems. PWS is caused by the lack of expression of paternal genes on chromosome 15q2-q13 due to a deletion (70-75%), uniparental disomy (25-30%) or imprinting center defect (<5%). The common PWS behavioral and psychiatric characteristics are very typical in all ethnicities and were reported worldwide. Still, each individual has a specific profile of these common traits and the severity of his or her symptoms varies over time. Behavioral problems are the most important factor affecting the quality of life of both the individuals and their families. There is a need for a standardized tool to assess the specific behavioral profile of each individual and its present severity, in order to enable physicians to tailor the specific treatment needed and assist in a more accurate clinical follow up. To the best of our knowledge no such a tool has been standardized and published. We developed, based on the literature (mainly Forster and Gourash's paradigm) and our clinical experience, a 37 item disease specific questionnaire, the "PWS Behavioral Questionnaire" (PWSBQ) for assessing behavior in PWS patients. The purpose of the present study was to validate this tool in the entire adolescent and adult PWS population in Israel. METHODS: The PWSBQ focuses on five major domains-abnormal emotional regulation, food-seeking related behavior, lack of flexibility, oppositional behavior and interpersonal problems and lastly body related behaviors. Caregivers of all Hebrew speaking individuals with PWS over the age of 12 years attending the Israeli national multidisciplinary PWS clinic were recruited. Of the 54 eligible individuals, 53 participated. They were interviewed with the PWSBQ and in addition filled the "Hyperphagia Questionnaire" and the "Child Behavioral Checklist" (CBCL). After verifying the questionnaire's content validity, all items on the PWSBQ were analyzed for internal reliability by calculating Cronbach's α. Criterion validity was evaluated by correlation testing with regard to the Hyperphagia Questionnaire and CBCL. In order to assess the questionnaire's interpretability, the correlation between the PWSBQ and the "Clinical Global Impression" (CGI) scores was evaluated. RESULTS: The PWSBQ total score was positively correlated with both the CBCL total score and the CGI score (0.662 and 0.549, p<0.001 respectively). Of the five domains, four had acceptable internal reliability (excluding the body related behaviors domain, which was thus removed from the total score). Criterion validity was established for the four domains remaining in the statistical analysis (abnormal emotional regulation, food seeking related behavior, lack of flexibility and oppositional behavior and interpersonal problems). CONCLUSIONS: Our findings suggest that the PWSBQ is a valid and reliable tool for the assessment of current behavioral problems among individuals with PWS. Although further research is needed in order to verify PWSBQ's ability to identify changes in the behavioral status of a given individual, it can now be used both in research and in a clinical setting, enabling the physician to plan the most suitable treatment based on the current behavioral status.

Prader-Willi syndrome can be diagnosed prenatally.

The aim of this study was to characterize the fetal phenotype of a cohort of individuals with confirmed diagnoses of Prader-Willi syndrome (PWS), a severe multi-system genetic disorder, diagnosed by a specific methylation test. We interviewed mothers of 106 individuals with PWS to obtain information about the pregnancy of their affected child. For 47 pregnancies of children younger than 10 years, we also reviewed the obstetric ultrasound and detailed obstetric history from medical records. We compared the PWS pregnancies with those of the sibling closest in age and with the general population. McNemars, Chi-square and Fisher exact tests were used for statistical analyses. Decreased fetal movements, small for gestational age (SGA), asymmetrical intrauterine growth (increased head/abdomen circumferences ratio) and polyhydramnios were found in 88%, 65%, 43%, and 34%, respectively (P < 0.001 vs. siblings and P < 0.0001 vs. the general population for all measurements). No severe morphological abnormalities were found. A combination of 2, 3, and 4 abnormalities was found in 27%, 29%, and 24% of pregnancies, respectively. Fourteen out of 15 umbilical artery Doppler studies were within the normal range (93%). The rare combination of asymmetrical intrauterine growth and polyhydramnios was found in 34% of PWS pregnancies (P < 0.0001 vs. the general population). Prenatal genetic screening for PWS by methylation testing is indicated when any combination of polyhydramnios, SGA or asymmetric intrauterine growth, with normal Doppler studies is present, particularly when asymmetrical intrauterine growth and polyhydramnios coexist.