8486 Age at diagnosis in Prader Willi Syndrome (PWS)

Prader-Willi syndrome (PWS) is suspected at birth if extreme hypotonia, difficulty in feeding, hypogonadism, and failure to thrive are present. Genetic diagnosis of PWS can generally be made within the first few months of life; however, a delayed diagnosis of PWS is frequently reported. Although the clinical characteristics of perinatal and neonatal patients with PWS have been reported, there are no such reports on the clinical characteristics of these patients in Japan. This retrospective, single-center study involved 177 Japanese patients with PWS and their medical data regarding the perinatal and neonatal periods were evaluated. The median maternal age at birth was 34 years; 12.7% of the mothers had a history of assisted reproductive technology (ART). Of the mothers, 13.5% reported polyhydramnios and 4.3% had oligohydramnios. Decreased fetal movement during pregnancy was reported by 76% of the mothers. A total of 60.5% of patients were born by cesarean section. Genetic subtypes included deletions (66.1%), uniparental disomy (31.0%), imprinting defects (0.6%), and other or unknown subtypes (2.3%). The median birth length was 47.5 cm and the median birthweight was 2476 g. Of the 160 patients, 14 (8.8%) were classified as small for gestational age. Most patients had hypotonia (98.8%), and 89.3% required gavage feeding at birth. Breathing problems, congenital heart disease, and undescended testis were noted in 33.1%, 7.0%, and 93.5% of patients, respectively. In our study, higher rates of ART, polyhydramnios, decreased fetal movements, cesarean section, hypotonia, feeding difficulties, and undescended testis were observed in PWS.

It's not about the height: Prader–Willi Syndrome. Effects of Growth Hormone Treatment

Long-term effects of growth hormone (GH) treatment in young children with Prader-Willi syndrome (PWS) have never been compared with untreated age-matched controls with PWS, and it is unclear if starting GH in the first year of life is safe and more effective than starting GH in early childhood. We investigated the effects of long-term GH on body composition, anthropometrics and cognition in young children with PWS compared to untreated controls and assessed whether starting GH in the first year of life is optimal and safe. An open-label, prospective study was performed, comparing GH-treated children with untreated controls, and comparing children who started GH in the first year of life (subgroup A) with children who started between 2–5 years (subgroup C). A total of 82 GH-treated children with PWS and 22 age-matched controls with PWS were included. The main outcome measures were body composition, anthropometrics, IQ, and safety parameters. After 8 years, GH-treated children had significantly better body composition and were taller than age-matched controls. Subgroup A had a lower FM% trajectory during treatment than subgroup C and showed a greater and longer-term increase in the LBM index. After 8 years, subgroup A had a lower trunk/peripheral fat ratio (p = 0.043) and higher IQ (p = 0.043). No adverse effects of starting GH in the first year were found. Children with PWS who received long-term GH had a better body composition and growth than untreated age-matched controls and starting GH in the first year of life was optimal and safe.

American College of Medical Genetics Statement on Diagnostic Testing for Uniparental Disomy

The effect of growth hormone therapy, adenotonsillectomy and genotype on obstructive sleep apnea in children with Prader-Willi syndrome

When definitive diagnostic testing is not available, as was the case for PWS when the 1993 criteria were developed, diagnostic criteria are important to avoid overdiagnosis and to ensure that diagnostic test development is performed on appropriate samples. When diagnostic testing is available, as is now the case for PWS, diagnostic criteria should serve to raise diagnostic suspicion, ensure that all appropriate people are tested, and avoid the expense of testing unnecessarily. Our results indicate that the sensitivities of most of the published criteria are acceptable. However, 16.7% of patients with molecular diagnosis did not meet the 1993 clinical diagnostic criteria retrospectively, suggesting that the published criteria may be too exclusive. A less strict scoring system may ensure that all appropriate people are tested. Accordingly, we suggest revised clinical criteria to help identify the appropriate patients for DNA testing for PWS. The suggested age groupings are based on characteristic phases of the natural history of PWS. Some of the features (eg, neonatal hypotonia, feeding problems in infancy) serve to diagnose the syndrome in the first few years of life, whereas others (eg, excessive eating) are useful during early childhood. Similarly, hypogonadism is most useful during and after adolescence. Some of the features like neonatal hypotonia and infantile feeding problems are less likely to be missed, whereas others such as characteristic facial features and hypogonadism (especially in prepubertal females) may require more careful and/or expert examination. The issue of who should have diagnostic testing is distinct from the determination of features among confirmed patients. Based on the sensitivities of the published criteria and our experience, we suggest testing all newborns/infants with otherwise unexplained hypotonia with poor suck. For children between 2 and 6 years of age, we consider hypotonia with history of poor suck associated with global developmental delay sufficient criteria to prompt testing. Between 6 and 12 years of age, we suggest testing those with hypotonia (or history of hypotonia with poor suck), global developmental delay, and excessive eating with central obesity (if uncontrolled). At the ages of 13 years and above, we recommend testing patients with cognitive impairment, excessive eating with central obesity (if uncontrolled), and hypogonadotropic hypogonadism and/or typical behavior problems (including temper tantrums and obsessive-compulsive features). Thus, we propose a lower threshold to prompt diagnostic DNA testing, leading to a higher likelihood of diagnosis of this disorder in which anticipatory guidance and intervention can significantly influence outcome.

The genetic disorder Prader-Willi syndrome (PWS) is mainly caused by the loss of multiple paternally expressed genes in chromosome 15q11-q13 (the PWS region). Early diagnosis of PWS is essential for timely treatment, leading to effectively easing some clinical symptoms. Molecular approaches for PWS diagnosis at the DNA level are available, but the diagnosis of PWS at the RNA level has been limited. Here, we show that a cluster of paternally transcribed snoRNA-ended long noncoding RNAs (sno-lncRNAs, sno-lncRNA1–5) derived from the SNORD116 locus in the PWS region can serve as diagnostic markers. In particular, quantification analysis has revealed that 6,000 copies of sno-lncRNA3 are present in 1 μL whole blood samples from non-PWS individuals. sno-lncRNA3 is absent in all examined whole blood samples of 8 PWS individuals compared to 42 non-PWS individuals and dried blood samples of 35 PWS individuals compared to 24 non-PWS individuals. Further developing a new CRISPR-MhdCas13c system for RNA detection with a sensitivity of 10 molecules per μL has ensured sno-lncRNA3 detection in non-PWS, but not PWS individuals. Together, we suggest that the absence of sno-lncRNA3 represents a potential marker for PWS diagnosis that can be detected by both RT-qPCR and CRISPR-MhdCas13c systems with only microlitre amount of blood samples. Such an RNA-based sensitive and convenient approach may facilitate the early detection of PWS.

Prader Willi syndrome (PWS) is a genetic condition caused by loss of the paternal copy of a region of imprinted genes on chromosome 15. There is severe muscular hypotonia in...

In developing countries, breast-feeding is both the cornerstone of child survival and the cause of about one-third of all infant HIV infections. Moreover, the same economic and development inequities that make breast-feeding so critical to infant survival in these settings also make formula feeding inaccessible, unfeasible, unaffordable, unsustainable, and unsafe (ie, not AFASS) for most families. This poignant dilemma has resulted in emotive and sometimes polarizing debate within the public health community as we have wrestled to quantify these competing risks, test interventions to reduce them, and modify policy as our understanding improves. Four articles in this issue of the Journalof Acquired Immune Deficiency Syndromes shed new light on this issue.1-4 To appreciate their design and findings, it is helpful to contextualize them within the rapidly evolving science and policy of HIV and infant feeding. HIV AND INFANT FEEDING: 1985-2000 Following the first reported case of breast-feeding-associated HIV transmission in 1985,5 Joint United Nations Programme on HIV/AIDS, United Nations Children's Fund, and World Health Organization (WHO) jointly published divergent infant feeding guidance for HIV-infected women in developing and developed countries in 19876 and 19927 recommending that “where the primary causes of infant deaths are infectious diseases and malnutrition” (ie, developing countries) all women should breast-feed-including those known to be HIV positive, but “where infectious diseases are not the primary cause of infant death” (ie, developed countries) HIV-positive women should avoid all breast-feeding. Between 1994 and 1997, data from 4 cohort studies of HIV-exposed breast-fed and non-breast-fed infants estimated that breast-feeding resulted in a 4%-22% excess transmission risk.8-11 As a result, United Nations' (UN) agencies issued revised guidance in 1998, acknowledging the substantial HIV infection risk associated with breast-feeding and recommending that “when children born to women living with HIV can be ensured uninterrupted access to a nutritionally adequate breast milk substitutes that are safely prepared and fed to them, they are at less risk of illness and death if they are not breast-fed.”12 In 2000, publication of findings from Kenya of the first randomized trial of breast versus formula feeding affirmed the 1998 UN guidance: HIV-infection-free survival at 24 months was significantly higher among HIV-exposed infants randomized to formula feeding compared with breast-feeding (70% versus 58%).13 Also published in 2000 was a WHO-commissioned pooled analysis of data from 6 developing countries on the effect of breast-feeding on mortality.14 This analysis demonstrated that the odds of infant death due to not breast-feeding rapidly declines with age, especially after 6 months: 5.8 [95% confidence interval (CI): 3.4-9.8] among infants under 2 months of age; 2.6 (95% CI: 1.6-3.9) among infants aged 4-5 months; 1.8 (95% CI: 1.2-2.8) among infants 6-8 months of age; 1.4 (95% CI: 0.8-2.6) among infants 9-11 months of age; and 1.6 (95% CI: 0.8-3.2) to 2.1 (95% CI: 1.1-4.0) during the second year of life. Finally, in 1999, the first evidence that exclusive breast-feeding carries a lower risk of postnatal transmission compared with mixed feeding was published.15 Accordingly, when the joint UN agencies updated HIV and infant feeding policy in October 2000, the authors reiterated the previous recommendation that HIV-infected mothers avoid all breast-feeding when an AFASS replacement feeding was available, but added “otherwise, exclusive breast-feeding is recommended during the first months of life.” The committee also added a specific recommendation that mothers who lack an AFASS alternative and initiate breast-feeding should discontinue breast-feeding “as soon as feasible.” It was hoped that this guidance would provide an optimal compromise, maximizing breast-feeding benefit while minimizing HIV transmission risk. The guidance did not specify an age for breast-feeding cessation; stated that the local circumstances, the individual woman's situation, and the risks of replacement feeding should be considered; and urged that specific guidance be given to mothers who replacement feed. However, this new guidance was widely interpreted as recommending that all HIV-positive mothers stop breast-feeding by 6 months and implementation of this policy was not always accompanied by effective nutrition counseling. Data reported in the 4 articles in this issue were collected when this “early breast-feeding cessation policy” was in place: Onyango-Makumbi et al4 (Kampala, Uganda) compare rates of serious gastroenteritis (GE) and mortality among HIV-exposed but uninfected infants enrolled in the HIV Network for Prevention Trials (HIVNET) 012 and HIV Immunoglobulin (HIVIGLOB) studies conducted before and after, respectively, early breast-feeding cessation policy was in place. Importantly, in both this study and the next one by Kafulafula et al, infants who became HIV-infected were censored from the analysis. Median duration of breast-feeding was 4.0 months in HIVNET 012 and 9.3 months in HIVIGLOB. Rates of serious GE were significantly higher in HIVIGLOB compared with HIVNET 012 (8.0 versus 3.1/1000 child-months [c-m]), and overall mortality was 50% higher, although did not reach statistical significance (3.2 versus 2.0 deaths/1000 c-m). Kafulafula et al3 (Malawi) compare GE and mortality rates among exposed but uninfected infants enrolled in the Nevirapine/AZT studies (NVAZ) and Post Exposure Prophylaxis for Infants (PEPI) studies, conducted before and after, respectively, early breast-feeding cessation policy was in place. At 9 months, 89% of NVAZ infants and 10% of PEPI infants were still breast-feeding. Rates of GE hospitalization between 7 and 12 months (2.28% versus 0.13%), GE mortality by 12 months (24 versus 12 deaths/1000 c-m), and total infant mortality (79 versus 67 deaths/1000 c-m) were all significantly higher among PEPI compared with NVAZ infants. Homsy et al2 (Tororo, Uganda) report findings from a cohort of 102 infants born to HIV-positive women receiving highly active antiretroviral therapy (HAART) treatment. Mothers were advised to stop breast-feeding between 3 and 6 months; median breast-feeding duration was 5 months. By 18 months, none of the infants had tested HIV positive but 23 (19%) had died. Mortality was 6.2 (95% CI: 1.4-27.0) times higher among infants breast-fed less than 6 months compared with longer than 6 months. Creek et al1 (Botswana) present investigation findings of a diarrhea outbreak that occurred in Botswana in early 2006 when free formula was being provided to HIV-positive women and early breast-feeding cessation was common among HIV-negative women. Among 153 children hospitalized for diarrhea, 88% were not breast-feeding; 64% and 18% were HIV exposed and infected, respectively. Of the 33 of the children (22%) who died, only 1 was breast-fed (a 1-month old who was also receiving cow milk and formula). Therefore, HIV infection was not associated with death. Major Implications of These Articles These articles demonstrate that in these settings, provision of feeding interventions for HIV-exposed infants focused only during the first few months of life is not long enough; breast-feeding continues to provide substantial protective benefits against GE and mortality into the second year of life. Interventions provided by the studies to reduce risks associated with replacement feeding may have reduced them, but did not prevent them. These included infant cotramoxazole, point-of-use water treatment, free formula and complementary food, intensive nutrition education, and free clinical care. One intervention not offered by any of these studies was a toilet. Poor sanitation may cause chronic tropical enteropathy, which may be a major cause of undernutrition and poor health for all infants16 but especially for those not breast-fed.17 Toilets may be particularly important for HIV-exposed non-breast-fed infants; in the MASHI (meaning “milk” in Setswana) study, only 3 factors were retained in a multivariate model, explaining 24-month mortality of HIV-exposed infants who were not breast-fed after 6 months: infant HIV status, birth weight, and whether the family had a latrine or not.18 Sadly, Africa, where most HIV-exposed children live, is also the only region in the world projected to have substantially more people without adequate sanitation in 2015 than in 2005.19 Ventilated lined pit latrines provide excellent sanitation for a family for up to 20 years (while also minimizing odor and flies) and can be built for <US $50. The Homsy article,2 together with other recently presented data from the Breastfeeding, Antiretroviral, and Nutrition Study (BAN),20 Kesho Bora,21 and Mma Bara (meaning “mother baby” in Setswana),22 studies, presents the very good news that maternal HAART, whether given for maternal treatment or postnatal transmission prophylaxis, reduces breast-feeding-associated transmission to low rates. Furthermore, based on results from Mitra,23 six-week extended dose nevirapine (SWEN),24 BAN,20 and PEPI,25 antiretroviral prophylaxis given to the breast-feeding infant provides comparable protection. Preliminary data from these studies also suggest that these regimens are safe. How long these drug interventions could or should be provided to infants or to women who are not on HAART for their own health remains to be determined based on risk to benefit and cost to benefit analyses. In this regard, it is relevant to note that the protective effect of breast-feeding on mortality in the WHO pooled analysis was similar for children 6-12 months and 12-24 months of age, suggesting that these interventions are likely to provide benefit (in addition to possible risk and certain cost) for the first 2 years of life. Another alternative that may extend safer breast-feeding after discontinuing drug prophylaxis is expressing and heat treating breast milk.26 This intervention may be easier to implement after 6 months when lactation is well established, infants can drink from a cup more easily, and milk comprises proportionately less of the infant's total diet. In addition to the short-term harm reported in these articles, early breast-feeding cessation may also engender longer term adverse effects. In the Zambian Exclusive Breastfeeding Study (ZEBS) study, which randomized infants at 4 months to continued breast-feeding or abrupt breast-feeding cessation, early cessation was associated with ∼ a 0.25 lower mean weight-for-age Z-score among 9-15 month infants,27 a difference associated with about a 10% greater under-5-year mortality rate in non-HIV-exposed infants.28 This risk may be even greater among HIV-exposed infants if the effects of growth faltering and HIV exposure (eg, sick or dead parents) are synergistic. There is one crucial issue not addressed in these reports: none present sufficient data to assess the balance of risks; all demonstrate that the risks of illness and death associated with not breast-feeding are high but none assess whether these rates exceed the HIV transmission rates that would have occurred had the mothers in HIVIGLOB, PEPI, and Tororo Uganda continued breast-feeding or had HIV-positive mothers in Botswana been breast-feeding during the diarrhea outbreak. Postnatal transmission data are not yet available for HIVIGLOB4 but have been published for NVAZ 29 and PEPI.25 Estimating this balance of risks must be circumspect because the cohorts were not concurrent and many differences could have influenced infection-free survival besides the drug intervention and breast-feeding duration. Nonetheless, although postnatal transmission was lower in PEPI than in NVAZ (3.5% versus 5.7% at 9 months3 and ∼8%25 versus 9.68%29 at 24 months), infection-free survival at 24 months among infants who were HIV polymerase chain reaction negative at 6 weeks was lower: ∼83% in all 3 PEPI arms25 (estimating from graphs in the article) compared with 87.4%29 in the NVAZ studies, suggesting that early breast-feeding cessation may have resulted in net harm. 2006 HIV AND INFANT FEEDING POLICY In October 2006, when HIV and infant feeding policy was again revised; new evidence included an additional evidence that early exclusive breast-feeding is protective against postnatal transmission compared with mixed feeding,30,31 findings from 2 randomized trials in which infection-free survival was comparable between infants randomized to formula or breast-feeding from birth (MASHI32) and between infants randomized at 4 months of age to continued breast-feeding or abrupt breast-feeding cessation (ZEBS33); and preliminary findings from the 4 studies published in this issue of the Journal of Acquired Immune Deficiency Syndromes. Reflecting these new data, the 2000 policy which had stated, “When replacement feeding is AFASS, avoidance of all breastfeeding by HIV-infected mothers is recommended… Otherwise, exclusive breastfeeding is recommended during the first months of life,” was rewritten to read “Exclusive breastfeeding is recommended for HIV-infected women for the first six months of life unless replacement feeding is AFASS for them…. When replacement feeding is AFASS, avoidance of all breastfeeding by HIV-infected women is recommended.” The 2006 guidance also specified that breast-feeding should continue beyond 6 months if a replacement feeding is still not AFASS. Thus, even though replacement feeding remains the best option for HIV-infected women in situations with plentiful nutritious foods and breastmilk substitutes, good sanitation, clean water, cooking fuel, accessible quality health care delivered by a well-functioning health care system, high levels of female education, low rates of underlying infant mortality, and broad social support; and even though there are examples of successful replacement feeding in Africa,34-36 this subtle shift (in nuance more than substance) in the recommendations reflected the participants' sentiments that: For the large majority of HIV-exposed infants, avoidance of breast-feeding will not improve infection-free survival and may reduce it. For the large majority of HIV-exposed infants, exclusive breast-feeding for the first 6 months of life, and continued breast-feeding after that for some yet undetermined duration, will provide the greatest chance of infection-free survival. Ironically, the HIV epidemic may be the best thing that ever happened to breast-feeding. It is difficult to imagine an experiment that could provide more compelling momentum for breast-feeding promotion than the natural one the HIV epidemic has provided: an incurable disease that infects up to 30%-40% of antenatal women in some African countries and is transmitted to infants through breast-feeding leads UN agencies and governments to promote and even freely provide formula for exposed infants. Moreover, scores of these infants are already under surveillance by scientists measuring and documenting numerous indices of infant health. In short, the HIV epidemic and our efforts to ameliorate its effect on children provided an ethical opportunity to observe what happens when large number of infants living in conditions of poverty are not breast-fed. If these observations lead to stronger breast-feeding policy and programming that in turn reduce the 1.4 million child deaths occurring each year due to suboptimal breast-feeding,37 we will have created one of the epidemic's very few silver linings.

High plasma ghrelin levels have been reported in Prader-Willi syndrome (PWS). However, little is known about plasma ghrelin in these children during the first years of life characterized by a failure to thrive. The objective of the study was to investigate total plasma ghrelin levels in children with PWS and controls from 2 months to 17 years. Forty children with PWS [24 boys, 16 girls, median age 3.6 yr, median body mass index (BMI) Z-score 0.3] were compared with 84 controls (57 boys, 27 girls, median age 4.2 yr median BMI Z-score 0.1). Children were then divided into two groups according to age and GH treatment. Median plasma ghrelin levels were significantly higher in children with PWS, compared with controls at any age (568 vs. 173, P < 0.0001) and decreased with age in both groups (P < 0.0001). In the whole group of PWS, we found an inverse relationship between ghrelin and BMI Z-score, insulin, homeostasis model assessment insulin resistance index, leptin, and lean mass. Plasma ghrelin levels were higher in children with PWS than controls, both in the youngest children below 3 yr who were not receiving GH (771 vs. 233, P < 0.0001) and in the children older than 3 yr, all of whom were treated with GH (428 vs. 159, P < 0.0001). Plasma ghrelin levels in children with PWS are elevated at any age, including during the first years of life, thus preceding the development of obesity.

Prader-Willi syndrome (PWS) is a complex genetic condition, affecting between 1:10,000 and 1:30,000. The prevalence of hip dysplasia in children with PWS is reportedly between 8% and 30%, but the long-term consequences of residual hip dysplasia remain largely unknown in this population. The purpose of this study was to comparatively estimate the number of total hip arthroplasty (THA) and total knee arthroplasty (TKA) procedures performed on adults with and without PWS, using a national hospital discharge database, in an effort to elucidate long-term outcomes and guide clinicians treating orthopaedic concerns in younger individuals with PWS. The National Inpatient Sample of the Healthcare Cost and Utilization Project is the largest all-payer inpatient care database, containing annual data from >7 million hospital stays; sampling weights and stratification variables are provided for producing estimates of >35 million hospitalizations nationwide. THA and TKA procedures were identified, then stratified by whether or not the patient had a diagnosis of PWS. The ages of the 2 groups and sex mix were compared, as was the length of stay for the procedure, and discharge status. From 2004 to 2014, 9.4 million patients nationwide, by weighted estimate, underwent THA (3.1 million) or TKA (6.3 million). Sixty-five patients were identified as having the diagnosis of PWS (39 with THA, 26 with TKA); 7 patients per million having hip or knee arthroplasties had PWS. Sixty-eight percent of those with PWS were younger than 50 years, compared with only 7% of those without PWS (P<0.001). The female:male prevalence was 47:53 for patients with PWS and 60:40 for the total group. The mean length of stay was similar, but patients with PWS were more likely to be transferred to another facility after surgery (77% vs. 36%; P=0.008). Hip dysplasia prevalence is higher in persons with PWS, but the rate of late treatment with THA is much lower than in the general population. We recommend only active observation for stable and improving hips in young children with PWS, as the consequences of overtreatment can be serious, including further delaying their neuromuscular development, and exposure to possibly unnecessary perioperative risks. Nation-wide database analysis, Level IV.

During the neonatal period the diagnosis of the Prader-Willi syndrome (PWS) is difficult because the syndrome is expressed mainly by severe hypotonia at this age and the typical clinical features of later life are not yet present. To identify all the PWS clinical markers in severe hypotonic newborns, which could facilitate an early diagnosis of the syndrome. Twenty-one PWS newborns (14 males and 7 females) with severe hypotonia at birth were evaluated. Paediatricians skilled in syndromology carried out a careful clinical examination. Fluorescent in situ hybridization (FISH) analysis and/or a methylation test was used to confirm the PWS clinical diagnosis. The clinical diagnosis of PWS was reached at a mean age of 7.4 mo with genetic confirmation at 11 mo of life. In 12 newborns at least 3 craniofacial features were present (57%), suggesting the diagnosis of PWS. Two craniofacial dysmorphic characteristics were described in 6 newborns and only 1 in 3 cases. Cryptorchidism was monolateral in 6 and bilateral in 7 patients; in one newborn both testes were in scrotum. A micropenis was described in one patient and hypoplasia of the labia minora was reported in two females. Diagnosis by means of dysmorphologic evaluation is difficult in the neonatal period. The presence of severe hypotonia should always induce neonatologists to perform specific genetic tests in order to obtain an early diagnosis of PWS.

During the neonatal period the diagnosis of the Prader‐Willi syndrome (PWS) is difficult because the syndrome is expressed mainly by severe hypotonia at this age and the typical clinical features of later life are not yet present. Aim: To identify all the PWS clinical markers in severe hypotonic newborns, which could facilitate an early diagnosis of the syndrome. Methods: Twenty‐one PWS newborns (14 males and 7 females) with severe hypotonia at birth were evaluated. Paediatricians skilled in syndromology carried out a careful clinical examination. Fluorescent in situ hybridization (FISH) analysis and/or a methylation test was used to confirm the PWS clinical diagnosis. Results: The clinical diagnosis of PWS was reached at a mean age of 7.4 mo with genetic confirmation at 11 mo of life. In 12 newborns at least 3 craniofacial features were present (57%), suggesting the diagnosis of PWS. Two craniofacial dysmorphic characteristics were described in 6 newborns and only 1 in 3 cases. Cryptorchidism was monolateral in 6 and bilateral in 7 patients; in one newborn both testes were in scrotum. A micropenis was described in one patient and hypoplasia of the labia minora was reported in two females. Conclusions: Diagnosis by means of dysmorphologic evaluation is difficult in the neonatal period. The presence of severe hypotonia should always induce neonatologists to perform specific genetic tests in order to obtain an early diagnosis of PWS.

Prader-Willi syndrome (PWS) is a complex multisystem genetic disorder that is caused by the lack of expression of paternally inherited imprinted genes on chromosome 15q11-q13. This syndrome has a characteristic phenotype including severe neonatal hypotonia, early-onset hyperphagia, development of morbid obesity, short stature, hypogonadism, learning disabilities, behavioral problems, and psychiatric problems. PWS is an example of a genetic condition caused by genomic imprinting. It can occur via 3 main mechanisms that lead to the absence of expression of paternally inherited genes in the 15q11.2-q13 region: paternal microdeletion, maternal uniparental disomy, and an imprinting defect. Over 99% of PWS cases can be diagnosed using DNA methylation analysis. Early diagnosis of PWS is important for effective long-term management. Growth hormone (GH) treatment improves the growth, physical phenotype, and body composition of patients with PWS. In recent years, GH treatment in infants has been shown to have beneficial effects on the growth and neurological development of patients diagnosed during infancy. There is a clear need for an integrated multidisciplinary approach to facilitate early diagnosis and optimize management to improve quality of life, prevent complications, and prolong life expectancy in patients with PWS.

IntroductionSleep abnormalities are recognized complications of Prader-Willi Syndrome (PWS). The prevalence of sleep disorders has varied across studies with a reported range of OSA from 44% to 100%.1 In prvious...