Disengagement of somatostatin neurons from lateral septum circuitry by oxytocin and vasopressin restores social-fear extinction and suppresses aggression outbursts in Prader-Willi syndrome model.

Background: Responding to social signals by expressing the correct behavior is not only challenged in autism, but also in diseases with high prevalence of autism, like Prader-Willi Syndrome (PWS). Clinical evidence suggests aberrant pro-social behavior in patients can be regulated by intranasal oxytocin (OXT) or vasopressin (AVP). However, what neuronal mechanisms underlie impaired behavioral responses in a socially-aversive context, and how can they be corrected, remains largely unknown. Methods: Using the Magel2 knocked-out (KO) mouse model of PWS (crossed with CRE-dependent transgenic lines), we devised optogenetic, physiological and pharmacological strategies in a social-fear-conditioning paradigm. Pathway specific roles of OXT and AVP signaling were investigated converging on the lateral septum (LS), a region which receives dense hypothalamic inputs. Results: OXT and AVP signaling promoted inhibitory synaptic transmission in the LS, which failure in Magel2KO mice disinhibited somatostatin (SST) neurons and disrupted social-fear extinction. The source of OXT and AVP deficits mapped specifically in the supraoptic nucleus→LS pathway of Magel2KO mice disrupting social-fear extinction, which could be corrected by optogenetic or pharmacological inhibition of SST-neurons in the LS. Interestingly, LS SST-neurons also gated the expression of aggressive behavior, possibly as part of functional units operating beyond local septal circuits. Conclusions: SST cells in the LS play a crucial role in integration and expression of disrupted neuropeptide signals in autism, thereby altering the balance in expression of safety versus fear. Our results uncover novel mechanisms underlying dysfunction in a socially-aversive context, and provides a new framework for future treatments in autism-spectrum disorders.

Should we routinely assess hypothalamic-pituitary-adrenal axis in pediatric patients with Prader-Willi syndrome?

Background: It has been reported that central adrenal insufficiency (CAI) in pediatric patients (pts) with Prader-Willi syndrome (PWS) may be a potential cause of their sudden death. In addition, the risk of CAI may increase during treatment with recombinant human growth hormone (rhGH). Objective: To prevent both over- and undertreatment with hydrocortisone, we evaluated the prevalence of CAI in a large multicenter cohort of pediatric pts with PWS analyzing adrenal response in the low-dose ACTH test (LDAT) and/or the glucagon stimulation test (GST) and reviewing the literature. Methods: A total of 46 pts with PWS were enrolled to the study, including 34 treated with rhGH with a median dose of 0.21 mg/kg/week. LDAT was performed in 46 pts, and GST was carried out in 13 pts. Both tests were conducted in 11 pts. The tests began at 8:00 a.m. Hormones were measured by radioimmunoassays. Serum cortisol response >181.2 ng/mL (500 nmol/L) in LDAT and >199.3 ng/mL (550 nmol/L) in GST was considered a normal response. Additionally, cortisol response delta (the difference between baseline and baseline) >90 ng/mL and doubling/tripling of baseline cortisol were considered indicators of normal adrenal reserve. Results: Three GSTs were not diagnostic (no hypoglycemia obtained). LDAT results suggested CAI in four pts, but in two out of four pts, and CAI was excluded in GST. GST results suggested CAI in only one patient, but it was excluded in LDAT. Therefore, CAI was diagnosed in 2/46 pts (4.3%), 1 treated and 1 untreated with rhGH, with the highest cortisol values of 162 and 175 ng/dL, but only in one test. However, in one of them, the cortisol delta response was >90 ng/mL and peak cortisol was more than tripled from baseline. Finally, CAI was diagnosed in one patient treated with rhGH (2.2%). Conclusion: We present low prevalence of CAI in pediatric pts with PWS according to the latest literature. Therefore, we do not recommend to routinely screen the function of the hypothalamic-pituitary-adrenal axis (HPAA) in all pts with PWS, both treated and untreated with rhGH. According to a review of the literature, signs and symptoms or low morning ACTH levels suggestive of CAI require urgent and appropriate diagnosis of HPAA by stimulation test. Our data indicate that the diagnosis of CAI should be confirmed by at least two tests to prevent overtreatment with hydrocortisone.

Psychiatric care for people with Prader-Willi syndrome-characteristics, needs and barriers.

BACKGROUND: Prader-Willi syndrome (PWS) is commonly associated with intellectual disability, but also with a specific behavioural phenotype and a high predisposition to psychiatric comorbidity. This study examines the psychiatric care situation of people with PWS. METHOD: A structured online questionnaire was administered to carers of people with PWS living in Germany, asking about demographic, diagnostic and treatment parameters as well as personal experiences. RESULTS: Of 77 people with PWS, 44.2% had at least one psychiatric comorbid diagnosis. The main reasons for seeking psychiatric care were emotional outbursts and aggressive behaviour. 34.9% reported that they were currently seeking psychiatric care without success. However, 32.5% of PWS had been treated with psychotropic medication, mainly antipsychotics. CONCLUSIONS: Psychiatric comorbidity appears to be undertreated in PWS, especially in the ambulatory setting. Uncertainty among mental health care providers may also lead to frequent off-label use of psychotropic medications.

Prostate-specific antigen (PSA) levels in men with Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is a rare genetic disorder typically characterized by body composition abnormalities, hyperphagia, behavioral challenges, cognitive dysfunction, and hormone deficiencies. Hypogonadism is common but knowledge on potential side effects of testosterone replacement is limited, in particular, the long-term effects on behavior and PSA. PATIENTS AND METHODS: Retrospective case studies of seven men, median age 46 years, with genetically verified PWS, testosterone treated hypogonadism and available PSA values were included. Long-term follow-up of PSA was accessible in four patients. Medical records were reviewed for adverse effects. RESULTS: Five men were treated with intramuscular testosterone undecanoate, two had no hypogonadism. Median PSA was 0.68 µg/L (0.23-1.3), median testosterone 15 nmol/L. After a median time of 17 years of testosterone replacement median PSA was 0.75 µg/L (range 0.46-1.4). Testosterone replacement was well tolerated, and no major behavioral changes were reported. Five were treated with growth hormone for >20 years. CONCLUSION: Levels of PSA were low. Long-term treatment with testosterone was working well and did not result in any clinically meaningful increase in PSA. Our results indicate that testosterone replacement is neither associated with serious adverse events regarding changes in behavior or effect on PSA. However, larger studies are needed to confirm our results.

Behavioral changes in patients with Prader-Willi syndrome receiving diazoxide choline extended-release tablets compared to the PATH for PWS natural history study.

BACKGROUND: Prader-Willi syndrome (PWS) is a rare neurobehavioral-metabolic disease caused by the lack of paternally expressed genes in the chromosome 15q11-q13 region, characterized by hypotonia, neurocognitive problems, behavioral difficulties, endocrinopathies, and hyperphagia resulting in severe obesity if energy intake is not controlled. Diazoxide choline extended-release (DCCR) tablets have previously been evaluated for their effects on hyperphagia and other behavioral complications of people with PWS in a Phase 3 placebo-controlled study of participants with PWS, age 4 and older with hyperphagia (C601) and in an open label extension study, C602. METHODS: To better understand the longer-term impact of DCCR, a cohort from PATH for PWS, a natural history study that enrolled participants with PWS age 5 and older, who met the C601 age, weight and baseline hyperphagia inclusion criteria and had 2 hyperphagia assessments ≥ 6 months apart, were compared to the C601/C602 cohort. Hyperphagia was measured using the Hyperphagia Questionnaire for Clinical Trials (HQ-CT, range 0-36). The primary analysis used observed values with no explicit imputation of missing data. A sensitivity analysis was conducted in which all missing HQ-CT assessments in the C601/C602 cohort were assigned the highest possible value (36), representing the worst-case scenario. Other behavioral changes were assessed using the Prader-Willi Syndrome Profile questionnaire (PWSP). RESULTS: Relative to the PATH for PWS natural history study cohort, the DCCR-treated C601/C602 cohort showed significant improvements in HQ-CT score at 26 weeks (LSmean [SE] -8.3 [0.75] vs. -2.5 [0.43], p < 0.001) and 52 weeks (LSmean [SE] -9.2 [0.77] vs. -3.4 [0.47], p < 0.001). The comparison between the cohorts remained significant in the worst-case imputation sensitivity analysis. There were also significant improvements in all domains of the PWSP at 26 weeks (all p < 0.001) and 52 weeks (all p ≤ 0.003) for C601/C602 participants compared to the PATH for PWS participants. CONCLUSION: Long-term administration of DCCR to people with PWS resulted in changes in hyperphagia and other behavioral complications of PWS that are distinct from the natural history of the syndrome as exemplified by the cohort from PATH for PWS. The combined effects of administration of DCCR should reduce the burden of the syndrome on the patient, caregivers and their families, and thereby may benefit people with PWS and their families. TRIAL REGISTRATION: Clinical study C601 was originally registered on ClinicalTrials.gov on February 22, 2018 (NCT03440814). Clinical study C602 was originally registered on ClinicalTrials.gov on October 22, 2018 (NCT03714373). PATH for PWS was originally registered on ClinicalTrials.gov on October 24, 2018 (NCT03718416).

Pharmacogenomics for Prader-Willi syndrome: caregiver interest and planned utilization.

Aim: The study aim was to determine caregiver interest and planned utilization of pharmacogenomic (PGx) results for their child with Prader-Willi syndrome. Methods: Caregivers consented to PGx testing for their child and completed a survey before receiving results. Results: Of all caregivers (n = 48), 93.8% were highly interested in their child's upcoming PGx results. Most (97.9%) planned to share results with their child's medical providers. However, only 47.9% of caregivers were confident providers would utilize the PGx results. Conclusion: Caregivers are interested in utilizing PGx but are uncertain providers will use these results in their child's care. More information about provider comfort with PGx utilization is needed to understand how PGx education would benefit providers and ultimately patients with PGx results.

Effect of semaglutide on weight loss and glycaemic control in patients with Prader-Willi Syndrome and type 2 diabetes.

Prader-Willi Syndrome (PWS) is the most common genetic cause of obesity, occurring in approximately 1 in 15,000 newborns. It results from the lack of expression of genes on the paternal allele of the chromosomal region 15q-11q13 (65-75% due to type 1 or type 2 deletion). Individuals with PWS experience associated symptoms such as hypotonia, hyperphagia, and early-onset obesity (before 5 years of age). Around 20% of adults with PWS also develop type 2 diabetes. Previous studies have shown the beneficial effects of GLP1-RA medications, such as exenatide and liraglutide, in treating type 2 diabetes in PWS. However, there is limited information available on the use of semaglutide in PWS. This study aimed to evaluate the effects of semaglutide on weight loss and glycaemic control in four patients with PWS and type 2 diabetes associated with obesity. The patients were started on weekly subcutaneous progressive doses of semaglutide.

Orthopedic manifestations in children with Prader-Willi syndrome.

BACKGROUND: Prader-Willi syndrome (PWS) is a rare genetic disease often associated with bone problems, mainly scoliosis and hip dysplasia (HD). This study aimed to analyze the clinical characteristics of orthopedic deformities in patients with PWS. METHODS: A retrospective study was conducted on 175 patients up to March 2023. The Cobb angle(CA) of the spine, the alpha angle of the hip joint, and the acetabular index (AI) were measured. This study aimed to evaluate the relationship between demographic parameters and bone deformities. RESULTS: Scoliosis was found in 66 patients (43.7%), including 52 (78.8%) with mild scoliosis, 10 (15.2%) with moderate scoliosis, and 4 (6.1%) with severe scoliosis. Only seven patients received orthopedic treatment (10.6%). The median age of scoliosis was 4.5 years old, and the prevalence of scoliosis increased rapidly at the age of 5 years and adolescence. The mean CA in this study increased gradually with age. HD was found in 47 patients (38.2%), and 6 patients received orthopedic treatment (12.7%). The median age at HD was 1.8 years old. The mean AI of the study population decreased with age. The prevalence of HD treated with recombinant human growth hormone (rhGH) was low. No significant differences were observed in sex, genotype, body mass index (BMI), obesity rate, or onset of scoliosis and HD. CONCLUSION: The prevalence of scoliosis and HD was higher in patients with PWS. The onset age and developmental trends of the different skeletal malformations were different. Early diagnosis and treatment are important for the prognosis and treatment of orthopedic diseases in patients with PWS.

Evaluating the effect of recombinant human growth hormone treatment on sleep-related breathing disorders in toddlers with Prader-Willi syndrome: a one-year retrospective cohort study.

BACKGROUND: Recombinant human growth hormone (rhGH) therapy is beneficial for children with Prader-Willi syndrome (PWS) in improving short stature and metabolism, but the effect of early rhGH treatment on respiratory and sleep parameters for PWS children under three years old remains elusive. Thus, this study aimed to investigate the impact of rhGH treatment on sleep-related breathing disorders (SRBDs) for toddlers with PWS. METHODS: A total of 17 age-matched PWS patients receiving rhGH treatment (rhGH group) and 17 control individuals not receiving rhGH treatment (non-rhGH group) were recruited for this study between October 2018 and January 2023. Data related to polysomnography-polygraphy (PSG) and serum levels of insulin-like growth factor (IGF-1) and insulin-like growth factor binding protein 3 (IGFBP-3) were collected. RESULTS: The mean age in the rhGH group was 20.76 ± 9.22 months, which was comparable to that of the non-rhGH group (25.23 ± 13.81 months). The demographic and anthropometric parameters were similar across the two groups after 52 weeks of treatment. Administration of rhGH to toddlers did not exert adverse effects on the obstructive apnea-hypopnea index (OAHI), central apnea index (CAI), oxygen desaturation index (ODI), mean percutaneous oxygen saturation (SpO2), lowest SpO2, duration when SpO2 is lower than 90%, or proportion of the patients with SpO2 lower than 90%. Furthermore, the increased IGF-1 z-score and IGFBP-3 level did not worsen SRBDs. CONCLUSION: Treatment with rhGH for 52 weeks on young toddlers with PWS showed no deleterious effects on SRBDs. This shed more light on the importance of initiating rhGH therapy early in PWS patients.

Schaaf-Yang Syndrome: Clinical Phenotype and Effects of 4 years of Growth Hormone Treatment.

INTRODUCTION: Schaaf-Yang syndrome (SYS) is a rare neurodevelopmental disorder caused by truncating mutations of the MAGEL2 gene, located in the Prader-Willi syndrome (PWS) region. PWS and SYS have phenotypic overlap. Patients with SYS are often treated with growth hormone (GH), but evidence for the effectiveness of the treatment in patients with SYS is limited. METHODS: This study describes 7 children with SYS. We studied their phenotype, genotype, and the effect of GH treatment on height and body mass index (BMI) during 4 years and on body composition during 1 year. RESULTS: All patients had a normal birth weight. Most patients had hypotonia and feeding difficulties after birth (86%). Full-scale IQ ranged from <50 to 92. All patients above the age of 2 years had psycho-behavioral problems. There were no apparent correlations between the phenotype and the location of the defect in the MAGEL2 gene. Mean (95% CI) height SDS increased significantly from -1.74 (-3.55; 0.07) at start to -0.05 (-1.87; 1.77) after 4 years of GH treatment. Mean (95% CI) BMI SDS decreased significantly from 2.01 (1.02; 3.00) to 1.22 (0.18; 2.26) after 6 months and remained the same during the rest of the follow-up. Fat mass percentage SDS decreased and lean body mass did not change during 1 year of treatment in 3 patients. CONCLUSION: Patients presented with a phenotype of hypotonia, respiratory insufficiency, and feeding difficulties after birth, endocrine disorders, intellectual disability, and behavioral problems. Treatment with GH significantly improved height SDS and BMI over the course of 4 years.

Diazoxide choline extended-release tablet in people with Prader-Willi syndrome: results from long-term open-label study.

OBJECTIVE: This study assessed the effect of 1-year administration of diazoxide choline extended-release tablet (DCCR) on hyperphagia and other complications of Prader-Willi syndrome (PWS). METHODS: The authors studied 125 participants with PWS, age ≥ 4 years, who were enrolled in the DESTINY PWS Phase 3 study and who received DCCR for up to 52 weeks in DESTINY PWS and/or its open-label extension. The primary efficacy endpoint was Hyperphagia Questionnaire for Clinical Trials (HQ-CT) score. Other endpoints included behavioral assessments, body composition, hormonal measures, and safety. RESULTS: DCCR administration resulted in significant improvements in HQ-CT (mean [SE] -9.9 [0.77], p < 0.0001) and greater improvements in those with more severe baseline hyperphagia (HQ-CT > 22). Improvements were seen in aggression, anxiety, and compulsivity (all p < 0.0001). There were reductions in leptin, insulin, and insulin resistance, as well as a significant increase in adiponectin (all p < 0.004). Lean body mass was increased (p < 0.0001). Disease severity was reduced as assessed by clinician and caregiver (both p < 0.0001). Common treatment-emergent adverse events included hypertrichosis, peripheral edema, and hyperglycemia. Adverse events infrequently resulted in discontinuation (7.2%). CONCLUSIONS: DCCR administration to people with PWS was well tolerated and associated with broad-ranging improvements in the syndrome. Sustained administration of DCCR has the potential to reduce disease severity and the burden of care for families.

Early psychomotor development and growth hormone therapy in children with Prader-Willi syndrome: a review.

Prader-Willi syndrome (PWS) is a rare genetic disorder caused by the loss of imprinted gene expression on the paternal chromosome 15q11-q13. PWS is characterized by varying degrees of early psychomotor developmental deficits, primarily in cognition, language, and motor development. This review summarizes the early mental cognitive development, language development, and motor development in patients with PWS, compares the correlation of genotype with phenotype, and provides an update regarding the effects and concerns related to potential main side effects of treatment with recombinant human growth hormone on early psycho-cognitive and motor function development along with the linear growth and body composition of children with PWS.Conclusion: Early psychomotor development is strongly correlated with the prognosis of patients with PWS; moreover, current studies support that the initiation of interventions at an early age can exert significant beneficial effects on enhancing the cognitive and linguistic development of patients with PWS and allow them to "catch up" with motor development.  What is Known: • Prader-Willi syndrome is a rare genetic disorder characterized by multisystem damage, and children with Prader-Willi syndrome are typically characterized by early developmental delays, specifically in the areas of cognitive and motor development. • Recombinant human growth hormone therapy is the only medical treatment approved for Prader-Willi syndrome. What is New: • Extensive presentation of psycho-cognitive and motor development features and genotype-phenotype correlation in children with Prader-Willi syndrome.  • The effects of growth hormone on early psychomotor development in children with Prader-Willi syndrome were thoroughly reviewed, including their short- and long-term outcomes and any associated adverse effects.

The outcomes of growth hormone therapy in the obstructive sleep apnea parameters of Prader-Willi syndrome patients: a systematic review.

PURPOSE: Prader-Willi syndrome is a serious genetic condition, capable of causing endocrinological imbalance, which has as one of its main treatments the growth hormone therapy. However, this therapy still causes some uncertainty concerning its effects on the respiratory parameters of those patients, especially in cases of obstructive sleep apnea, therefore, presenting a need for the analysis of the relationship between the therapy and the otolaryngologic condition. METHODS: A systematic review following the PRISMA model was developed, with searches for keywords made in the databases PubMed (MEDLINE), Scopus, and Web of Science and registration in the PROSPERO platform (CRD42023404250). RESULTS: Three randomized controlled trials were considered eligible for inclusion in the review. None of the studies demonstrated statistically significant modifications in the obstructive sleep apnea parameters of Prader-Willi patients related to the growth hormone administration. CONCLUSIONS: Growth hormone therapy is safe for Prader-Willi syndrome patients when analyzing their obstructive sleep apnea parameters.

Prevalence of Sleep-Disordered Breathing in Prader-Willi Syndrome.

Introduction: Sleep-disordered breathing (SDB) is common in patients with Prader-Willi Syndrome (PWS). However, the prevalence of SDB varies widely between studies. Early identification of SDB and factors contributing to its incidence is essential, particularly when considering growth hormone (GH) therapy. Objectives: The aims of the study were to describe the prevalence and phenotypes of sleep-disordered breathing (SDB) in patients with Prader-Willi syndrome (PWS) and to determine the effects of age, gender, symptoms, GH therapy and body mass index on SDB severity. Methods: This study was a retrospective chart review of all patients with genetically confirmed Prader-Willi syndrome who underwent diagnostic overnight polysomnography (PSG) in the sleep laboratory at Sidra Medicine. Clinical and PSG data of enrolled patients were collected. Results: We identified 20 patients (nine males, eleven females) with PWS who had overnight sleep polysomnography (PSG) at a median age (IQR) of 5.83 (2.7-12) years. The median apnea-hypopnea index (AHI) was 8.55 (IQR 5.8-16.9) events/hour. The median REM-AHI was 27.8 (IQR 15-50.6) events/hour. The median obstructive apnea-hypopnea index (OAHI) was 7.29 (IQR 1.8-13.5) events/hour. The median central apnea-hypopnea index (CAHI) was 1.77 (IQR 0.6-4.1) events/hour. Nineteen patients (95%) demonstrated SDB by polysomnography (PSG) based on AHI ≥1.5 events/hour. Nine patients (45%) were diagnosed with obstructive sleep apnea (OSA). Three patients (15%) were diagnosed with central sleep apnea (CSA). Seven patients (35%) were diagnosed with mixed sleep apnea. No correlations were observed between AHI and age, gender, BMI, symptoms, or GH therapy. However, REM-AHI was significantly correlated with BMI (P=0.031). Conclusion: This study shows a high prevalence of SDB among our patients with PWS. Obstructive sleep apnea was the predominant phenotype. BMI was the only predictor for high REM-AHI. Further studies of large cohorts are warranted to define SDB in PWS and design the appropriate treatment.

Cognitive function during 3 years of growth hormone in previously growth hormone-treated young adults with Prader-Willi syndrome.

CONTEXT: Most patients with Prader-Willi syndrome (PWS) have mild to moderate cognitive impairment. Growth hormone (GH) treatment has positive short- and long-term effects on cognition in children with PWS. Few studies, however, have investigated the effects of GH on cognitive functioning in adults with PWS. OBJECTIVE: To investigate the effects of 3 years of GH treatment on cognitive functioning and behavior in young adults with PWS who were treated with GH during childhood. DESIGN: Open-label, prospective study. SETTING: Dutch PWS Reference Center. METHODS: Patients were treated with 0.33 mg GH/m²/day (∼0.012 mg/kg/day; 33% of childhood dose). Cognitive functioning was measured by Wechsler Adult Intelligence (WAIS) tests. Behavior was studied by a developmental behavior checklist-parents/caregivers (DBC-P). RESULTS: Forty-six young adults with PWS with a median age of 19 (IQR 17-21) years were investigated. Estimated mean (95% CI) total, verbal, and performance IQ remained stable during 3 years of GH-treatment. Total IQ being 66 (63-69) at the start and 67 (64-71) after 3 years (P = .30); Verbal IQ being 65 (62-68) and 66 (62-70), respectively (P = .31) and performance IQ being 67 (63-70) and 67 (63-72) resp. (P = .42). Estimated mean Total DBC score did not significantly change during 3 years of GH-treatment, being 36.3 at start and 36.5 after 3 years (P = .94) (P50). CONCLUSIONS: Three years of GH-treatment in young adults with PWS with 33% of the pediatric dose, maintains total, verbal, and performance IQ. The emotional and behavioral disturbances remained stable and were similar compared to peers with other intellectual disabilities.

The Arduous Path to Drug Approval for the Management of Prader-Willi Syndrome: A Historical Perspective and Call to Action.

Prader-Willi syndrome (PWS) is a neuroendocrine genetic disorder resulting from the loss of paternally expressed imprinted genes in chromosome 15q11-q13 [...].

Effectiveness of a transdisciplinary approach on hyperphagia management among patients with Prader Willi syndrome.

BACKGROUND: One of the main characteristics of Prader Willi syndrome (PWS) is hyperphagia and obesity. This study sought to evaluate behaviours related to hyperphagia in individuals with PWS under a non-pharmacological transdisciplinary approach. METHODS: This observational study included PWS patients under a traditional non-pharmacological nutritional approach immersed within a regular transdisciplinary treatment (RTT) and a control group of PWS individuals without RTT. All individuals were evaluated using the Hyperphagia Questionnaire for Clinical Trials (HQ-CT). RESULTS: Forty-three individuals were evaluated. The mean age at baseline (treatment onset) was 18.4±8.3 years in the RTT group and 19.1±6.9 years in the control group (p=0.74). Hyperphagia-related behaviours were significantly lower among those under RTT (RTT 5.7±3.7 vs control 13.1±7.5, p<0.0001). This was also identified within the three categories: arguing or manipulating to obtain food (2.71±2.1 vs 5.41±3.2, p=0.003), sneaking food (1.33±1.5 vs 3.55±3.3, p=0.007), and anger or tantrums related to food (1.67±1.8 vs 4.09±2.7, p=0.001). After a mean treatment duration of 41.0 months, the RTT group had a reduction in body mass index (baseline 38.7±17.1kg/m2 vs follow-up 29.2±9.2kg/m2; p<0.0001). A significant association between RTT duration and BMI reduction (p=0.037) was identified. CONCLUSION: We observed a positive impact on behaviours related to hyperphagia and a BMI reduction in PWS individuals in a context of a non-pharmacological nutritional approach as part of an RTT.

Long-term effects of GH therapy in adult patients with Prader-Willi syndrome: a longitudinal study.

Introduction: Prader-Willi syndrome (PWS) is a complex disorder resulting from the failure of expression of paternal alleles in the PWS region of chromosome 15. The PWS phenotype resembles that observed in the classic non-PWS GH deficiency (GHD), including short stature, excessive fat mass, and reduced muscle mass. To date, a small number of studies on the long-term effects of GH treatment are available in adult subjects with PWS. Methods: In this longitudinal study, 12 obese subjects with PWS (GHD/non-GHD 6/6) were treated for a median of 17 years, with a median GH dose of 0.35 mg/day. The median age was 27.1 years. Anthropometric, body composition, hormonal, biochemical, and blood pressure variables were analyzed in all subjects. Results: Waist circumference was significantly lower at the end of the treatment period (p-value=0.0449), while body mass index (BMI) did not differ significantly. Compared to the baseline, a highly significant reduction of Fat Mass % (FM%) was observed (p-value=0.0005). IGF-I SDS values significantly increased during GH therapy (p-value=0.0005). A slight impairment of glucose homeostasis was observed after GH therapy, with an increase in the median fasting glucose levels, while insulin, HOMA-IR, and HbA1c values remained unchanged. Considering GH secretory status, both subjects with and without GHD showed a significant increase in IGF-I SDS and a reduction of FM% after GH therapy (p-value= 0.0313 for all). Discussion: Our results indicate that long-term GH treatment has beneficial effects on body composition and body fat distribution in adults with PWS associated with obesity. However, the increase in glucose values during GH therapy should be considered, and continuous surveillance of glucose metabolism is mandatory during long-term GH therapy, especially in subjects with obesity.

A rare occurrence of non-classic congenital adrenal hyperplasia and type 1 diabetes mellitus in a girl with Prader-Willi Syndrome: Case report and review of the literature.

Prader-Willi syndrome (PWS) is a rare genetic disorder resulting from lack of expression of the paternally derived chromosome 15q11-13, associated with several complications, including pubertal disorders, short stature, hyperphagia, obesity, glucose metabolism abnormalities, scoliosis, obstructive sleep apnea syndrome (OSAS) and behavioral problems. We report the case of a girl affected by PWS who presented at the age of 5.9 with premature pubarche, accelerated linear growth and advanced bone age (BA). She was subsequently diagnosed with non-classic congenital adrenal hyperplasia (CAH) confirmed by genetic analysis. Considering the clinical, biochemical, and genetic findings, hydrocortisone therapy was started to prevent rapid BA acceleration and severe compromission of final height. During infancy, short stature and low levels of insulin-like growth factor-1 (IGF-1) for age and gender led to suspicion of growth hormone deficiency (GHD), confirmed by stimulation testing (arginine and clonidine). rhGH therapy was administered and continued until final height was reached. During endocrinological follow up she developed impaired glucose tolerance with positive markers of ß-cell autoimmunity (anti-glutamic acid decarboxylase antibodies, GAD Ab), which evolved over time into type 1 diabetes mellitus and insulin therapy with a basal-bolus scheme and an appropriate diet were needed.