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Antonino Crinò,1Danilo Fintini,1 Sarah Bocchini,1 Chiara Carducci,1 Graziano Grugni,2 1Autoimmune Endocrine Diseases Unit, Bambino Gesù Children’s Hospital, Research Institute, Palidoro, Rome, 2Division of Auxology, Italian Auxological Institute, Research Institute, Piancavallo, Verbania, Italy Abstract: Prader–Willi syndrome (PWS) represents the most common form of genetic obesity. Thanks to the advances in medical care and technology, many persons with PWS live longer and survive to adulthood. Currently, because of the many physical and behavioral manifestations, transitional health care is not easy for these patients and is considered a very important issue. Moreover, very few studies have examined these transitional problems in young adults with PWS. In recent years, there has been great interest in improving transition planning and support for young people with PWS reaching adulthood. In this article, we underline the main clinical problems in transition and give some advice to make this period less difficult and easier for adolescents with PWS. Special attention should be paid to obesity, diabetes mellitus, hypertension, osteoporosis, and sleep apnea during the period of transition. In PWS, for an effective transition from childhood to adulthood, a multidisciplinary team is needed, and should maintain the same approach to food, environment, and psychiatric issues. For comprehensive care, it is necessary to involve adult endocrinologists and other medical specialists in conjunction with the pediatric team. Parental involvement is, however, a great help for supervising adolescents with PWS during this particular period. Keywords: Prader–Willi, transition period, intellectual disabilities

We tested the hypothesis that patients with Prader-Willi syndrome (PWS) may be at lower risk of developing non-alcoholic fatty liver disease (NAFLD) because of a higher insulin sensitivity. Twenty-one PWS patients and 42 control subjects closely similar for age, gender, pubertal stage and body mass index (CNT), were studied. Metabolic profile and body composition were assessed. NAFLD was established by a validated method of US grading (range from G0 to G3). PWS patients showed a significantly better metabolic profile (lower waist circumference, fasting glucose levels, HOMA-IR, cholesterol, transaminase levels and trunk fat mass/fat mass ratio). Furthermore, NAFLD G1stage was significantly more frequent in PWS subjects (P 0.05), whereas G2 stage was significantly more frequent in control patients (P 0.05). NAFLD grading seems to correlate with body composition in PWS, also after adjustment for sex and GH treatment. To our knowledge, this is the first report suggesting a reduced risk of NAFLD in PWS children.

Background: Influence of growth hormone on energy expenditure and physical performance is clearly known. Objective and hypotheses: The aim of our study is to evaluate the energy expenditure (EE) during physical (PA) and sedentary activities (SA), in a group of children/adolescents affected by growth hormone deficiency (GHD) compared to healthy subjects, using an objective measure as SenseWear Armband (SWA-BodyMedia). Patients, methods and results: These preliminary data included 13 untreated, consecutive GHD children and adolescents (6 males) (GH peak 3 Mets) (1.5 ±0.8 vs 2.3±1 h/d), especially moderate (3-6 Mets)(1.4±0.8 vs 2.2±0.9 h/d; 5.8±3.1 vs 9.2±3.9% of daily hours) compared with healthy subjects. A tendency to spend more time in sedentary activities was found in GHD group (16±4 vs 14±3 h/d), although not statistically significant. In multivariate regression IGF1 and BMISD resulted positive predictors of EE/daily (cal/daily) in GHD children. Conclusions: In conclusion our preliminary results seem to confirm that children affected by growth hormone deficiency showed lower energy expenditure as calories/daily and spent less time in physical activities compared to normal children. This result seems correlate to IGF1 values indicating a possible role of GH in physical performance. Further evaluations on greater number of patients, before and after GH therapy, are ongoing to confirm our findings.

Purpose: We aimed to investigate a cohort of female and male patients with idiopathic central precocious puberty (CPP), negative for Makorin Ring Finger Protein 3 (MKRN3) defect, by molecular screening for Delta-like 1 homolog (DLK1) defects. DLK1 is an imprinted gene, whose mutations have been described as a rare cause of CPP in girls and adult women with precocious menarche, obesity and metabolic derangement. Methods: We enrolled 14 girls with familial CPP and 13 boys with familial or sporadic CPP from multiple academic hospital centers. Gene sequencing of DLK1 gene was performed. Circulating levels of DLK1 were measured and clinical and biochemical characteristics were described in those with DLK1 defects. Results: A novel heterozygous mutation in DLK1, c.288_289insC (p.Cys97Leufs*16), was identified in a male proband, his sister and their father. Age at onset of puberty was in line with previous reports in the girl and 8years in the boy. The father with untreated CPP showed short stature. No metabolic derangement was present in the father except hypercholesterolemia. Undetectable Dlk1 serum levels indicated the complete lack of protein production in the three affected patients. Conclusion: A DLK1 defect has been identified for the first time in a boy, underscoring the importance of genetic testing in males with idiopathic or sporadic CPP. The short stature reported by his untreated father suggests the need for timely diagnosis and treatment of subjects with DLK1 defects.

Background and aims Prader–Willi syndrome (PWS) is characterized by a high incidence of altered glucose metabolism (AGM). However, epidemiological data on impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and type 2 diabetes mellitus (T2DM) are still discordant. Methods and results We performed a multicenter study based on 274 PWS patients [144 females, aged 20.3 ± 10.4 yrs (range: 8.1–50.1 years)] evaluating the prevalence for AGM in the entire group, and according to age (children 18 yrs), Body Mass Index (BMI = kg/m2), gender, genotypes (deletion or uniparental disomy for chromosome 15), and GH therapy (GHT) (untreated, previously or currently treated). Altogether, AGM was detected in 67 (24.4%) of patients (0.7% IFG, 10.2% IGT, 13.5% T2DM). The prevalence of AGM was correlated to age (p = 0.001), BMI (p = 0.001) and HOMA-IR (p = 0.001). However, gender, genotype, and GHT did not influence AGM development in univariate analysis. These data were confirmed as positive predictors when inserted in a multivariate analysis model. Conclusion This study is the first report on the prevalence of AGM in a large population of PWS. Overall, PWS subjects show a high prevalence of AGM that appears more common in obese and adult subjects. Our data confirm the main role of obesity on the individual metabolic risk clustering in PWS, and thus reinforce the concept that improvement in weight control remains the most important goal of any PWS treatment program.

Context Hypogonadism in Prader-Willi syndrome (PWS) is generally attributed to hypothalamic dysfunction or to primary gonadal defect. MKRN3, a maternal imprinted gene located on 15q11.2-q13 region, encodes makorin ring finger protein 3, whose deficiency causes precocious puberty, an extremely rare symptom in PWS. Objective This study aimed to evaluate MKRN3 levels in patients with PWS and to analyze its correlation with sexual hormone levels, insulin resistance and Body Mass Index (BMI). Methods We performed an observational cross-sectional study and enrolled 80 patients with genetically confirmed diagnosis of PWS with median age of 9.6 years. Results MKRN3 levels were measurable in 49 PWS patients with a geometric mean of 34.9 +/- 22 pg/ml (median: 28.4). Unmeasurable levels of MKRN3 were found in 31 patients. No statistically significant differences were found between patients with and without measurable MKRN3 levels for any clinical, biochemical, or genetic characteristics. However, MKRN3 levels were inversely correlated with HOMA-IR index (p: 0.005) and HbA1c (p: 0.046) values. No statistically significant correlations were found between MKRN3 and LH, estradiol and testosterone concentrations, pubertal development and genetic defect, whereas a direct correlation with FSH was found (p: 0.007). Conclusions The typical genetic defect of PWS should lead to unmeasurable levels of the MKRN3 protein due to the inactivation of the paternal allele. Measurable circulating MKRN3 could suggest the possible involvement of tissue-specific imprinting mechanisms and other regulatory factors in gene expression. Correlations with HOMA-IR index, HbA1c, and FSH suggest peripheral actions of MKRN3, but future studies are warranted to investigate this topic.

Background Prader–Willi syndrome (PWS) is a rare and complex genetic disease, with numerous implications on metabolic, endocrine, neuropsychomotor systems, and with behavioural and intellectual disorders. Rare disease patient registries are important scientific tools (1) to collect clinical and epidemiologic data, (2) to assess the clinical management including the diagnostic delay, (3) to improve patients’ care and (4) to foster research to identify new therapeutic solutions. The European Union has recommended the implementation and use of registries and databases. The main aims of this paper are to describe the process of setting up the Italian PWS register, and to illustrate our preliminary results. Materials and methods The Italian PWS registry was established in 2019 with the aims (1) to describe the natural history of the disease, (2) to determine clinical effectiveness of health care services, (3) to measure and monitor quality of care of patients. Information from six different variables are included and collected into this registry: demographics, diagnosis and genetics, patient status, therapy, quality of life and mortality. Results A total of 165 patients (50.3% female vs 49.7% male) were included into Italian PWS registry in 2019–2020 period. Average age at genetic diagnosis was 4.6 years; 45.4% of patients was less than 17 years old aged, while the 54.6% was in adult age (> 18 years old). Sixty-one percent of subjects had interstitial deletion of the proximal long arm of paternal chromosome 15, while 36.4% had uniparental maternal disomy for chromosome 15. Three patients presented an imprinting centre defect and one had a de novo translocation involving chromosome 15. A positive methylation test was demonstrated in the remaining 11 individuals but the underlying genetic defect was not identified. Compulsive food-seeking and hyperphagia was present in 63.6% of patients (prevalently in adults); 54.5% of patients developed morbid obesity. Altered glucose metabolism was present in 33.3% of patients. Central hypothyroidism was reported in 20% of patients; 94.7% of children and adolescents and 13.3% of adult patients is undergoing GH treatment. Conclusions The analyses of these six variables allowed to highlight important clinical aspects and natural history of PWS useful to inform future actions to be taken by national health care services and health professionals.

Background/ObjectivesThe present study aimed to validate the Italian version of the Hyperphagia Questionnaire (HQ), a 11-items questionnaire developed to assess hyperphagia in individuals with Prader-Willi syndrome (PWS). This is a complex neurodevelopmental disorder characterized by endocrine dysfunction, hypotonia, intellectual disability, psychiatric disorders and obesity.MethodsParents of 219 individuals with PWS (age range 3–54 years; Mage = 17.90; 108 Males), recruited in 12 hospitals in Italy responded to HQ during routine visits. In function of the level of analyses the sample was divided into two subgroups ( years) or into four age-subgroups (2.5–4.5; 4.5–8; 8–18; >18 years) corresponding to different clinical stages.ResultsConfirmatory factor analysis (CFA) confirmed the three hyperphagic subdimensions of the original structure (behavior, drive, and severity), but one item was dropped out, reducing the final version to 10 items. Using multi-group CFA, HQ showed satisfactory indexes of measurement invariance by age. Good indexes of internal consistency (Cronbach's alpha and McDonald's Omega coefficients) were found for each subdimension. The three hyperphagia subdimensions positively converged with other food-related measures: emotional overeating, food enjoyment, food responsiveness, and satiety responsiveness. A significant increase of all hyperphagic subdimensions was found across age groups. Higher hyperphagic levels were found in participants with higher body mass index. Hyperphagic drive differently increased in function of the interaction between age and underlying genetic mechanisms.ConclusionThe Italian version of the HQ is a psychometrically valid and reliable instrument for assessing hyperphagia in individuals with PWS. This tool may prove useful to evaluate the efficacy of pharmacologic and rehabilitative treatments.

Pediatric patients with Prader-Willi syndrome (PWS) can be treated with recombinant human GH (rhGH). These patients are highly sensitive to rhGH and the standard doses suggested by the international guidelines often result in IGF-1 above the normal range. We aimed to evaluate 1 the proper rhGH dose to optimize auxological outcomes and to avoid potential overtreatment, and 2 which patients are more sensitive to rhGH. In this multicenter real-life study, we recruited 215 patients with PWS older than 1 year, on rhGH at least for 6 months, from Italian Centers for PWS care. We collected auxological parameters, rhGH dose, IGF-1 at recruitment and (when available) at start of treatment. The rhGH dose was 4.3 (0.7/8.4) mg/m2/week. At recruitment, IGF-1 was normal in 72.1% and elevated in 27.9% of the patients. In the group of 115 patients with IGF-1 available at start of rhGH, normal pretreatment IGF-1 and uniparental disomy were associated with elevated IGF-1 during the therapy. No difference in height and growth velocity was found between patients treated with the highest and the lowest range dose. The rhGH dose prescribed in Italy seems lower than the recommended one. Normal pretreatment IGF-1 and uniparental disomy are risk factors for elevated IGF-1. The latter seems to be associated with higher sensitivity to GH. In case of these risk factors, we recommend a more accurate titration of the dose to avoid overtreatment and its potential side effects.