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Background: To evaluate the impact of coronavirus disease 2019 (COVID-19) on polysomnographic evaluation in patients with Prader-Willi syndrome (PWS). Patients and methods: A retrospective cohort study of two consecutive overnight polysomnograms (PSG) in 92 PWS patients (mean age 9.1, range 3.1–22 years). 57/92 participants (35 female) had a COVID-19 infection between the two consecutive examinations. 35 patients (21 female) had no infection (control group). Distribution of genetics was as follows: 13/57 (22.8%) deletion, 19/57 (33.3%) uniparental disomy, 2/57 (3,5%) imprinting defect, 3/57 (5.3%) non-deletion, 20/57 (35.1%) diagnosed by analyses of the methylation pattern of chromosome 15q11-13. Mean time interval between COVID-19 infection and post-COVID-19 evaluation was 96.2 days. Results: Course of COVID-19 infection was asymptomatic 8/82 (9.8%), mild 63/82 (76.8%), medium 11/84 (13.4%). The five most frequently experienced symptoms in PWS patients were fever (56.1%); headache (45.1%); cold (42.7%); cough (31.7%) and body aches (21.95%). PWS patients who had COVID-19 infection had significantly lower mean oxygen saturation (SpO2) measured by pulse oximetry (post 94.8% vs. pre 95.7%, p = 0.001), lower detected lowermost SpO2 (post 86.2 vs. pre 87.3%, p = 0.003), and higher occurrence of hypopnoea (post 13.9 vs. pre 10.7, p = 0.001). Time in optimal SpO2 (95–100%) decreased significantly (post 54.3% vs. pre 73.8%, p = 0.001), whereas an increase was observed in time in suboptimal SpO2 (90–95%) (post 45.5% vs. 25.8%, p = 0.001) and in time in poor SpO2 (< 90%) (post 0.7% vs. pre 0.2%, p = 0.030). Body-Mass-Index (BMI)-SDS for PWS showed no differences between the groups at any time. BMI-SDS-differences showed no influence on differences in SpO2 evaluations. In the genetic subgroup with deletion there was a statistically significant effect on an increased number of OSA (p = 0.027). The genetic subgroup with uniparental disomy (UPD) was associated with a reduced risk of higher HF (p = 0.035) and less hypopnea (p = 0.011). Conclusion: PWS patients predominantly experienced only mild to medium symptoms during COVID-19 infection without necessity of hospitalisation. However, on average three months after infection, differences in PSG evaluations were still apparent, manifesting in lower SpO2 and more frequent hypopnea. A long-lasting impairment of the pulmonary system due to the COVID-19 infection might be responsible. [ABSTRACT FROM AUTHOR]

Temple syndrome is a rare imprinting disorder, caused by alterations in the critical imprinted region 14q32 of chromosome 14. It is characterized by pre- and postnatal growth retardation, truncal hypotonia and facial dysmorphism in the neonatal period. We report an 18-year-old girl with a late diagnosis of Temple syndrome presenting with all typical signs and symptoms including small for gestational age at birth, feeding difficulties, muscle hypotonia and delayed developmental milestones, central precocious puberty, truncal obesity and reduced growth. The patient is the second reported in the literature with signs of clinical and biochemical hyperandrogenism and the first treated with Dehydrocortisone®, with a good response. The clinical diagnosis of this patient was made after long-term follow up at a single center for rare endocrine diseases, and a molecular genetics diagnosis of complete hypomethylation of 14q32 chromosome imprinting center (DLK/GTL2) was recently established. Growth hormone treatment was not given and although precocious puberty was treated in line with standard protocols, her final height remained below the target range. Increased awareness of Temple syndrome and timely molecular diagnosis enables improvement of clinical care of these patients as well as prevention of inherent metabolic consequences. [ABSTRACT FROM AUTHOR]

Purpose: Transcutaneous auricular vagus nerve stimulation (taVNS) is an emerging non-invasive neuromodulation therapy. This study aimed to explore the therapeutic use of taVNS, optimal stimulation parameters, effective sham protocols, and safety. Methods: A scoping review was conducted. Five databases and grey literature were searched. The data extracted included stimulation parameters, adverse events (AEs), and therapeutic effects on clinical outcomes. Results: 109 studies were included. taVNS was used across 21 different clinical populations, most commonly in psychiatric, cardiac, and neurological disorders. Overall, 2,214 adults received active taVNS and 1,017 received sham taVNS. Reporting of stimulation parameters was limited and inconsistent. taVNS appeared to have a favourable therapeutic effect across a wide range of clinical populations with varied parameters. Three sham protocols were reported but their effectiveness was documented in only two of the 54 sham-controlled studies. Most reported adverse events were localised to stimulation site. Conclusion: There is growing evidence for taVNS therapeutic effect. taVNS appears safe and tolerable. Sham protocols need evaluation. Standardised and comprehensive reporting of both stimulation parameters and adverse events is required. Two different questionnaires have been proposed to evaluate adverse events and the effectiveness of sham methods in blinding participants. IMPLICATIONS FOR REHABILITATION: Transcutaneous auricular vagus nerve stimulation (taVNS) showed therapeutic effect across a wide range of clinical populations including depression, epilepsy, and stroke There is a preliminary indication that daily/weekly dose and overall duration of treatment are important to show therapeutic effectiveness When using taVNS as an intervention, the questionnaires proposed in this review should be used to evaluate blinding effectiveness and adverse events [ABSTRACT FROM AUTHOR]

Background/objectives: Euchromatic histone lysine methyltransferase 2 (EHMT2, also known as G9a) is a mammalian histone methyltransferase that catalyzes the dimethylation of histone 3 lysine 9 (H3K9). On human chromosome 15, the parental-specific expression of Prader–Willi Syndrome (PWS)-related genes, such as SNRPN and SNORD116, are regulated through the genetic imprinting of the PWS imprinting center (PWS-IC). On the paternal allele, PWS genes are expressed whereas the epigenetic maternal silencing of PWS genes is controlled by the EHMT2-mediated methylation of H3K9 in PWS-IC. Here, we measured the effects of RNA interference of EHMT2 on the maternal expression of genes deficient in PWS in mouse model and patient iPSC-derived cells. Methods: We used small interfering RNA (siRNA) oligonucleotides and lentiviral short harpin RNA (shRNA) to reduce Ehtm2/EHMT2 expression in mouse Snord116 deletion primary neurons, PWS patient-derived induced pluripotent stem cell (iPSC) line and PWS iPSC-derived neurons. We then measured the expression of transcript or protein (if relevant) of PWS genes normally silenced on the maternal allele. Results: With an approximate reduction of 90% in EHMT2 mRNA and more than 80% of the EHMT2 protein, we demonstrated close to a 2-fold increase in the expression of maternal transcripts for SNRPN and SNORD116 in PWS iPSCs treated with siEHMT2 compared to PWS iPSC siControl. A similar increase in SNORD116 and SNRPN RNA expression was observed in PWS iPSC-derived neurons treated with shEHMT2. Conclusions: RNAi reduction in EHMT2 activates maternally silenced PWS genes. Further studies are needed to determine whether the increase is therapeutically relevant. This study confirms the role of EHMT2 in the epigenetic regulation of PWS genes. [ABSTRACT FROM AUTHOR]

Angelman syndrome (AS) and Prader-Willi syndrome (PWS), two distinct neurodevelopmental disorders, result from loss of expression from imprinted genes in the chromosome 15q11-13 locus most commonly caused by a megabase-scale deletion on either the maternal or paternal allele, respectively. Each occurs at an approximate incidence of 1/15,000 to 1/30,000 live births and has a range of debilitating phenotypes. Patient-derived induced pluripotent stem cells (iPSCs) have been valuable tools to understand human-relevant gene regulation at this locus and have contributed to the development of therapeutic approaches for AS. Nonetheless, gaps remain in our understanding of how these deletions contribute to dysregulation and phenotypes of AS and PWS. Variability across cell lines due to donor differences, reprogramming methods, and genetic background make it challenging to fill these gaps in knowledge without substantially increasing the number of cell lines used in the analyses. Isogenic cell lines that differ only by the genetic mutation causing the disease can ease this burden without requiring such a large number of cell lines. Here, we describe the development of isogenic human embryonic stem cell (hESC) lines modeling the most common genetic subtypes of AS and PWS. These lines allow for a facile interrogation of allele-specific gene regulation at the chromosome 15q11-q13 locus. Additionally, these lines are an important resource to identify and test targeted therapeutic approaches for patients with AS and PWS. [ABSTRACT FROM AUTHOR]

Background: Prader-Willi syndrome (PWS) is a rare genetic neurodevelopmental disorder. Individuals with PWS face a range of cognitive, behavioral, and emotional challenges that require comprehensive and lifelong care, posing significant demands on their caregivers. The study is not only aimed to assess the psychological conditions of caregivers of adult subjects with PWS focusing on psychological distress and coping, but also to shed light on a crucial yet often overlooked aspect of healthcare. This study aims to compare the psychological well-being of individuals with PWS and their caregivers, providing valuable insights that can potentially improve the quality of care for these individuals. The sample recruited at the Division of Auxology, IRCCS Istituto Auxologico Italiano, was composed of 30 adult subjects with PWS (11 men and 19 women; mean age ± SD: 36.4 ± 10.31 years; mean Body Mass Index (BMI): 35.7 ± 8.92: kg/m2) and their caregivers (10 men and 20 women). To assess the psychological condition of caregivers, the Italian-validated versions of the Depression Anxiety and Stress Scale (DASS-21) and the Coping Orientation to the Problems Experiences (COPE) were used, while to assess the psychological well-being of individuals with PWS and their caregivers, the Italian validated version of the Psychological General Well-Being Index (PGWBI) was used. Results: Depression (p < 0.001), Stress (p = 0.050), and Total score (p = 0.009) of DASS 21 were higher in the caregivers of subjects with PWS than in the general population. PGWBI scores of caregivers were significantly lower than in individuals with PWS in Positive Well-being (p < 0.001), General Health (p = 0.006), Vitality (p = 0.004), and the total score (p = 0.006). The depression subscale of PGWBI was higher in caregivers than in subjects with PWS. Correlations between the subscales of COPE and the total score of PGWBI in caregivers revealed that the Avoidance subscale of COPE had a negative significant correlation with the total score of PGWBI (p = 0.003). Conclusions: Our results highlighted several critical insights into the profound emotional and psychological challenges faced by the caregivers of individuals with PWS. [ABSTRACT FROM AUTHOR]

Exercise for people with Prader-Willi syndrome (PWS) is important for their health and wellbeing and can provide opportunities for community participation. However, they may find it difficult to participate in some contexts, such as community gyms because social and environmental barriers in these settings may compound difficulties caused by physical impairments or intellectual disability. This study aims to observe and understand the actions and interactions of people with PWS when they exercise in community gyms. A focussed ethnographic study will be conducted. Field notes will be taken in community gyms where people with PWS are participating in a structured exercise program for six months as part of a randomised control trial called PRESTO. Up to ten participants will be observed, with at least three observations planned per participation during the program. Gym sessions observed will be approximately 1 hour long. Within the framework of interpretive description, reflective thematic analysis will be used to interpret observational data. Our findings will inform how best to support people with PWS to exercise at a community gym. Trial Registration Number: ACTRN12620000416998; Australian and New Zealand Clinical Trial Registry. [ABSTRACT FROM AUTHOR]

Background: Multi-locus imprinting disturbance (MLID) with methylation defects in various differentially methylated regions (DMRs) has recently been identified in approximately 150 cases with imprinting disorders (IDs), and deleterious variants have been found in genes related to methylation maintenance of DMRs, such as those encoding proteins constructing the subcortical maternal complex (SCMC), in a small fraction of patients and/or their mothers. However, integrated methylation analysis for DMRs and sequence analysis for MLID-causative genes in MLID cases and their mothers have been performed only in a single study focusing on Beckwith-Wiedemann syndrome (BWS) and Silver-Russell syndrome (SRS) phenotypes. Results: Of 783 patients with various IDs we have identified to date, we examined a total of 386 patients with confirmed epimutation and 71 patients with epimutation or uniparental disomy. Consequently, we identified MLID in 29 patients with epimutation confirmed by methylation analysis for multiple ID-associated DMRs using pyrosequencing and/or methylation-specific multiple ligation-dependent probe amplification. MLID was detected in approximately 12% of patients with BWS phenotype and approximately 5% of patients with SRS phenotype, but not in patients with Kagami-Ogata syndrome, Prader-Willi syndrome, or Angelman syndrome phenotypes. We next conducted array-based methylation analysis for 78 DMRs and whole-exome sequencing in the 29 patients, revealing hypomethylation-dominant aberrant methylation patterns in various DMRs of all the patients, eight probably deleterious variants in genes for SCMC in the mothers of patients, and one homozygous deleterious variant in ZNF445 in one patient. These variants did not show gene-specific methylation disturbance patterns. Clinically, neurodevelopmental delay and/or intellectual developmental disorder (ND/IDD) was observed in about half of the MLID patients, with no association with the identified methylation disturbance patterns and genetic variants. Notably, seven patients with BWS phenotype were conceived by assisted reproductive technology (ART). Conclusions: The frequency of MLID was 7.5% (29/386) in IDs caused by confirmed epimutation. Furthermore, we revealed diverse patterns of hypomethylation-dominant methylation defects, nine deleterious variants, ND/IDD complications in about half of the MLID patients, and a high frequency of MLID in ART-conceived patients. [ABSTRACT FROM AUTHOR]

Introduction: Prader-Willi syndrome is a rare genetic disorder characterized by hypotonia, obesity, hypogonadism, and various psychiatric and endocrine abnormalities. Case report: we present a case of an eleven-year-old girl diagnosed with bilateral bronchopneumonia, Prader-Willi syndrome, type 2 diabetes, hypothyroidism, and vitamin D deficiency. The patient underwent clinical examination, laboratory and radiological investigations, and multidisciplinary consultations. Results: complications in respiratory, endocrine, and cardiovascular systems were identified. Conclusion: this case highlights the need for a holistic approach in treating patients with complex comorbidities. [ABSTRACT FROM AUTHOR]

Background: Prader–Willi syndrome (PWS) is a rare genetic disorder characterized by distinctive physical, cognitive, and behavioral manifestations, coupled with profound alterations in appetite regulation, leading to severe obesity and metabolic dysregulation. These clinical features arise from disruptions in neurodevelopment and neuroendocrine regulation, yet the molecular intricacies of PWS remain incompletely understood. Methods: This study aimed to comprehensively profile circulating neuromodulatory factors in the serum of 53 subjects with PWS and 34 patients with non-syndromic obesity, utilizing a proximity extension assay with the Olink Target 96 neuro-exploratory and neurology panels. The ANOVA p-values were adjusted for multiple testing using the Benjamani–Hochberg method. Protein–protein interaction networks were generated in STRING V.12. Corrplots were calculated with R4.2.2 by using the Hmisc, Performance Analytics, and Corrplot packages Results: Our investigation explored the potential genetic underpinnings of the circulating protein signature observed in PWS, revealing intricate connections between genes in the PWS critical region and the identified circulating proteins associated with impaired oxytocin, NAD metabolism, and sex-related neuromuscular impairment involving, CD38, KYNU, NPM1, NMNAT1, WFIKKN1, and GDF-8/MSTN. The downregulation of CD38 in individuals with PWS (p < 0.01) indicates dysregulation of oxytocin release, implicating pathways associated with NAD metabolism in which KYNU and NMNAT1 are involved and significantly downregulated in PWS (p < 0.01 and p < 0.05, respectively). Sex-related differences in the circulatory levels of WFIKKN1 and GDF-8/MSTN (p < 0.05) were also observed. Conclusions: This study highlights potential circulating protein biomarkers associated with impaired oxytocin, NAD metabolism, and sex-related neuromuscular impairment in PWS individuals with potential clinical implications. [ABSTRACT FROM AUTHOR]

To assess whether the use of assisted reproductive technology (ART) therapy for conception is associated with imprinting disorders in children and the impact of parental factors related to infertility. A nationwide register-based cohort study. Swedish national registers and nationwide quality IVF register. All liveborn singletons in Sweden (N = 2,084,127) between 1997 and 2017 with follow-up to December 31, 2018. The use of specific methods implemented in ART. The International Classification of Diseases version 10 was used to identify three distinct imprinting disorder groups: Beckwith-Wiedemann syndrome (BWS), Prader-Willi syndrome (PWS), and Silver-Russell syndrome (SRS), as well as central precocious puberty. The Cox model combined with inverse probability treatment weights was used to estimate the weighted hazard ratio (wHR) with a 95% confidence interval (CI), accounting for multiple confounders. A total of 1,044 children were diagnosed with the disorders of interest, and 52 of them were conceived using ART therapy. The overall risk of being diagnosed with any of the studied imprinting disorders was elevated in children conceived using ART therapy compared with all other children (HR, 1.84; 95% CI, 1.38–2.45). After adjusting for parental background factors, the association was partially attenuated (wHR, 1.50; 95% CI, 0.97–2.32), but remained in the weighted comparison restricted to children of couples with known infertility (wHR, 1.52; 95% CI, 1.05–2.21). For the specific diagnoses of PWS/SRS, and BWS compared with children of couples with known infertility, children conceived with ART therapy showed a small excess risk, which could not be distinguished from the null (wHR, 1.56; 95% CI, 0.93–2.62 and 1.80; 95% CI, 0.99–3.28, respectively). Further subgroup analysis showed that the combined use of intracytoplasmic sperm injection and cryopreserved embryos was associated with a higher risk of both PWS/SRS (wHR, 4.60; 95% CI, 1.72–12.28) and BWS (wHR, 6.69; 95% CI, 2.09–21.45). The number of central precocious puberty cases in children conceived using ART therapy was too small (N = 3) to make any meaningful inference. The combined use of intracytoplasmic sperm injection and cryopreserved embryos was associated with small elevated risks of PWS/SRS, and BWS in children, independent of parental factors related to infertility. [ABSTRACT FROM AUTHOR]

PWS Smart-Start is a behavioral caregiver training program developed specifically for caregivers of children with Prader-Willi syndrome (PWS) ages 3 to 14. The purpose of the current study was to evaluate the acceptability and preliminary efficacy of the program. Thirty-four caregivers of children with PWS received the PWS Smart-Start training using online live video-coaching across a 10-week period. The impact of the training on a variety of variables including caregiver and child behavior, caregiver stress and burnout, and family functioning were evaluated using a quasi-experimental pretest posttest design. Results indicated statistically significant decreases across child behavior challenges and parental stress and burnout following the training. Statistically significant improvements were also seen in parenting practices, the quality of the parent–child relationship, and family quality of life. Results of social validity measures indicated caregiver satisfaction with the program. These preliminary results indicate that the PWS Smart-Start program has the potential to not only support children with PWS through behavioral challenges but also reduce caregiver stress and burnout and improve a variety of aspects of family life. Future research is needed to replicate and further validate these results and to extend the exploration of other behavior analytic interventions for this population. [ABSTRACT FROM AUTHOR]

Background: Prader–Willi syndrome (PWS) is a genetic disorder characterised by hyperphagia, intellectual disability and increased propensity to a range of medical disorders. To better characterise the clinical presentation of PWS across the lifespan, this study reports on the demographics and clinical diagnosis of individuals with PWS hospitalised in the United States. Methods: The National Inpatient Sample, an all‐payor administrative claims database of hospitalisations in the United States, was queried for patients with a coded diagnosis of PWS from October 2019 through December 2021. Hospitalisations for patients with PWS were matched to five non‐PWS hospitalisations based on age, sex, year and hospital characteristics. Results: There were 4400 (95% CI: 3,885 to 4,915) PWS hospitalisations, with a median age of 24. Compared to controls, PWS hospitalisations had longer hospital stays (median 5 vs. 3 days) and higher in‐hospital mortality (2.2% vs. 1.3%). Infectious (19.0%) and respiratory (16.2%) diagnoses were most common for PWS patients. Codes for overweight or obesity were present in 38.1% of PWS hospitalisations, with Hispanic ethnicity was associated with a higher odds of overweight/obesity in PWS patients (aOR 1.73; 95% CI: 1.11–2.71). Conclusions: PWS hospitalisations are characterised by higher healthcare utilisation and complexity compared to matched controls. The high prevalence of obesity and significant rates of infectious and respiratory conditions highlight specific health challenges for PWS patients. Validation of the Q87.11 administrative claims code is an essential step for ongoing health services research in this condition. [ABSTRACT FROM AUTHOR]

Background: Prader–Willi syndrome (PWS) is a congenital disease caused by a rare and generally non‐inherited genetic disorder. The inability to recognise facial expressions of emotion is an apparent social cognition deficit in people diagnosed with PWS. The main objective of the present study is to compare the ability to recognise emotional facial expression, in both non‐contextualised and contextualised scenarios, among the main subtypes of PWS and a control group. Methods: The sample consisted of 46 children divided into three groups: deletion (n = 10), maternal uniparental disomy (mUPD) (n = 13) and control (n = 23). The protocol included the Facially Expressed Emotion Labeling and the Deusto‐e‐Motion 1.0. Results: The control group recognised facial emotions more accurately and quickly in both non‐contextualised and contextualised scenarios than children with PWS, regardless of genetic subtype. Despite no differences being detected between PWS subtypes when non‐contextualised scenarios were analysed, in contextualised situations, a longer reaction time was observed in children with the mUPD subtype. Conclusions: This is the first study to assess the ability to recognise emotional facial expressions in contextualised situations among PWS subtypes and a control group. The findings suggest that some of the social cognitive deficits evidenced in children with mUPD PWS may be similar to those in autism spectrum disorder. [ABSTRACT FROM AUTHOR]

Despite therapy with growth hormone (GH) in children with Prader–Willi syndrome (PWS), low bone mineral density and various orthopedic deformities have been observed often. Therefore, this study aimed to analyze bone markers, with an emphasis on vitamin K-dependent proteins (VKDPs), in normal-weight children with PWS undergoing GH therapy and a low-energy dietary intervention. Twenty-four children with PWS and 30 healthy children of the same age were included. Serum concentrations of bone alkaline phosphatase (BALP), osteocalcin (OC), carboxylated-OC (Gla-OC), undercarboxylated-OC (Glu-OC), periostin, osteopontin, osteoprotegerin (OPG), sclerostin, C-terminal telopeptide of type I collagen (CTX-I), and insulin-like growth factor-I (IGF-I) were determined using immunoenzymatic methods. OC levels and the OC/CTX-I ratios were lower in children with PWS than in healthy children (p = 0.011, p = 0.006, respectively). Glu-OC concentrations were lower (p = 0.002), but Gla-OC and periostin concentrations were higher in patients with PWS compared with the controls (p = 0.005, p < 0.001, respectively). The relationships between IGF-I and OC (p = 0.013), Gla-OC (p = 0.042), and the OC/CTX-I ratio (p = 0.017) were significant after adjusting for age in children with PWS. Bone turnover disorders in children with PWS may result from impaired bone formation due to the lower concentrations of OC and the OC/CTX-I ratio. The altered profile of OC forms with elevated periostin concentrations may indicate more intensive carboxylation processes of VKDPs in these patients. The detailed relationships between the GH/IGF-I axis and bone metabolism markers, particularly VKDPs, in children with PWS requires further research. [ABSTRACT FROM AUTHOR]

This study aims to explore the food management strategies among caregivers/family members of children with Prader–Willi Syndrome (PWS) using the lens of 'familialisation' of a health problem and the sociology of food socialization. Food intake among individuals with PWS is a main concern for parents, caregivers, and medical practitioners as it affects their physical, mental, and social well-being throughout their lives. Earlier studies on PWS and food intake centered around dietary management, dietary intake and growth, nutritional treatment and pharmacological approaches, nutritional phases, and weight gain. However, little has been done to understand the challenges of managing children with PWS from the sociological lens of food management strategies and socialization among families in Malaysia. This study is based on an investigation involving eight children with PWS and 46 family members and caregivers through lab observations and reflexive interviews. Ten food management strategies were identified that were adopted by the caregivers and families, which were influenced by cultural factors, family norms, and formal and informal support systems. The findings will influence future behavioral interventions to ensure the empowerment and well-being of individuals with PWS and their families. [ABSTRACT FROM AUTHOR]

Context Several endocrine abnormalities were reported in children with Prader–Willi syndrome (PWS), including hypothyroidism. Growth hormone (GH) treatment may impact the thyroid hormone axis by direct inhibition of T4 or TSH secretion or by increased peripheral conversion of free T4 (FT4) to T3. Objective The objective of this study is to evaluate thyroid function during GH treatment in a large group of children with PWS. Methods Serum FT4, T3, and TSH are measured in a 2-year randomized controlled GH trial (RCT) and 10-year longitudinal GH study (GH treatment with 1.0 mg/m²/day [∼0.035 mg/kg/day]). Results Forty-nine children with PWS were included in the 2-year RCT (median [interquartile range, IQR] age: GH group 7.44 [5.47-11.80] years, control group 6.04 [4.56-7.39] years). During the first 6 months, median (IQR) FT4 standard deviation score (SDS) decreased in the GH group from −0.84 (−1.07 to −0.62) to −1.32 (−1.57 to −1.08) (P <.001) and T3 SDS increased from 0.31 (−0.01-0.63) to 0.56 (0.32-0.79) (P =.08), while in the control group, FT4 and T3 SDS remained unchanged. In our 10-year GH study, 240 children with PWS (median [IQR] age: 1.27 (0.54-4.17) years] were included. Between 2 and 10 years, median (IQR) FT4 SDS remained unchanged, being −0.87 (−0.98 to −0.77) after 2 years and −0.88 (−1.03 to −0.74) after 10 years (P =.13). TSH SDS decreased from −0.35 (−0.50 to −0.21) after 2 years to −0.68 (−0.84 to −0.53) after 10 years (P <.001). Conclusions Our findings suggest that GH treatment decreases FT4 levels, due to increased peripheral conversion of FT4 to T3 in the first months of treatment, but thereafter, FT4 and T3 normalize and remain stable during long-term GH treatment in almost all children and adolescents with PWS. [ABSTRACT FROM AUTHOR]

Objectives: Children with Prader‐Willi Syndrome (PWS) may develop premature pubarche (PP). We investigated the frequency of PP, and its potential precursors and sequelae, in PWS. Design, Patients and Measurements: A chart review of children with PWS treated at our institution between 1990 and 2021 was performed. PP was defined as Tanner stage 2 (TS2) pubic hair in girls <8 and boys <9 years old. Demographic, anthropometric, and laboratory data were collected to assess predisposing factors and consequences of PP in comparison to patients with PWS who had normal pubarche (NP). Results: Analysis included 43 children with PWS, 23 (53.5%) with PP and 20 (46.5%) with NP. Median age at pubarche was 7.0 years in PP group and 10.0 years in NP group. Age at pubarche was not correlated with age of recombinant human growth hormone (rhGH) initiation, body mass index (BMI) z‐score, or homeostasis model assessment of insulin resistance (HOMA‐IR) at pubarche. BMI z‐score at pubarche was modestly correlated with degree of pubarchal BA advancement (p = 0.033). Those with PP were more likely to have a lower high‐density lipoprotein (HDL) (1.05 mmol/L vs. 1.41 mmol/L in the NP group, p = 0.041). The difference between target and final height did not differ between groups (p = 0.507). Conclusion: PP is common in PWS but does not compromise final height in comparison to the NP group. Obesity and insulin resistance were not associated with PP in children with PWS, contrary to what has been seen in obese children without PWS. [ABSTRACT FROM AUTHOR]

The neurodevelopmental disorders Prader-Willi syndrome (PWS) and Schaaf-Yang syndrome (SYS) both arise from genomic alterations within human chromosome 15q11–q13. A deletion of the SNORD116 cluster, encoding small nucleolar RNAs, or frameshift mutations within MAGEL2 result in closely related phenotypes in individuals with PWS or SYS, respectively. By investigation of their subcellular localization, we observed that in contrast to a predominant cytoplasmic localization of wild-type (WT) MAGEL2, a truncated MAGEL2 mutant was evenly distributed between the cytoplasm and the nucleus. To elucidate regulatory pathways that may underlie both diseases, we identified protein interaction partners for WT or mutant MAGEL2, in particular the survival motor neuron protein (SMN), involved in spinal muscular atrophy, and the fragile-X-messenger ribonucleoprotein (FMRP), involved in autism spectrum disorders. The interactome of the non-coding RNA SNORD116 was also investigated by RNA-CoIP. We show that WT and truncated MAGEL2 were both involved in RNA metabolism, while regulation of transcription was mainly observed for WT MAGEL2. Hence, we investigated the influence of MAGEL2 mutations on the expression of genes from the PWS locus, including the SNORD116 cluster. Thereby, we provide evidence for MAGEL2 mutants decreasing the expression of SNORD116 , SNORD115 , and SNORD109A , as well as protein-coding genes MKRN3 and SNRPN , thus bridging the gap between PWS and SYS. [Display omitted] Mutations within MAGEL2 from chromosomal region 15q11–q13 cause Schaaf-Yang syndrome, which is phenotypically related to Prader-Willi syndrome, caused by deletion of the SNORD116 cluster within the same locus. We correlate mutations within MAGEL2 to spinal muscular atrophy and autism and also demonstrate its influence on the abundance of SNORD116. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Prader-Willi syndrome (PWS) is characterized by a complex clinical condition, whose typical features lead to impaired motor and functional skills. To date, limited data is available as regards symmetry of gait in PWS. The aim of this study was to characterize lower-limb asymmetry during gait in a group of Prader-Willi Syndrome (PWS) individuals by using the synchronized cyclograms and to compare it with those of two different control groups, a normal-weight group and an obese group. A total of 18 PWS, 30 normal weight (NW) and 28 obese individuals (OG) matched for age, sex and height were assessed via 3D gait analysis. Gait spatio-temporal parameters were computed together with angle-angle diagrams, characterized in terms of their geometric features (i.e. area, orientation, and trend symmetry index). Individuals with PWS exhibit reduced speed, stride length and cadence and increased duration of both stance and double support phase than the other groups. OG was characterized by the same pattern when compared to NW. With respect to inter-limb symmetry, individuals with PWS exhibited significantly larger cyclogram areas at hip joint with respect to the other two groups (203.32 degrees2 vs. 130.73 degrees2 vs. 111.59 degrees2) and significantly higher orientation angle (4.17° vs. 2.11° vs. 1.22°) and Trend Symmetry (3.72 vs. 2.02 vs. 1.21) with respect to the other two groups at knee joint; no differences were found at ankle joint. Both individuals with PWS and those of OG exhibited reduced ROM at knee and ankle joints with respect with normal weight, but no statistically significant differences were observed between PWS and OG. The obtained results may provide novel and useful insights to understand better the impairments in motor control associated with this pathological state, supporting clinics in the identification of the best rehabilitation program for this rare pathological state, aimed to improve stability and motor control. • limited data is available as regards symmetry of gait in patients with Prader-Willi syndrome. • symmetry can be assessed through the calculation of several geometric properties of the cyclogram. • patients with Prader-Willi syndrome present altered spatio-temporal parameters and poor inter-limb symmetry. [ABSTRACT FROM AUTHOR]

Introduction: The purpose of this study was to evaluate the usefulness and relevance of projective techniques such as house‐tree‐person (HTP) and family in individuals with Prader‐Willi syndrome (PWS), who have a limited ability to identify and verbalize emotions and express them often using behaviors. Methods: We included individuals with genetic confirmation of PWS immersed in a regular transdisciplinary treatment in an institution dedicated to rare diseases. All individuals were evaluated using the HTP and family projective techniques. These instruments are commonly administered to the general population and, in this case, to people with mild to moderate intellectual disabilities, including difficulties in their communication abilities. Results: A total of 25 individuals with PWS between 10 and 41 years old (15 men and 10 women) were included. We identified the presence of graphic indicators corresponding to the behavioral phenotype of individuals with PWS, such as anxiety, stubbornness, emotional lability, difficulty in achieving adequate externalization and identification of emotions, impulsivity, aggressive traits, poor social skills, need for support and interaction, low self‐concept, and compulsive behaviors. Conclusions: In the present study, we demonstrated the usefulness of graphic techniques to elucidate aspects of behavior, emotions, and thoughts that individuals with PWS cannot formulate due to expression and communication difficulties. [ABSTRACT FROM AUTHOR]

Daily experiences of mothers caring for children with Prader-Willi syndrome (PWS) are largely unknown and unvoiced. Knowledge of PWS has generally focused on pathology of the disorder. This emphasis overlooks the challenging moments of everyday life caring for children with PWS. Storied accounts of mothers caring for children with PWS offer expanded narratives to medicalized descriptions of experience. An understanding of everyday challenges in managing physical and mental health issues of PWS including hyperphagia and anxiety may create shifts in social and clinical perspectives. This understanding could improve practices in health and social care for families with PWS. This narrative inquiry studied everyday experience using storied accounts. Participants were mothers caring for children aged 3–17 years with genetically confirmed PWS who were experiencing hyperphagia. Four participants were recruited, and each interviewed 8–12 times over 12 months. Field texts and narrative accounts were co-composed through a collaborative process of analysis. Engaging with participants' day-to-day experiences offered insights into their work of nurturing, caring, and contributing to the care of a child with PWS. Narrative threads focused on complexity and rarity and include the desire to be normal, how ordinary becomes extraordinary, isolation, behaviors and normative standards, and alternative stories of mothering. Recommendations for practice and policy include (a) challenges of mothering a child with complexity, (b) moving beyond functionality and impairment to participation and quality of life, (c) re-storying narratives and supports for families, and (d) engaging with mothers to determine care priorities. [ABSTRACT FROM AUTHOR]

Purpose: An investigation for the co-occurrence of two unrelated genetic disorders of muscular dystrophy and Prader-Willi syndrome (PWS) (OMIM#176270) using joint whole genome sequencing (WGS). Methods: Trio WGS joint analysis was performed to investigate the genetic etiology in a proband with PWS, prolonged muscular hypotonia associated hyperCKemia, and early-onset obesity. The parents were unaffected. Results: Results showed maternal isodisomy uniparental disomy (UPD) in chromosome 15, expanding from 15q11.2 to 15q22.2, including PWS regions at 15q11.2–15q13. Maternal heterodisomy was detected from 15q22.2 to 15q26.3. A pathogenic variant, NM_000070.3(CAPN3):c.550del (p.Thr184fs), was identified at 15q15.1 in a heterozygous state in the mother that was homozygous in the proband due to maternal isodisomy. Conclusion: This is the first study of the concurrent molecular etiology of PWS and calpainopathy (OMIM#253600) in the same patient. This report highlights the utility of joint analysis and the need for the assessment of autosomal recessive disease in regions of isodisomy in patients with complex and unexplained phenotypes. [ABSTRACT FROM AUTHOR]

Background: Prader-Willi syndrome (PWS) is a genetic disorder characterized by abnormalities in the 15q11-q13 region. Understanding the correlation between genotype and phenotype in PWS is crucial for improved genetic counseling and prognosis. In this study, we aimed to investigate the correlation between genotype and phenotype in 45 PWS patients who previously underwent methylation-sensitive high-resolution melting (MS-HRM) for diagnosis. Results: We employed methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) and Sanger sequencing, along with collecting phenotypic data from the patients for comparison. Among the 45 patients, 29 (64%) exhibited a deletion of 15q11-q13, while the remaining 16 (36%) had uniparental disomy. No statistically significant differences were found in the main signs and symptoms of PWS. However, three clinical features showed significant differences between the groups. Deletion patients had a higher prevalence of myopia than those with uniparental disomy, as well as obstructive sleep apnea and an unusual skill with puzzles. Conclusions: The diagnostic tests (MS-HRM, MS-MLPA, and Sanger sequencing) yielded positive results, supporting their applicability in PWS diagnosis. The study's findings indicate a general similarity in the genotype-phenotype correlation across genetic subtypes of PWS. [ABSTRACT FROM AUTHOR]

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. Conclusions: Our results suggest that living in SH is associated with benefits for physical health and behavior without negatively affecting QOL. [ABSTRACT FROM AUTHOR]

Background: Children with Prader-Willi Syndrome (PWS) display impaired pretend play abilities, reflective of broader social-cognitive challenges. Pretend play interventions for children with PWS demonstrate preliminary efficacy for improving cognitive and affective processes in play. It is unknown which specific intervention strategies, such as prompting, summarization, and modeling, most effectively improve these skills. The present study examined the effectiveness of different interventionist strategies on eliciting child behaviors within pretend play intervention sessions. Methods: Participants included 21 children (ages 6–12) with PWS who participated in a pretend play intervention. Recorded intervention sessions were coded for interventionist strategies and child pretend play skills. By pairing each interventionist strategy with the immediately following child behavior, it was possible to discern the frequency of how often certain intervention strategies immediately preceded various child pretend play skills. Results: All intervention strategies were followed by child pretend play over 50% of the time. Interventionist summarizing/reflection and modeling most often preceded child pretend play, as well as specific skills of imagination and organization. Prompting, followed by modeling, most often preceded affect expression. Conclusions: Interventionist strategies of summarization and modeling may most effectively facilitate pretend play. Prompts for emotions may be more effective to elicit affect expression, potentially due to social-cognitive difficulties inherent in PWS. Children with developmental differences may benefit from adults who engage in play as a partner, rather than direct the play, to help the child stay on-task and learn target behaviors. This insight may strengthen future efforts to support socioemotional skills through pretend play. [ABSTRACT FROM AUTHOR]

Introduction: Prader–Willi syndrome (PWS) represents a difficult challenge for spine surgeons, due to the association of a structural scoliosis, with a prevalence between 15 and 86%. Conservative therapy is a viable option, but surgery is increasingly becoming the treatment of choice. Methods: The authors reviewed a series of 15 patients affected by PWS treated at their institution between 2008 and 2023. The mean age at index treatment was 9 years and 3 months (range 1–15 years) with a prevalence of female subjects. Primary scoliotic curve ranged from 14 to 102°, and mean thoracic kyphosis was 56° (range 20–75°). Eleven patients underwent conservative treatment, while four were treated surgically. Results: Mean follow-up was 5 years and 3 months (range 2–12 years). Among the 11 patients treated conservatively, only two showed improvements of the coronal curve, while the remaining nine displayed a worsening of the deformity during follow-up. Complication rate after surgery was 75%. One patient developed paraplegia after pedicle screw positioning. One patient displayed rod breakage and PJK that required revision surgery proximally. Hardware deep infection was seen in one case where it was necessary to proceed with instrumentation removal after 10 years. Discussion and conclusions: Spine surgery represents a convincing option in patients affected by PWS, but the risks of complications are high. Correct patient selection must be the main objective, and multilevel pedicle screw fixation should be the procedure of choice. Traditional growing rod should be prudently evaluated in every single case. [ABSTRACT FROM AUTHOR]

Introduction: Prader-Willi syndrome (PWS) is characterized by a switch from failure to thrive to excessive weight gain and hyperphagia in early childhood. An elevated, more unfavorable ratio between acylated and unacylated ghrelin (AG/UAG ratio) might play a role in the underlying mechanisms of this switch. We aimed to assess the evolution of the appetite-regulating hormones acylated ghrelin (AG) and unacylated ghrelin (UAG) and the AG/UAG ratio and their association with the change in eating behavior in children with PWS, compared to healthy age-matched controls. Methods: A longitudinal study was conducted in 134 children with PWS and 157 healthy controls, from the Netherlands, France, and Belgium. Levels of AG and UAG and the AG/UAG ratio were measured and nutritional phases as reported for PWS were scored. Results: The AG/UAG ratio was lower in the first years of life in PWS than in controls and started to increase from the age of 3 years, resulting in a high-normal AG/UAG ratio compared to controls. The AG levels remained stable during the different nutritional phases (p = 0.114), while the UAG levels decreased from 290 pg/mL in phase 1a to 137 pg/mL in phase 2b (p < 0.001). The AG/UAG ratio increased significantly from 0.81 in phase 2a to 1.24 in phase 2b (p = 0.012). Conclusions: The change from failure to thrive to excessive weight gain and hyperphagia in infants and children with PWS coincides with an increase in AG/UAG ratio. The increase in AG/UAG ratio occurred during phase 2a, thus before the onset of hyperphagia. [ABSTRACT FROM AUTHOR]

Objective: Prader-Willi syndrome (PWS) and Bardet-Biedl syndrome (BBS) are causes of pediatric syndromic obesity. We aimed to investigate a possible role for ghrelin and glucagon-like peptide-1 (GLP-1) in the pathophysiology of PWS and BBS. Methods: The study included 12 children with PWS, 12 children with BBS, 13 pediatric obese controls (OC) and 12 pediatric lean controls (LC). Fasting serum ghrelin and GLP-1 levels were measured by ELISA. Results: In the PWS group, no significant difference was detected for median ghrelin levels when compared with OC and LC, which were 0.96 (0.69-1.15), 0.92 (0.72-1.20) and 1.13 (0.84-1.29) ng/mL, respectively. Similarly, there was no difference in PWS median GLP-1 levels when compared with OC and LC; 1.86 (1.5-2.94), 2.24 (1.62-2.78) and 2.06 (1.8-3.41) ng/mL, respectively. In the BBS group, there was no difference in median ghrelin levels when compared with OC and LC; 1.05 (0.87-1.51), 0.92 (0.72-1.20) and 1.13 (0.84-1.29) ng/ mL, respectively. Neither was there a significant difference in median GLP-1 levels; 2.46 (1.91-4.17), 2.24 (1.62-2.78) and 2.06 (1.8-3.41) ng/mL for BBS, OC and LC, respectively. Conclusion: There were no differences in median fasting ghrelin or GLP-1 levels when comparing patients with PWS and BBS with obese or lean peers. However, similar studies with larger series are needed. [ABSTRACT FROM AUTHOR]

Background: Prader–Willi syndrome (PWS), a genetically determined disorder, the most frequent cause of early onset obesity, is associated with physical and cognitive dysfunctions and behavioural disturbances; these disturbances are frequently treated with psychotropic medication. The aim of this cross‐sectional study was to describe the characteristics of the first large national sample of persons with PWS in Spain and analyse the relationships of those characteristics with key demographic and clinical factors, particularly with obesity and the regular use of psychotropic medication. Methods: Participants were recruited among all members of the Spanish Prader–Willi Association who agreed to take part in the study and fulfilled its inclusion criteria. Family and patient demographic features, family size and birth order, intelligence quotient (IQ), anthropometric measures, lifestyle habits, behavioural disturbances (with the Aberrant Behavior Checklist) and clinical data, as well as use of psychotropic drugs and their side effects (with the UKU scale), were collected in genetically confirmed cases of PWS. Bivariate and logistic regression analyses were used for determining the associations of demographic and clinical factors with both obesity and the regular use of psychotropic medication. Results: The cohort included 177 participants (aged 6–48 years), that is, 90 (50.8%) males and 87 (49.2%) females. Behavioural disturbances were present in a range of 75% to 93% of participants; psychotropic medication was prescribed to 81 (45.8%) of them. Number of siblings showed a direct correlation with IQ, especially among males, and inappropriate speech was more intense in only‐child females. Obesity was, in parallel, strongly associated with ascending age and with not being currently under growth hormone (GH) treatment. Participants taking any psychotropic medication were characterised by more frequent age ≥30 years, high level of hyperactivity and a psychiatric diagnosis. Conclusions: Characterisation of persons with PWS in Spain confirms their physical and behavioural phenotype and supports the long‐term application of GH therapy and the rational use of psychotropic medication. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Diagnosing imprinting defects in neonates and young children presents challenges, often necessitating molecular analysis for a conclusive diagnosis. The isolation of genetic material from oral swabs becomes crucial, especially in settings where blood sample collection is impractical or for vulnerable populations like newborns, who possess limited blood volumes and are often too fragile for invasive procedures. Oral swab samples emerge as an excellent source of DNA, effectively overcoming obstacles associated with rare diseases. Methods: In our study, we specifically addressed the determination of the quality and quantity of DNA extracted from oral swab samples using NaCl procedures. Results: We compared these results with extractions performed using a commercial kit. Subsequently, the obtained material underwent MS–HRM analysis for loci associated with imprinting diseases such as Prader–Willi and Angelman syndromes. Conclusions: Our study emphasizes the significance of oral swab samples as a reliable source for obtaining DNA for MS–HRM analysis. NaCl extraction stands out as a practical and cost-effective method for genetic studies, contributing to a molecular diagnosis that proves particularly beneficial for patients facing delays in characterization, ultimately influencing their treatment. [ABSTRACT FROM AUTHOR]

Responding to social signals by expressing the correct behavior is not only challenged in autism but also in diseases with a high prevalence of autism, such as Prader-Willi syndrome. Clinical evidence suggests that aberrant prosocial behavior in patients can be regulated by intranasal oxytocin (OXT) or vasopressin (AVP). However, the neuronal mechanisms that underlie impaired behavioral responses in a socially aversive context, and how can they be corrected, remain largely unknown. Using the Magel2 knockout mouse model of Prader-Willi syndrome (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 that receives dense hypothalamic inputs. OXT and AVP signaling promoted inhibitory synaptic transmission in the LS, the failure of which in Magel2 knockout 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 Magel2 knockout mice with disrupted 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 that operate beyond local septal circuits. 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 provide a new framework for future treatments for autism spectrum disorder. [ABSTRACT FROM AUTHOR]

Prader-Willi syndrome (PWS) is a rare genetic disorder characterized by hypothalamic dysfunction, hypotonia, cognitive deficits, and hyperphagia, primarily resulting from genetic abnormalities on chromosome 15. Among its varied manifestations, musculoskeletal issues, notably scoliosis, pose important challenges in management. This study aims to investigate differences in postural-motor development and spinal range of movement between preadolescents and adolescents with PWS, with and without scoliosis, while also exploring the potential impact of scoliosis on caregiving burden, an aspect yet to be thoroughly explored in existing literature. This observational study evaluated 13 individuals diagnosed with PWS, including 5 with scoliosis (PWS-Sc) and 7 without (PWS-NSc). Inclusion criteria comprised ages 8 to 18 years, confirmed PWS diagnosis through genetic testing, and scoliosis diagnosis. Anamnestic data, physical examinations, and surface measurements were collected, along with parental burden assessments using the Zarit Burden Interview (ZBI). Both groups displayed delays in achieving postural-motor milestones, with the PWS-Sc group exhibiting a more pronounced delay, although statistical significance was not achieved. The main curve magnitude in the PWS-Sc group averaged 31.5° Cobb, with 60% of cases presenting an S-shaped curve. Surface measurements of physiological curves did not differ significantly between groups, but the scoliosis-affected group exhibited lower lumbar extension values (p=0.04). The overall ZBI revealed higher scores in the PWS-Sc group, although statistical significance was not reached. However, significant differences were observed in single questions score evaluating aspects such as social life and caregiver uncertainty (p=0.04 and p=0.03, respectively). Despite the small sample size, delays in achieving postural-motor milestones, particularly in individuals with scoliosis, were observed. The differences recorded in lumbo-pelvic movement suggest that tailored interventions may be beneficial. The heightened caregiving burden in the scoliosis group underscores the need for targeted support. Early intervention and ongoing monitoring should be important for accurate diagnosis and appropriate care, potentially with psychological support for caregivers. [ABSTRACT FROM AUTHOR]

The genotype–phenotype relationship in PWS patients is important for a better understanding of the clinical phenotype and clinical characteristics of different genotypes of PWS in children. We aimed to explore the influence of specific gene changes on the clinical symptoms of PWS and the value of early screening and early intervention of the condition. All data in this study were extracted from the database of the XiaoPang Weili Rare Disease Care Center. The collected information included basic demographics, maternal pregnancy information, endocrine abnormalities, growth and development abnormalities, and other clinical phenotypes. The relationships between genotypes and phenotypes in the major categories of PWS were analyzed. A total of 586 PWS cases with confirmed molecular diagnosis and genotyping were included in this study. Among them, 83.8% belonged to the deletion type, 10.9% the uniparental disomy (UPD) type, and 5.3% the imprinting defect (ID) type. Age‐wide comparison among the three groups: The rate of hypopigmentation in the deletion group was higher than that in the UPD group (88.8% vs. 60.9%; p < 0.05); A total of 62 patients (14.2%) had epilepsy; and no statistical significance was found among the three groups (p = 0.110). Age‐wide comparison between the deletion and non‐deletion types: the rate of skin hypopigmentation and epilepsy in the deletion group was significantly higher than that in the non‐deletion group (88.8% vs. 68.4%, p < 0.001; 15.9% vs. 7.6%, p = 0.040). The intergroup comparison for the >2‐year age group: there were significant intergroup differences in the language development delay among the three groups (p < 0.001). The incidence of delayed language development was the highest in the deletion group, followed by the UPD group, and the lowest in the ID group. The rates of obesity and hyperphagia in the deletion group were also higher than those in the non‐deletion group (71.1% vs. 58.9%, p = 0.041; 75.7% vs. 62.0%, p = 0.016). There are significant differences in the rates of skin hypopigmentation and language developmental delay among the deletion, UPD, and ID genotypes. The patients with deletion type had significantly higher rates of lighter skin color, obesity, hyperphagia, language developmental delay, and epilepsy. The results of this study will help clinicians better understand the impact of different PWS molecular etiologies on specific phenotypes. [ABSTRACT FROM AUTHOR]

Bardet‐Biedl syndrome (BBS) is a genetic disorder characterized by early‐onset obesity, polydactyly, genital and kidney anomalies, developmental delay and vision loss due to rod‐cone dystrophy. BBS is an autosomal recessive disorder with >20 implicated genes. The genotype–phenotype relationship in BBS is not clear, and there may be additional modifying factors. The underlying mechanism is dysfunction of primary cilia. In BBS, receptor trafficking in and out of the cilia is compromised, affecting multiple organ systems. Along with early‐onset obesity, hyperphagia is a prominent symptom and contributes significantly to clinical morbidity and caregiver burden. While there is no cure for BBS, setmelanotide is a new pharmacotherapy approved for treatment of obesity in BBS. The differential diagnosis for BBS includes other ciliopathies, such as Alstrom syndrome, and other genetic obesity syndromes, such as Prader‐Willi syndrome. Careful clinical history and genetic testing can help determine the diagnosis and a multidisciplinary team is necessary to guide clinical management. [ABSTRACT FROM AUTHOR]

Background: The 15q11–q13 region is a genetic locus with genes subject to genomic imprinting, significantly influencing neurodevelopment. Genomic imprinting is an epigenetic phenomenon that causes differential gene expression based on the parent of origin. In most diploid organisms, gene expression typically involves an equal contribution from both maternal and paternal alleles, shaping the phenotype. Nevertheless, in mammals, including humans, mice, and marsupials, the functional equivalence of parental alleles is not universally maintained. Notably, during male and female gametogenesis, parental alleles may undergo differential marking or imprinting, thereby modifying gene expression without altering the underlying DNA sequence. Neurodevelopmental disorders, such as Prader–Willi syndrome (PWS) (resulting from the absence of paternally expressed genes in this region), Angelman syndrome (AS) (associated with the absence of the maternally expressed UBE3A gene), and 15q11–q13 duplication syndrome (resulting from the two common forms of duplications—either an extra isodicentric 15 chromosome or an interstitial 15 duplication), are the outcomes of genetic variations in this imprinting region. Methods: Conducted a genomic study to identify the frequency of pathogenic variants impacting the 15q11–q13 region in an ethnically homogenous population from Bangladesh. Screened all known disorders from the DECIPHER database and identified variant enrichment within this cohort. Using the Horizon analysis platform, performed enrichment analysis, requiring at least >60% overlap between a copy number variation and a disorder breakpoint. Deep clinical phenotyping was carried out through multiple examination sessions to evaluate a range of clinical symptoms. Results: This study included eight individuals with clinically suspected PWS/AS, all previously confirmed through chromosomal microarray analysis, which revealed chromosomal breakpoints within the 15q11–q13 region. Among this cohort, six cases (75%) exhibited variable lengths of deletions, whereas two cases (25%) showed duplications. These included one type 2 duplication, one larger atypical duplication, one shorter type 2 deletion, one larger type 1 deletion, and four cases with atypical deletions. Furthermore, thorough clinical assessments led to the diagnosis of four PWS patients, two AS patients, and two individuals with 15q11–q13 duplication syndrome. Conclusion: Our deep phenotypic observations identified a spectrum of clinical features that overlap and are unique to PWS, AS, and Dup15q syndromes. Our findings establish genotype–phenotype correlation for patients impacted by variable structural variations within the 15q11–q13 region. [ABSTRACT FROM AUTHOR]

Background: Anthropology is a scientific discipline which applies scientific methods to identify and quantitate inter-individual variations in body structure and function. Anthropometry assesses craniofacial dysmorphology in genetic disorders and helps to detect phenotypic differences in diseases with common underlying cause. This study is part of a comprehensive cross-sectional study of craniofacial and oral findings in Egyptian school children. This paper focused on establishing the norms of Egyptian male school children and its utility in determining the differences in facial measurements of a child with Prader–Willi syndrome (PWS). Thirty craniofacial measurements were taken from 55 healthy Egyptian school children aged 12–14 years with mean age 13 ± 0.64 and a PWS child aged 13.6 years. The PWS measurements were compared with healthy children of the same age using computed Z-score. Results: Morphological face height of the PWS child was within the normal range. However, upper face height and nose height were significantly lower with Z-scores of - 3.18 and - 2.7, respectively; right and left mandibular body length and upper lip height were significantly higher than the mean of healthy children with corresponding Z-scores of 2.95, 2.48, and 2.33. Conclusions: By establishing the norms of Egyptian male school children and utilizing these data, we can identify the difference in facial measurements among children with abnormalities like PWS. This information can be used during periodic checkups as a simple, non-invasive, and economical method for the detection of these abnormalities.

We present a series of microdeletion and microduplication syndromes (MMSs) observed in our clinical practice over a three-year period from 2020 to 2023. Microdeletion and microduplication syndromes, characterized by chromosomal deletions or duplications of less than five megabases, pose challenges in terms of diagnosis, especially prenatal and clinical management. Clinically, MMSs encompass a broad spectrum of manifestations, ranging from intellectual disability and developmental delays to congenital anomalies, facial dysmorphisms, and neurobehavioral abnormalities. Notable examples include well-characterized syndromes such as DiGeorge syndrome (22q11.2 deletion), Prader–Willi syndrome (15q11–q13 deletion), and Williams syndrome (7q11 deletion). Our study focuses on the genetic foundations and prenatal ultrasound findings of these syndromes, with an emphasis on cases associated with intellectual disability. Using SNP array technology, we delve into the evolving landscape of diagnostic methods, providing a nuanced understanding of copy number variations (CNVs) and their implications. Prenatal diagnosis allows for the early detection of MMSs, enabling parents and healthcare providers to make informed decisions about the pregnancy and plan for appropriate medical care and interventions. Beyond theoretical considerations, our article bridges the gap between research and practical application by offering insights derived from clinical cases. Through the presentation of specific cases, we aim to contribute valuable data to the broader discourse on MMSs, fostering knowledge exchange and enhancing the medical community's awareness of these complex genetic conditions. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Prader-Willi syndrome (PWS) is a rare, neurodevelopmental disorder caused by the lack of expression of paternally imprinted genes on chromosome 15q11-13. PWS features a complex behavioral phenotype, including hyperphagia, anxiety, compulsivity, rigidity, repetitive speech, temper outbursts, aggressivity, and skin-picking. Questionnaires exist for measuring hyperphagia, but not for the aggregation of other problems that are distinctive to PWS. A PWS-specific tool is needed for phenotypic research, and to help evaluate treatment efficacy in future clinical trials aimed at attenuating PWS's hyperphagia and related problems. In this 4-phase study, we leveraged our expertise in PWS with feedback from families and specialists to validate the PWS Profile, a novel, informant-based measure of behavioral and emotional problems in this syndrome. Results: The authors developed a bank of 73 items that tapped both common and less frequent but clinically significant problems in PWS (Phase 1). An iterative feedback process with families and stakeholders was used to ensure content and construct validity (Phase 2). After adding, omitting, or revising items, in Phase 3, we pilot tested the measure in 112 participants. Results were reviewed by an international team of PWS specialists and revised again (Phase 3). The final, 57-item Profile was then administered to 761 participants (Phase 4). Principal component factor analyses (n = 873) revealed eight conceptually meaningful factors, accounting for 60.52% of test variance, and were readily interpretated as: Rigidity, Insistence; Aggressive Behaviors; Repetitive Questioning, Speech; Compulsive Behaviors; Depression, Anxiety; Hoarding; Negative Distorted Thinking; and Magical Distorted Thinking. Factors were internally consistent and showed good test-retest reliability and convergent validity with existent measures of behavioral problems. Profile factors were not related to IQ, BMI, or parental SES. Three Profile factors differed across PWS genetic subtypes. Age and gender differences were found in only one Profile factor, Hoarding. Conclusions: The PWS Profile is a valid, psychometrically-sound questionnaire that already has shown responsivity to treatment in a previous clinical trial. The Profile can extend the reach of future clinical trials by evaluating the impact of novel agents not only on hyperphagia, but also on the emotional and behavioral problems that characterize PWS. [ABSTRACT FROM AUTHOR]

Background: Prader–Willi syndrome (PWS) is a rare and complex neurodevelopmental disorder resulting from absent paternal expression of maternally imprinted genes at chromosomal locus 15q11-13. This absence of expression occurs as a consequence of a deletion on the chromosome 15 of paternal origin (ca. 70%), a chromosome 15 maternal uniparental disomy (mUPD; ca. 25%), or an imprinting centre defect (IC; ca. 1–3%). At birth, individuals with PWS are severely hypotonic and fail to thrive. Hyperphagia and characteristic physical and neuropsychiatric phenotypes become apparent during childhood. The risk for the development of a co-morbid psychotic illness increases during the teenage years, specifically in those with PWS due to the presence of an mUPD. The primary aim of this literature review is to inform clinical practice. To achieve this, we have undertaken a systematic analysis of the clinical research literature on prevalence, presentation, course, characteristics, diagnosis and treatment of psychotic illness in people with PWS. The secondary aim is to identify clinical aspects of psychotic illness in PWS in need of further investigation. Methods and findings: A systematic literature review on psychosis in PWS was conducted on the databases Web of Knowledge, PubMed and Scopus, using the terms “((Prader–Willi syndrome) OR (Prader Willi Syndrome)) AND ((psychosis) OR (psychotic illness))”. All articles written in English and reporting original human research were reviewed. In all but three of the 16 cohort studies in which the genetic types were known, the authors reported higher rates of psychosis in people with PWS resulting from an mUPD, compared to those with the deletion subtype of PWS. When psychosis was present the presentation was psychosis similar regardless of genetic type and was usually characterised by an acute onset of hallucinations and delusions accompanied by confusion, anxiety and motor symptoms. Conclusions: The onset of confusion, an affective cyclical pattern with the presence of abnormal mental beliefs and experiences, usually of rapid onset is suggestive of the development of psychotic illness. Phenomenologically, this psychosis in people with PWS is atypical in comparison to schizophrenia and bipolar disorder in the general population. The relationship to psychosis in the general population and the optimum treatments remain uncertain. [ABSTRACT FROM AUTHOR]

Oxytocin (Oxt) regulates thermogenesis, and altered thermoregulation results in Prader-Willi syndrome (PWS), Schaaf-Yang syndrome (SYS), and Autism spectrum disorder (ASD). PWS is a genetic disorder caused by the deletion of the paternal allele of 15q11-q13, the maternal uniparental disomy of chromosome 15, or defects in the imprinting center of chromosome 15. PWS is characterized by hyperphagia, obesity, low skeletal muscle tone, and autism spectrum disorder (ASD). Oxt also increases muscle tonicity and decreases proteolysis while PWS infants are hypotonic and require assisted feeding in early infancy. This evidence inspired us to merge the results of almost 20 years of studies and formulate a new hypothesis according to which the disruption of Oxt's mechanism of thermoregulation manifests in PWS, SYS, and ASD through thermosensory abnormalities and skeletal muscle tone. This review will integrate the current literature with new updates on PWS, SYS, and ASD and the recent discoveries on Oxt's regulation of thermogenesis to advance the knowledge on these diseases. [ABSTRACT FROM AUTHOR]

Background: DNA methylation is one of the most stable and well-characterized epigenetic alterations in humans. Accordingly, it has already found clinical utility as a molecular biomarker in a variety of disease contexts. Existing methods for clinical diagnosis of methylation-related disorders focus on outlier detection in a small number of CpG sites using standardized cutoffs which differentiate healthy from abnormal methylation levels. The standardized cutoff values used in these methods do not take into account methylation patterns which are known to differ between the sexes and with age. Results: Here we profile genome-wide DNA methylation from blood samples drawn from within a cohort composed of healthy controls of different age and sex alongside patients with Prader–Willi syndrome (PWS), Beckwith–Wiedemann syndrome, Fragile-X syndrome, Angelman syndrome, and Silver–Russell syndrome. We propose a Generalized Additive Model to perform age and sex adjusted outlier analysis of around 700,000 CpG sites throughout the human genome. Utilizing z-scores among the cohort for each site, we deployed an ensemble based machine learning pipeline and achieved a combined prediction accuracy of 0.96 (Binomial 95% Confidence Interval 0.868 - 0.995). Conclusion: We demonstrate a method for age and sex adjusted outlier detection of differentially methylated loci based on a large cohort of healthy individuals. We present a custom machine learning pipeline utilizing this outlier analysis to classify samples for potential methylation associated congenital disorders. These methods are able to achieve high accuracy when used with machine learning methods to classify abnormal methylation patterns. [ABSTRACT FROM AUTHOR]

One complex area of learning disability nursing relates to caring for people with rare neurodevelopmental disorders, which often affect physical health, mental health, social activities and family life. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

To analyze the risk for genetic aberrations and pregnancy outcomes in pregnancies with isolated polyhydramnios. This was a retrospective study of singleton pregnancies complicated by isolated polyhydramnios that underwent genetic amniocentesis between 2016 and 2021. Clinical and laboratory data were collected and reviewed for these cases, including maternal demographics, prenatal sonographic findings, chromosomal microarray results, and pregnancy outcomes. A total of 94 singleton pregnancies were included. Three (3.2%) cases with chromosomal abnormalities were detected, including 2 case of trisomy 21 and 1 of 22q21.1 microdeletion. One case was diagnosed as Prader-Willi syndrome caused by maternal uniparental disomy of chromosome 15. Perinatal death occurred in 1 case with severe polyhydramnios, and was retrospectively diagnosed as Bartter syndrome. Of the 90 infants survived, two were identified to have single gene disorders after birth by whole exome sequencing. We first attempted to determine the value of exome sequencing in pregnancies with isolated polyhydramnios. Our results warrant more studies to evaluate advanced genetic testing technologies used in such pregnancies. [ABSTRACT FROM AUTHOR]

The most prevalent type of syndromic obesity is referred to as Prader-Willi Syndrome (PWS), being determined by the lack of expression of paternal genes on chromosome 15q11.2-q13 due to genomic or epigenetic variations, such as DNA and histone methylation or acetylation. The syndrome is frequently associated with behavioral disorders, intellectual deficiencies, short stature, polyphagia, hypogonadism and muscular hypotonia, all stemming from the multiple endocrine dysfunctions characterizing this condition. Cardiovascular (CV) anomalies can manifest even in the early stages of life, and those with PWS have an elevated risk of early onset cardiovascular diseases. The somatic and behavioral aspects of the syndrome interact intricately to cause this increased risk for CV pathologies. Changes in the GH-IGF axis are seen in most Prader-Willi Syndrome (PWS) patients, irrespective of obesity. Specific cardiovascular features of GHD in adult PWS patients include reduced cardiac mass, decreased ejection fraction, and diminished chronotropic response to dobutamine. [ABSTRACT FROM AUTHOR]

Introduction: Caring for individuals with rare diseases can be challenging and represent a burden. Nevertheless, this has been scarcely explored in Prader–Willi syndrome (PWS). Therefore, we sought to explore the psychological impact of caregiving, as well as the differences between main caregivers and other family members. Methods: Different evaluation tools and scales were used taking into consideration the impact on caregivers. The scales were administered to those relatives who are immersed in the usual dynamics of the patient, differentiating between the main caregiver and other relatives living in the family home. Results: A total of 33 families of patients with genetic confirmation of PWS were included. In this survey, 32% of primary caregivers reported a high probability of anxiety, compared with 19% of non‐primary caregivers (p = 0.27). Concerning depression, 40% of primary caregivers related possible or probable cases of depression compared with non‐primary caregivers 13% (p = 0.04). Regarding caregiver burden evaluated using the Zarit scale, 61% of the main caregivers presented high levels of overload, compared with 29% of the other relatives (p = 0.005). Family functioning evaluated using the APGAR scale showed a total lower response from primary caregivers, but no statistically relevant results were found [25.4 ± 6.7 vs. 26.0 ± 8.2 (p = 0.72)]. Conclusion: In this study, we observed that caring for people with PWS can have a significant effect on the mental health, burden and quality of life of caregivers, with a greater impact among primary caregivers compared with the other living relatives. [ABSTRACT FROM AUTHOR]