Search Results (139)

Background and Clinical Significance: Prader–Willi syndrome (PWS) is an imprinting disorder not typically associated with severe congenital sensorineural hearing loss (SNHL). When profound SNHL is present in an infant with a known syndrome, an independent monogenic etiology should be considered. We report the first molecularly confirmed case of PWS co-occurring with biallelic pathogenic TMC1 variants causing congenital SNHL, outlining diagnostic challenges, cochlear implant (CI) outcomes, and implications for blended phenotypes. Case Presentation: A male infant with PWS due to a paternal 15q11.2–q13 deletion failed newborn hearing screening. Diagnostic auditory brainstem response and auditory steady-state response confirmed bilateral severe-to-profound SNHL. Temporal bone CT/MRI were normal. Comprehensive genetic testing identified compound heterozygous TMC1 variants consistent with autosomal recessive DFNB7/11 hearing loss, plus two variants of uncertain significance in SERPINB6 and EPS8L2. Sequential bilateral cochlear implantation was performed (left ear at 14 months, right at 20 months), followed by auditory–verbal therapy. Over four years, the child showed steady improvements in hearing and early-speech development. Conclusions: Early genomic evaluation is essential when clinical features appear atypical for a known syndrome. Identifying TMC1-related deafness enabled timely cochlear implantation and measurable gains. This case highlights that severe congenital SNHL in a syndromic infant may reflect a distinct monogenic disorder rather than phenotypic expansion of the primary syndrome, emphasizing the importance of recognizing blended phenotypes to guide precision-care strategies in rare disorders. Full article

Prader–Willi syndrome (PWS) is a rare, multisymptomatic genetic disorder caused by the absence or dysfunction of specific genes on chromosome 15. The genetic abnormality is anticipated to cause a dysfunction of the hypothalamus, which is also central in the regulation of the autonomic nervous system (ANS). Typical symptoms of PWS indicating a hypothalamic dysfunction include muscular hypotonia, poor growth, short stature, and feeding difficulties in infancy, which in early childhood are replaced by hyperphagia, leading to a high risk of obesity. Other characteristics, such as sleep difficulties, altered pain perception, delayed gastric emptying and constipation, blood pressure irregularities and dysregulated stress response, altered temperature regulation, delayed pupillary reaction, and urine retention and incontinence, all indicate a dysfunction of ANS. The ANS is usually divided into three parts: the sympathetic nervous system (SNS), which activates the fight-or-flight response during stress; the parasympathetic nervous system (PNS), which promotes calm and digestion; and the independent enteric nervous system (ENS), which regulates the gastrointestinal tract. Noradrenaline is the main neurotransmitter for the SNS, and acetylcholine for the PNS, while the ENS is regulated mainly by acetylcholine and serotonin. However, the ENS is modulated by both the SNS and the PNS, as well as many neuropeptides. Peptides regulating behavior, metabolism, appetite, and satiety have been extensively studied in PWS. However, studies of the role of neuropeptides in regulating other autonomic functions are limited and remain poorly understood. This review aims to synthesize current evidence from both animal models and human studies to explore potential mechanisms by which neuropeptides may contribute to autonomic dysfunction in individuals with PWS. Full article

Background/Objectives: Developing and implementing clinical trials for rare diseases is complicated by the incomplete understanding of the varied genotype and subsequent phenotypic differences of a condition, particularly when low numbers of subjects are enrolled in a study. Moreover, a small-scale clinical study may indicate a positive outcome but have too small of a sampling population to adequately evaluate unwanted outcomes. Prader–Willi syndrome (PWS) is one such genetic disorder with varied subtypes and heterogeneity, where little progress has been made in treatment discoveries. Recently, the FDA approved diazoxide choline for treating key features of hyperphagia and obesity associated with PWS based on clinical trial experience. Diazoxide choline activates the ATP-sensitive potassium channel (KATP) of pancreatic beta cells, inhibiting the release of insulin. One of the subunits of KATP is the protein Kir6.2, the gene product of KCNJ11. Methods: Web-based programs and datasets were used to study the gene and protein functional enrichments of Kir6.2 and KCNJ11, including shared gene and/or protein–protein interactions, and biological processes and functions. Results: Four essential domains of related functions were identified: (1) apoptosis, protein degradation, and inflammation; (2) the coupling of G proteins needed for KATP channel activation; (3) glucose metabolism and control; and (4) the maintenance of intracellular ionic homeostasis. Conclusions: Cellular metabolism in the pancreas is linked to membrane excitability by KATP, which regulates insulin production, energy production and storage, appetite regulation, and fatty acid synthesis. As such, diazoxide choline may influence several biological systems beyond pancreatic and metabolic functions. Full article

Data on the interplay between muscle, bone, and adipose tissue metabolism in normal-weight children with Prader–Willi syndrome (PWS) undergoing growth hormone (GH) therapy and dietary interventions are limited. This study aimed to assess the myokine profile and explore the associations between myokines, bone markers, adipokines, and body composition in these patients. The study included 26 children with PWS and 26 age-matched healthy controls. Serum levels of irisin, myostatin (MSTN), fibroblast growth factor-2, insulin-like growth factor-I (IGF-I), IGF-binding protein-2, bone alkaline phosphatase (BALP), osteocalcin (OC), carboxylated OC (Gla-OC), periostin, soluble receptor activator of nuclear factor kappa-B ligand, tartrate-resistant acid phosphatase 5b, leptin/soluble leptin receptor, adiponectin, and proinsulin were measured using immunoenzymatic assays. Children with PWS had significantly lower lean mass (p = 0.047) and a higher fat mass/lean mass ratio (p < 0.001) than controls. Irisin levels were lower in the PWS group (p = 0.031), while MSTN levels were similar between the groups. In patients, irisin positively correlated with BALP (p = 0.025) and negatively correlated with Gla-OC (p = 0.041) and periostin (p = 0.005). MSTN was positively associated with proinsulin (p = 0.001) and negatively associated with lean mass (p = 0.015). OC concentration was lower in the PWS group and correlated positively with lean mass (p = 0.052). Children with PWS exhibit altered myokine, osteokine, and adipokine profiles, as well as differences in body composition. Reduced irisin and osteocalcin levels, along with the negative association between MSTN and lean mass, may impair muscle development and bone metabolism. These imbalances could also contribute to future metabolic disorders in patients with PWS. Full article

Assisted reproductive technologies (ARTs) have revolutionized infertility treatment, leading to the birth of over 10 million children worldwide. Despite their success, increasing concerns have been expressed regarding the potential long-term outcomes of ART-conceived individuals, particularly in relation to imprinting disorders (IDs). IDs result from the abnormal expression of imprinted genes, which are expressed in a parent-of-origin-specific manner and regulated by epigenetic mechanisms (e.g., DNA methylation). Disruption of these processes, through environmental, genetic, or procedural factors, can lead to disorders such as Beckwith–Wiedemann syndrome (BWS), Silver–Russell syndrome (SRS), Angelman syndrome (AS), and Prader–Willi syndrome (PWS). These syndromes are characterized by distinct clinical features, including growth abnormalities, neurodevelopmental delay, endocrine dysfunction, and cancer predisposition. ART procedures, especially ovarian hyperstimulation, in vitro fertilization (IVF), and embryo culture, coincide with critical periods of epigenetic reprogramming and may contribute to epimutations in imprinting control regions. In this review, we explored epidemiology, molecular mechanisms, and prenatal diagnostic strategies related to these four IDs in the context of ART. The findings suggest a higher prevalence of BWS and SRS in ART-conceived children. The data regarding AS and PWS are more controversial, with conflicting results across populations and methodologies. Although a causal link between ART and IDs remains debated, evidence suggests the potential contribution of ART procedures to epigenetic dysregulation in susceptible individuals. Further large-scale, methodologically rigorous studies will be essential to clarify this association and inform safer ART practices. Full article

Background: Prader–Willi syndrome (PWS) is a rare syndrome that presents in about 1 in 25,000 newborns. It is characterized by a typical phenotype that includes short stature, hypothyroidism and hypogonadism, cognitive and developmental delays, slow growth, obesity, and, in most patients, scoliosis. These patients generally have a life expectancy of less than 60 years, with respiratory distress being the leading cause of death; scoliosis is not the primary cause of these respiratory problems, but may contribute to their worsening. Therefore, accurately diagnosing and managing scoliosis is crucial for improving the life expectancy of PWS patients. Previous studies have shown a limited effectiveness of bracing due to a combination of factors, including generalized hypotonia, rapid early progression, poor brace compliance, and thus frequent progression to surgical intervention. Case presentation: This case report presents a 20-year follow-up of a female patient with PWS. Multiple clinical parameters were collected at every follow-up appointment. Throughout this extended observation and treatment period, the patient used two push-up braces of different rigidity, resulting in improvements in the thoracic and lumbar Cobb angle and the thoracic angle of trunk rotation. The treatment protocol was based on a shared decision with the parents and the patient. Conclusions: This case demonstrates how consistent and thorough follow-up can result in a successful, conservative treatment of a severe secondary scoliosis, thereby preventing the need for a major surgical procedure during growth. Full article

Background: Prader–Willi Syndrome (PWS) is a genetic neurodevelopmental disorder caused by an alteration of the paternal chromosome 15q11-q13. Youth with PWS present hyperphagia, increased fat/decreased muscle mass, hypotonia, and decreased metabolic rate with risk of obesity. Thermoregulation problems have been previously reported with hypothermia in adults or hyperthermia in children/infants with PWS. Methods: We retrospectively examined a cohort of 44 youths with PWS, 8–16 years old, presenting with a medical history of temperature dysregulation (TD), hypothermia or hyperthermia. Participants with (n = 10) and without (n = 34) a history of TD were compared for anthropometrics, body composition, medical history, and motor characteristics. Results: Youth with TD presented with hypothermia (n = 8), hyperthermia (n = 2), or both conditions (n = 2). Non-parametric statistics showed no significant differences in age, anthropometrics, body composition, or motor characteristics between the groups (p ≥ 0.064). Those with TD presented with a higher frequency of sleep apnea versus those without (50% vs. 18%; p = 0.038). Conclusions: The prevalence of TD in the cohort was one in five youth with PWS, suggesting that the problem is not isolated. The results do not suggest that anthropometrics, body composition, or motor characteristics explain differences in temperature excursions in youths with PWS. Possible physiological mechanisms and future research are discussed. Full article

Background/Objectives: Prader–Willi Syndrome (PWS) is a neurodevelopmental disease associated with multiple behavioral features, including a prevalence for psychosis. The genetic causes of PWS are well characterized and involve the silencing or deletion of the paternal copy of a region of chromosome 15q11–13. One gene within this region, Snord116, a non-coding RNA, has been determined to have a determinant role in the manifestation of PWS. However, it remains unclear as to how the deletion of this allele can affect activity in the brain and influence psychosis-like behaviors. Methods: In this study, we assessed the effects of the microdeletion of the paternal copy of Snord116 on regional neural activity in psychosis-associated brain regions and psychosis-like behaviors in mice. Results: The results suggest that Snord116 deletion causes increased c-Fos expression in the hippocampus and anterior cingulate cortex. Snord116 deletion also results in behavioral phenotypes consistent with psychosis, most notably in stressful paradigms, with deficits in sensorimotor gating and augmented contextual as well as cued fear conditioning. Conclusions: These results implicate the targets of Snord116 in the presentation of a psychosis-like state with regional specificity. Full article

Background: Currently, there is a lack of data regarding the reliability of different anthropometric, instrumental, and biochemical indexes in detecting metabolic syndrome (MetS) in pediatric patients with Prader–Willi syndrome (PWS). Therefore, this study aimed to compare the accuracy of different indices to identify the simplest and most accurate predictor of MetS in this at-risk population. Methods: We conducted a multicenter study involving 124 children and adolescents with PWS (61 males and 63 females), aged 13.6 ± 3.7 years. For each participant, we assessed all components of MetS, defined according to either the Identification and prevention of Dietary- and lifestyle-induced health EFfects In Children and infantS (IDEFICS) study or the International Diabetes Federation (IDF) criteria, based on age. The following indexes were calculated: Body Mass Index (BMI), BMI standard deviation score (BMI-SDS), tri-ponderal mass index, body mass fat index, fat mass index, fat-free mass index, body shape index, visceral adiposity index, waist-to-height ratio, cardiometabolic index, total cholesterol/high-density lipoprotein cholesterol (HDL-C) ratio, and triglycerides/HDL-C (TG/HDL-C) ratio. Results: MetS was identified in 24 subjects (9 females and 15 males), representing 19.4% of the sample. When comparing the receiver operating characteristic (ROC) curves, the TG/HDL-C ratio and cardiometabolic index demonstrated significantly better performance than the other indices in detecting MetS, with no difference between the two. As a result, we focused on the TG/HDL-C ratio since it is the simplest measure, requiring no additional anthropometric data compared to the cardiometabolic index. Additionally, applying age- and gender-specific thresholds can further improve its accuracy. Conclusions: The TG/HDL-C ratio, which requires only two standard biochemical markers, provides the same accuracy as more complex indexes in detecting MetS in children and adolescents with PWS, making it the optimal predictor for MetS in this population. Full article

Background and Clinical Significance: Prader–Willi syndrome (PWS) is a rare genetic disease caused by imprinted gene dysfunction, typically involving deletion of the chromosome 15q11.2-q13 region, balanced translocation, or related gene mutations in this region. PWS presents with complex and varied clinical manifestations. Abnormalities can be observed from the fetal stage and change with age, resulting in growth, developmental, and metabolic issues throughout different life stages. Case Presentation: We report the prenatal characteristics observed from the second to third trimester of pregnancy in a neonate with PWS. Prenatal ultrasound findings included a single umbilical artery, poor abdominal circumference growth from 26 weeks, normal head circumference and femur length growth, increased amniotic fluid volume after 30 weeks, undescended fetal testicles in the third trimester, small kidneys, and reduced fetal movement. The male infant was born at 38 weeks of gestation with a birth weight of 2580 g. He had a weak cry; severe hypotonia; small eyelid clefts; bilateral cryptorchidism; low responsiveness to medical procedures such as blood drawing; and poor sucking, necessitating tube feeding. Blood methylation-specific multiple ligation-dependent probe amplification (MS-MLPA) showed paternal deletion PWS. Notably, this case revealed two previously unreported prenatal features in PWS: a single umbilical artery and small kidneys. Conclusions: Through literature review and our case presentation, we suggest that a combination of specific sonographic features, including these newly identified markers, may aid clinicians in the early diagnosis of PWS. Full article

Background: Uniparental disomy (UPD) refers to the condition in which both chromosomes (or part of chromosome) of a pair are inherited from the same parent. There are two types of UPD: uniparental isodisomy (both chromosomes inherited from one parent are identical copies) and uniparental heterodisomy (two different chromosomes are inherited from one parent). UPD presents two primary developmental risks: recessive trait inheritance or an imprinting disorder. These risks may coexist, leading to an ultra-rare comorbidity. Managing the comorbidities associated with rare diseases presents unique clinical challenges. Results: The existence of such phenomena is evidenced by our case report of a boy who was ultimately diagnosed with two rare diseases: Prader–Willi syndrome (PWS), due to the maternal uniparental disomy of chromosome 15 (UPD), and autosomal recessive Lodder–Merla type 1 syndrome, linked to a novel pathogenic variant in the G protein subunit β 5 (GNB5) gene, as detailed in this paper. Conclusions: An unusual or severe phenotype in a patient diagnosed with PWS should invariably prompt the consideration of a comorbid genetic disease attributable to genes located in the PWS critical region of chromosome 15q, or elsewhere on chromosome 15. In cases of epileptic encephalopathy with cardiac arrhythmia, prompt consultation with a cardiologist and comprehensive genetic testing are essential to reduce the risks associated with untreated arrhythmia and ensure the provision of appropriate and safe anti-epileptic therapy. The presented case provides further support for the hypothesis that uniparental disomy may serve as an underlying cause of Lodder–Merla syndrome. This underscores the significance of comprehensive genetic testing, encompassing parental testing and familial cascade testing (in selected cases where there is consanguinity, or the likelihood of close common ancestral background between partners) to establish the recurrence risk. Full article

Background/Objectives: This study compared metabolic syndrome (MetS) features in patients with Prader-Willi syndrome (PWS) to those in age-, BMI-, and gender-matched subjects with essential obesity (EOB). Methods: Thirty-two PWS patients (23 females, 9 males; median age 31.6 years; BMI 42.0 kg/m²) underwent several assessments, including anthropometric measurements, body composition via bio-impedance analysis, basal metabolic rate (BMR) using indirect calorimetry, and blood sampling. Results: Their data were compared to a matched EOB group (23 females, 9 males; median age 31.4 years; BMI 43.5 kg/m²). The study groups (PWS and EOB) were subsequently divided into two subgroups based on the International Diabetes Federation criteria for the definition of MetS. Results showed that individuals with PWS had significantly lower (p < 0.001) body weight (BW, −20.9%), height (−8.9%), fat-free mass (FFM, −23.5%), and fat mass (FM, −19.2%) in absolute terms compared to EOB subjects. However, the relative percentages of FFM and FM were similar. Absolute BMR was 25.5% (p < 0.001) lower in the PWS group; however, this difference disappeared when adjusted for FFM or body weight (BW). Metabolic outcomes were broadly similar between the groups, except for higher fasting glucose (+7.3%) and HbA1c levels (+7.9%), and lower fasting insulin (−29.0%) in PWS patients. Conclusions: Moreover, PWS subjects exhibited higher total cholesterol (+9.6%) and HDL-cholesterol (+19.8%), suggesting a more favourable lipid profile and no extra risk beyond severe obesity. Full article

Prader-Willi syndrome (PWS) is a rare genetic disorder. The main characteristics are muscular hypotonia, failure to thrive and feeding problems in infancy, which switch to hyperphagia in early childhood and continue into adulthood. Due to hyperphagia, the risk of developing morbid obesity is high without treatment. PWS is considered a hypothalamic disease, and within the hypothalamus the arcuate nucleus (AC) is of central importance for controlling metabolism, hunger, and satiety. The AC has been studied in several animal models as well as in humans, including PWS. The function of AC is regulated by several neuropeptides and proteins produced within the central nervous system such as oxytocin, orexin, tachykinins as well as the hypothalamic hormones, regulating the adeno-hypophyseal hormones, also acting as neurotransmitters. Additionally, there are many peripheral hormones among which insulin, leptin, adiponectin, ghrelin, and glucagon-like peptide (GLP-1) are the most important. High levels of adiponectin and ghrelin have consistently been reported in PWS, but dysregulation and deviating levels of many other factors and hormones have also been demonstrated in both individuals with PWS and in animal models. In this review, we focus on the role of AC and peptides and proteins produced within the central nervous system in the regulation of hunger and satiety in PWS. Full article

Background: Prader–Willi syndrome (PWS) is a rare genetic disorder mapping to the imprinted 15q11-13 locus, specifically at the paternally expressed snord116 region, which has been implicated in controlling epigenetic mechanisms. Some aspects of the PWS-related clinical phenotype, such as the high mortality rate in adulthood, might be attributed to accelerated epigenetic ageing. Objectives: The aim of the present case–control study was to evaluate epigenetic age, age acceleration, vascular age (VA), and vascular ageing in adults with PWS (n = 24; F/M = 11/13; age = 36.8 [26.6; 45.3] years; body mass index, BMI = 36.8 [33.9; 44.8] kg/m²), compared with a sex- and age-matched group of subjects with essential obesity (EOB) (n = 36; F/M = 19/17; age = 43.4 [30.6; 49.5] years; BMI = 44.8 [41.2; 51.7] kg/m²). Results: In subjects with PWS, there was a younger epigenetic age and a lower age acceleration than in subjects with EOB. No differences were found between VA and vascular ageing in the two groups. Epigenetic age was associated with chronological age and VA within each group. For each group, no relevant associations of epigenetic age or age acceleration with demographic, biochemical, and clinical parameters were found. When considering individuals with PWS, there were no associations of epigenetic age with growth hormone (GH) deficiency, duration of hormone replacement therapy, and plasma levels of insulin-like growth factor 1 (IGF-1). Conclusions: The hypothesis of accelerated epigenetic ageing in PWS should be rejected. Additionally, considering the existence of a SNORD116-dependent epigenetic dysregulation in PWS, the results of the present study might be misleading, since an epigenetics-based approach was used to measure ageing. Full article

Background: Prader–Willi Syndrome (PWS) is a rare, genetic, multi-systemic disorder. Its main characteristics are muscular hypotonia, behavioral problems, intellectual disability, endocrine deficiencies, hyperphagia, and a high risk of morbid obesity and related comorbidities. This study aimed to investigate the rate of comorbidity, prescription of endocrine medications, and mortality in individuals with PWS compared to the general population. Methods: The association between PWS and outcomes were investigated in a matched cohort study of individuals born in the period of 1930–2018 with data from Swedish national health and welfare registers. Each individual was matched with 50 non-PWS comparisons. The associations between PWS, outcomes and prescribed endocrine medications were estimated through Cox proportional hazard models, presented as Hazard Ratios (HR) with 95% Confidence Intervals (CIs). Results: Among 360 individuals (53% men) with PWS, 16% had diabetes mellitus, 6% heart failure, 4% vein thrombosis, 2% atrial fibrillation, 2% coronary heart disease, and 1% pulmonary embolism. Individuals with PWS had an increased rate of heart failure (HR: 23.85; 95% CI: 14.09–40.38), diabetes mellitus (HR: 17.49; 95% CI: 12.87–23.74), vein thrombosis (HR: 10.44; 95% CI: 5.69–19.13), pulmonary embolism (HR: 5.77; 95% CI: 2.27–14.67), atrial fibrillation (HR: 5.19; 95% CI: 2.48–10.86), and coronary heart disease (HR: 3.46; 95% CI: 1.50–7.97) compared to non-PWS individuals. Somatotropin was prescribed in 63%, antidiabetics in 18%, and thyroid hormones in 16% of the PWS individuals (<1%, 2%, and 3%, respectively, in non-PWS individuals). The rate of mortality was fifteen times higher in PWS than in non-PWS, with a mean age at death of 42 years. Conclusions: The rates of diabetes mellitus and cardiovascular comorbidities were higher in individuals with PWS. As expected, the prescription of somatotropin was high, but the endocrine prescription pattern also reflected the high prevalence of diabetes mellitus and thyroid illness. Although the mean age at death was older than previously reported, a higher awareness and intensified efforts to avoid obesity, as well as the prevention and early treatment of cardiovascular and endocrine comorbidity, are crucial aims in the care of people with PWS. Full article