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The Journal of Clinical Endocrinology... Apr 2024Children with skeletal dysplasias have not been consistently managed by pediatric endocrinologists despite the recognized expertise of these practitioners in managing...
Children with skeletal dysplasias have not been consistently managed by pediatric endocrinologists despite the recognized expertise of these practitioners in managing genetic growth disorders. Growth-altering treatments have broadened the role of the pediatric endocrinologist to manage and sometimes become primary coordinators for genetic disorders such as Turner syndrome and Prader-Willi syndrome. We illustrate how recent advances in understanding the pathophysiology of skeletal disorders and the development of targeted treatments provide an opportunity for pediatric endocrinologists to further expand their role in managing certain skeletal dysplasias, including achondroplasia.
Topics: Child; Humans; Endocrinologists; Osteochondrodysplasias; Achondroplasia; Prader-Willi Syndrome
PubMed: 38078681
DOI: 10.1210/clinem/dgad726 -
International Journal of Obesity (2005) Feb 2024Pediatric obesity is a highly prevalent chronic disease, which has traditionally been treated with lifestyle therapy alone. Yet for many youth, lifestyle intervention as... (Review)
Review
Pediatric obesity is a highly prevalent chronic disease, which has traditionally been treated with lifestyle therapy alone. Yet for many youth, lifestyle intervention as a monotherapy is often insufficient for achieving clinically significant and durable BMI reduction. While metabolic/bariatric surgery achieves robust and long-lasting outcomes, it is neither widely accessible nor wanted by most pediatric patients and families. In the past 3 years, this treatment gap between lifestyle therapy and metabolic/bariatric surgery has been filled with a number of landmark clinical trials examining the safety and efficacy of anti-obesity medication (AOM) for use in children and adolescents. These trials include studies of liraglutide, phentermine/topiramate ER, semaglutide, and setmelanotide, all of which have led to FDA and/or EMA approval. Concurrent with this developing evidence base, in 2023, the American Academy of Pediatrics published their first Clinical Practice Guideline on the assessment and management of childhood obesity. The Guideline includes the recommendation that pediatric health care providers should offer AOM to youth ages ≥12 years with obesity. Recognizing that AOM use in the pediatric population will likely become the standard of care and to provide perspective on the recently generated data regarding new AOM, this narrative review summarizes the published randomized controlled trials (RCTs) from the past 10 years that examine AOM for the pediatric population. This report additionally includes RCTs examining AOM for special populations of pediatric obesity including monogenic obesity, Bardet Biedl syndrome, Prader Willi syndrome, and hypothalamic obesity. Finally, the clinical application of AOM for children and adolescents, as well as future directions and challenges are discussed.
PubMed: 38321079
DOI: 10.1038/s41366-024-01465-y -
Diabetes, Obesity & Metabolism Apr 2024Bardet-Biedl syndrome (BBS) is a genetic disorder characterized by early-onset obesity, polydactyly, genital and kidney anomalies, developmental delay and vision loss... (Review)
Review
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.
Topics: Humans; Bardet-Biedl Syndrome; Obesity; Obesity, Morbid
PubMed: 38383825
DOI: 10.1111/dom.15494 -
Journal of Intellectual Disability... May 2024Prader-Willi syndrome (PWS), a genetically determined disorder, the most frequent cause of early onset obesity, is associated with physical and cognitive dysfunctions...
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.
Topics: Male; Female; Humans; Prader-Willi Syndrome; Spain; Cross-Sectional Studies; Obesity; Psychotropic Drugs
PubMed: 38246690
DOI: 10.1111/jir.13123 -
Frontiers in Endocrinology 2024Prader-Willi syndrome (PWS) is a rare disease, which shows a peculiar clinical phenotype, including obesity, which is different from essential obesity (EOB).... (Comparative Study)
Comparative Study
INTRODUCTION
Prader-Willi syndrome (PWS) is a rare disease, which shows a peculiar clinical phenotype, including obesity, which is different from essential obesity (EOB). Metabolomics might represent a valuable tool to reveal the biochemical mechanisms/pathways underlying clinical differences between PWS and EOB. The aim of the present (case-control, retrospective) study was to determine the metabolomic profile that characterizes PWS compared to EOB.
METHODS
A validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) targeted metabolomic approach was used to measure a total of 188 endogenous metabolites in plasma samples of 32 patients with PWS (F/M = 23/9; age: 31.6 ± 9.2 years; body mass index [BMI]: 42.1 ± 7.0 kg/m), compared to a sex-, age- and BMI-matched group of patients with EOB (F/M = 23/9; age: 31.4 ± 6.9 years; BMI: 43.5 ± 3.5 kg/m).
RESULTS
Body composition in PWS was different when compared to EOB, with increased fat mass and decreased fat-free mass. Glycemia and HDL cholesterol were higher in patients with PWS than in those with EOB, while insulinemia was lower, as well as heart rate. Resting energy expenditure was lower in the group with PWS than in the one with EOB, a difference that was missed after fat-free mass correction. Carrying out a series of Tobit multivariable linear regressions, adjusted for sex, diastolic blood pressure, and C reactive protein, a total of 28 metabolites was found to be associated with PWS (vs. non-PWS, i.e., EOB), including 9 phosphatidylcholines (PCs) ae, 5 PCs aa, all PCs aa, 7 lysoPCs a, all lysoPCs, 4 acetylcarnitines, and 1 sphingomyelin, all of which were higher in PWS than EOB.
CONCLUSIONS
PWS exhibits a specific metabolomic profile when compared to EOB, suggesting a different regulation of some biochemical pathways, fundamentally related to lipid metabolism.
Topics: Humans; Prader-Willi Syndrome; Female; Male; Adult; Metabolomics; Case-Control Studies; Retrospective Studies; Obesity, Morbid; Metabolome; Young Adult; Body Mass Index; Body Composition; Chromatography, Liquid; Tandem Mass Spectrometry
PubMed: 38812813
DOI: 10.3389/fendo.2024.1386265 -
The Journal of Clinical Endocrinology... Aug 2023Prader-Labhart-Willi syndrome (PWS) is a rare genetic disorder characterized by intellectual disability, behavioural problems, and hypothalamic dysfunction combined with...
CONTEXT
Prader-Labhart-Willi syndrome (PWS) is a rare genetic disorder characterized by intellectual disability, behavioural problems, and hypothalamic dysfunction combined with specific dysmorphisms. In PWS, growth hormone treatment is given primarily to improve body composition, yet lean body mass (LBM) does not normalize. Male hypogonadism is frequent in PWS and becomes evident during puberty. While LBM increases in normal boys during puberty, it is not known whether LBM and muscle mass concomitantly increase in PWS during spontaneous or induced puberty.
OBJECTIVE
To describe the peripubertal increment in muscle mass in boys with PWS undergoing growth hormone treatment.
DESIGN
Single-center, retrospective descriptive study, using data from 4 years before until 4 years after onset of puberty.
SETTING
Primary referral centre for PWS.
PATIENTS
Thirteen boys diagnosed with genetically proven PWS. The mean age at onset of puberty was 12.3 years; the mean observation period before (after) onset of puberty was 2.9 (3.1) years.
INTERVENTION
Puberty was induced upon pubertal arrest. All boys received internationally standardized growth hormone treatment.
MAIN OUTCOME MEASURE
Lean mass index (LMI) determined by dual energy X-ray absorptiometry.
RESULTS
LMI increased by 0.28 kg/m2 per year before puberty and by 0.74 kg/m2 per year after the onset of puberty. The time before puberty explained less than 10% of the variation in LMI, whereas the time after puberty onset explained about 25%.
CONCLUSION
Boys with PWS showed a recognizable increment in LMI during both spontaneous and induced puberty compared with the prepubertal phase, which was within the trajectories of normal boys. Therefore, timely testosterone substitution in the absence or at arrest of puberty during growth hormone treatment is important to optimize peak LBM in PWS.
Topics: Humans; Male; Child; Prader-Willi Syndrome; Retrospective Studies; Body Composition; Puberty; Growth Hormone
PubMed: 36869831
DOI: 10.1210/clinem/dgad101 -
Clinical Endocrinology Jun 2024Children with Prader-Willi Syndrome (PWS) may develop premature pubarche (PP). We investigated the frequency of PP, and its potential precursors and sequelae, in PWS.
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.
PubMed: 38935853
DOI: 10.1111/cen.15108 -
American Journal of Medical Genetics.... Oct 2023Current published guidelines for routine care of women with Prader-Willi syndrome (PWS) do not include recommendations for gynecologic examinations. We describe our...
Current published guidelines for routine care of women with Prader-Willi syndrome (PWS) do not include recommendations for gynecologic examinations. We describe our experience with gynecological examinations in women with PWS and offer recommendations for routine health care for these patients. Data were collected on all 41 PWS females ages ≥12 year, followed in our national Israeli multidisciplinary clinic between the years 2011 and 2022. Menstrual data and findings on external gynecological examination, including evaluation of the vulva and hymen were recorded at yearly visits. During the gynecological evaluation the topic of sexual education was discussed. Pelvic ultrasound, specifically for antral follicular count, was performed for those visiting the clinic during 2020-2022. Blood samples for luteinizing hormone (LH), follicular stimulating hormone (FSH), and estradiol were obtained routinely and DEXA scans for bone density were done when indicated. Of the 41 women, (median age at start of follow-up 17 years, range [12.3-39], BMI 30.4 kg/m [IQR 23.5-37.1]), 39 women agreed to external gynecological examination. Eleven women (27%) had spontaneous menses, with menarche at the age of 14 to as late as 31 years. The hymen was intact in all except one. Poor hygiene was observed in eight women, three women with vulvovaginitis, and five with irritated vulva related to poor hygiene. Gynecological ultrasound was performed in 27 women. In 22, endometrial thickness was less than 5 mm. The median antral follicular count (AFC) was 6 (<10th percentile for age). No correlation between AFC and menstruation or BMI was found. Mean FSH level was 5.7 ± 3.6 IU, LH was 2.29 ± 2.23, and estradiol was 128 ± 76 pmol/L. Data on DEXA measurements were available in 25 women aged 16-39. Median spine T score was -1.3 (range between 0.5 and -3.7), and hip T score was -1.2 (range between 0.8 and -3.3). A negative correlation was found between endometrial thickness and the presence of osteopenia or osteoporosis (r = -0.5, p = 0.013). Despite our recommendations, only eight of 14 women agreed to hormonal treatment or contraception. One woman who received treatment had a thromboembolic event. Routine health care for women with PWS should include gynecological examinations. The gynecological evaluation should include external genital examination, assessment of hygiene, obtaining a blood sample for hormone levels, and documenting a history of sexual experience or sexual abuse. Hormonal treatment or contraception should be offered when appropriate.
Topics: Humans; Adult; Female; Adolescent; Child; Young Adult; Gynecological Examination; Prader-Willi Syndrome; Luteinizing Hormone; Follicle Stimulating Hormone; Estradiol
PubMed: 37408363
DOI: 10.1002/ajmg.a.63343 -
Epilepsy & Behavior : E&B Jun 2024To estimate the prevalence of epilepsy and febrile seizures and their association with genotype, i.e., 15q11-q13 deletions, uniparental chromosome 15 disomy (UPD) and... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
To estimate the prevalence of epilepsy and febrile seizures and their association with genotype, i.e., 15q11-q13 deletions, uniparental chromosome 15 disomy (UPD) and other mutations, in the population with Prader-Willi syndrome (PWS).
METHODS
A systematic search of Medline, Scopus, Web of Science and the Cochrane Library was conducted. Studies estimating the prevalence of seizures, epilepsy and febrile seizures in the PWS population were included. Meta-analyses of the prevalence of epilepsy and febrile seizures and their association with genotype using the prevalence ratio (PR) were performed.
RESULTS
Fifteen studies were included. The prevalence of epilepsy was 0.11 (0.07, 0.15), similar to the prevalence of febrile seizures, with a prevalence of 0.09 (0.05, 0.13). The comparison "deletion vs. UPD" had a PR of 2.03 (0.90, 4.57) and 3.76 (1.54, 9.18) for epilepsy and febrile seizures.
CONCLUSIONS
The prevalence of seizure disorders in PWS is higher than in the general population. In addition, deletions in 15q11-q13 may be associated with a higher risk of seizure disorders. Therefore, active screening for seizure disorders in PWS should improve the lives of these people. In addition, genotype could be used to stratify risk, even for epilepsy, although more studies or larger sample sizes are needed.
Topics: Humans; Prader-Willi Syndrome; Epilepsy; Prevalence; Genotype; Chromosomes, Human, Pair 15
PubMed: 38663143
DOI: 10.1016/j.yebeh.2024.109803 -
Journal of Clinical Medicine Jun 2024: Strict regimens of restricted caloric intake and daily physical exercise are life-saving in Prader-Willi syndrome (PWS) but are extremely challenging in home...
: 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. : 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. : 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. : Our results suggest that living in SH is associated with benefits for physical health and behavior without negatively affecting QOL.
PubMed: 38893034
DOI: 10.3390/jcm13113323