Obesity among adolescents poses a significant global health concern with profound short- and long-term impact on physical and mental well-being. The intricate relationship between obesity and the onset of diabetes remains ambiguous, particularly in cases where the manifestation may differ from that observed in individuals with uncomplicated obesity. Herein, we present the case of a 14-year-old male adolescent with Prader-Willi phenotype and subsequent obesity, exhibiting symptoms of polyuria and polydipsia over a 10-day period, indicative of potential diabetes mellitus (DM). Laboratory assessments revealed a hemoglobin A1c level of 10%, confirming the suspected diagnosis. Notably, despite the absence of ketosis, elevated C-peptide levels and the presence of slightly positive islet-cell antibodies warranted further investigation. While the presence of antibodies typically aligns with a diagnosis of type 1 DM, recent research has highlighted the occurrence of anti-insulin pancreatic cell antibodies in type 2 DM cases. This article aims to delve into the multifaceted issues surrounding adolescent obesity, atypical presentations of DM with positive antibodies, and the long-term management of patients with genetic syndromes.

Rare neurological diseases include a vast group of heterogenous syndromes with primary impairment(s) in the peripheral and/or central nervous systems. Such rare disorders may have overlapping phenotypes, despite their distinct genetic etiology. One unique aspect of rare neurological diseases is their potential common association with altered epigenetic mechanisms. Epigenetic mechanisms include regulatory processes that control gene expression and cellular phenotype without changing the composition of the corresponding DNA sequences. Epigenetic factors include three types of proteins, the \"readers, writers, and erasers\" of DNA and DNA-bound proteins. Thus, epigenetic impairments of many neurological diseases may contribute to their pathology and manifested phenotypes. Here, we aim to provide a comprehensive review on the general etiology of selected rare neurological diseases, that include Rett Syndrome, Prader-Willi Syndrome, Rubinstein-Taybi Syndrome, Huntington\'s disease, and Angelman syndrome, with respect to their associated aberrant epigenetic mechanisms.

OBJECTIVE: Clinical benefits of growth hormone (GH) in Prader-Willi syndrome (PWS) are proven and scoliosis is a known association of both PWS and GH therapy. The aims of this study were to assess GH prescribing practices and growth outcomes over time, the prevalence and predictors of scoliosis in GH-treated PWS children, and the near-final height of GH-treated PWS patients.
METHODS: This is a retrospective, descriptive study evaluating data from all clinic visits of patients aged 0-18 years with PWS, seen through the Children\'s Hospital at Westmead between March 1992 and May 2022 (n=75).
RESULTS: A total of 64 patients were treated with GH (visits = 1,414). In the recent decade, the diagnosis of PWS and GH commencement were made significantly earlier in life. The prevalence of scoliosis was 41 %, in which age was the only significant predictor for scoliosis (odds ratio 1.19: 95 % CI [1.08-1.31; p=0.001]) adjusted for other predictors. In patients with data available at the age 16 years (23/28 treated with GH), those who were GH treated had significantly higher height SDS vs. nontreated group (SDS -0.67 vs. -2.58; p=0.0001) and lower BMI SDS (1.18 vs. 2.37; p<0.001).
CONCLUSIONS: Significant improvements in growth and body composition were seen in the GH-treated group vs. non-treated group of children with PWS. There were no significant modifiable clinical predictors of scoliosis in children with PWS, but our findings confirm the high prevalence of scoliosis in GH-treated children with PWS reinforcing the need for close surveillance.

Congenital disorders of ventilatory control typically manifest as central apneas, periodic breathing, and hypoventilation in the neonatal period, but some may present at a later age. Obstructive apneas may be the initial presentation, and some may have associated autonomic nervous system dysfunction. Individuals with these disorders can have absent or impaired ventilatory and arousal responses to hypoxemia and hypercapnia. This article discusses the presentation, pathophysiology, evaluation, and management of congenital central hypoventilation syndrome, rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) syndrome, Prader-Willi syndrome, and myelomeningocele.

OBJECTIVE: 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.
CONCLUSIONS: 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.

BACKGROUND: 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.

Human cell line models, including the neuronal precursor line LUHMES, are important for investigating developmental transcriptional dynamics within imprinted regions, particularly the 15q11-q13 Angelman (AS) and Prader-Willi (PWS) syndrome locus. AS results from loss of maternal UBE3A in neurons, where the paternal allele is silenced by a convergent antisense transcript UBE3A-ATS, a lncRNA that terminates at PWAR1 in non-neurons. qRT-PCR analysis confirmed the exclusive and progressive increase in UBE3A-ATS in differentiating LUHMES neurons, validating their use for studying UBE3A silencing. Genome-wide transcriptome analyses revealed changes to 11 834 genes during neuronal differentiation, including the upregulation of most genes within the 15q11-q13 locus. To identify dynamic changes in chromatin loops linked to transcriptional activity, we performed a HiChIP validated by 4C, which identified two neuron-specific CTCF loops between MAGEL2-SNRPN and PWAR1-UBE3A. To determine if allele-specific differentially methylated regions (DMR) may be associated with CTCF loop anchors, whole genome long-read nanopore sequencing was performed. We identified a paternally hypomethylated DMR near the SNRPN upstream loop anchor exclusive to neurons and a paternally hypermethylated DMR near the PWAR1 CTCF anchor exclusive to undifferentiated cells, consistent with increases in neuronal transcription. Additionally, DMRs near CTCF loop anchors were observed in both cell types, indicative of allele-specific differences in chromatin loops regulating imprinted transcription. These results provide an integrated view of the 15q11-q13 epigenetic landscape during LUHMES neuronal differentiation, underscoring the complex interplay of transcription, chromatin looping, and DNA methylation. They also provide insights for future therapeutic approaches for AS and PWS.

Prader-Willi syndrome (PWS) is a rare disorder characterised by varying nutritional phases that occur throughout the lifespan, ranging from failure to thrive to hyperphagia. If uncontrolled, the imbalance between energy intake and expenditure results in obesity development and increased morbidity and mortality risk. Although measures of energy requirements for accurate nutrition assessment are vital, the evidence appears sparse and heterogeneous; hence, the aim of this review was to examine the available literature on energy expenditure predicted or measured using various methods in individuals with PWS. Studies were sought that presented methods and results on resting energy expenditure or basal metabolic rate. A narrative synthesis was completed to present the study characteristics and results. Methods of determining energy requirements included predictive equations and indirect calorimetry. Differences amongst ages, growth hormone therapy, fasting status, and measures in which results were presented were limitations to appropriately summarising and identifying trends in energy expenditure. Indirect calorimetry was identified as the most accurate method; however, it is not widely available in all settings. Further research is encouraged to support the development of valid and reliable predictive equations that will better inform and improve the efficiency of clinical practice in supporting people with PWS.

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

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