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.

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.

BACKGROUND: Prader-Willi syndrome (PWS) is a rare neurobehavioral-metabolic disease caused by the lack of paternally expressed genes in the chromosome 15q11-q13 region, characterized by hypotonia, neurocognitive problems, behavioral difficulties, endocrinopathies, and hyperphagia resulting in severe obesity if energy intake is not controlled. Diazoxide choline extended-release (DCCR) tablets have previously been evaluated for their effects on hyperphagia and other behavioral complications of people with PWS in a Phase 3 placebo-controlled study of participants with PWS, age 4 and older with hyperphagia (C601) and in an open label extension study, C602.
METHODS: To better understand the longer-term impact of DCCR, a cohort from PATH for PWS, a natural history study that enrolled participants with PWS age 5 and older, who met the C601 age, weight and baseline hyperphagia inclusion criteria and had 2 hyperphagia assessments ≥ 6 months apart, were compared to the C601/C602 cohort. Hyperphagia was measured using the Hyperphagia Questionnaire for Clinical Trials (HQ-CT, range 0-36). The primary analysis used observed values with no explicit imputation of missing data. A sensitivity analysis was conducted in which all missing HQ-CT assessments in the C601/C602 cohort were assigned the highest possible value (36), representing the worst-case scenario. Other behavioral changes were assessed using the Prader-Willi Syndrome Profile questionnaire (PWSP).
RESULTS: Relative to the PATH for PWS natural history study cohort, the DCCR-treated C601/C602 cohort showed significant improvements in HQ-CT score at 26 weeks (LSmean [SE] -8.3 [0.75] vs. -2.5 [0.43], p < 0.001) and 52 weeks (LSmean [SE] -9.2 [0.77] vs. -3.4 [0.47], p < 0.001). The comparison between the cohorts remained significant in the worst-case imputation sensitivity analysis. There were also significant improvements in all domains of the PWSP at 26 weeks (all p < 0.001) and 52 weeks (all p ≤ 0.003) for C601/C602 participants compared to the PATH for PWS participants.
CONCLUSIONS: Long-term administration of DCCR to people with PWS resulted in changes in hyperphagia and other behavioral complications of PWS that are distinct from the natural history of the syndrome as exemplified by the cohort from PATH for PWS. The combined effects of administration of DCCR should reduce the burden of the syndrome on the patient, caregivers and their families, and thereby may benefit people with PWS and their families.
BACKGROUND: Clinical study C601 was originally registered on ClinicalTrials.gov on February 22, 2018 (NCT03440814). Clinical study C602 was originally registered on ClinicalTrials.gov on October 22, 2018 (NCT03714373). PATH for PWS was originally registered on ClinicalTrials.gov on October 24, 2018 (NCT03718416).

OBJECTIVE: The effect of recombinant human growth hormone (rhGH) on sleep-disordered breathing (SDB) in Malaysian children with Prader-Willi syndrome (PWS) is under-investigated. We determined (1) the short- and long-term effects of rhGH and (2) factors associated with worsening SDB in children with PWS receiving rhGH.
METHODS: This retrospective study included children with PWS (with and without rhGH) who had undergone at least 1 polysomnography. Outcomes measured were the presence of SDB before and after starting rhGH and the progress of SDB with and without rhGH. Serial insulin-like growth factor 1 (IGF-1) measurements were recorded.
RESULTS: One-hundred and thirteen polysomnograms were analyzed. The majority (92.3%) of initial polysomnograms showed SDB, with a median (interquartile range) apnea-hypopnea index of 5.0 (2.6, 16.3) events/h. The age for receiving rhGH was a median (IQR) of 1.9 (0.7, 3.4) years. One-third (36.8%) had worsening SDB after initiating rhGH, which was associated with higher IGF-1 levels post-rhGH (P = .007). After a median of 5 years of rhGH, 73.6% maintained or reduced their positive airway pressure settings. Without rhGH, 80% had increased their positive airway pressure settings. Worsening SDB while on rhGH was associated with higher body mass index, lower rhGH dose, higher IGF-1 levels, and non-15q deletion.
CONCLUSIONS: The majority of Malaysian children with PWS had SDB. At initiation of rhGH, one-third of patients had worsening SDB, associated with increased IGF-1 levels. Stabilization of SDB was more frequently seen in those receiving long-term rhGH. Worsening SDB while on rhGH was associated with a higher body mass index, receiving a lower dose of rhGH, higher IGF-1 levels, and non-15q deletion.
BACKGROUND: Tan YT, Azanan MS, Hng SY, et al. Long-term effect of growth hormone on sleep-disordered breathing in Malaysian children with Prader-Willi syndrome: a retrospective study. J Clin Sleep Med. 2024;20(8):1291-1299.

[This corrects the article DOI: 10.3389/fendo.2023.1168648.].

Recombinant human growth hormone (rhGH) therapy is beneficial for children with Prader-Willi syndrome (PWS) in improving short stature and metabolism, but the effect of early rhGH treatment on respiratory and sleep parameters for PWS children under three years old remains elusive. Thus, this study aimed to investigate the impact of rhGH treatment on sleep-related breathing disorders (SRBDs) for toddlers with PWS.
A total of 17 age-matched PWS patients receiving rhGH treatment (rhGH group) and 17 control individuals not receiving rhGH treatment (non-rhGH group) were recruited for this study between October 2018 and January 2023. Data related to polysomnography-polygraphy (PSG) and serum levels of insulin-like growth factor (IGF-1) and insulin-like growth factor binding protein 3 (IGFBP-3) were collected.
The mean age in the rhGH group was 20.76 ± 9.22 months, which was comparable to that of the non-rhGH group (25.23 ± 13.81 months). The demographic and anthropometric parameters were similar across the two groups after 52 weeks of treatment. Administration of rhGH to toddlers did not exert adverse effects on the obstructive apnea-hypopnea index (OAHI), central apnea index (CAI), oxygen desaturation index (ODI), mean percutaneous oxygen saturation (SpO2), lowest SpO2, duration when SpO2 is lower than 90%, or proportion of the patients with SpO2 lower than 90%. Furthermore, the increased IGF-1 z-score and IGFBP-3 level did not worsen SRBDs.
Treatment with rhGH for 52 weeks on young toddlers with PWS showed no deleterious effects on SRBDs. This shed more light on the importance of initiating rhGH therapy early in PWS patients.

This study assessed the effect of 1-year administration of diazoxide choline extended-release tablet (DCCR) on hyperphagia and other complications of Prader-Willi syndrome (PWS).
The authors studied 125 participants with PWS, age ≥ 4 years, who were enrolled in the DESTINY PWS Phase 3 study and who received DCCR for up to 52 weeks in DESTINY PWS and/or its open-label extension. The primary efficacy endpoint was Hyperphagia Questionnaire for Clinical Trials (HQ-CT) score. Other endpoints included behavioral assessments, body composition, hormonal measures, and safety.
DCCR administration resulted in significant improvements in HQ-CT (mean [SE] -9.9 [0.77], p < 0.0001) and greater improvements in those with more severe baseline hyperphagia (HQ-CT > 22). Improvements were seen in aggression, anxiety, and compulsivity (all p < 0.0001). There were reductions in leptin, insulin, and insulin resistance, as well as a significant increase in adiponectin (all p < 0.004). Lean body mass was increased (p < 0.0001). Disease severity was reduced as assessed by clinician and caregiver (both p < 0.0001). Common treatment-emergent adverse events included hypertrichosis, peripheral edema, and hyperglycemia. Adverse events infrequently resulted in discontinuation (7.2%).
DCCR administration to people with PWS was well tolerated and associated with broad-ranging improvements in the syndrome. Sustained administration of DCCR has the potential to reduce disease severity and the burden of care for families.

Given the lack of data on dietary quality in young individuals with Prader-Willi syndrome (PWS) in Poland, a multiple case study was conducted in which anthropometric measurements and 7-day dietary records were collected from 20 subjects with PWS. The study group consisted of 8 females and 12 males with a mean age of 14.8 years and a mean BMI of 21.6. Based on BMI analysis, five subjects were overweight, including two subjects who were obese. The study showed that 35% of the subjects had energy intakes above the recommended levels. Protein deficiency was found in one subject in the analyzed diets. However, fat intake was excessive in four subjects, and the majority exceeded the recommended intake of saturated fatty acids. Vitamin E and B12 deficiencies were found in 40% and 85% of the subjects, respectively. All subjects had inadequate intakes of vitamin D and iodine, while the majority had deficiencies in sodium and copper intakes. Calcium intake was deficient in 35% of the subjects. However, most subjects met recommendations for the intakes of other minerals, vitamins, and fiber. These findings confirm the suboptimal dietary patterns of Polish individuals with PWS, with deficits observed in the intake of certain vitamins and minerals.

Prader-Willi syndrome (PWS) is a rare, complex, genetic disorder characterized by hyperphagia, hypotonia, delayed psychomotor development, low muscle mass and hypothalamic dysfunction. Adults with PWS often have obesity, hypertension and type 2 diabetes mellitus (DM2), known risk factors for cardiovascular disease (CVD) and chronic kidney disease (CKD). Early symptoms of CVD and CKD may be masked by intellectual disability and inability to express physical complaints. Furthermore, kidney diseases are often asymptomatic. Therefore, renal and cardiovascular disease might be missed in patients with PWS. Microalbuminuria is an early sign of microvascular damage in the kidneys and other vascular beds. Therefore, we screened our adult PWS cohort for the presence of elevated urinary albumin and (micro)albuminuria.
We retrospectively collected anthropometric measurements, blood pressure, medical history, medication use, urine dipstick and biochemical measurements form electronic patient files. In addition, we performed a systematic literature review on kidney disease in PWS.
We included 162 adults with genetically confirmed PWS (56% male, median age 28 years), of whom 44 (27%) had DM2. None had known CVD. All subjects had normal estimated glomerular filtration rate (eGFR) according to non-PWS reference intervals. Elevated urinary albumin or (micro)albuminuria was present in 28 (18%); 19 out of 75 (25%) had an increased urinary albumin-to-creatinine ratio (UACR) and 10 out of 57 (18%) had an increased urinary protein-to-creatinine ratio. Elevated urinary albumin was present at a young age (median age 26 (IQR 24-32) years) and was associated with an significantly higher BMI and LDL-cholesterol levels and higher prevalence of DM2, hypertension and dyslipidemia than those with normal UACR (p=0.027, p=0.019, p<0.001, p<0.001, p=0.011 and respectively).
Upon screening, one in every five adults with PWS had increased urinary albumin or (micro)albuminuria, early signs of microvascular disease. All had normal eGFR, according to non-PWS reference intervals, and none had a formal diagnosis of CVD. As muscle mass is low in PWS, creatinine levels and eGFR may be spuriously normal. Urinalysis in this patient group can be used as a screening tool for microvascular (kidney) disease. We propose an algorithm for the detection and management of microvascular disease in adults with PWS.

Prader-Willi syndrome (PWS) is a complex disorder resulting from the failure of expression of paternal alleles in the PWS region of chromosome 15. The PWS phenotype resembles that observed in the classic non-PWS GH deficiency (GHD), including short stature, excessive fat mass, and reduced muscle mass. To date, a small number of studies on the long-term effects of GH treatment are available in adult subjects with PWS.
In this longitudinal study, 12 obese subjects with PWS (GHD/non-GHD 6/6) were treated for a median of 17 years, with a median GH dose of 0.35 mg/day. The median age was 27.1 years. Anthropometric, body composition, hormonal, biochemical, and blood pressure variables were analyzed in all subjects.
Waist circumference was significantly lower at the end of the treatment period (p-value=0.0449), while body mass index (BMI) did not differ significantly. Compared to the baseline, a highly significant reduction of Fat Mass % (FM%) was observed (p-value=0.0005). IGF-I SDS values significantly increased during GH therapy (p-value=0.0005). A slight impairment of glucose homeostasis was observed after GH therapy, with an increase in the median fasting glucose levels, while insulin, HOMA-IR, and HbA1c values remained unchanged. Considering GH secretory status, both subjects with and without GHD showed a significant increase in IGF-I SDS and a reduction of FM% after GH therapy (p-value= 0.0313 for all).
Our results indicate that long-term GH treatment has beneficial effects on body composition and body fat distribution in adults with PWS associated with obesity. However, the increase in glucose values during GH therapy should be considered, and continuous surveillance of glucose metabolism is mandatory during long-term GH therapy, especially in subjects with obesity.