Bone mineral density in young adults with Prader-Willi syndrome: A randomized, placebo-controlled, crossover GH trial

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Bone mineral density during 3 years of growth hormone in previously GH-treated young adults with PWS

Objective: In children with Prader-Willi syndrome (PWS), growth hormone ( GH) treatment has positive effects on bone mineral density (BMD). Two 1-year studies did not show a differe nce between GH or placebo on BMD in young adults with PWS. However, there are no studies investigating BM D during longer-term GH treatment in young adults with PWS. Design: Open-label, a prospective study in 43 young adults with PWS. Methods: BMD of the total body (BMDTBSDS) and lumbar spine (BMADLSSDS) measured by DXA. Results: In the total group, estimated mean (95% CI) of BMD TB remained similar during 3 years of GH, being -0.76 (-1.11 to -0.41) SDS at start and -0.90 (-1.27 to -0.54) SDS after 3 years (P = 0.11), as did BMADLS, being -0.36 (-0.72 to 0.01) SDS and -0.46 (-0.77 to -0.16) SDS, respectively (P = 0.16). In men, there was a significant decrease in BMDTBSDS during 3 years of GH, while BMAD LSSDS remained similar. In women, both BMDTBSDS and BMADLSSDS remained similar. BMDTBSDS was associated with female sex, lean body mass and age. The majority of patients received sex steroid replacement therapy (SSRT). Conclusions: During 3 years of combined GH and SSRT treatment, BMD remained stable in the normal range in young adults with PWS. However, men showed a decline in BMD TBSDS, probably due to insufficient SSRT. We recommended to continue GH treatment in young adults with PWS a nd to start SSRT during adolescence unless puberty progresses normally

Three years of growth hormone treatment in young adults with Prader-Willi syndrome: sustained positive effects on body composition

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Evidence for Accelerated Biological Aging in Young Adults with Prader-Willi Syndrome

Contains fulltext : 221496.pdf (Publisher’s version ) (Open Access

Limited additional value of karyotyping cultured amniotic fluid cell colonies in addition to microarray on uncultured cells for confirmation of abnormal non-invasive prenatal testing results

Objectives: Non-invasive prenatal testing (NIPT) allows the detection of placental chromosome aberrations. To verify whether the fetus also has the chromosome aberration, diagnostic follow-up testing is required. The aim of this retrospective study was to assess the added value of analyzing amniotic fluid (AF) cell cultures in addition to uncultured AF cells for the detection of fetal mosaicism. Method: NIPT was performed as part of the Dutch TRIDENT study. Cytogenetic studies in uncultured AF were performed using single nucleotide polymorphism (SNP)-array. Cultured AF cell colonies (in situ method) were investigated with fluorescent in situ hybridization and/or karyotyping. Clinical outcome data were collected in cases with discordant results. Results: Between April 2014 and December 2021, 368 amniocenteses were performed after a chromosomal aberration was detected with NIPT. Excluding 134 cases of common aneuploidies (confirmed by quantitative fluorescence polymerase chain reaction), 29 cases with investigation of uncultured cells only and 1 case without informed consent, 204 cases were eligible for this study. In 196 (96%) cases, the results in uncultured and cultured cells were concordant normal, abnormal or mosaic. Five cases (2%) showed mosaicism in cultured AF cells, whereas uncultured AF cells were normal. Two (1%) of these, one mosaic trisomy 13 and one mosaic trisomy 16, were considered true fetal mosaics. Conclusion: The added value of investigating AF cell cultures in addition to uncultured cells is limited to two of 204 (1%) cases in which true fetal mosaicsm would otherwise be missed. The clinical relevance of one (trisomy 13) remained unknown and the other case also showed ultrasound anomalies, which determined pregnancy management. This seems to justify limiting prenatal cytogenetic confirmatory testing to SNP arrays on uncultured AF cells, considerably shortening the reporting time.</p

Oxytocin in young children with Prader-Willi syndrome: Results of a randomized, double-blind, placebo-controlled, crossover trial investigating 3 months of oxytocin

Context: Prader-Willi syndrome (PWS) is characterized by hypothalamic dysfunction, hyperphagia and a typical behavioural phenotype, with characteristics of autism spectrum disorder (ASD) like stubbornness, temper tantrums and compulsivity. It has been suggested that the oxytocin system in patients with PWS is dysfunctional. In ASD, intranasal oxytocin treatment has favourable effects on behaviour. Objective: To evaluate the effects of 3 months of twice daily intranasal oxytocin (dose range 16-40 IU/day), compared to placebo, on behaviour and hyperphagia in children with PWS. Design: Randomized, double-blind, placebo-controlled, crossover study in the Dutch PWS Reference Center. Patients: Twenty-six children with PWS aged 3-11 years. Main outcome measures: (Change in) behaviour and hyperphagia measured by Oxytocin Questionnaire and Dykens hyperphagia questionnaire. Results: In the total group, no significant effects of oxytocin on social behaviour or hyperphagia were found. However, in boys, the Oxytocin Questionnaire scores improved significantly during oxytocin treatment, compared to a deterioration during placebo (4.5 (−0.8 to 15.3) vs. −4.0 (−11.3 to 0.8), P =.025). The Dykens hyperphagia questionnaire scores remained similar during oxytocin treatment, while there was a deterioration during placebo (0.0 (−0.8 to 4.3) vs. −3.5 (−6.0 to 0.0), P =.046). Patients with a deletion had significant improvements in both questionnaire scores during oxytocin treatment, but deteriorations during placebo. Oxytocin treatment was well tolerated, and there were no serious adverse events. Conclusions: Intranasal oxytocin treatment has positive effects on social and eating behaviour in 3-11 years aged boys with PWS and in children with a deletion without safety concerns. Intranasal oxytocin in children with PWS might be considered, but individual effects should be carefully evaluated and treatment discontinued if no effects are found

Free Insulin-like Growth Factor (IGF)-I in Children with PWS

In children with Prader-Willi syndrome (PWS), the standard growth hormone (GH) dose often results in high immunoreactive IGF-I levels. These high immunoreactive IGF-I levels lead to concern because their long-term effects are unknown. As a result, clinicians have to lower the GH dose, which worsens body composition and quality of life. As clinical features do not seem to correspond to immunoreactive IGF-I values, it is questionable whether immunoreactive IGF-I is a suitable marker for GH dosing, or whether another parameter better reflects IGF-I bioavailability and bioactivity. We, therefore, investigate serum immunoreactive IGF-I, free IGF-I and IGFBP-3 levels in 70 GH-treated children with PWS. Our study showed that, although immunoreactive IGF-I levels were high (&gt;2 SDS) in the vast majority of prepubertal and pubertal children, free IGF-I SDS levels were &lt;0 SDS in most and &lt;1 SDS in all. Free IGF-I correlated with the immunoreactive IGF-I, IGFBP-3 and IGF-I/IGFBP-3 ratio. We conclude that there is a major discrepancy between immunoreactive and free IGF-I levels. While in the majority of GH-treated children with PWS, immunoreactive IGF-I levels were high, free IGF-I levels were &lt;0 SDS in most. Our data appear to be very reassuring and suggest that free IGF-I levels should also be taken into consideration when the immunoreactive IGF-I levels are &gt;2 SDS in GH-treated children with PWS

Prevalence of growth hormone (GH) deficiency in previously GH-treated young adults with Prader-Willi syndrome

Objective: Some features of subjects with Prader-Willi syndrome (PWS) resemble those seen in growth hormone deficiency (GHD). Children with PWS are treated with growth hormone (GH), which has substantially changed their phenotype. Currently, young adults with PWS must discontinue GH after attainment of adult height when they do not fulfil the criteria of adult GHD. Limited information is available about the prevalence of GHD in adults with PWS. This study aimed to investigate the GH/insulin-like growth factor (IGF-I) axis and the prevalence of GHD in previously GH-treated young adults with PWS. Design: Cross-sectional study in 60 young adults with PWS. Measurements: Serum IGF-I and IGFBP-3 levels, GH peak during combined growth hormone-releasing hormone (GHRH)-arginine stimulation test. Results: Serum IGF-I was <−2 standard deviation scores (SDS) in 2 (3%) patients, and IGFBP-3 was within the normal range in all but one patient. Median (IQR) GH peak was 17.8 μg/L (12.2; 29.7) [~53.4 mU/L] and below 9 μg/L in 9 (15%) patients. Not one patient fulfilled the criteria for adult GHD (GH peak < 9 μg/L and IGF-I < −2 SDS), also when BMI-dependent criteria were used. A higher BMI and a higher fat mass percentage were significantly associated with a lower GH peak. There was no significant difference in GH peak between patients with a deletion or a maternal uniparental disomy (mUPD). Conclusions: In a large group of previously GH-treated young adults with PWS, approximately 1 in 7 exhibited a GH peak <9 μg/L during a GHRH-arginine test. However, none of the patients fulfilled the consensus criteria for adult GHD

Complementing the phenotypical spectrum of TUBA1A tubulinopathy and its role in early-onset epilepsies

TUBA1A tubulinopathy is a rare neurodevelopmental disorder associated with brain malformations as well as early-onset and intractable epilepsy. As pathomechanisms and genotype-phenotype correlations are not completely understood, we aimed to provide further insights into the phenotypic and genetic spectrum. We here present a multicenter case series of ten unrelated individuals from four European countries using systematic MRI re-evaluation, protein structure analysis, and prediction score modeling. In two cases, pregnancy was terminated due to brain malformations. Amongst the eight living individuals, the phenotypic range showed various severity. Global developmental delay and severe motor impairment with tetraparesis was present in 63% and 50% of the subjects, respectively. Epilepsy was observed in 75% of the cases, which showed infantile onset in 83% and a refractory course in 50%. One individual presented a novel TUBA1A-associated electroclinical phenotype with evolvement from early myoclonic encephalopathy to continuous spike-and-wave during sleep. Neuroradiological features comprised a heterogeneous spectrum of cortical and extracortical malformations including rare findings such as cobblestone lissencephaly and subcortical band heterotopia. Two individuals developed hydrocephalus with subsequent posterior infarction. We report four novel and five previously published TUBA1A missense variants whose resulting amino acid substitutions likely affect longitudinal, lateral, and motor protein interactions as well as GTP binding. Assessment of pathogenic and benign variant distributions in synopsis with prediction scores revealed sections of variant enrichment and intolerance to missense variation. We here extend the clinical, neuroradiological, and genetic spectrum of TUBA1A tubulinopathy and provide insights into residue-specific pathomechanisms and genotype-phenotype correlations