Daytime sleepiness and emotional and behavioral disturbances in Prader-Willi syndrome.

Individuals with Prader-Willi syndrome (PWS) often have excessive daytime sleepiness and emotional/behavioral disturbances. The objective of this study was to examine whether daytime sleepiness was associated with these emotional/behavioral problems, independent of nighttime sleep-disordered breathing, or the duration of sleep. Caregivers of individuals with PWS (aged 3 to 25 years) completed the Pediatric Sleep Questionnaire (PSQ), Epworth Sleepiness Scale for Children and Adolescents (ESS-CHAD), and the parent version of the Developmental Behavior Checklist (DBC-P). Sleep adequacy was adjusted for age by computing sleep duration against age-specific recommendations. The associations between ESS-CHAD and the total DBC and its subscale scores were evaluated by linear regression, adjusted for sleep-related breathing difficulties, sleep adequacy, and body mass index (BMI). There were 54 responses for individuals with PWS (including 22 males) aged 4.4-24.0 (mean 12.5) years. Daytime sleepiness predicted a substantial proportion of the variance in total DBC-P scores in the unadjusted model (28%; ß = 0.028; p < 0.001) and when adjusted for sleep adequacy, BMI, and sleep-related breathing difficulties (29%; ß = 0.023; p = 0.007). This relationship was not moderated by BMI Z-scores, but the relationship was more prominent for children younger than 12 years than for children older than 12 years.Conclusions: These findings provide preliminary novel evidence that daytime sleepiness may drive the expression of emotional/behavioral disturbances, and should be explored as a potential modifiable risk factor for these disturbances in PWS, particularly pre-adolescent children.

Sleep-disordered breathing in Australian children with Prader-Willi syndrome following initiation of growth hormone therapy.

AIM: In children with Prader-Willi syndrome (PWS), growth hormone (GH) improves height and body composition; however, may be associated with worsening sleep-disordered breathing (SDB). Some studies have reported less SDB after GH initiation, but follow-up with polysomnography is still advised in most clinical guidelines. METHODS: This retrospective, multicentre study, included children with PWS treated with GH at seven PWS treatment centres in Australia over the last 18 years. A paired analysis comparing polysomnographic measures of central and obstructive SDB in the same child, before and after GH initiation was performed with Wilcoxon signed-rank test. The proportion of children who developed moderate/severe obstructive sleep apnoea (OSA) was calculated with their binomial confidence intervals. RESULTS: We included 112 patients with available paired data. The median age at start of GH was 1.9 years (range 0.1-13.5 years). Median obstructive apnoea hypopnoea index (AHI) at baseline was 0.43/h (range 0-32.9); 35% had an obstructive AHI above 1.0/h. Follow-up polysomnography within 2 years after the start of GH was available in 94 children who did not receive OSA treatment. After GH initiation, there was no change in central AHI. The median obstructive AHI did not increase significantly (P = 0.13), but 12 children (13%, CI95% 7-21%) developed moderate/severe OSA, with clinical management implications. CONCLUSIONS: Our findings of a worsening of OSA severity in 13% of children with PWS support current advice to perform polysomnography after GH initiation. Early identification of worsening OSA may prevent severe sequelae in a subgroup of children.

Associations Between Hyperphagia, Symptoms of Sleep Breathing Disorder, Behaviour Difficulties and Caregiver Well-Being in Prader-Willi Syndrome: A Preliminary Study.

Prader-Willi syndrome (PWS) is a rare genetic disorder characterised by neurodevelopmental delays, hyperphagia, difficulties with social communication and challenging behaviours. Individuals require intensive supervision from caregivers which may negatively affect caregiver quality of life. This study used data collected in the Australasian PWS Registry (n = 50, mean age 11.2 years) to evaluate associations between child behaviours and caregiver mental well-being. Symptoms of sleep-related breathing disorder, child depression and social difficulties were associated with poorer caregiver mental and physical well-being. Growth hormone therapy use was associated with better caregiver mental and physical well-being. Optimising management of problematic behaviours and sleep disturbances have the potential to support caregivers who are the most vital network of support for individuals affected by PWS.

Role of cross-campus multidisciplinary team meetings in decision-making for children and adolescents with differences of sex development/intersex.

AIM: Management of children with differences/disorders of sex development (DSD) is complex with limited evidence to guide clinical decisions. Regular multidisciplinary team meetings were set up in Sydney and Melbourne paediatric hospitals to enable systematic peer review of complex decision-making. We aim to describe the workload and role of these meetings. METHODS: The multidisciplinary team forum includes invited representatives from endocrinology, urology, gynaecology, genetics, psychology, social work, clinical ethics, laboratory and hospital executive and meetings occur 1-3 times monthly. Descriptive data were collected from de-identified meeting referrals and minutes between August 2012 to August 2018 (Sydney) and January 2014 to August 2018 (Melbourne). RESULTS: A total of 192 referrals (142 new and 50 follow-ups) aged 1 week to 17 years were discussed across the two sites. 46, XY DSD (n = 81) was the most common sub-classification. Consideration of surgical options and optimal management of gonads with malignant potential were amongst the common reasons for referral to the multidisciplinary team meetings. Surgical interventions were considered but not recommended after review for 38 of 154 (24.7%) procedures. Gonad retention to allow potential functional benefit was recommended in 15/46 (32.6%) referrals. Evidence of premalignant or malignant changes was found in 20/57 (35%) gonads removed, with dysgenetic features and atrophy/streak features in 6 (10.5%) and 27 (47.4%) gonads respectively. CONCLUSION: Formal DSD multidisciplinary team meetings provide a framework and opportunity for multi and interdisciplinary discussions amongst representatives from several specialities to help make complex decision-making.

Analysis of variants in GATA4 and FOG2/ZFPM2 demonstrates benign contribution to 46,XY disorders of sex development.

BACKGROUND: GATA-binding protein 4 (GATA4) and Friend of GATA 2 protein (FOG2, also known as ZFPM2) form a heterodimer complex that has been shown to influence transcription of genes in a number of developmental systems. Recent evidence has also shown these genes play a role in gonadal sexual differentiation in humans. Previously we identified four variants in GATA4 and an unexpectedly large number of variants in ZFPM2 in a cohort of individuals with 46,XY Differences/Disorders of Sex Development (DSD) (Eggers et al, Genome Biology, 2016; 17: 243). METHOD: Here, we review variant curation and test the functional activity of GATA4 and ZFPM2 variants. We assess variant transcriptional activity on gonadal specific promoters (Sox9 and AMH) and variant protein-protein interactions. RESULTS: Our findings support that the majority of GATA4 and ZFPM2 variants we identified are benign in their contribution to 46,XY DSD. Indeed, only one variant, in the conserved N-terminal zinc finger of GATA4, was considered pathogenic, with functional analysis confirming differences in its ability to regulate Sox9 and AMH and in protein interaction with ZFPM2. CONCLUSIONS: Our study helps define the genetic factors contributing to 46,XY DSD and suggests that the majority of variants we identified in GATA4 and ZFPM2/FOG2 are not causative.

Effect of Turner's syndrome and X-linked imprinting on cognitive status: analysis based on pedigree data.

The effects of a monosomy of either the maternally or paternally derived X chromosome in Turner's syndrome (TS) on general neurocognitive status and some executive abilities were assessed using the maximum likelihood estimators for pedigree data. This method increases the power of analysis by accounting for the effect of background heritable variation on a trait. The sample comprised 42 females with regular non-mosaic X monosomy and their non-affected relatives. Wechsler neurocognitive scores and several executive function tests' scores, including the Behaviour Dyscontrol Scale (BDS-2), the Wisconsin Card Sorting Test (WCST), and the Rey Complex Figure Test (RCFT), were considered in the analysis. Results showed a significant effect of TS on all Wechsler index and subtest scores, with greatest deficits observed in Arithmetic, Block Design, Object Assembly and Picture Arrangement, and on the total BDS, RCFT and WCST scores, regardless of parental origin of the single X-chromosome. Our data also showed a significantly higher effect of a paternally derived X chromosome in diminishing the performance on several Wechsler scores relevant to verbal skills, which might suggest X-linked imprinting loci relevant to these skills. Possible reasons for the inconsistency of the results concerning X-linked imprinting of cognitive loci using TS patients are discussed, and the relevance of pedigree analysis to future studies of this problem is emphasized.

Expression of the IGF system in normal and diabetic transgenic (mRen-2)27 rat eye.

PURPOSE: In the present study, a recently described model of diabetic eye disease was used to investigate the distribution of the insulin-like growth factor (IGF) system in the eyes of transgenic (mRen-2)27 rats (exhibiting hypertension and elevated serum and ocular renin levels) with streptozotocin-induced diabetes. METHODS: Female transgenic (mRen-2)27 rats were randomized to receive either streptozotocin (diabetic) or citrate buffer (control). After 10 months, the rats were killed and the eyes fixed and embedded in paraffin. In situ hybridization (ISH) was used to document the cellular distribution of mRNAs for components of the IGF system (IGF-I, IGF-I receptor [IGFIR] and IGF binding proteins [IGFBP]1 to -6) in the eyes. RESULTS: In nondiabetic rats, mRNA for IGFBP-1, -5, and -6; IGF-I; and IGFIR were detected in the retina. In addition, IGF-I mRNA was present in the cornea, IGFBP-1 mRNA was observed in the cornea and iris, and IGFBP-5 and -6 mRNAs were identified in the ciliary body, iris, and cornea. mRNAs for IGFBP-2, -3, and -4 were not found in the eyes. In diabetic rats, reduced levels of IGFBP-6 mRNA were detectable, whereas levels of IGFBP-5 mRNA were increased in the inner and outer retina, rods and cones, iris, cornea, and ciliary body. Other components of the IGF system in the eye were unchanged with diabetes. CONCLUSIONS: In the diabetic (mRen-2)27 rat, IGFBP-6 is downregulated and IGFBP-5 is upregulated by induction of diabetes. Because these IGFBPs may respectively have IGF-enhancing and IGF-inhibitory effects, these findings suggest a possible net IGF-enhancing effect induced by diabetes, providing further evidence for a role of the IGF system in the development of diabetic retinopathy.