CHD8, a major autism gene, functions in chromatin remodelling and has various roles involving several biological pathways. Therefore, unsurprisingly, previous studies have shown that intellectual developmental disorder with autism and macrocephaly (IDDAM), the syndrome caused by pathogenic variants in CHD8, consists of a broad range of phenotypic abnormalities. We collected and reviewed 106 individuals with IDDAM, including 36 individuals not previously published, thus enabling thorough genotype–phenotype analyses, involving the CHD8 mutation spectrum, characterization of the CHD8 DNA methylation episignature, and the systematic analysis of phenotypes collected in Human Phenotype Ontology (HPO). We identified 29 unique nonsense, 25 frameshift, 24 missense, and 12 splice site variants. Furthermore, two unique inframe deletions, one larger deletion (exons 26–28), and one translocation were observed. Methylation analysis was performed for 13 patients, 11 of which showed the previously established episignature for IDDAM (85%) associated with CHD8 haploinsufficiency, one analysis was inconclusive, and one showing a possible gain-of-function signature instead of the expected haploinsufficiency signature was observed. Consistent with previous studies, phenotypical abnormalities affected multiple organ systems. Many neurological abnormalities, like intellectual disability (68%) and hypotonia (29%) were observed, as well as a wide variety of behavioural abnormalities (88%). Most frequently observed behavioural problems included autism spectrum disorder (76%), short attention span (32%), abnormal social behaviour (31%), sleep disturbance (29%) and impaired social interactions (28%). Furthermore, abnormalities in the digestive (53%), musculoskeletal (79%) and genitourinary systems (18%) were noted. Although no significant difference in severity was observed between males and females, individuals with a missense variant were less severely affected. Our study provides an extensive review of all phenotypic abnormalities in patients with IDDAM and provides clinical recommendations, which will be of significant value to individuals with a pathogenic variant in CHD8, their families, and clinicians as it gives a more refined insight into the clinical and molecular spectrum of IDDAM, which is essential for accurate care and counselling.
BACKGROUND: Structured transitional care (TC) is the planned, purposeful transfer from pediatric to adult care that aims to maintain high quality, developmentally appropriate continuous care. Relatively little is known about how endocrine TC is structured internationally, the process of TC and what outcomes are a priority for endocrine TC. This pilot study aimed to better understand endocrine TC and identify key elements for successful implementation internationally. METHODS: The Donabedian framework (structure-process-outcome) guided the international web-based survey examining TC programs for adolescents and young adults (AYAs) 16–25 years-old. The survey examined: 1) best practices i.e. six core elements of TC (Center for Health Care Transition Improvement ‘Got Transition’); 2) nursing involvement; 3) perceived importance of the ‘10 priority outcomes’ identified by an international multidisciplinary Delphi process (Fair et al. JAMA Pediatrics, 2016); and 4) promoters/barriers to implementation. Descriptive analysis was conducted for close-ended questions and thematic analysis for open-ended questions. Rankings by endocrine clinics were compared to the ‘10 priority outcomes’. RESULTS: Invitations were sent to authors of publications/posters on endocrine TC from the past 10 years. Eight responses were recorded from academic medical centers across seven countries with structured (n=3), semi-structured (n=2) and unstructured TC (n=3). Only 2/8 received institutional funding. Two practices involved nurses in assessing transition readiness and cited direct clinical care, therapeutic education and emotional support for AYAs/families as important contributions. Groups lacking nursing involvement expressed desire for a nursing role if financed. The most commonly used ‘Got Transition’ core elements were: providing supporting materials, confirming adult visit and consulting with adult providers. Only one group formally collected TC outcome data. “Self-management” was rated the most important TC outcome. “Understanding the condition/complications” and “attending medical appointments” were seen as having relatively higher priority for endocrine TC. Barriers related to lack of financial support and low institutional priority. Involving key stakeholders facilitated implementation. Having a dedicated nurse was noted as an opportunity for improving TC. CONCLUSIONS: Implementation of structured TC has been piecemeal and most practices do not fully utilize recommended best practices (‘Got Transition’). Few practices formally collect outcome data. The major perceived barrier to implementing TC is financial. Practices incorporating nurses value discipline-specific contributions. These pilot data point to a role for nursing in providing comprehensive, high quality, comprehensive care for AYAs with chronic endocrine conditions.
Introduction: Prader-Willi syndrome (PWS) is a complex hypothalamic disorder, combining hypotonia, intellectual disability (ID), pituitary hormone deficiencies and hyperphagia. In PWS, up to 3% of patients die every year. In half of the patients, the cause of death is obesity related and / or of cardiovascular (CV) origin. Obesity is caused by hyperphagia combined with a low energy expenditure. Untreated hormone deficiencies like hypogonadism and hypothyroidism can cause low muscle mass and low basal rest metabolism (BRM) leading to this low energy expenditure. Patients with PWS should exercise one hour daily to compensate for their low BRM. However, hormone deficiencies usually cause fatigue, leading to exercise intolerance. Musculoskeletal and / or behavioral problems can also cause reduced physical activity. The subsequent sedentary lifestyle can induce CV risk factors like hypertension, hypercholesterolemia and diabetes mellitus (DM). Another risk factor often present in PWS is sleep apnea, which can be central (CSA), obstructive (OSA) or both. Both CSA and OSA can lead to pulmonary hypertension and a further increase in obesity. The above mentioned health problems often remain unnoticed and untreated, which is partly due to the behavioral phenotype of PWS (patients seldomly report pain and hardly ever complain about physical problems). However, if left untreated, these risk factors can cause CV complications leading to hospital admission or even death. To reveal yet undiagnosed health problems, we performed a systematic health screening among adults with PWS. Methods: We systematically screened 115 adults with PWS (mean age 31.4 ± 12.1 y, mean BMI 31.8 ± 9,5 kg/m2) for the presence of undiagnosed health problems and cardiovascular risk factors. Based on a medical questionnaire, medical file search, extensive interview, thorough physical examination and biochemical measurements we made an overview of the undiagnosed health problems in adults with PWS. If possible, we performed polygraphy to test for sleep apnea. Results: Undiagnosed health problems (hypertension, DM, hypercholesterolemia, sleep apnea, hypothyroidism and hypogonadism) were present in 50% of the patients. 10% had multiple undiagnosed health problems simultaneously. All males and 94% of females had hypogonadism and 15% had hypothyroidism. Hypertension and / or hypercholesterolemia were present in 20% and DM was present in 16%. One third of patients was not on a diet and 22% exercised less than 30 minutes a day. Sleep apnea was present in 17 of 26 patients tested. Conclusion: We detected a striking number of undiagnosed health problems among adults with PWS which, if left untreated, can pose a serious health threat. Systematic screening is needed to detect these problems in an early phase. This will prevent burdensome and expensive complications and might even reduce mortality in this vulnerable patient population.
Introduction Transition from paediatric to adult endocrinology is a challenge for adolescents, their families and their healthcare professionals. Previous studies show that up to 25% of young adults with endocrine disorders are lost to follow-up once they move out of paediatric care. This poses a health risk for young adults, as lack of medical treatment and surveillance can have both psycho-social and physical consequences. Apart from absenteeism from school or work, this can lead to serious and expensive medical complications like Addison crisis. Methods In 2019 we studied electronic medical records of 387 patients who were over 15 years old when they attended the paediatric endocrine outpatient clinic (OPC) of our medical centre in 2013-2014. We collected data from medical charts, the hospital digital agenda and medical correspondence. Results Of 387 adolescents, 161 (42%) did not need adult endocrine follow-up because paediatric endocrine care was only puberty- or growth-related. Forty-six patients did not enter regular transition because they 1) participated in a pilot to improve transition (N=10), 2) had intellectual disability (ID) and transferred to ID care (N=28), or 3) died (N=8, mostly cancer-related). Hundred-and-eighty patients entered regular transition: 49 (27%) to a regional hospital and 131 (73%) within our university hospital. Of these 131 patients, 33 (25%) were lost to follow up; in 24 of them (73%), the invitation for the adult OPC had never been sent. Loss to follow up occurred when three subsequent critical steps failed: 1) the adult endocrinologist had not received or read the paediatrician’s referral letter and/or had not invited the patient; 2) the paediatrician had not checked whether the appointment was really made and received by the patient and 3) the patients and/or caregivers had not alarmed the hospital when no invitation for an appointment was received. Conclusion We found a 25% dropout during transfer from paediatric to adult tertiary endocrine care. Starting the transition process early and in a structured manner, as well as assigning a transition coordinator, can prevent part of the dropouts. However, 73% of all dropouts appeared to be attributable to failure of practical, logistic steps. In order to prevent this part of the dropouts, we provide practical recommendations for all three parties involved: 1) the adult endocrinologist should carefully read paediatricians’ letters and check whether action is required (i.e. check whether an appointment is requested) 2) the paediatrician should ascertain whether the appointment is really made and received by the patient 3) the patients and/or caregivers should be instructed to alarm the hospital when they do not receive the appointment. These actions require relatively little effort and may prevent the part of drop-outs that is caused by logistic failures.
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