Prader-Willi Syndrome: guidance for children and transition into adulthood.

Prader Willi syndrome (PWS) is a rare orphan disease and complex genetic neurodevelopmental disorder, with a birth incidence of approximately 1 in 10,000-30,000. Management of people with PWS requires a multi-disciplinary approach, ideally through a multi-disciplinary team (MDT) clinic with community support. Hypotonia, poor feeding and faltering growth are characteristic features in the neonatal period, followed by hyperphagia and risk of rapid weight gain later in childhood. Children and adolescents (CA) with PWS usually display developmental delay and mild learning disability, and can develop endocrinopathies, scoliosis, respiratory difficulties (both central and obstructive sleep apnoea), challenging behaviours, skin picking, and mental health issues especially into adulthood. This consensus statement is intended to be a reference document for clinicians managing children and adolescents (up to 18 years of age) with PWS. It considers the bio-psycho-social domains of diagnosis, clinical assessment, and management in the paediatric setting as well as during and after transition to adult services. The guidance has been developed from information gathered from peer-reviewed scientific reports and from the expertise of a range of experienced clinicians in the United Kingdom and Ireland involved in the care of patients with PWS.

Diabetes control is worse in children and young people with type 1 diabetes requiring interpreter support.

Introduction: Language barriers can pose a significant hurdle to successfully educating children and young people with type 1 diabetes (CYPD) and their families, potentially influencing their glycaemic control. Methods: Retrospective case-control study assessing HbA1c values at 0, 3, 6, 9, 12 and 18 months post-diagnosis in 41 CYPD requiring interpreter support (INT) and 100 age-, sex- and mode-of-therapy-matched CYPD not requiring interpreter support (CTR) in our multi-diverse tertiary diabetes centre. Data were captured between 2009-2016. English indices of deprivation for each cohort are reported based on the UK 2015 census data. Results: The main languages spoken were Somali (27%), Urdu (19.5%), Romanian (17%) and Arabic (12%), but also Polish, Hindi, Tigrinya, Portuguese, Bengali and sign language. Overall deprivation was worse in the INT group according to the Index of Multiple Deprivation (IMD [median]: INT 1.642; CTR 3.741; p=0.001). The median HbA1c was higher at diagnosis in the CTR group (9.95% [85.2 mmol/mol] versus 9.0% [74.9 mmol/mol], p=0.046) but was higher in the INT group subsequently: the median HbA1c at 18 months post diagnosis was 8.3% (67.2 mmol/mol; INT) versus 7.9% (62.8 mmol/mol; CTR) (p=0.014). There was no hospitalisation secondary to diabetes-related complications in either cohorts. Summary and conclusions: Glycaemic control is worse in CYPD with language barriers. These subset of patients also come from the most deprived areas which adds to the disadvantage. Health care providers should offer tailored support for CYP/families with language barriers, including provision of diabetes-specific training for interpreters, and explore additional factors contributing to poor glycaemic control. The findings of this study suggest that poor health outcomes in CYPD with language barriers is multifactorial and warrants a multi-dimensional management approach.

Management aspects of congenital adrenal hyperplasia during adolescence and transition to adult care.

The adolescent period is characterised by fundamental hormonal changes, which affect sex steroid production, cortisol metabolism and insulin sensitivity. These physiological changes have a significant impact on patients with congenital adrenal hyperplasia (CAH). An essential treatment aim across the lifespan in patients with CAH is to replace glucocorticoids sufficiently to avoid excess adrenal androgen production but equally to avoid cardiometabolic risks associated with excess glucocorticoid intake. The changes to the hormonal milieu at puberty, combined with poor adherence to medical therapy, often result in unsatisfactory control exacerbating androgen excess and increasing the risk of metabolic complications due to steroid over-replacement. With the physical and cognitive maturation of the adolescent with CAH, fertility issues and sexual function become a new focus of patient care in the paediatric clinic. This requires close surveillance for gonadal dysfunction, such as irregular periods/hirsutism or genital surgery-associated symptoms in girls and central hypogonadism or testicular adrenal rest tumours in boys. To ensure good health outcomes across the lifespan, the transition process from paediatric to adult care of patients with CAH must be planned carefully and early from the beginning of adolescence, spanning over many years into young adulthood. Its key aims are to empower the young person through education with full disclosure of their medical history, to ensure appropriate follow-up with experienced physicians and facilitate access to multispecialist teams addressing the complex needs of patients with CAH.

Quality of Life in Children and Young People With Congenital Adrenal Hyperplasia-UK Nationwide Multicenter Assessment.

CONTEXT: Quality of life (QoL) has been inconsistently reported in children and young people (CYP) with congenital adrenal hyperplasia (CAH). OBJECTIVE: Assess QoL in CYP with CAH in the UK alongside biometric and androgen profiles. DESIGN: To define the evidence base for health care delivery, we conducted a cross-sectional study in CYP with CAH in the UK. Questionnaire results were compared with normative data and between groups, and modelled for association with sex, height, weight, body mass index, or steroid biomarkers of CAH control. SETTING: Tertiary care in 14 UK centers. PATIENTS: Results from 104 patients, 55% female, mean age 12.7 years (SD 3.0), paired responses from parents. INTERVENTIONS: Strengths and Difficulties questionnaire (SDQ) and pediatric QoL questionnaire. MAIN OUTCOME MEASURE: Total QoL scores as assessed by SDQ and a pediatric QoL questionnaire in comparison to normative data. RESULTS: Total scores were worse in parents than normative data, but similar in patients. Patient QoL was rated better in social functioning but worse in emotional, school, and peer domains by patients, and worse in total scores and domains of peer problems, and psychosocial, emotional, and school functioning by parents. Parents consistently scored QoL of their children lower than their child. Larger height-SD score and lower weight-SD score were associated with better QoL. Girls with lower steroid biomarkers had worse SDQ scores. CONCLUSIONS: In CYP with CAH, reduced height, increased weight, and hormonal biomarkers consistent with overtreatment were associated with worse QoL; addressing these problems should be prioritized in clinical management.Clinical Trials Registration Number: SCH/15/088.

Health status of children and young persons with congenital adrenal hyperplasia in the UK (CAH-UK): a cross-sectional multi-centre study.

Objective: There is limited knowledge on the onset of comorbidities in congenital adrenal hyperplasia (CAH) during childhood. We aimed to establish the health status of children with CAH in the UK. Design and methods: This cross-sectional multicentre study involved 14 tertiary endocrine UK units, recruiting 101 patients aged 8-18 years with classic 21-hydroxylase deficiency and 83 controls. We analysed demographic, clinical and metabolic data, as well as psychological questionnaires (Strengths and Difficulties (SDQ), Paediatric Quality of Life (PedsQL)). Results: Patient height SDS in relation to mid-parental height decreased with age, indicating the discrepancy between height achieved and genetic potential height. Bone age was advanced in 40.5% patients, with a mean difference from the chronological age of 1.8 (±2.3) years. Patients were more frequently overweight (27%) or obese (22%) compared to controls (10.8% and 10.8%, respectively, P < 0.001). No consistent relationship between glucocorticoid dose and anthropometric measurements or hormonal biomarkers was detected. A small number of patients had raised total cholesterol (3.0%), low HDL (3.0%), raised LDL (7.0%) and triglycerides (5.0%). SDQ scores were within the 'high' and 'very high' categories of concern for 16.3% of patients. 'School functioning' was the lowest PedsQL scoring dimension with a median (interquartile range) of 70 (55-80), followed by 'emotional functioning' with a median of 75 (65-85). Conclusions: Our results show an increased prevalence of problems with growth and weight gain in CAH children and suggest reduced quality of life. This highlights the urgent need to optimise management and monitoring strategies to improve long-term health outcomes.

Treatment of congenital adrenal hyperplasia in children aged 0-3 years: a retrospective multicenter analysis of salt supplementation, glucocorticoid and mineralocorticoid medication, growth and blood pressure.

Objectives: International guidelines recommend additional salt supplementation during infancy in classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. The influence of corticoid medication and growth has not been assessed. Aim: To investigate the current use of salt supplementation, fludrocortisone (FC) and hydrocortisone (HC) dosage as well as weight, height, BMI and blood pressure (BP) in CAH children aged 0-3 years. Methods: Retrospective multicentre analysis using data from the I-CAH registry. Salt-treated (ST) and non-salt-treated (NST) children were compared regarding FC and HC dosage, weight, height and BP at 0, 3, 6, 9, 12, 18, 24, 30, and 36 months. Results: We analysed 2483 visits of 331 patients born after year 2000 in 13 countries (male, n = 145) with 203 ST patients (61%). NST children had significantly higher FC dosages at 1.5-4.5 months and higher HC dosages until 1.5 months of age. No differences in weight, length and BP between subgroups were observed. Children of the whole cohort showed increased BMI-SDS during the study period and about half of the reported BP readings were >P95. Conclusion: In children treated with additional salt supplementation, FC and HC dosages are lower during the first months of life but without differences in weight, length and BP until 3 years of age compared to NST children. All children showed an increase in BMI-SDS and a high rate of BP readings >P95 until 3 years, indicating the start of weight gain and negative effects on blood pressure already in very early life.

International practice of corticosteroid replacement therapy in congenital adrenal hyperplasia: data from the I-CAH registry.

OBJECTIVE: Despite published guidelines no unified approach to hormone replacement in congenital adrenal hyperplasia (CAH) exists. We aimed to explore geographical and temporal variations in the treatment with glucocorticoids and mineralocorticoids in CAH. DESIGN: This retrospective multi-center study, including 31 centers (16 countries), analyzed data from the International-CAH Registry. METHODS: Data were collected from 461 patients aged 0-18 years with classic 21-hydroxylase deficiency (54.9% females) under follow-up between 1982 and 2018. Type, dose and timing of glucocorticoid and mineralocorticoid replacement were analyzed from 4174 patient visits. RESULTS: The most frequently used glucocorticoid was hydrocortisone (87.6%). Overall, there were significant differences between age groups with regards to daily hydrocortisone-equivalent dose for body surface, with the lowest dose (median with interquartile range) of 12.0 (10.0-14.5) mg/m2/day at age 1-8 years and the highest dose of 14.0 (11.6-17.4) mg/m2/day at age 12-18 years. Glucocorticoid doses decreased after 2010 in patients 0-8 years (P < 0.001) and remained unchanged in patients aged 8-18 years. Fludrocortisone was used in 92% of patients, with relative doses decreasing with age. A wide variation was observed among countries with regards to all aspects of steroid hormone replacement. CONCLUSIONS: Data from the I-CAH Registry suggests international variations in hormone replacement therapy, with a tendency to treatment with high doses in children.

Causes, patterns and severity of androgen excess in 487 consecutively recruited pre- and post-pubertal children.

Objective Androgen excess in childhood is a common presentation and may signify sinister underlying pathology. Data describing its patterns and severity are scarce, limiting the information available for clinical decision processes. Here, we examined the differential diagnostic value of serum DHEAS, androstenedione (A4) and testosterone in childhood androgen excess. Design Retrospective review of all children undergoing serum androgen measurement at a single center over 5 years. Methods Serum A4 and testosterone were measured by tandem mass spectrometry and DHEAS by immunoassay. Patients with at least one increased androgen underwent phenotyping by clinical notes review. Results In 487 children with simultaneous DHEAS, A4 and testosterone measurements, we identified 199 with androgen excess (140 pre- and 59 post-pubertal). Premature adrenarche (PA) was the most common pre-pubertal diagnosis (61%), characterized by DHEAS excess in 85%, while A4 and testosterone were only increased in 26 and 9% respectively. PCOS was diagnosed in 40% of post-pubertal subjects, presenting equally frequent with isolated excess of DHEAS (29%) or testosterone (25%) or increases in both A4 and testosterone (25%). CAH patients (6%) predominantly had A4 excess (86%); testosterone and DHEAS were increased in 50 and 33% respectively. Concentrations increased above the two-fold upper limit of normal were mostly observed in PA for serum DHEAS (>20-fold in the single case of adrenocortical carcinoma) and in CAH for serum androstenedione. Conclusions Patterns and severity of childhood androgen excess provide pointers to the underlying diagnosis and can be used to guide further investigations.

The Birmingham Registry for Twin and Heritability Studies (BiRTHS).

In this article we present the protocol of the Birmingham Registry for Twin Heritability Studies (BiRTHS), which aims to establish a long-term prospective twin registry with twins identified from the antenatal period and subjected to detailed follow-up. We plan to investigate the concordance in anthropometrics and early childhood phenotypes between 66 monozygotic and 154 dizygotic twin pairs in the first 2 years of recruitment. In this project we plan to determine the relative contributions of heritability and environment to fetal growth, birth size, growth in infancy and development up to 2 years of age in an ethnically mixed population. Twins will be assessed with the Griffitth's Mental Development Scales, which will enable us to obtain detailed information on development. As maternal depression may have an effect on the twins' neurodevelopment, the Edinburgh Postnatal Depression Scale will be used at various stages during pregnancy and after delivery to assess maternal depressive symptoms. The increasing prevalence of obesity in both adults and children has raised concerns about the effect of maternal obesity in pregnancy on fetal growth. The prospective study design gives us the opportunity to obtain data on maternal nutrition (reflected by body mass index) and ante- and postnatal growth and development of twins.