Obesity-Associated GNAS Mutations and the Melanocortin Pathway.

BACKGROUND: GNAS encodes the Gαs (stimulatory G-protein alpha subunit) protein, which mediates G protein-coupled receptor (GPCR) signaling. GNAS mutations cause developmental delay, short stature, and skeletal abnormalities in a syndrome called Albright's hereditary osteodystrophy. Because of imprinting, mutations on the maternal allele also cause obesity and hormone resistance (pseudohypoparathyroidism). METHODS: We performed exome sequencing and targeted resequencing in 2548 children who presented with severe obesity, and we unexpectedly identified 22 GNAS mutation carriers. We investigated whether the effect of GNAS mutations on melanocortin 4 receptor (MC4R) signaling explains the obesity and whether the variable clinical spectrum in patients might be explained by the results of molecular assays. RESULTS: Almost all GNAS mutations impaired MC4R signaling. A total of 6 of 11 patients who were 12 to 18 years of age had reduced growth. In these patients, mutations disrupted growth hormone-releasing hormone receptor signaling, but growth was unaffected in carriers of mutations that did not affect this signaling pathway (mean standard-deviation score for height, -0.90 vs. 0.75, respectively; P = 0.02). Only 1 of 10 patients who reached final height before or during the study had short stature. GNAS mutations that impaired thyrotropin receptor signaling were associated with developmental delay and with higher thyrotropin levels (mean [±SD], 8.4±4.7 mIU per liter) than those in 340 severely obese children who did not have GNAS mutations (3.9±2.6 mIU per liter; P = 0.004). CONCLUSIONS: Because pathogenic mutations may manifest with obesity alone, screening of children with severe obesity for GNAS deficiency may allow early diagnosis, improving clinical outcomes, and melanocortin agonists may aid in weight loss. GNAS mutations that are identified by means of unbiased genetic testing differentially affect GPCR signaling pathways that contribute to clinical heterogeneity. Monogenic diseases are clinically more variable than their classic descriptions suggest. (Funded by Wellcome and others.).

Parental concerns about genital differences in children with congenital adrenal hyperplasia persist regardless of the selected intervention.

BACKGROUND: Congenital Adrenal Hyperplasia (CAH) due to 21-hydroxylase deficiency (21HD) can affect the in utero development of the genital anatomy of people with the 46XX karyotype. Health professionals engage parents in decision-making regarding managing genitals with this difference, including genital surgery options and patient communication. AIM: We sought to investigate parental communication with their daughters regarding clitoral size variation related to neonatal CAH. METHODS: Semistructured in-person interviews of 24 parents of chromosomal XX children with clitoral size variation attributable to a neonatal CAH diagnosis comprised 3 management categories: (1) clitoral reduction surgery (RS) (7 parents, 9 children), (2) clitoral concealment surgery (CS) (8 parents, 8 children), and no surgery on or around the clitoris (NS) (9 parents, 7 children). OUTCOMES: Four representative themes, Obvious Choice, Still Different, Parental Burden, and Ignorance Is Bliss, were common across all 3 treatment groups. RESULTS: For most parents, none of the 3 options of genital appearance alteration via clitoral reduction, clitoral concealment surgery, or avoidance of clitoral surgery ameliorated concerns, with most parents expressing an aversion to educating their child on the topic of genital differences, past treatment, or future function. CLINICAL IMPLICATIONS: Reliance on surgical treatment pathways to manage this psychosocial concern is ineffective in alleviating parental uncertainty without the application of psychosocial interventions. STRENGTHS AND LIMITATIONS: This was a qualitative study but was limited to parents of children with a specific genital difference, without direct exploration of parental values regarding the clitoris or the application of adequate psychosocial care. CONCLUSION: Healthcare services must have an impact on parental ability to engage in essential communication with their children in cases such as clitoral size variation related to neonatal CAH. Improved communication skills allow parents to engage in more genuine decision-making and adapt to enduring genital reality, including possible future sexual challenges for their adult child, without resorting to burdensome strategies focused on attempts to perpetuate a benevolent ignorance.

Combined resistance and aerobic exercise intervention improves fitness, insulin resistance and quality of life in survivors of childhood haemopoietic stem cell transplantation with total body irradiation.

PURPOSE: To investigate the effects of a supervised combined resistance and aerobic training programme on cardiorespiratory fitness, body composition, insulin resistance and quality of life (QoL) in survivors of childhood haematopoietic stem cell transplantation (HSCT) with total body irradiation (TBI). PARTICIPANTS: HSCT/TBI survivors (n = 20; 8 females). Mean (range) for age at study and time since HSCT/TBI was 16.7 (10.9-24.5) and 8.4 (2.3-16.0) years, respectively. METHODS: After a 6-month run-in, participants undertook supervised 45- to 60-minute resistance and aerobic training twice weekly for 6 months, with a 6-month follow-up. The following assessments were made at 0, 6 (start of exercise programme), 12 (end of exercise programme) and 18 months: Body composition via dual energy X-ray absorptiometry, homeostatic model assessment of insulin resistance (HOMA-IR), cardiorespiratory fitness (treadmill-based peak rate of oxygen uptake (VO2 peak) test), QoL questionnaires (36-Item Short Form Health Survey (SF-36) and Minneapolis-Manchester Quality of Life Instrument (MMQL). RESULTS: Results expressed as mean (standard deviation) or geometric mean (range). There were significant improvements in VO2 peak (35.7 (8.9) vs 41.7 (16.1) mL/min/kg, P = 0.05), fasted plasma insulin (16.56 (1.48-72.8) vs 12.62 (1.04-54.97) mIU/L, P = 0.03) and HOMA-IR (3.65 (0.30-17.26) vs 2.72 (0.22-12.89), P = 0.02) after the exercise intervention. There were also significant improvements in the SF-36 QoL general health domain (69.7 (14.3) vs 72.7 (16.0), P = 0.001) and the MMQL school domain (69.1 (25.2) vs (79.3 (21.6), P = 0.03) during the exercise intervention. No significant changes were observed in percentage body fat, fat mass or lean mass. CONCLUSION: The supervised 6-month combined resistance and aerobic exercise programme significantly improved cardiorespiratory fitness, insulin resistance and QoL in childhood HSCT/TBI survivors, with no change in body composition, suggesting a metabolic training effect on muscle. These data support a role for targeted physical rehabilitation services in this group at high risk of diabetes and cardiovascular disease.

Cognitive behavioural therapy stabilises glycaemic control in adolescents with type 1 diabetes-Outcomes from a randomised control trial.

BACKGROUND: To compare the impact of cognitive behavioural therapy (CBT) with non-directive supportive counselling (NDC) on glycaemic control and psychological well-being in adolescents with type 1 diabetes mellitus (T1DM). MATERIALS AND METHODS: Participants aged 11 to 16 years with T1DM (duration ≥1 year) from 4 UK-based paediatric diabetes centres were randomised to receive either 6 weekly sessions of 1-to-1 CBT (n = 43) or NDC (n = 42), with 2 further sessions at 6 and 12 months. Follow-up continued for 12 months postintervention. Outcome measures included glycated haemoglobin A1c (HbA1c) and psychological scores. RESULTS: The HbA1c levels were available in 33 patients in each group for analysis. Between group difference of the overall changes in HbA1c across the study period was statically significant (P = .018). Geometric mean (range) HbA1c in the NDC group deteriorated from 68 (46-113) to 78 (48-128) mmol/mol (ie, 8.4 [6.4-12.5]% to 9.3 [6.5-13.9]%; P = .001), but was maintained in the CBT group from 72 (46-129) to 73 (51-128) mmol/mol (P = .51) (ie, 8.7 [6.4-14]% to 8.9 [6.8-13.9]%). More patients who have undergone CBT showed an improved or maintained HbA1c levels at 24 months (62.5% vs 35.5%, P = .032). Patients offered CBT with depressive scores in the lowest tertile (least depressive symptoms) showed improvement in HbA1c over time from 70 (46-102) to 67 (57-87) mmol/mol (P = .041) (ie, 8.6 [6.4-11.5]% to 8.3 [7.4-10.1]%), but not in the NDC group. The CBT showed borderline improvements in Children's Health Locus of Control (internal) scores over time compared with NDC (P = .05). The self-efficacy score showed significant improvement in both CBT (P < .001) and NDC (P = .03) groups over time. CONCLUSIONS: CBT demonstrated better maintenance of glycaemic control compared with NDC.

Reduced insulin sensitivity in childhood survivors of haematopoietic stem cell transplantation is associated with lipodystropic and sarcopenic phenotypes.

BACKGROUND: Survivors of childhood acute lymphoblastic leukaemia (ALL) treated with haematopoietic stem cell transplantation and total body irradiation (HSCT/TBI) have a high cardiometabolic risk despite lacking overt clinical obesity. This study characterised body composition using different methodologies and explored associations with reduced insulin sensitivities in a group of ALL survivors treated with/without HSCT/TBI. PROCEDURE: Survivors of childhood ALL treated with HSCT/TBI (n = 20,10 M) were compared with Chemotherapy-only (n = 31), and an obese non-leukaemic controls (n = 30). All subjects (aged 16-26 years) were investigated with: auxology (BMI, waist and hip circumferences), DEXA (total and regional fat, fat-free mass), abdominal MRI (subcutaneous, visceral, intramuscular fat), oral glucose tolerance tests (impaired glucose tolerance or diabetes, insulin sensitivity) and serum adiponectin. RESULTS: HSCT/TBI Group displayed a higher prevalence of abnormal glucose tolerance (45%); lower insulin sensitivity; lower lean mass with higher prevalence of reduced fat-free mass index (from DEXA); higher visceral and intramuscular, and lower subcutaneous fat on MRI, compared with the Chemotherapy-only and Obese controls. BMI was lowest in HSCT/TBI Group. Waist-to-hip and android-to-gynoid ratios were similar between HSCT/TBI and Obese Groups. Insulin sensitivity adjusted for visceral fat mass was lower in the HSCT/TBI than the Chemotherapy-only and Obese groups. Adiponectin in the HSCT/TBI Group was lower than the Chemotherapy-only group, and correlated negatively with time post HSCT/TBI. CONCLUSIONS: HSCT/TBI survivors have an increased risk of abnormal glucose tolerance and reduced insulin sensitivity with reduced subcutaneous and increased visceral fat distribution, increased total fat mass and reduced lean mass.

Evaluating Eating Behaviour, Energy Homeostasis, and Obesity in Childhood-Onset Craniopharyngioma: A Feasibility Study.

INTRODUCTION: Craniopharyngiomas are rare brain tumours (incidence 1.1-1.7 cases/million/year). Although non-malignant, craniopharyngioma causes major endocrine and visual morbidities including hypothalamic obesity, yet mechanisms leading to obesity are poorly understood. This study investigated the feasibility and acceptability of eating behaviour measures in patients with craniopharyngioma to inform the design of future trials. METHODS: Patients with childhood-onset craniopharyngioma and controls matched for sex, pubertal stage, and age were recruited. After an overnight fast, participants received the following measures: body composition, resting metabolic rate, oral glucose tolerance test including magnetic resonance imaging (patients only), appetite ratings, eating behaviour, and quality of life questionnaires, ad libitum lunch, and an acceptability questionnaire. Data are reported as median ± IQR, with effect size measure (Cliff's delta) and Kendall's tau for correlations, due to the small sample size. RESULTS: Eleven patients (median age = 14 years; 5 F/6 M) and matched controls (median age = 12 years; 5 F/6 M) were recruited. All patients had received surgery, and 9/11 also received radiotherapy. Hypothalamic damage post-surgery was graded (Paris grading): grade 2 n = 6; grade 1 n = 1; grade 0 n = 2. The included measures were deemed highly tolerable by participants and their parent/carers. Preliminary data suggest a difference in hyperphagia between patients and controls (d = 0.5), and a relationship between hyperphagia with body mass index standard deviation score (BMISDS) in patients (τ = 0.46). DISCUSSION: These findings demonstrate that eating behaviour research is feasible and acceptable to craniopharyngioma patients and there is an association between BMISDS and hyperphagia in patients. Thus, food approach and avoidance behaviours may be useful targets for interventions to manage obesity in this patient group.

Psychological Care of Children and Families with Variations or Differences in Sex Development.

The paediatric clinical psychology literature provides applicable evidence for use in specialist healthcare settings and services. The general approach of psychological care of children and families with paediatric conditions is recognizable as preventative and destigmatizing, aimed to maximize personal agency with shared responsibility for achieving best outcomes via multi-professional teamwork. Recent commentaries regarding healthcare for children with differences in sex development (DSD) have noted service-level pitfalls, including poor teamwork and underuse of early and integrated psychological intervention. Psychological research regarding the variously termed DSD, variations in sex development, variation in sex characteristics, or intersex has historically centred around the assessment of sex differences, gender identity, and the impact of including hormone influences on brain and behaviour. Psychological research in this specialist area has not focussed on the evaluation of specific clinical interventions or psychotherapeutic models but has investigated psychological aspects of multi-professional healthcare provision. There are new goals for psychological care of children with variations or differences in sex development (V/DSD). These require a framework of good communication to enable those receiving care to come to know and articulate their own hopes for treatment and support. Paediatric psychological intervention studies involving larger clinical groups such as diabetes provide evidence applicable to DSD populations. A risk of stigma is recognized as inherent to some physical interventions within routine paediatric care of people with V/DSD. Psychological care and intervention should be aimed at minimizing these risks via questioning and examining their assumed need. Psychological approaches can provide a foundation for ethical and rights-based multi-professional care of children with V/DSD.

Why do parents recommend clitoral surgery? Parental perception of the necessity, benefit, and cost of early childhood clitoral surgery for congenital adrenal hyperplasia (CAH).

Historically, medical management of Congenital Adrenal Hyperplasia (CAH) in girls typically involved feminising surgery, which meant reducing the size and/or visibility of the enlarged clitoris. This practice may have become less routine but remains a common response to genital differences associated with CAH. Parents typically give permission for the child to undergo surgery in early childhood and recommend other parents facing a similar situation do the same. The current report is based on a qualitative content analysis of interviews with sixteen parents whose daughters with CAH had undergone one of two forms of clitoral surgery. We observed that: (i) some parents were initially unconcerned about their child's genital presentation; (ii) in general, clitoral surgery was considered as a readily available and natural response to the child's bodily difference; (iii) the parents acknowledged that there would be some risk but anticipated various benefits; and (iv) there was an absence of ethical considerations when the parents evaluated the various effects of surgery afterwards. We conclude from our analysis that parents of girls with CAH may not receive psychologically and ethically informed counselling to encourage critical reflections prior to authorizing genital surgery.

Rapid-onset obesity, hypothalamic dysfunction, hypoventilation, and autonomic dysregulation syndrome - neuro-endocrine tumours (ROHHAD-NET): case series and learning points.

OBJECTIVES: Rapid-onset obesity with hypoventilation, hypothalamic dysfunction, autonomic dysregulation (ROHHAD) is a rare syndrome associated with high morbidity and mortality. Diagnosis is often challenging. We describe three cases of ROHHAD with heterogeneous presentations but some consistent clinical features, including hyperprolactinaemia at diagnosis. We highlight when the diagnosis of ROHHAD should be considered at an early stage. CASE PRESENTATION: All three patients presented between 4 and 6 years old with rapid-onset obesity. They all have central hypoventilation requiring nocturnal BiPAP, varying degrees of hypothalamic dysfunction with hyperprolactinaemia being a consistent feature, and autonomic dysfunction. One patient has a neuro-endocrine tumour (NET) and two have glucose dysregulation. CONCLUSIONS: High prolactin was a consistent early feature. Central hypoventilation and NET may present later and therefore regular sleep studies and screening for NETs are required. A high suspicion of ROHHAD is warranted in patients with rapid, early-onset obesity and hyperprolactinaemia without structural pituitary abnormality.

Exploring eating behavior and psychological mechanisms associated with obesity in patients with craniopharyngioma: a scoping review protocol.

OBJECTIVE: The objective of the review is to explore the evidence on the behavioral and psychological mechanisms underlying the development of obesity in patients with craniopharyngioma. The review will map the available evidence, identify gaps in the literature, and find avenues of future intervention. INTRODUCTION: Craniopharyngiomas are low-grade intracranial tumors of the supersellar region. Obesity is associated with the tumor or surgery or radiotherapy to treat the tumor; however, the behavioral and psychological processes contributing to that association are not clear. This review will provide a synthesized evidence base of the relevant research. INCLUSION CRITERIA: This review will consider published studies with all types of study designs, including patients with childhood- or adult-onset craniopharyngioma. Articles assessing factors that may impact eating behavior will be included based on the following categories: eating behavior, obesity, neuroimaging, endocrine response, energy expenditure, sleep, and neuropsychology. METHODS: MEDLINE, Embase, and PsycINFO will be searched, in addition to the Cochrane Library, Web of Science, Scopus, ClinicalTrials.gov, NICE evidence search, and International Standard Randomised Controlled Trial Number (ISRCTN). No limits will be placed on the scope of the search. The methodology will follow a three-stage process with two independent reviewers at each stage, including an initial database search, screening of titles and abstracts of retrieved studies, full-text assessment for inclusion criteria, and hand-searching of reference lists. Data will be extracted using a standardized charting form and summarized in tables. The data will be synthesized using a narrative summary and diagrammatic map and will be based on the evidence for each of the proposed research categories.

Genetic Analysis of Pediatric Primary Adrenal Insufficiency of Unknown Etiology: 25 Years' Experience in the UK.

CONTEXT: Although primary adrenal insufficiency (PAI) in children and young people is often due to congenital adrenal hyperplasia (CAH) or autoimmunity, other genetic causes occur. The relative prevalence of these conditions is poorly understood. OBJECTIVE: We investigated genetic causes of PAI in children and young people over a 25 year period. DESIGN SETTING AND PARTICIPANTS: Unpublished and published data were reviewed for 155 young people in the United Kingdom who underwent genetic analysis for PAI of unknown etiology in three major research centers between 1993 and 2018. We pre-excluded those with CAH, autoimmune, or metabolic causes. We obtained additional data from NR0B1 (DAX-1) clinical testing centers. INTERVENTION AND OUTCOME MEASUREMENTS: Genetic analysis involved a candidate gene approach (1993 onward) or next generation sequencing (NGS; targeted panels, exomes) (2013-2018). RESULTS: A genetic diagnosis was reached in 103/155 (66.5%) individuals. In 5 children the adrenal insufficiency resolved and no genetic cause was found. Pathogenic variants occurred in 11 genes: MC2R (adrenocorticotropin receptor; 30/155, 19.4%), NR0B1 (DAX-1; 7.7%), CYP11A1 (7.7%), AAAS (7.1%), NNT (6.5%), MRAP (4.5%), TXNRD2 (4.5%), STAR (3.9%), SAMD9 (3.2%), CDKN1C (1.3%), and NR5A1/steroidogenic factor-1 (SF-1; 0.6%). Additionally, 51 boys had NR0B1 variants identified through clinical testing. Although age at presentation, treatment, ancestral background, and birthweight can provide diagnostic clues, genetic testing was often needed to define the cause. CONCLUSIONS: PAI in children and young people often has a genetic basis. Establishing the specific etiology can influence management of this lifelong condition. NGS approaches improve the diagnostic yield when many potential candidate genes are involved.

Peripheral neuropathy is an early complication of type 2 diabetes in adolescence.

OBJECTIVE: To screen for microvascular complications in adolescents with type 2 diabetes mellitus (T2DM). SUBJECTS AND METHODS: Seven adolescents with T2DM were assessed for early secondary complications. Median duration of diabetes was 1.8 (0.8-3.0) yr. All were assessed as follows: blood pressure, ophthalmologic examination for diabetic retinopathy, renal function, full blood count and vitamin B12 levels (to exclude B12 malabsorption - a side effect of metformin), random urine for microalbuminuria, an electrocardiogram (ECG) rhythm strip and podiatry performed by an experienced podiatrist. Testing for peripheral neuropathy included foot pulse palpation, tendo-Achilles reflexes, plantar callus test, large nerve fibre function (vibration and threshold for light touch/pressure) assessed by a 128-Hz tuning fork, and by the standard 10-g Semmes-Weinstein monofilament test, and small nerve fibre function (pain) assessed by pinprick neurotip. RESULTS: Four adolescents had evidence of peripheral neuropathy on clinical examination, with abnormal large and small nerve fibre function. Six had plantar callus present, and four had weak but palpable posterior tibial pulses. All had normal tendo-Achilles reflex and normal response to vibration. None had diabetic retinopathy or hypertension. Renal function, full blood count (FBC), B12 levels and ECGs were normal. None of 120 adolescents with type 1 diabetes mellitus (T1DM) assessed by the same podiatrist had any signs of peripheral neuropathy. CONCLUSIONS: Unlike T1DM, peripheral neuropathy can be present soon after diagnosis in those with T2DM. Children with T2DM need surveillance for complications from the time of diagnosis.

The hypothalamic-pituitary-adrenal axis in childhood cancer survivors.

Endocrine abnormalities are common among childhood cancer survivors. Abnormalities of the hypothalamic-pituitary-adrenal axis (HPAA) are relatively less common, but the consequences are severe if missed. Patients with tumours located and/or had surgery performed near the hypothalamic-pituitary region and those treated with an accumulative cranial radiotherapy dose of over 30 Gy are most at risk of adrenocorticotrophic hormone (ACTH) deficiency. Primary adrenal insufficiency may occur in patients with tumours located in or involving one or both adrenals. The effects of adjunct therapies also need to be considered, particularly, new immunotherapies. High-dose and/or prolonged courses of glucocorticoid treatment can result in secondary adrenal insufficiency, which may take months to resolve and hence reassessment is important to ensure patients are not left on long-term replacement steroids inappropriately. The prevalence and cumulative incidences of HPAA dysfunction are difficult to quantify because of its non-specific presentation and lack of consensus regarding its investigations. The insulin tolerance test remains the gold standard for the diagnosis of central cortisol deficiency, but due to its risks, alternative methods with reduced diagnostic sensitivities are often used and must be interpreted with caution. ACTH deficiency may develop many years after the completion of oncological treatment alongside other pituitary hormone deficiencies. It is essential that health professionals involved in the long-term follow-up of childhood cancer survivors are aware of individuals at risk of developing HPAA dysfunction and implement appropriate monitoring and treatment.

Which factors are associated with a successful outcome in a weight management programme for obese children?

AIMS AND OBJECTIVE: To identify factors important in determining whether an obese child achieves significant reductions in Body Mass Index Standard Deviation Score (BMI SDS) within a UK, hospital-based paediatric obesity service aimed at lifestyle modification. DESIGN: Observational Study. SUBJECTS: 137 obese children (63 boys) who have attended our childhood obesity service within the last three and a half years at The Royal Hospital for Children, Bristol, UK. MEASUREMENTS: BMI SDS with a target reduction of - 0.5 or greater. RESULTS: 70% of children achieved reductions in BMI SDS with 18% achieving the target reduction. In those attending the clinic for a year or more the levels improved to 83% and 28% respectively. Age was found to be the most important predictor with younger children achieving larger reductions in BMI SDS. More boys than girls were likely to achieve target reductions in BMI SDS and those without a parental history of obesity were more likely to achieve greater reductions in BMI SDS. Socio-economic status did not appear to impact upon the child's level of success. CONCLUSIONS: In families of obese children, motivated to seek help by attending a hospital-based weight control clinic, improvements in BMI are possible by a simple approach of education and continued support. Improvement is greatest in younger children with maximal benefit being seen in boys without a parental history of obesity. We believe this emphasizes the importance of identifying significant obesity in primary school aged children, who seem most likely to benefit from simple lifestyle modification, while many older children may require additional intervention programmes to improve BMI.

In-frame seven amino-acid duplication in AIP arose over the last 3000 years, disrupts protein interaction and stability and is associated with gigantism.

OBJECTIVE: Mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are associated with pituitary adenoma, acromegaly and gigantism. Identical alleles in unrelated pedigrees could be inherited from a common ancestor or result from recurrent mutation events. DESIGN AND METHODS: Observational, inferential and experimental study, including: AIP mutation testing; reconstruction of 14 AIP-region (8.3 Mbp) haplotypes; coalescent-based approximate Bayesian estimation of the time to most recent common ancestor (tMRCA) of the derived allele; forward population simulations to estimate current number of allele carriers; proposal of mutation mechanism; protein structure predictions; co-immunoprecipitation and cycloheximide chase experiments. RESULTS: Nine European-origin, unrelated c.805_825dup-positive pedigrees (four familial, five sporadic from the UK, USA and France) included 16 affected (nine gigantism/four acromegaly/two non-functioning pituitary adenoma patients and one prospectively diagnosed acromegaly patient) and nine unaffected carriers. All pedigrees shared a 2.79 Mbp haploblock around AIP with additional haploblocks privately shared between subsets of the pedigrees, indicating the existence of an evolutionarily recent common ancestor, the 'English founder', with an estimated median tMRCA of 47 generations (corresponding to 1175 years) with a confidence interval (9-113 generations, equivalent to 225-2825 years). The mutation occurred in a small tandem repeat region predisposed to slipped strand mispairing. The resulting seven amino-acid duplication disrupts interaction with HSP90 and leads to a marked reduction in protein stability. CONCLUSIONS: The c.805_825dup allele, originating from a common ancestor, associates with a severe clinical phenotype and a high frequency of gigantism. The mutation is likely to be the result of slipped strand mispairing and affects protein-protein interactions and AIP protein stability.

Mature subcutaneous and visceral adipocyte concentrations of adiponectin are highly correlated in prepubertal children and inversely related to body mass index standard deviation score.

CONTEXT: Adiponectin is an adipocyte-specific protein with insulin-sensitizing properties. Several studies have examined the expression of adiponectin mRNA or tissue/secreted protein levels in fat obtained from adults, but none has assessed tissue levels in childhood. PATIENTS: Paired subcutaneous (Sc) and visceral (V) fat samples were obtained from 12 normal-weight children. MAIN OUTCOME MEASURES: Mature adipocytes were isolated and total adiponectin levels determined by ELISA. Insulin sensitivity and lipid parameters were assessed in fasting blood samples taken at the time of biopsy collection. RESULTS: A positive correlation was seen between the adiponectin concentration within the Sc and V mature adipocytes derived from each child (r = 0.924; P < 0.001). After logarithmic transformation of the Sc and V adiponectin concentrations (log-Sc and log-V) to render the data Gaussian, both log-Sc and log-V were found to be lower in those children with higher body mass index sd score (r = -0.621 and r = -0.357 respectively), although this reached statistical significance only in the Sc adipocytes (P = 0.03). Age was not related to either log-Sc or log-V adiponectin levels, although a significant negative association was seen with serum adiponectin (r = -0.589; P = 0.04). Log-Sc or log-V did not correlate with serum adiponectin concentrations, markers of insulin sensitivity, or circulating lipid levels. CONCLUSIONS: These data indicate a relationship between total adiponectin levels in different tissue compartments, suggesting either some form of interaction or coregulation by systemic factors, possibly related to body size/fat mass. Serum concentrations of total adiponectin were inversely related to age but showed no relationship with either tissue levels or body mass index sd score.

Novel mutations of the growth hormone 1 (GH1) gene disclosed by modulation of the clinical selection criteria for individuals with short stature.

Subtle mutations in the growth hormone 1 (GH1) gene have been regarded as a comparatively rare cause of short stature. Such lesions were sought in a group of 41 individuals selected for short stature, reduced height velocity, and bone age delay; a group of 11 individuals with short stature and idiopathic growth hormone deficiency (IGHD); and a group of 154 controls. Heterozygous mutations were identified in all three groups but disproportionately in the individuals with short stature, both with (odds ratio 25.2; 95% CI, 5.1-132.2) and without (odds ratio 3.6; 95% CI, 1.0-12.9) IGHD. Twenty-four novel GH1 gene lesions were found. Thirteen novel missense mutations were characterized by assaying the signal transduction activity of in vitro expressed variants; six (T27I, K41R, N47D, S71F, S108R, and T175A) exhibited a reduced ability to activate the JAK/STAT pathway. Molecular modeling suggested that both K41R and T175A might compromise GH receptor binding. Seven GH variants (R16C, K41R, S71F, E74K, Q91L, S108C, and a functional polymorphism, V110I) manifested reduced secretion in rat pituitary cells after allowance had been made for the level of expression attributable to the associated GH1 proximal promoter haplotype. A further leader peptide variant (L-11P) was not secreted. Eleven novel mutations in the GH1 gene promoter were assessed by reporter gene assay but only two, including a GH2 gene-templated gene conversion, were found to be associated with a significantly reduced level of expression. Finally, a novel intron 2 acceptor splice-site mutation, detected in a family with autosomal dominant type II IGHD, was shown to lead to the skipping of exon 3 from the GH1 transcript. A total of 15 novel GH1 gene mutations were thus considered to be of probable phenotypic significance. Such lesions are more prevalent than previously recognized and although most may be insufficient on their own to account for the observed clinical phenotype, they are nevertheless likely to play a contributory role in the etiology of short stature.

Abnormal liver function in children with metabolic syndrome from a UK-based obesity clinic.

AIM: To examine transaminitis in obese children, its association with glucose metabolism and the metabolic syndrome and the response to weight loss through lifestyle modification. METHODS: 216 children (90 male), aged 2.9-17.6 (median 12.4 years) with median body mass index (BMI) SD score (SDS) of 3.36 (range 1.92-6.22) attending a hospital obesity clinic in Bristol (UK) underwent an oral glucose tolerance test (OGTT) with fasting lipid and liver profile. Auxological measures included weight, height, waist circumference, percentage body fat. Parental history of type 2 diabetes (T2DM) was recorded. The 2007 International Diabetes Federation definition of metabolic syndrome was used. 90 children undergoing a trial of lifestyle modification to improve weight were re-assessed at 12 months. RESULTS: 34/216 (16%) children had raised alanine aminotransferase (ALT) (>40 IU/l) with greater prevalence in boys (23% vs 10%, p=0.01) and in those with a parental history of T2DM (30% vs 13.2% p=0.019). Patients with transaminitis were more likely to fulfil the criteria for metabolic syndrome (p<0.001) and have subtle abnormalities in glucose metabolism during an OGTT with elevated glucose levels at 90 (p=0.041) and 120 (p=0.014) min and a greater glucose area-under-the-curve (p=0.014). Improvement in BMI SDS over 1 year correlated with improvement in ALT levels (τ = -0.29, p<0.001). CONCLUSION: Prevalence of transaminitis is significant in obese children and is associated with components of the metabolic syndrome. Lifestyle-based improvement in BMI SDS offers an effective tool for correcting transaminitis and should remain the central component of therapy.

Clinical measures of adiposity and percentage fat loss: which measure most accurately reflects fat loss and what should we aim for?

OBJECTIVE: To determine which clinical measure of childhood obesity should be monitored to best reflect change in adiposity in a weight management programme and estimate the degree of change needed to be relatively certain of fat reduction. SUBJECTS: 92 obese children with a mean (range) age of 12.8 (6.9-18.9) years and a mean body mass index standard deviation score (BMI SDS) of +3.38 (+2.27 to +4.47) attending a hospital-based clinic on a regular, 3 monthly basis. MEASUREMENTS: Pairs of weight and height measured up to 2.41 years apart used to derive BMI as kg/m2, and adjusted for age and gender to give weight and BMI SDS (BMI-z score) using British 1990 Growth Reference Data. Contemporaneous adiposity estimated by fatness measured by a bioimpedance segmental body composition analyser. RESULTS: Changes in BMI-z scores, compared to BMI, weight and weight SDS, most accurately reflected loss of fat. Reductions of 0.25, 0.5, 0.75, and 1 BMI SDS equate to expected mean falls in total body fat percentage of 2.9%, 5.8%, 8.7% and 11.6%. Approximate 95% prediction intervals indicated that a fall in BMI SDS of at least 0.6 over 6-12 months (or 0.5 over 0-6 months) is consistent with actual fat loss. CONCLUSION: Change in BMI-z score best reflects percentage fat loss compared to BMI, weight and weight SDS. The wide variation in likely percentage fat loss for a given BMI SDS reduction means a loss of 0.5-0.6 is required to be relatively certain of definite percentage fat reduction.