A longitudinal study investigating change in BMI z-score in primary school-aged children and the association of child BMI z-score with parent BMI.

BACKGROUND: This paper aims to explore change in BMI z-score through childhood and the association between parent BMI and child BMI z-score. This is important to understand for the development of effective obesity interventions. METHODS: Data from the longitudinal B-ProAct1v study (1837 participants) were analysed. A paired sample t-test examined changes in child BMI z-score between Year 1 and 4. Multivariable linear regression models examined the cross-sectional associations between child BMI z-score and parent BMI in Year 1 and 4. The influence of change in parental BMI between Year 1 and Year 4 on child BMI z-score in Year 4 was explored through regression analyses, adjusted for baseline BMI z-score. RESULTS: There was a strong association between child BMI z-score at Year 1 and 4. Child mean BMI z-score score increased from 0.198 to 0.330 (p = < 0.005) between these timepoints. For every unit increase in parent BMI, there was an increase in child BMI z-score of 0.047 in Year 1 (p = < 0.005) and of 0.059 in Year 4 (p = < 0.005). Parental BMI change was not significantly associated with Year 4 child BMI z-score. CONCLUSION: The key indicator of higher child BMI at Year 4 is high BMI at Year 1. Further studies are needed to explore the impact of parental weight change on child BMI z-score and whether interventions targeted at overweight or obese parents, can improve their child's BMI z-score.

Continuing rise of Type 2 diabetes incidence in children and young people in the UK.

AIMS: To estimate the incidence of Type 2 diabetes in children aged <17 years, compare this with similar data 10 years ago, and characterize clinical features at diagnosis in the UK and Republic of Ireland. METHODS: Using the British Paediatric Surveillance Unit reporting framework, cases of Type 2 diabetes diagnosed in children aged <17 years between 1 April 2015 and 30 April 2016 were reported each month. RESULTS: A total of 106 cases were reported, giving a UK incidence of 0.72/100 000 (95% CI 0.58-0.88). Children from ethnic minorities had significantly higher incidence compared with white children (0.44/100 000) with rates of 2.92/100 000 and 1.67/100 000, in Asian and BACBB (black/African/Caribbean/black British) children respectively. Sixty-seven percent were girls and 81% had a family history of Type 2 diabetes. The mean BMI sd score at diagnosis was 2.89 (2.88, girls; 2.92, boys); 81% were obese. Children of Asian ethnicity had a significantly lower BMI sd score compared with white children (P<0.001). There was a trend in increased incidence from 2005 to 2015, with a rate ratio of 1.35 (95% CI 0.99-1.84), although this was not statistically significant (P=0.062). There was statistical evidence of increased incidence among girls (P=0.03) and children of South-Asian ethnicity (P=0.01) when comparing the 2005 and 2015 surveys. CONCLUSIONS: Type 2 diabetes remains far less common than Type 1 diabetes in childhood in the UK, but the number of cases continues to rise, with significantly increased incidence among girls and South-Asian children over a decade. Female gender, family history, non-white ethnicity and obesity were found to be strongly associated with the condition.

Parental beliefs about portion size, not children's own beliefs, predict child BMI.

BACKGROUND: Increases in portion size are thought by many to promote obesity in children. However, this relationship remains unclear. Here, we explore the extent to which a child's BMI is predicted both by parental beliefs about their child's ideal and maximum portion size and/or by the child's own beliefs. METHODS: Parent-child (5-11 years) dyads (N = 217) were recruited from a randomized controlled trial (n = 69) and an interactive science centre (n = 148). For a range of main meals, parents estimated their child's 'ideal' and 'maximum tolerated' portions. Children completed the same tasks. RESULTS: An association was found between parents' beliefs about their child's ideal (ß = .34, p < .001) and maximum tolerated (ß = .30, p < .001) portions, and their child's BMI. By contrast, children's self-reported ideal (ß = .02, p = .718) and maximum tolerated (ß = -.09, p = .214) portions did not predict their BMI. With increasing child BMI, parents' estimations aligned more closely with their child's own selected portions. CONCLUSIONS: Our findings suggest that when a parent selects a smaller portion for their child than their child self-selects, then the child is less likely to be obese. Therefore, public health measures to prevent obesity might include instructions to parents on appropriate portions for young children.

The Measurement of Ammonia in Human Breath and its Potential in Clinical Diagnostics.

Ammonia is an important component of metabolism and is involved in many physiological processes. During normal physiology, levels of blood ammonia are between 11 and 50 µM. Elevated blood ammonia levels are associated with a variety of pathological conditions such as liver and kidney dysfunction, Reye's syndrome and a variety of inborn errors of metabolism including urea cycle disorders (UCD), organic acidaemias and hyperinsulinism/hyperammonaemia syndrome in which ammonia may reach levels in excess of 1 mM. It is highly neurotoxic and so effective measurement is critical for assessing and monitoring disease severity and treatment. Ammonia is also a potential biomarker in exercise physiology and studies of drug metabolism. Current ammonia testing is based on blood sampling, which is inconvenient and can be subject to significant analytical errors due to the quality of the sample draw, its handling and preparation for analysis. Blood ammonia is in gaseous equilibrium with the lungs. Recent research has demonstrated the potential use of breath ammonia as a non-invasive means of measuring systemic ammonia. This requires measurement of ammonia in real breath samples with associated temperature, humidity and gas characteristics at concentrations between 50 and several thousand parts per billion. This review explores the diagnostic applications of ammonia measurement and the impact that the move from blood to breath analysis could have on how these processes and diseases are studied and managed.

Hyperglycaemia-induced chemoresistance in breast cancer cells: role of the estrogen receptor.

Breast cancer patients with diabetes respond less well to chemotherapy; in keeping with this we determined previously that hyperglycaemia-induced chemoresistance in estrogen receptor (ERα) positive breast cancer cells and showed that this was mediated by fatty acid synthase (FASN). More recent evidence suggests that the effect of metabolic syndrome and diabetes is not the same for all subtypes of breast cancer with inferior disease-free survival and worse overall survival only found in women with ERα positive breast cancer and not for other subtypes. Here we examined the impact of hyperglycaemia on ERα negative breast cancer cells and further investigated the mechanism underlying chemoresistance in ERα with a view to identifying strategies to alleviate hyperglycaemia-induced chemoresistance. We found that hyperglycaemia-induced chemoresistance was only observed in ERα breast cancer cells and was dependent upon the expression of ERα as chemoresistance was negated when the ERα was silenced. Hyperglycaemia-induced an increase in activation and nuclear localisation of the ERα that was downstream of FASN and dependent on the activation of MAPK. We found that fulvestrant successfully negated the hyperglycaemia-induced chemoresistance, whereas tamoxifen had no effect. In summary our data suggests that the ERα may be a predictive marker of poor response to chemotherapy in breast cancer patients with diabetes. It further indicates that anti-estrogens could be an effective adjuvant to chemotherapy in such patients and indicates the importance for the personalised management of breast cancer patients with diabetes highlighting the need for clinical trials of tailored chemotherapy for diabetic patients diagnosed with ERα positive breast cancers.

Adolescent experiences of anti-obesity drugs.

Only two anti-obesity drugs (AODs) are frequently prescribed in paediatric obesity, orlistat and metformin. Meta-analyses show modest benefit in clinical trials, yet analyses of prescribing databases show high levels of discontinuation in routine clinical practice. Increased understanding of young people's experiences taking AOD could result in improved prescribing and outcomes. Semi-structured interviews were conducted with young people aged 13-18 years and their parents from three specialist obesity clinics, analysed using a general thematic coding methodology. Theme saturation was achieved after interviews with 15 young people and 14 parents (13 parent-child dyads). Three models were developed. Model 1 explored factors influencing commencement of AOD. Six themes emerged: medication as a way out of obesity, enthusiasm and relief at the prospect of pharmaceutical treatment, last ditch attempt for some but not all, passive acceptance of medication, fear as a motivating factor, and unique treatments needed for unique individuals. Model 2 described the inter-relationship between dosing and side effects; side effects were a significant experience for many young people, and few adhered to prescribed regimens, independently changing lifestyle and dosage to tolerate medications. Model 3 described the patient-led decision process regarding drug continuation, influenced primarily by side effects and efficacy. Use of AODs is challenging for many adolescents. Multiple factors were identified that could be targeted to improve concordance and maximize efficacy.

Adolescents' views and experiences of treatments for Type 2 diabetes: a qualitative study.

AIM: To explore adolescents' views and experiences of different treatments for Type 2 diabetes, in order to improve treatment concordance and consider how the current treatment pathway for adolescent Type 2 diabetes could be improved. METHODS: In-depth interviews were held with 12 adolescents who had been diagnosed with Type 2 diabetes. Adolescents were sampled from a UK cohort study. Data were analysed thematically. RESULTS: Interviewees struggled to maintain lifestyle changes. Insulin, metformin and liraglutide were described as effective but, in some cases, as resulting in side effects. Injected treatments were viewed less favourably than oral medications. Weight loss surgery was considered an acceptable treatment for obese adolescents who had tried other treatments for their diabetes. It was apparent that some adolescents had not been surprised by their diagnosis and did not fully appreciate the implications of having diabetes. It was also evident that some individuals had not told peers about their diagnosis due to fearing how they would react. Factors identified as improving treatment concordance included reminders and viewing treatment as effective and easy to take. CONCLUSIONS: Adolescents want treatments that are effective, discrete, easy to take and do not make them different from their peers. As liraglutide was described as effective, and surgery viewed as acceptable in certain circumstances, greater consideration should be given to their potential role in treating adolescent Type 2 diabetes. Practitioners need to ensure that adolescents appreciate the implications of having diabetes and may want to address adolescents' concerns regarding how others view this condition.

Can foster care ever be justified for weight management?

Article nine of the UN Convention of the Rights of the Child states that 'Children must not be separated from their parents unless it is in the best interests of the child.' We describe the impact that placing a child into care can have on long-standing and intractable obesity when this is a component of a child safeguarding strategy. Significant weight loss was documented in a male adolescent following his placement into foster care due to emotional harm and neglect within his birth family. The child's body mass index (BMI) dropped from a peak of 45.6 to 35 over 18 months. We provide brief details of two further similar cases and outcomes. Childhood obesity is often not the sole concern during safeguarding proceedings. Removal from an 'obesogenic' home environment should be considered if failure by the parents/carers to address the obesity is a major cause for concern. It is essential that all other avenues have been explored before removing a child from his birth family. However, in certain circumstances we feel it may be justified.

Cost and effectiveness of treatment options for childhood obesity.

UNLABELLED: What is already known about this subject Approximately one-fifth of children in the UK are obese. There are currently few, effective interventions available in the UK. There are very little data on relative cost-effectiveness of childhood obesity interventions, which hampers the commissioning of future services. What this study adds Simple multi-component obesity interventions can be provided at relatively low cost per 0.1 body mass index standard deviation score (BMI SDS) improvement. More intensive and effective interventions incur greater cost per 0.1 BMI SDS reduction but this may be justified given the improved overall BMI SDS reduction attained. OBJECTIVE: To describe the costs and outcomes of three models of care for childhood obesity previously evaluated in two 2-arm pilot randomized trials in England. The treatments were (i) a hospital clinic (control in both trials), comprising a multidisciplinary team of consultant, dietitian and exercise specialist; (ii) a nurse-led primary care clinic replicating the service provided by the hospital and (iii) an intensive intervention using Mandometer®, a behaviour modification tool aimed at encouraging slower eating and better recognition of satiety. METHOD: Patient-level data on resources used to deliver each intervention were collected during the trials. Apart from the cost of the Mandometer® the majority of cost was staff time, dependent on discipline and grade. Outcome for both trials was body mass index standard deviation score (BMI SDS) measured at 12 months. RESULTS: Cost and outcome data were available for 143 children in total. Cost per child was £1749 (SD £243) in the Mandometer® group, £301 (£76) in the primary care group, and £263 (£88) and £209 (£81) in the hospital groups. Mean reduction in BMI SDS was 0.40 (0.35), 0.17 (0.26), 0.15 (0.25) and 0.14 (0.32), respectively. CONCLUSION: Intensive management using Mandometer® was effective but costly (£432 per 0.1 reduction in BMI SDS) compared to conventional care (range £153-£173). A total of 26% children receiving conventional care achieved a clinically meaningful reduction in BMI SDS; however, use of Mandometer® training may be justified in children not responding to conventional lifestyle interventions.

Clinical presentation of 6q24 transient neonatal diabetes mellitus (6q24 TNDM) and genotype-phenotype correlation in an international cohort of patients.

AIMS/HYPOTHESIS: 6q24 transient neonatal diabetes mellitus (TNDM) is a rare form of diabetes presenting in the neonatal period that remits during infancy but, in a proportion of cases, recurs in later life. We aim to describe the clinical presentation of 6q24 TNDM in the largest worldwide cohort of patients with defined molecular aetiology, in particular seeking differences in presentation or clinical history between aetiological groups. METHODS: One-hundred and sixty-three patients with positively diagnosed 6q24 TNDM were ascertained from Europe, the Americas, Asia and Australia. Clinical data from referrals were recorded and stratified by the molecular aetiology of patients. RESULTS: 6q24 TNDM patients presented at a modal age of one day, with growth retardation and hyperglycaemia, irrespective of molecular aetiology. There was a positive correlation between age of presentation and gestational age, and a negative correlation between adjusted birthweight SD and age of remission. Congenital anomalies were significantly more frequent in patients with paternal uniparental disomy of chromosome 6 or hypomethylation of multiple imprinted loci defects than in those with 6q24 duplication or isolated hypomethylation defects. Patients with hypomethylation had an excess representation of assisted conception at 15%. CONCLUSIONS/INTERPRETATION: This, the largest case series of 6q24 TNDM published, refines and extends the clinical phenotype of the disorder and confirms its clinical divergence from other monogenic TNDM in addition to identifying previously unreported clinical differences between 6q24 subgroups.

How does physical activity and fitness influence glycaemic control in young people with Type 1 diabetes?

AIMS: To assess physical activity and fitness levels of young people with Type 1 diabetes compared with siblings without diabetes, and to investigate the association between physical activity, physical fitness and glycaemic control (HbA(1c)) in those young people with diabetes. METHODS: The study consisted of 97 young people aged 8 to 16 years (62% male) from a Paediatric Diabetes Service in South West England. Sixty participants (67% male) had Type 1 diabetes and 37 participants (54% male) were siblings without diabetes (control group). We measured weight, height and waist circumference, calculated BMI and waist-height ratio and recorded pubertal status, blood pressure and current insulin regimen information. We assessed physical activity by accelerometry, from which we calculated light and moderate-to-vigorous intensity activity. We measured physical fitness by multistage sub-maximal bicycle ergometer test. We obtained HbA(1c) by venipuncture. RESULTS: There were no differences between the young people with diabetes and siblings without diabetes in body composition, blood pressure, physical activity and fitness. Moderate-to-vigorous physical activity was associated with better glycaemic control, accounting for 30-37% (R(2) = 0.295-0.374) of the variance for HbA(1c). Physical fitness was not associated with HbA(1c). CONCLUSIONS: Moderate-to-vigorous physical activity was associated with better glycaemic control while fitness was not. Findings suggest that developing strategies to increased moderate-to-vigorous physical activity may prove an effective method of improving glycaemic control in young people with diabetes.

Assessment of childhood obesity in secondary care: OSCA consensus statement.

This expert opinion provides detailed guidance on assessing obesity in secondary paediatric practice. This guidance builds on existing recommendations from National Institute of Health and Clinical Excellence in the UK, and is evidence based where possible. Guidance is provided on which obese children and young people are appropriate to be seen in secondary care and relevant history and investigations, and guidance on when further investigation of causes and obesity-related comorbidity is appropriate.

Serum levels of pigment epithelium-derived factor (PEDF) are positively associated with acanthosis nigricans in obese adolescents.

INTRODUCTION: Circulating pigment epithelium-derived factor, or serine protease inhibitor F1, is upregulated during adipogenesis, contributing to obesity-induced insulin resistance. Furthermore, pigment epithelium-derived factor is abundant in stage I melanosomes and has been reported to increase pigment granules and the appearance of mature melanosomes in retinal pigment epithelium. As acanthosis nigricans is a well-recognized clinical marker of insulin resistance, we hypothesized that increased pigment epithelium-derived factor might be associated with the generation of acanthosis nigricans. METHODS: Acanthosis nigricans, anthropometric measurements, circulating total PEDF and metabolic profiles were assessed in 28 obese adolescents in a hospital-based obesity clinic. RESULTS: Subjects with acanthosis nigricans (n = 10) showed greater plasma levels of pigment epithelium-derived factor (PEDF) than those without [geometric mean 23.55 (range 15.2-40.2) vs. 9.01 (range 5.5-18.7) µg/ml; P < 0.001]. Although pigment epithelium-derived factor was positively correlated with the homeostasis model assessment for insulin resistance (HOMA-IR) (r = 0.779, P < 0.001; 95% CI 0.573-0.892), as previously reported, for the same degree of insulin resistance, those with acanthosis nigricans exhibited a 2.1-fold (95%CI 2.0-2.3) higher level of pigment epithelium-derived factor. CONCLUSIONS: While acanthosis nigricans is undoubtedly associated with insulin resistance, its appearance is not ubiquitous in patients at any given level of HOMA-IR. The higher levels of pigment epithelium-derived factor in those with acanthosis nigricans compared with those without, with similar levels of resistance, suggest that pigment epithelium-derived factor levels are associated with acanthosis nigricans.

Normalizing eating behavior reduces body weight and improves gastrointestinal hormonal secretion in obese adolescents.

HYPOTHESIS: Retraining obese adolescents to eat more slowly will lead to beneficial changes in circulating concentrations of gastrointestinal satiety hormones. METHODS: Ghrelin and peptide tyrosine-tyrosine were measured during an oral glucose tolerance test, at baseline and at 12 months during a randomized trial assessing the clinical effectiveness of a device (Mandometer) designed to retrain eating behavior. This computerized scale provided real-time feedback during meals in the intervention arm (n = 14) to slow down the speed of eating. The control group (n = 13) received only standard care aimed at improving lifestyle behavior. The Mandometer elicited greater improvements in weight loss than standard care. RESULTS: Compared with baseline, only those using the Mandometer exhibited lower mean levels of fasting ghrelin (48.14 ± 18.47 vs. 68.45 ± 17.78 pg/ml; P = 0.002) and mean ghrelin area under the curve (72.08 ± 24.11 vs. 125.50 ± 29.72 pg/ml × min; P < 0.001) at 12 months. Absolute mean suppression in ghrelin at 60 min was enhanced (-40.50 ± 21.06 vs. -12.14 ± 19.74 pg/ml × min; P = 0.001). Peptide tyrosine-tyrosine response at 90 min remained unaltered in the standard care arm, whereas those in the Mandometer arm increased (P < 0.001): the mean 90-min response increased by 72 pg/ml [95% confidence interval (CI) 52-92 pg/ml] between baseline and 12 months. In a partial correlation analysis adjusting for change (Δ) in body mass index sd scores, Δ meal duration correlated negatively with Δ absolute suppression in ghrelin at 60 min (r = -0.58; P = 0.037; 95% CI -0.79 to -0.27) and Δ ghrelin area under the curve (r = -0.62; P = 0.025; 95% CI -0.81 to -0.31). CONCLUSIONS: Retraining obese adolescents to eat more slowly has a significant impact on the gastrointestinal hormone response to a carbohydrate load, suggesting that externally modifiable eating behaviors actually regulate the hormonal response to food.

The role of pharmacotherapy in the prevention and treatment of paediatric metabolic syndrome--Implications for long-term health: part of a series on Pediatric Pharmacology, guest edited by Gianvincenzo Zuccotti, Emilio Clementi, and Massimo Molteni.

The metabolic syndrome (MetS) is defined as a clustering of risk factors predisposing to the future development of cardiovascular disease and Type 2 diabetes mellitus (T2DM). Its clinical relevance, above and beyond recognition and treatment of each of the component parts, is still hotly debated--especially within paediatric medicine. Prevention and treatment strategies for adult MetS focus on weight management, as obesity and insulin resistance are known to be at the central axis of the definition, alongside pharmacotherapy of integrally linked conditions such as hypertension and dyslipidaemia. In children and adolescents, however, opportunities for pharmacotherapy are currently limited and interventions aimed at weight management remain the sole treatment paradigm in the majority of cases. This is primarily due to a lack of long-term data relating to the degree of cardiovascular disease and T2DM risk from paediatric MetS, as well as concerns relating to safety and side effect profiles of currently available pharmacotherapies in those who are still growing and developing. Coupled with continuing concern about the recently recognised adverse effects of past and proposed anti-obesity drugs, this indicates that a new era of pharmacotherapy for paediatric MetS is unlikely to be imminent. In fact, the overall paucity of effective current interventions for paediatric MetS is concerning, especially given the fact that approximately 25-33% of all obese paediatric patients likely harbour the condition. It is therefore essential at the present time to concentrate efforts on properly testing the safety and efficacy of currently available products in well-constructed randomised controlled trials in obese adolescents. However, not all obese children and adolescents appear equally at-risk of long-term, weight-related morbidity and a change in emphasis is possibly warranted--one that moves away from simple weight reduction for all and more to a model of reducing long-term risk of cardiovascular disease and T2DM in those at greatest metabolic risk.

Hyperinsulinaemic hypoglycaemia and diabetes mellitus due to dominant ABCC8/KCNJ11 mutations.

AIMS/HYPOTHESIS: Dominantly acting loss-of-function mutations in the ABCC8/KCNJ11 genes can cause mild medically responsive hyperinsulinaemic hypoglycaemia (HH). As controversy exists over whether these mutations predispose to diabetes in adulthood we investigated the prevalence of diabetes in families with dominantly inherited ATP-sensitive potassium (K(ATP)) channel mutations causing HH in the proband. METHODS: We studied the phenotype of 30 mutation carriers (14 children and 16 adults) from nine families with dominant ABCC8/KCNJ11 mutations. Functional consequences of six novel missense mutations were examined by reconstituting the K(ATP) channel in human embryonic kidney 293 (HEK293) cells and evaluating the effect of drugs and metabolic poisoning on the channels using the (86)Rb flux assay. RESULTS: The mutant channels all showed a lack of (86)Rb efflux on exposure to the channel agonist diazoxide or metabolic inhibition. In the families, dominant ABCC8/KCNJ11 mutations were associated with increased birthweight (median + 1.56 SD score [SDS]). Fourteen children had HH and five adults were reported with HH or hypoglycaemic episodes (63%). Progression from hypoglycaemia to diabetes mellitus occurred in two individuals. Eight adults had a history of gestational diabetes in multiple pregnancies or were diabetic (diagnosed at a median age of 31 years). Within these families, none of the 19 adults who were not carriers of the ABCC8/KCNJ11 mutation was known to be diabetic. CONCLUSIONS/INTERPRETATION: The phenotype associated with dominant ABCC8/KCNJ11 mutations ranges from asymptomatic macrosomia to persistent HH in childhood. In adults, it may also be an important cause of dominantly inherited early-onset diabetes mellitus.

Hyperglycaemia confers resistance to chemotherapy on breast cancer cells: the role of fatty acid synthase.

The prognosis for women with breast cancer is adversely affected by the comorbidities of obesity and diabetes mellitus (DM), which are conditions associated with elevated levels of circulating fatty acids, hyperglycaemia and hyperinsulinaemia. We investigated the effects of exposure of non-malignant and malignant human breast epithelial cells to elevated levels of fatty acids and glucose on their growth, survival and response to chemotherapeutic agents. We found that palmitate induced cell death in the non-malignant cells but not in the malignant cells, which was abrogated through the inhibition of ceramide production and by oleate but not by IGF1. Fatty acid synthase (FAS) is responsible for the de novo synthesis of fatty acids from sugars, and is over-expressed in many epithelial cancers. Abundance of FAS was higher in malignant cells than in non-malignant cells, and was up-regulated by IGF1 in both cell types. IGF-induced growth of non-malignant cells was unaffected by suppression of FAS expression, whereas that of malignant cells was blocked as was their resistance to palmitate-induced cell death. Palmitate did not affect cell proliferation, whereas oleate promoted the growth of non-malignant cells but had the opposite effect, that is, inhibition of IGF1-induced growth of malignant cells. However, when the phosphatidylinositol 3-kinase pathway was inhibited, oleate enhanced IGF1-induced growth in both cell types. Hyperglycaemia conferred resistance on malignant cells, but not on non-malignant cells, to chemotherapy-induced cell death. This resistance was overcome by inhibiting FAS or ceramide production. Understanding the mechanisms involved in the associations between obesity, DM and breast cancer may lead to more effective treatment regimens and new therapeutic targets.

Diazoxide-responsive hyperinsulinemic hypoglycemia caused by HNF4A gene mutations.

OBJECTIVE: The phenotype associated with heterozygous HNF4A gene mutations has recently been extended to include diazoxide responsive neonatal hypoglycemia in addition to maturity-onset diabetes of the young (MODY). To date, mutation screening has been limited to patients with a family history consistent with MODY. In this study, we investigated the prevalence of HNF4A mutations in a large cohort of patients with diazoxide responsive hyperinsulinemic hypoglycemia (HH). SUBJECTS AND METHODS: We sequenced the ABCC8, KCNJ11, GCK, GLUD1, and/or HNF4A genes in 220 patients with HH responsive to diazoxide. The order of genetic testing was dependent upon the clinical phenotype. RESULTS: A genetic diagnosis was possible for 59/220 (27%) patients. K(ATP) channel mutations were most common (15%) followed by GLUD1 mutations causing hyperinsulinism with hyperammonemia (5.9%), and HNF4A mutations (5%). Seven of the 11 probands with a heterozygous HNF4A mutation did not have a parent affected with diabetes, and four de novo mutations were confirmed. These patients were diagnosed with HI within the first week of life (median age 1 day), and they had increased birth weight (median +2.4 SDS). The duration of diazoxide treatment ranged from 3 months to ongoing at 8 years. CONCLUSIONS: In this large series, HNF4A mutations are the third most common cause of diazoxide responsive HH. We recommend that HNF4A sequencing is considered in all patients with diazoxide responsive HH diagnosed in the first week of life irrespective of a family history of diabetes, once K(ATP) channel mutations have been excluded.

Pancreatic hypoplasia presenting with neonatal diabetes mellitus in association with congenital heart defect and developmental delay.

Congenital pancreatic hypoplasia is a rare cause of neonatal diabetes. We report on a series of three patients with pancreatic agenesis and congenital heart defects. All had abdominal scan evidence of pancreatic agenesis. In addition, Patient 1 had a ventricular septal defect, patent ductus arteriosus and pulmonary artery stenosis; Patient 2 had a truncus arteriosus and Patient 3 had tetralogy of Fallot. Two of the three patients have developmental delay. All three patients were isolated cases within the family. Investigations included sequencing of GCK, ABCC8, IPF1, NEUROD1, PTF1A, HNF1B, INS, ISL1, NGN3, HHEX, G6PC2, TCF7L2, SOX4, FOXP3 (Patients 1 and 2), GATA4 and KCNJ11 genes (all three patients), but no mutations were found. Genetic investigation to exclude paternal UPD 6, methylation aberrations and duplications of 6q24 was also negative in all three. 22q11 deletion was excluded in all three patients. Array CGH in Patient (1) showed a approximately 250 kb, paternally inherited duplication of chromosome 12q [arr cgh 12q24.33 (B35:CHR12:131808577-132057649++) pat], not found in the other two patients. Permanent neonatal diabetes mellitus due to pancreatic hypoplasia with congenital heart defects has been reported before and may represent a distinct condition. We discuss this rare association and review previously reported literature.