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.

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.

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.

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.

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.

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.

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.

Elevated glucose concentrations during an oral glucose tolerance test are associated with the presence of metabolic syndrome in childhood obesity.

AIMS: To investigate whether changes in glucose concentrations during an OGTT in obese children reflect the presence of peripheral insulin resistance and/or cardiovascular risk factors more closely than single measurements of fasting plasma glucose (FPG). METHODS: One hundred and twenty-two obese children attending our Paediatric Obesity Service underwent formal OGTTs, following the measurement of blood pressure and fasting levels of insulin, glucose and lipid profiles in the majority. Fasting insulin was used as a surrogate measure of insulin sensitivity. Three different child-specific definitions for metabolic syndrome were used to identify clustering of cardiovascular risk factors in 65 of these children. RESULTS: In the whole group, 10.7% had IGT but changes in glucose during the OGTT were not influenced by age, sex, pubertal status or raw (or age- and sex-adjusted) body mass index (BMI). During the OGTT, FPG, glucose at 60 min and area under the glucose curve correlated highly with fasting insulin. Children with metabolic syndrome (defined using any of three definitions) had comparable FPG levels to those without metabolic syndrome, but they demonstrated significantly elevated glucose levels at 60 min. On sub-group analysis, obese children with normal carbohydrate metabolism were significantly more likely to have a 1 h glucose level > or = 7.8 mmol/l if they had metabolic syndrome (P = 0.026). CONCLUSIONS: These data suggest that an elevated 1 h post-load glucose measurement is seen in obese children who have a coexistent clustering of cardiovascular risk factors.

Childhood obesity.

The prevalence of childhood obesity continues to increase worldwide. Its presence is associated with significant adverse effects on health including an increased propensity to type II diabetes, cardiovascular, respiratory, and liver disease. In the vast majority of children, obesity is lifestyle-related, yet there is a dearth of evidence on how to best develop effective prevention and treatment strategies. This review outlines the importance of childhood and adolescent growth on long-term health, the definitions used to define obesity in children (along with up-to-date prevalence data), causes and consequences, and aspects of prevention and management.

Clinical, enzymatic and molecular characterization of nine new patients with malonyl-coenzyme A decarboxylase deficiency.

We report nine new patients with malonic aciduria associated with enzyme-confirmed malonyl-CoA decarboxylase (MCD) deficiency in eight. Clinical details were available on eight, and molecular genetic characterization was obtained for nine. As for 15 previously described patients, cardinal clinical manifestations included developmental delay and cardiomyopathy; metabolic perturbations (e.g. acidosis) and seizures, however, were infrequent or not observed in our patients. For all, detection of elevated malonic acid in urine (+/- increased C3DC acylcarnitine by analysis employing tandem mass spectrometry) led to pursuit of enzyme studies. MCD activities (nmol/h PER mg protein) revealed: control (n = 22), 16.2 +/- 1.8 (SEM; range 5.7-46.2); patients (n = 8, assayed in duplicate), 1.7 +/- 0.3 (10% of parallel control; range 0.6-2.8). Molecular characterization by DNA sequence analysis and multiplex ligation-dependent probe amplification revealed nine novel mutations (c.796C>T; p.Gln266X, c.481delC; p.Leu161CysfsX18, c.1367A>C; p.Tyr456Ser, c.1319G>T; p.Ser440Ile, c.1430C>T; p.Ser477Phe, c.899G>T; p.Gly300Val, c.799-1683_949-1293del3128, and two other large genomic deletions comprising exons 1 or the complete gene) and two known mutations in the MLYCD gene. Our findings increase the number of enzyme-confirmed MCD-deficient patients by >50%, and expand our understanding of the phenotypic and molecular heterogeneity of this rare disorder.

Neonatal diabetes.

BACKGROUND: Nine distinct genetic conditions have been identified in the last 12 years causing neonatal diabetes mellitus through failure of normal pancreatic development, islet cell dysfunction or beta-cell destruction. This review will focus on the three conditions about which our understanding of the pathology - and in some cases the treatment options - has greatly increased: transient neonatal diabetes mellitus, permanent neonatal diabetes due to 'channelopathies' and immune dysregulation, polyendocrinopathy, enteropathy X-linked syndrome. CONCLUSIONS: Effective treatment of neonatal diabetes requires thorough understanding of the disease processes underlying this highly variable condition. As our knowledge of pancreatic development and physiology expands, so, too, do the treatment options for some patients.

Obesity and disability - a short review.

The prevalence of both obesity and disability is increasing globally and there is now growing evidence to suggest that these two health priorities may be linked. This paper explores the evidence linking obesity to muscular-skeletal conditions, mental health disorders and learning disabilities in both adult and child populations. The impact of obesity on the four most prevalent disabling conditions in the UK (arthritis, mental health disorders, learning disabilities and back ailments) has been examined through novel data analysis of the 2001 Health Survey for England and UK Back Exercise And Manipulation trial data. Together these analyses strongly suggest that whether the cause or result of disability, obesity is undeniably implicated, thus presenting a serious public health priority. Future research efforts are required to strengthen the evidence base examining obesity in back disorders, mental health and learning disabilities, in order to improve current clinical management.

Transient neonatal diabetes, a disorder of imprinting.

Transient neonatal diabetes (TND) is a rare but distinct type of diabetes. Classically, neonates present with growth retardation and diabetes in the first week of life. Apparent remission occurs by 3 months but there is a tendency for children to develop diabetes in later life. Evidence suggests it is the result of overexpression of an imprinted and paternally expressed gene/s within the TND critical region at 6q24. Two imprinted genes, ZAC (zinc finger protein associated with apoptosis and cell cycle arrest) and HYMAI (imprinted in hydatidiform mole) have been identified as potential candidates. Three genetic mechanisms have been shown to result in TND, paternal uniparental isodisomy of chromosome 6, paternally inherited duplication of 6q24, and a methylation defect at a CpG island overlapping exon 1 of ZAC/HYMAI.

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.

An assessment of pancreatic endocrine function and insulin sensitivity in patients with transient neonatal diabetes in remission.

AIMS: To examine derived indices of beta cell function, peripheral insulin sensitivity, and the pancreatic response to intravenous glucose loading in children with a previous history of transient neonatal diabetes currently in remission, repeated after a period of two or more years. METHODS: The standard intravenous glucose tolerance test (IVGTT) was used to measure the first phase insulin response (FPIR) cumulatively at one and three minutes. In addition, fasting insulin and glucose values were used to estimate insulinogenic indices (beta cell function) and QUICKI (insulin sensitivity). PATIENTS: Six patients with known previous transient neonatal diabetes currently in remission with no exogenous insulin requirement were tested. Control data from 15 children of a similar age were available for derived fasting indices of beta cell functional capacity and insulin sensitivity. RESULTS: One child had a subnormal insulin secretory response to intravenous glucose that remained abnormal two and four years later. The other children had relatively normal or entirely normal responses over two years. Measures of beta cell function and insulin sensitivity in the fasting state showed comparable results to those obtained from normal controls. CONCLUSIONS: Most children with transient neonatal diabetes in remission have no evidence of beta cell dysfunction or insulin resistance in the fasting state, although they might have been expected to show subtle defects given the tendency to relapse in adolescence. Measures of insulin response to intravenous glucose loading are often normal but suggest future recurrence if profoundly abnormal.

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.

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.

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.