OBJECTIVE-Insulin gene (INS) mutations have recently been described as a cause of permanent neonatal diabetes (PND). We aimed to determine the prevalence, genetics, and clinical phenotype of INS mutations in large cohorts of patients with neonatal diabetes and permanent diabetes diagnosed in infancy, childhood, or adulthood. RESEARCH DESIGN AND METHODS-The INS gene was sequenced in 285 patients with diabetes diagnosed before 2 years of age, 296 probands with maturity-onset diabetes of the young (MODY), and 463 patients with young-onset type 2 diabetes (nonobese, diagnosed Ͻ45 years). None had a molecular genetic diagnosis of monogenic diabetes. RESULTS-We identified heterozygous INS mutations in 33 of141 probands diagnosed at Ͻ6 months, 2 of 86 between 6 and 12 months, and none of 58 between 12 and 24 months of age. Three known mutations (A24D, F48C, and R89C) account for 46% of cases. There were six novel mutations: H29D, L35P, G84R, C96S, S101C, and Y103C. INS mutation carriers were all insulin treated from diagnosis and were diagnosed later than ATP-sensitive K ϩ channel mutation carriers (11 vs. 8 weeks, P Ͻ 0.01). In 279 patients with PND, the frequency of KCNJ11, ABCC8, and INS gene mutations was 31, 10, and 12%, respectively. A heterozygous R6C mutation cosegregated with diabetes in a MODY family and is probably pathogenic, but the L68M substitution identified in a patient with young-onset type 2 diabetes may be a rare nonfunctional variant.CONCLUSIONS-We conclude that INS mutations are the second most common cause of PND and a rare cause of MODY. Insulin gene mutation screening is recommended for all diabetic patients diagnosed before 1 year of age.

BackgroundCongenital hyperinsulinism (CHI) is a clinically heterogeneous condition. Mutations in eight genes (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, HNF4A and HNF1A) are known to cause CHI.AimTo characterise the clinical and molecular aspects of a large cohort of patients with CHI.MethodologyThree hundred patients were recruited and clinical information was collected before genotyping. ABCC8 and KCNJ11 genes were analysed in all patients. Mutations in GLUD1, HADH, GCK and HNF4A genes were sought in patients with diazoxide-responsive CHI with hyperammonaemia (GLUD1), raised 3-hydroxybutyrylcarnitine and/or consanguinity (HADH), positive family history (GCK) or when CHI was diagnosed within the first week of life (HNF4A).ResultsMutations were identified in 136/300 patients (45.3%). Mutations in ABCC8/KCNJ11 were the commonest genetic cause identified (n=109, 36.3%). Among diazoxide-unresponsive patients (n=105), mutations in ABCC8/KCNJ11 were identified in 92 (87.6%) patients, of whom 63 patients had recessively inherited mutations while four patients had dominantly inherited mutations. A paternal mutation in the ABCC8/KCNJ11 genes was identified in 23 diazoxide-unresponsive patients, of whom six had diffuse disease. Among the diazoxide-responsive patients (n=183), mutations were identified in 41 patients (22.4%). These include mutations in ABCC8/KCNJ11 (n=15), HNF4A (n=7), GLUD1 (n=16) and HADH (n=3).ConclusionsA genetic diagnosis was made for 45.3% of patients in this large series. Mutations in the ABCC8 gene were the commonest identifiable cause. The vast majority of patients with diazoxide-responsive CHI (77.6%) had no identifiable mutations, suggesting other genetic and/or environmental mechanisms.

Concordance with growth hormone (GH) therapy in 75 children was objectively assessed using data on GP prescriptions over 12 months. 23% missed .2 injections/ week. Lower concordance was associated with longer duration on GH therapy (p,0.005), lack of choice of delivery device (p,0.005) and short prescription durations (p,0.005), and predicted lower height velocities (p,0.05).Concordance with drug therapy is often poor in chronic non-life-threatening conditions such as growth hormone (GH) deficiency.1 Motivation may be low as the benefits are not immediately apparent and daily subcutaneous injections may present a significant burden.Concordance with GH therapy has been related to patient and family education, timing and location of education sessions, and the type of healthcare professional providing the education.2 3 In a retrospective observational study we examined whether various differences in GH prescribing policies were associated with objectively measured treatment concordance and short-term growth outcomes. METHODSWe collected data on 75 GH deficient children receiving GH therapy who attended a regional paediatric endocrine clinic at Addenbrooke's Hospital, Cambridge during 1999-2003 We sent a postal questionnaire to the children's general practitioners (GPs) who issued the GH prescriptions under a shared care agreement. Data on 11 patients were obtained from an outreach clinic where GH prescriptions were provided directly by a designated local consultant paediatrician. The questionnaire requested details on the number of issued prescriptions and the total GH dose (or number of vials/cartridges) issued with each prescription during three specific 12-month periods (1999-2000, 2000-2001 and 2002-2003). Most of the data returned by GPs was in the form of computerised printouts. We approached 66 GP practices and 58 replied (response rate 88%).GH devices used included automatic injection devices (n = 38), manual injection pen devices (n = 33) and needle-free injection devices (n = 4). According to a gradual change in clinic policy, children had been either allocated to a specific GH device by the nurse specialist or consultant, or had been offered a free choice of devices. All children and parents received training on GH delivery from one nurse specialist (SB). Patients were seen in the regional clinic every 4-6 months for assessment of height by the nurse specialists and review of GH doses. ConcordanceConcordance was objectively assessed in each child by comparing total expected GH usage as documented in the clinic records and letters to the total amount of GH prescribed by GPs during a 12-month period. From the expected daily dose (mg/day) (A), the expected annual GH requirement for each patient (B) was calculated. The number of issued prescriptions and the number of vials provided with each prescription enabled calculation of the total amount of GH prescribed by the GP over the same 12-month period (C). The annual deficit (D) in GH prescribed compared to that expected was calculated as (D = B2C). ...