No abstract

The R337H TP53 mutation is a low-penetrance molecular defect that predisposes to adrenocortical tumour (ACT) formation in Brazilian and possibly other populations. Additional genetic defects may be responsible for the variable expression of ACTs in these cases. The inhibin asubunit gene (INHA) on 2q33-qter has been implicated in mouse adrenocortical tumourigenesis. We studied 46 pediatric patients with ACTs from Brazil for INHA genetic alterations; 39 of these patients were heterozygous carriers of the R337H TP53 mutation. We first mapped the INHA gene by radiation hybrid analysis and determined 10 linked microsatellite markers in an area flanked by D2S1371 and D2S206 on 2q33-qter. These markers were then used for loss of heterozygozity (LOH) studies in nine paired germline and tumour DNA samples. Mapping placed the INHA gene in close proximity to D2S2848 (SHGC11864) with a log of odds (LOD) score of 5.84. LOH for at least one marker in the region was identified in 8/9 tumours (89%). Six patients were heterozygous for three INHA mutations: one in exon 1, 127C.G, and two in exon 2, 3998G.A and 4088G.A, all leading to amino acid substitutions (P43A, G227R, and A257T, respectively). A257T is located in a conserved INHA region, highly homologous to transforming growth factor-b; both G227R and A257T change polarity, and, in addition, G227R changes the pH. We conclude that these sequence alterations and the detected 2q allelic changes suggest that INHA may be one of the contributing factors needed for ACT formation in pediatric patient carriers of the R337H TP53 mutation.A drenocortical tumours (ACTs) are rare, with an estimated incidence in the US of 0.3 per million per year. 1 In southern Brazil, the incidence is 10-15 times greater, despite no evidence of occupational, endemic, or transmissable diseases that predispose to ACTs. Recently, a germline mutation of the TP53 gene (R337H) was described in 35 of 36 Brazilian children with ACTs. 2 The same mutation was then identified by Latronico and co-workers in adult, as well as additional paediatric, Brazilian patients with ACTs. 3 Furthermore, low-penetrance mutations of the TP53 gene were recently identified in other populations. 4 It appears likely that the tumourigenic effect of the low-penetrance R337H mutation is related to pH-induced conformational changes in the p53 protein 5 6 and/or other factors.In the case of ACTs in the Brazilian population, it has long been hypothesised that additional germline or somatic mutations of other genes with an established tumourigenic role may act in synergy, or may even be required for adrenocortical tumourigenesis.

Data were reviewed from 73 consecutive medical charts of children and adolescents with type 1 diabetes mellitus using insulin pumps for more than 6 months at The Hospital for Sick Children, Toronto, Canada. Statistically significant differences in HbA1c (-0.8%), body mass index (+1.45 kg/m2) and total daily dose of insulin (-0.23 U/kg/day) were found between the start of pump use and evaluation 6-30 months later. There was a close correlation between the HbA1c before and after 6-30 months of pump therapy.