The natural mutant receptor hGRαV423A causes primary generalized glucocorticoid resistance by affecting multiple steps in the cascade of glucocorticoid receptor action, which primarily involve decreased ability to bind to target glucocorticoid response elements and delayed translocation into the nucleus.

Mutations in the Wilms' tumor suppressor gene 1 (WT1), most commonly within exons 8 or 9 or intron 9, are found in cases with the overlapping conditions of Denys-Drash and Frasier syndromes, as well as in patients with steroid-resistant nephrotic syndrome (SRNS). This study investigated the presence of WT1 gene mutations in cases with childhood SRNS, along with an evaluation of their clinical outcome. Twenty-seven Greek children with sporadic (19 cases) and familial (8 cases) SRNS were tested. Four phenotypically female patients with sporadic SRNS were found to carry de novo WT1 mutations, including two cases with p.R394W, and one case each with p.R366H, or n.1228+5G>A. Karyotype analysis found 46XX in three cases, but 46XY in one. No phenotype-genotype correlations were apparent in the WT1 gene positive cases since their clinical presentation varied broadly. Interestingly, one patient with a pathological WT1 nucleotide variation responded fully to combined therapy with cyclosporine A and corticosteroids. This study further illustrates that investigation of WT1 gene mutations is clinically useful to support definitive diagnosis in children presenting with SRNS in order to direct the most appropriate clinical management.

The alleged dominance of diffuse attenuation of the glomerular basement membrane (GBM) in young children and females with Alport's Syndrome (AS) suggests that it might be the initial ultrastructural manifestation of type IV collagen defects. We carried out a 'blind' review of 130 renal biopsies obtained from 100 patients with AS, emphasizing the electron microscopy changes, and related the findings to the clinical presentation and outcome. The intracapillary distribution of (1) thickened, (2) attenuated and (3) normal GBM was assessed individually as: none (grade 0), <25% (grade 1), 25-50% (grade 2) and >50% (grade 3). Deafness was defined as persistent loss of > or =30 dBs. Proteinuria was measured as protein/creatinine ratios in early morning urine. Heavy proteinuria (> or =200 mg/mmol) correlated significantly with the presence of segmental and global glomerulosclerosis and foam cells. Comparing grades 0+1 vs. 3 GBM changes, using a 2x2 chi(2) test, there were significant correlations between grade 3 GBM thickening and male sex (P =0.005), heavy proteinuria (P =0.02) and deafness (P <0.001). GBM thickening did not correlate with age at the initial biopsy, but repeat biopsies demonstrated increasing thickening with age. The grades of GBM attenuation did not correlate with either age at biopsy or sex. In 11 biopsies with atypical lamina densa changes in thickened GBM segments, there were no differences in clinicopathological correlations compared with classical biopsies. Our data indicate that diffuse GBM attenuation can be an ultrastructural variant of the Alport nephropathy, but do not support the contention that it is the initial lesion.

p i t a l des Enfants. 168. Cours de 1'Argonne-33077 Bordeaux-F M E-95 P l a s m Thy,l obul i n (Tg) i n hypothyroid children under L. Thyroxine therapy (L.T.).