Clinical and molecular characterization of patients with heterozygous mutations in wilms tumor suppressor gene 1.

BACKGROUND AND OBJECTIVES: The Wilms tumor suppressor gene 1 (WT1) plays an essential role in urogenital and kidney development. Genotype/phenotype correlations of WT1 mutations with renal function and proteinuria have been observed in world-wide cohorts with nephrotic syndrome or Wilms tumor (WT). This study analyzed mid-European patients with known constitutional heterozygous mutations in WT1, including patients without proteinuria or WT. DESIGN, SETTING, PARTICIPANTS & MEASUREMENTS: Retrospective analysis of genotype, phenotype, and treatment of 53 patients with WT1 mutation from all pediatric nephrology centers in Germany, Austria, and Switzerland performed from 2010 to 2012. RESULTS: Median age was 12.4 (interquartile range [IQR], 6-19) years. Forty-four of 53 (83%) patients had an exon mutation (36 missense, eight truncating), and nine of 53 (17%) had an intronic lysine-threonine-serine (KTS) splice site mutation. Fifty of 53 patients (94%) had proteinuria, which occurred at an earlier age in patients with missense mutations (0.6 [IQR, 0.1-1.5] years) than in those with truncating (9.7 [IQR, 5.7-11.9]; P<0.001) and splice site (4.0 [IQR, 2.6-6.6]; P=0.004) mutations. Thirteen of 50 (26%) were treated with steroids and remained irresponsive, while three of five partially responded to cyclosporine A. Seventy-three percent of all patients required RRT, those with missense mutations significantly earlier (at 1.1 [IQR, 0.01-9.3] years) than those with truncating mutations (16.5 [IQR, 16.5-16.8]; P<0.001) and splice site mutations (12.3 [IQR, 7.9-18.2]; P=0.002). Diffuse mesangial sclerosis was restricted to patients with missense mutations, while focal segmental sclerosis occurred in all groups. WT occurred only in patients with exon mutations (n=19). Fifty of 53 (94%) patients were karyotyped: Thirty-one (62%) had XY and 19 (38%) had XX chromosomes, and 96% of male karyotypes had urogenital malformations. CONCLUSIONS: Type and location of WT1 mutations have predictive value for the development of proteinuria, renal insufficiency, and WT. XY karyotype was more frequent and associated with urogenital malformations in most cases.

Normal adult height after steroid-withdrawal within 6 months of pediatric kidney transplantation: a 20 years single center experience.

Long-term corticosteroid treatment impairs growth in children after kidney transplantation (KTx). The impact of steroid withdrawal with respect to adult height remains to be elucidated. In this single-center retrospective analysis linear growth and graft function in 74 pediatric KTx patients transplanted between 1981 and 2001 was investigated. Mean follow up was 8.5years. Steroids were weaned off between months 4 and 6. Steroid withdrawal resulted in sustained catch-up growth after KTx. Absolute and standardized height velocity in prepubertal patients during the first year post-KTx was 8.9cm/year and +2.9 SD score (SDS), respectively (P<0.001 versus healthy children). Mean adult height amounted to -0.5±1.1 SDS and -1.0±1.3 SDS in prepubertal and pubertal patients and was within the normal range (>-2 SD) in 94% and 80% of them. Multiple regression analysis revealed age and standardized height at KTx as independent predictors of adult height (model r(2) =0.48). Overall graft survival at 5 and 10years was 92% and 71%, respectively. Steroid withdrawal during month 4-6 after KTx in prepubertal patients results in an adult height within the normal range, whereas catch-up growth is limited in pubertal patients.