Fenfluramine—induced irreversible pulmonary hypertension

Abstract

<h3>Background and objectives</h3> The Wilms tumor suppressor gene 1 (<i>WT1</i>) plays an essential role in urogenital and kidney development. Genotype/phenotype correlations of <i>WT1</i> 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 <i>WT1</i>, including patients without proteinuria or WT. <h3>Design, setting, participants &amp; measurements</h3> Retrospective analysis of genotype, phenotype, and treatment of 53 patients with <i>WT1</i> mutation from all pediatric nephrology centers in Germany, Austria, and Switzerland performed from 2010 to 2012. <h3>Results</h3> 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]; <i>P</i>&lt;0.001) and splice site (4.0 [IQR, 2.6–6.6]; <i>P=</i>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]; <i>P&lt;</i>0.001) and splice site mutations (12.3 [IQR, 7.9–18.2]; <i>P</i>=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 (<i>n</i>=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. <h3>Conclusions</h3> Type and location of <i>WT1</i> 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.