Clinical spectrum of Denys-Drash and Frasier syndrome

Abstract

Denys-Drash syndrome (DDS) and Frasier syndrome (FS) are two related conditions caused by mutations of the Wilms tumor gene, WT1. Both syndromes are characterized by male pseudohermaphroditism, a progressive glomerulopathy, and the development of genitourinary tumors. DDS and FS have previously been distinguished by differences in nephropathy, with DDS patients demonstrating diffuse mesangial sclerosis (DMS) in contrast to focal and segmental glomerulosclerosis (FSGS) in FS patients. The clinicopathological features and genotype analysis of two patients with WT1 mutations are presented in this report. Genotype analysis of the first patient revealed a previously undescribed mutation in exon 8 of the WT1 gene. The second patient presented with a rapidly progressive nephropathy characterized histologically by DMS, but was found to have the genetic mutation seen in FS patients. A summary of all reported patients with the characteristic mutation associated with FS demonstrates the clinical overlap of this syndrome with DDS. This suggests that both these conditions should be considered as part of the spectrum of disease due to WT1 gene mutations rather than as separate diseases. Clinical classification remains important for prognosis, as the underlying renal disease appears to predict the progression of nephropathy independently of the genetic abnormality.

Lack of Puberty Despite Elevated Estradiol in a 46,XY Phenotypic Female with Frasier Syndrome

“…In the case of our patient, a novel mutation, +1 G to A in intron 9 of WT1, was detected. The position of this mutation was very close to but different from previously reported mutations in FS [12]. As far as we know, five different mutations have been reported in intron 9 of the WT1 gene: +2T>C, +4C>T, +5G>A, +5G>T, and +6T>A.…”

Clinical and Molecular Characterization of Patients with Heterozygous Mutations in Wilms Tumor Suppressor Gene 1

“…Among our patients with intronic KTS splice site mutations and delayed manifestation of nephropathy, only one patient showed the full classic syndromal picture of a FS. DDS and FS can be regarded as extremes of the spectrum of disease due to WT1 gene mutations rather than as separate diseases (30). Patients with truncating mutations do not clearly fit with either DDS or FS.…”

Inherited Podocytopathies

“…WT1, a transcription factor, was positionally cloned on the basis of its role in the development of Wilms tumor (53,54). Frasier syndrome and DenysDrash syndrome are related and overlapping syndromes caused by mutations in WT1 (55)(56)(57)(58). Both syndromes are characterized by the development of male pseudohermaphroditism and glomerular disease.…”