A review of the phenotypic variation due to the Denys-Drash syndrome-associated germlineWT1 mutation R362X

Abstract

The gene WT1 is required for the normal development and function of the urogenital tract. Constitutional mutations are associated with familial Wilms tumor and syndromes such as Denys-Drash syndrome (DDS) characterized by nephropathy, genital anomalies and often a predisposition to Wilms tumor. We report a case of constitutional WT1 mutation in an XX female with multifocal Wilms tumor but no genital anomalies or renal dysfunction and, for the first time, review patients previously reported with this germline mutation. The mutation (1084C>T) changes the amino acid arginine at position 362 to the translation stop codon TGA (R362X) resulting in a predicted truncated protein lacking three of the four zinc finger domains necessary for correct functioning of the gene. This constitutional mutation has been reported to cause a variety of phenotypes in eleven different patients, including the classical Denys-Drash phenotype of diffuse mesangial sclerosis which leads to early renal failure, genital anomalies in XY individuals and Wilms tumors. The absence of mesangial sclerosis and renal failure in our patient excludes DDS. Our case differs from those previously described as the normal kidney tissue shows some small subcapsular glomeruli indicating that the WT1 mutation has impaired nephron development. This patient extends the range and variation of phenotypes that may arise from a specific germline mutation in WT1

Genotype/Phenotype Correlation in Nephrotic Syndrome Caused by WT1 Mutations

“…Other nonsense mutations of WT1 were previously reported with a variety of phenotypes, almost always with WT occurrence (26,27). (6) NS patients with missense mutations presented in this cohort either in the form of DDS with WT or in the form of isolated NS.…”

Common critical pathways in embryogenesis and cancer

“…b-catenin mutations occur in medulloblastomas, hepatoblastomas and Wilm's tumours [23]. Wilm's tumours can occur in Denys-Drash syndrome, a familial disorder secondary to germline mutations in WT1 [24]. Wnt 1 functions as a mammary oncogene in mouse mammary tumour virus infected mice [25].…”

Denys Drash Syndrome Presenting with Renal Failure in the Early Period

“…Disgenetik gonadlarda neoplazi gelişme ihtimali %20-30'dur, bunların da %50-54'ü gonadoblastomdur. Bu nedenle erken dönemde yapılan gonadektomi ile invaziv lezyonların önleneceği düşünülmektedir (1,(3)(4)(5)(6)10). Hastalar gonadoblastom ve Wilms Tümörü geliştirme riski açısından mutlaka takip edilmelidir.…”