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A rare genetic, syndromic glomerular disorder characterized by the association of nephropathy presenting as persistent proteinuria or overt nephrotic syndrome, Wilms tumor and genitourinary structural defects. In addition, disorders of testicular development are common in subjects with 46,XY karyotype.
ORPHA:220Classification level: Disorder
The prevalence is not known. Fewer than 300 cases have been reported in the literature to date.
Presentation is typically of infantile nephrotic syndrome progressing to end-stage renal disease (ESRD) within 1 to 15 years. Alternatively, initial clinical presentation may be with ambiguous external genitalia (e.g. hypospadias, cryptorchidism) in 46,XY individuals or uni- or bilateral Wilms tumor (WT). Affected individuals with 46,XY karyotype may have a wide range of disorders of testicular development ranging from undervirilized male to complete sex reversal, and carry a risk of developing gonadoblastoma in dysgenic gonads. Congenital anomalies of kidney and urinary tract (CAKUT) including duplex or horseshoe kidney, urogenital sinus and vesico-ureteric reflux, are present in ~10% of individuals. Genotype-phenotype correlations have been described; in particular, missense pathogenic variants affecting DNA-binding are associated with severe nephropathy and progression to ESRD within 1-3 years, and truncating variants are associated with a high risk (>85%) of developing WT and having a CAKUT (25%) while proteinuria is typically diagnosed in the second decade of life .
Constitutional pathogenic variants in the Wilms tumor predisposing genes, WT1 (11p13), most of which are located in exons 8 and 9, have been described in the majority of individuals. WT1 encodes for a protein that serves as regulatory transcription factor important both for renal and gonadal development.
Diagnosis is suspected on infantile presentation of glomerulopathy with either urogenital abnormalities and/or WT. Careful renal ultrasonography (US) for WT should be performed in any subject found to have early onset nephrotic syndrome. Diffuse mesangial sclerosis is the classic finding on renal biopsy, although other types of nephropathy are common. Imaging is used to assess internal genitalia. Identification of WT1 pathogenic variant confirms diagnosis. Karyotype testing is recommended for all individuals with ambiguous genitalia or gonadal dysgenesis.
The differential diagnosis includes WAGR syndrome, Frasier syndrome, Meacham syndrome, congenital nephrotic syndrome of the Finnish type, idiopathic nephrotic syndrome, and isolated diffuse mesangial sclerosis
Undervirilized / ambiguous genitalia in 46,XY individuals may sometimes be noted on prenatal US. Prenatal genetic testing is possible if the pathogenic variant has been previously identified in a family.
The pattern of inheritance is autosomal dominant with non-full penetrance and variable expressivity. Most of the patients have a de novo mutation. Precise evaluation of the risk of reoccurrence requires genetic testing of the index case and his/her biological parents. Where karyotyping is indicated, pre-test genetic counseling on the possibility of detecting sex reversal is recommended.
Management and treatment
Multidisciplinary management should involve a nephrologist, urologist, endocrinologist, oncologist and surgeons. The nephrotic syndrome is resistant to corticosteroids and immunosuppressive drugs. Chronic renal failure is managed initially with nephroprotective medical therapy, followed by renal replacement therapies or transplantation when ESRD occurs. Patients with ESRD are recommended to undergo bilateral nephrectomy at the time of placement of a peritoneal dialysis catheter or renal transplantation to prevent WT development/relapse. Early gonadectomy should be considered in 46,XY with complete gonadal dysgenesis in order to prevent tumorigenesis. WT is treated by nephrectomy with or without chemotherapy.
The prognosis varies widely with most of the subjects living into adulthood. The primary cause of death is renal failure and disseminated WT but respiratory and heart failure have also been reported. Nephrotic syndrome does not recur after kidney transplantation. 46, XY individuals with complete gonadal dysgenesis are infertile.
- Summary information
- Slovak (2007, pdf)