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The following summary is from Orphanet, a European reference portal for information on rare diseases and orphan drugs.
Orpha Number: 347
A rare genetic, syndromic glomerular disorder characterized by the association of progressive glomerular nephropathy and 46,XY complete gonadal dysgenesis with a high risk of developing gonadoblastoma.
To date, less than 150 cases have been described.
Nephropathy is the hallmark of the disease. It develops during childhood presenting as persistent proteinuria and subsequently steroid-resistant nephrotic syndrome (SRNS) and progresses to end-stage renal disease (ESRD) in the second or third decade of life. On renal biopsy, focal segmental glomeruloscrelosis (FSGS) is the most common histopathological finding. Individuals have a 46, XY karyotype and present with female external genitalia, complete gonadal dysgenesis and have a higher risk of gonadoblastoma. These individuals are later evaluated for delayed puberty or primary amenorrhea. Since (modest) breast development occurs also without estrogen stimulus, failure to recognize a delayed puberty is not rare. In addition, the clinical picture may be confused by attributing pubertal delay to previous immunosuppressive therapy, renal insufficiency itself or renal transplantation. Complete gonadal dysgenesis results in infertility, female external genitalia and presence of Mullerian structures. Wilms tumor is not common in individuals with Frasier syndrome.
Frasier syndrome has been associated to specific pathogenic variants affecting nucleotides 4-5 of the intron 9 (previously referred to as IVS9+4; IVS9+5) in the WT1 gene (11p13). WT1 encodes for a protein that serves as regulatory transcription factor important both for renal and gonadal development.
The diagnosis is suspected on childhood onset of progressive glomerulopathy with findings of FSGS on histological analysis. Phenotypic females with delayed puberty or primary amenorrhea, should be carefully evaluated for signs of nephropathy. When the clinical findings suggest the diagnosis of WT1 associated disorders, single gene testing of the hotspot 8-9 exons with adjacent introns can be performed. Karyotype testing is recommended for all individuals with WT1 intron 9 pathogenic variants.
The main differential diagnosis is idiopathic steroid-resistant nephrotic syndrome, and other WT1 associated diseases including Denys-Drash syndrome, genetic steroid resistant nephrotic syndrome and disorders of testicular development.
Most affected individuals have a de novo pathogenic variant and hence negative family history; however, autosomal dominant inheritance has been reported. Where karyotyping is indicated, pre-testing genetic counselling on the possibility of detecting sex reversal should be offered.
Management and treatment
Management is multidisciplinary and should involve a nephrologist for management of chronic renal failure (initially with nephroprotective medical therapy and afterwards with renal replacement therapies or transplantation when ESRD occurs), an endocrinologists for treatment of associated disorder of testicular development, and oncologists and surgeons to evaluate the need for an early gonadectomy in order to prevent tumorigenesis. Preemptive bilateral gonadectomy at the time of renal transplant or placement of a peritoneal dialysis catheter might be an option.
There is limited information on life expectancy. After kidney transplantation, nephrotic syndrome does not recur. 46,XY individuals with complete gonadal dysgenesis are infertile.
Visit the Orphanet disease page for more resources.
Source: GARD Last updated on 05-01-20
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