Exonic WT1 pathogenic variants in 46,XY DSD associated with gonadoblastoma

Objective: The literature regarding gonadoblastoma risk in exonic WT1 pathogenic variants is sparse. We aim to describe the phenotypic and genotypic characteristics of Asian-Indian patients with WT1 pathogenic variants and systematically review the literature on association of exonic WT1 pathogenic variants and gonadoblastoma. Design: Combined retrospective-prospective analysis Methods: 46,XY DSD patients with WT1 pathogenic variants detected by clinical exome sequencing from a cohort of 150 index patients and their affected relatives were included. The PubMed database was searched for the literature on gonadoblastoma with exonic WT1 pathogenic variants. Results: The prevalence of WT1 pathogenic variants among 46,XY DSD index patients was 2.7% (4/150). All the four patients had atypical genitalia and cryptorchidism. None of them had Wilms' tumor till the last follow-up, whereas one patient had late-onset nephropathy. 11p13 deletion was present in one patient with aniridia. The family with p.Arg458Gln pathogenic variant had varied phenotypic spectrum of Frasier syndrome; two siblings had gonadoblastoma, one of them had growing teratoma syndrome (first report with WT1). On literature review, of >100 exonic point pathogenic variants, only eight variants (p.Arg462Trp, p.Tyr177*, p.Arg434His, p.Met410Arg, p.Gln142*, p.Glu437Lys, p.Arg458* and p.Arg458Gln) in WT1 were associated with gonadoblastoma in a total of 15 cases (including our two cases). Conclusions: WT1 alterations account for 3% of 46,XY DSD patients in our cohort. 46,XY DSD patients harboring exonic WT1 pathogenic variants carry a small but definitive risk of gonadoblastoma; hence, these patients require a gonadoblastoma surveillance with a more stringent surveillance in those harboring a gonadoblastoma-associated variant.

Frasier Syndrome: A Rare Cause of Refractory Steroid-Resistant Nephrotic Syndrome

Frasier syndrome is a rare disease that affects the kidneys and genitalia. Patients who have Frasier syndrome develop nephrotic syndrome (NS) featuring focal segmental glomerulosclerosis (FSGS) that is resistant to steroid treatment in early childhood. Male patients can have female external genitalia (pseudo-hermaphroditism) at birth and develop gonado-blastoma in their adolescence. Frasier syndrome is caused by mutations in the splice donor site at intron 9 of the Wilms’ tumor WT1 gene; these mutations result in an imbalanced ratio of WT1 protein isoforms and affect the development of the urogenital tract, podocyte function, and tumor suppression. Here, we report on a patient with long-term refractory NS who developed a malignant mixed germ cell tumor arising in a gonado-blastoma of the ovary 8 years after the onset of proteinuria.

Suspicion of Frasier's syndrome in the nephrology unit of the Internal Medicine department of the HUEH: Case study and review of the literature.

ObjectiveFrasier syndrome is a rare genetic nephropathy characterized by the presence of progressive glomerulopathy with proteinuria associated with male pseudo hermaphroditism. This case study described a picture of a young boy where the clinical suspicion context reminded the Frasier Syndrome. To our knowledge, this case is the first described in Haiti.Case studyThis is a 19 years old young phenotypically male, born with a genital anomaly, was seen on referral at the nephrology/dialysis unit of the internal medicine department of HUEH for evaluation and follow-up. Insidious progression of symptoms had occurred over 3 years. Over three months of outpatient follow-up, he had four sets of renal labs drawn, and all showed impaired renal function. At the ultrasound a bilateral cryptorchidism is described in the inguinal, and presence of functional ovaries with follicles of variable size scattered in the parenchyma. So, in the light of these anamnestic, clinical and paraclinical findings we concluded to the diagnosis of end-stage renal failure by progressive glomerulopathy in a context of Frasier's syndrome.ConclusionWith any clinical picture consisting of genital anomalies at birth, renal symptomatology during childhood and the diagnosis of renal failure during adolescence, rare genetic nephropathies, such as Frasier syndrome must be considered.