New Pathogenic Variant in WT1 Disorder in Previously Healthy 3-Year Old Patient
Clinical Genetics and Therapeutics
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Primary Categories:
- Clinical Genetics
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Secondary Categories:
- Clinical Genetics
Introduction
WT1 disorder is an autosomal dominant condition characterized by congenital, infantile, or childhood onset of steroid-resistant nephrotic syndrome (SRNS), a progressive glomerulopathy that does not respond to standard steroid therapy. The WT1 gene is isolated from the short arm of chromosome 11 which encodes the zinc finger DNA-binding protein, WT1. WT1 is required for normal formation of the genitourinary system and mesothelial tissue for gonadal development. WT1 disorder encompasses multiple previously described conditions such as Frasier Syndrome, Denys-Drash Syndrome, and Meacham Syndrome due to distinct clinical findings; however, are now understood to represent a continuum of features caused by a WT1 heterozygous pathogenic variant. Features of WT1 disorders include glomerulopathy in over 95% of patients, disorders of testicular development, development of Wilms tumors in 38-43% of patients, congenital anomalies of the kidney and urinary tract (CAKUT), and gonadoblastoma in 5% of patients.
Case Presentation
We report a case of a 3-year-old previously healthy male with past medical history of cryptorchidism s/p surgical orchiopexy at 6 months of age with no history of renal abnormalities. Patient presented to emergency department after father had noticed altered mental status in the setting of poor oral intake and fussiness for the past 2 weeks. Patient was found to have acute kidney failure and hypoxemia in the setting of cardiogenic shock requiring PICU admission for continuous renal replacement therapy.
Diagnostic Workup
During admission, evaluation of renal biopsy showed evidence of global and segmental glomerlosclersosis, global effacement of foot processes of >90%, and severe interstitial fibrosis. Concerns for an acute on chronic renal failure prompted consult by Genetics for evaluation for conditions of chronic renal disease. A limited gene panel for chronic renal diseases was completed where patient was found to be heterozygous for a likely pathogenic variant in the WT1 gene (1407C>G; p.Asp469Glu).
Outcome and Follow-Up
Patient remained hospitalized for 2 months and remains on peritoneal dialysis for renal failure management with continued cancer screening in the outpatient setting.
Discussion
Our patient’s exact variant, 1407C>G, has not been previously described in literature; however, same missense change has been seen of Asp469Glu. In previous studies, it has been seen that pathogenic variants found in exons 8 and 9 result in the most damaging phenotypes due to the encoded DNA binding regions. These result in more severe phenotypes than truncating mutations. In addition, it was seen that Histidine or Cysteine changes in the zinc-finger of the WT1 protein also presented with more severe and earlier onset of renal failure. In the patient previously documented with the same missense change as our patient, age of onset similarly occurred at 3 years of age; however, did not progress to end-stage kidney disease.
Conclusion
With an unknown condition of patients with similar pathogenic variant as our patient, it leads to management dilemmas of surveillance for renal tumors as well as concerns for renal transplant and future risks or recurrence.
WT1 disorder is an autosomal dominant condition characterized by congenital, infantile, or childhood onset of steroid-resistant nephrotic syndrome (SRNS), a progressive glomerulopathy that does not respond to standard steroid therapy. The WT1 gene is isolated from the short arm of chromosome 11 which encodes the zinc finger DNA-binding protein, WT1. WT1 is required for normal formation of the genitourinary system and mesothelial tissue for gonadal development. WT1 disorder encompasses multiple previously described conditions such as Frasier Syndrome, Denys-Drash Syndrome, and Meacham Syndrome due to distinct clinical findings; however, are now understood to represent a continuum of features caused by a WT1 heterozygous pathogenic variant. Features of WT1 disorders include glomerulopathy in over 95% of patients, disorders of testicular development, development of Wilms tumors in 38-43% of patients, congenital anomalies of the kidney and urinary tract (CAKUT), and gonadoblastoma in 5% of patients.
Case Presentation
We report a case of a 3-year-old previously healthy male with past medical history of cryptorchidism s/p surgical orchiopexy at 6 months of age with no history of renal abnormalities. Patient presented to emergency department after father had noticed altered mental status in the setting of poor oral intake and fussiness for the past 2 weeks. Patient was found to have acute kidney failure and hypoxemia in the setting of cardiogenic shock requiring PICU admission for continuous renal replacement therapy.
Diagnostic Workup
During admission, evaluation of renal biopsy showed evidence of global and segmental glomerlosclersosis, global effacement of foot processes of >90%, and severe interstitial fibrosis. Concerns for an acute on chronic renal failure prompted consult by Genetics for evaluation for conditions of chronic renal disease. A limited gene panel for chronic renal diseases was completed where patient was found to be heterozygous for a likely pathogenic variant in the WT1 gene (1407C>G; p.Asp469Glu).
Outcome and Follow-Up
Patient remained hospitalized for 2 months and remains on peritoneal dialysis for renal failure management with continued cancer screening in the outpatient setting.
Discussion
Our patient’s exact variant, 1407C>G, has not been previously described in literature; however, same missense change has been seen of Asp469Glu. In previous studies, it has been seen that pathogenic variants found in exons 8 and 9 result in the most damaging phenotypes due to the encoded DNA binding regions. These result in more severe phenotypes than truncating mutations. In addition, it was seen that Histidine or Cysteine changes in the zinc-finger of the WT1 protein also presented with more severe and earlier onset of renal failure. In the patient previously documented with the same missense change as our patient, age of onset similarly occurred at 3 years of age; however, did not progress to end-stage kidney disease.
Conclusion
With an unknown condition of patients with similar pathogenic variant as our patient, it leads to management dilemmas of surveillance for renal tumors as well as concerns for renal transplant and future risks or recurrence.