Rare WT1 Gene Variant Drives Infant Kidney Failure in Unusual Case Report

A previously healthy nine-month-old boy who arrived at a hospital with abdominal swelling, diarrhea and poor feeding has become the subject of a striking case report in pediatric nephrology, one that shows how a single misspelled letter in the WT1 gene can produce a kidney disease unlike anything the textbook pictures suggest. Within fourteen months of his first symptoms, the child had progressed to end-stage kidney disease and begun peritoneal dialysis, yet he carried no Wilms tumor, no complete gonadal dysgenesis and none of the classic biopsy features that usually announce Denys-Drash syndrome, the condition most tightly linked to WT1. His doctors eventually classified him as having an incomplete form of that syndrome, and the case, published in Discover Pediatrics, argues forcefully that genetic testing should reach infants with nephrotic syndrome far earlier than it often does.

Nephrotic syndrome is defined by nephrotic-range proteinuria, hypoalbuminemia and edema, and it is the most frequent glomerular disease in children, with reported incidence ranging from 1.15 to 16.9 per 100,000 children, most often appearing between one and ten years of age. Clinicians separate it by timing: congenital nephrotic syndrome appears in the first three months of life, while infantile nephrotic syndrome emerges between four and twelve months. More than 80 percent of congenital cases are caused by genetic variants in genes such as NPHS1, NPHS2, WT1, LAMB2 and PLCE1. Infantile disease usually runs a gentler course, with slower progression to end-stage kidney disease, and its genetic variants are of the non-Finnish type. After the first year of life, minimal change disease dominates and 85 percent of patients respond to steroids, which is why routine biopsy and genetic testing are generally reserved for children with warning signs such as macroscopic hematuria, unexplained acute kidney injury, sustained hypertension, low complement levels or systemic symptoms.

The infant in this report undermined that comfortable algorithm at every turn. After a normal pregnancy and spontaneous vaginal delivery, he presented with abdominal distention, diarrhea and hyporexia. His parents were not consanguineous, and there was no family history of kidney disease, although his father had an isolated unilateral cleft lip and palate. On examination he was eutrophic, but doctors suspected an acute abdomen and noted cryptorchidism, with non-palpable testes, without hypospadias. After hydration failed to relieve the distention and intestinal obstruction was suspected, an exploratory laparotomy was performed 48 hours later. Surgeons found only 600 milliliters of transparent fluid and renal micro-cysts, and kidney samples were taken at the surgeon’s discretion. The postoperative course was rocky: the child needed vasopressors and mechanical ventilation for four days and developed septic shock and acute kidney injury, with serum creatinine rising from 24.75 to 150.28 micromoles per liter, though dialysis was not required.

Laboratory results on day seven of hospitalization made the diagnosis unmistakable. Albumin had fallen to 25 grams per liter, cholesterol and triglycerides were elevated, and proteinuria reached 300 milligrams per square meter per hour, firmly in the nephrotic range, while the urinalysis showed no hematuria. Steroids were started, and once the critical illness had passed he was referred for pediatric nephrology assessment. At the receiving institution he had stage 1 hypertension requiring three antihypertensive medications, moderate palpebral and peripheral edema, and confirmed bilateral cryptorchidism. Treatment was intensified with prednisone at 2 milligrams per kilogram per day, rate-adjusted cefepime, daily albumin infusions, furosemide and spironolactone, a low-sodium diet and titrated antihypertensives. Renal ultrasound showed appropriately sized kidneys with diminished cortical thickness but no cysts. Serologies for HIV, hepatitis B and C, TORCH, EBV and syphilis were negative, complement C3 and C4 were normal, echocardiography and thyroid function were unremarkable, and a geneticist excluded other extra-renal manifestations in a child with a 46XY karyotype.

The kidney biopsy, available one month after discharge, deepened the puzzle. Among more than 50 glomeruli, 16 percent showed focal and segmental glomerulosclerosis, not otherwise specified, and 4 percent showed global sclerosis. Diffuse mesangial sclerosis, the histological hallmark classically associated with WT1 disease, was absent, as was mesangial expansion, but marked glomerular hypertrophy was present. Most distinctive was a radial pseudo-cystic dilation of the proximal tubules, accompanied by mild tubular atrophy of 15 percent and moderate interstitial fibrosis of 30 percent, plus moderate thickening of the arterial muscular layer. Immunofluorescence was positive only for C1q, at two to three plus, and IgM at one to three plus; electron microscopy was unavailable at the institution, so podocyte effacement and mesangial deposits could not be assessed. Taken together, the findings were interpreted as secondary to a genetic nephrotic syndrome, though the pattern pointed as readily toward NPHS2 or NPHS1 variants as toward WT1.

Whole exome sequencing resolved the question. It identified a heterozygous missense likely pathogenic variant in exon 9 to 10 of the WT1 gene: c.1433A>G, resulting in the amino acid substitution p.His478Arg, classified according to American College of Medical Genetics and Genomics and Association for Molecular Pathology criteria. The variant, listed in ClinVar with sufficient evidence for dosage pathogenicity, affects the fourth zinc finger of the WT1 protein. Parental testing was not possible, so the variant could not be confirmed as de novo. After six weeks of steroids without response, cyclosporine had been started at 5 milligrams per kilogram per day, later reduced to 3.8 based on plasma concentrations; once the genetic result arrived, cyclosporine was withdrawn four weeks later, because proteinuria was unchanged and the likelihood of altering the disease course seemed low.

The clinical course that followed was aggressive. Chronic kidney failure progressed, with estimated glomerular filtration rate falling to 10 milliliters per minute per 1.73 square meters, loss of corticomedullary differentiation on imaging, and no tumors detected during ultrasound surveillance every three months. Peritoneal dialysis began at 20 months of age, by which time the child had significant undernutrition, weighing 8.2 kilograms at 82 centimeters in height. Bilateral nephrectomy is scheduled to reduce proteinuria, improve weight gain and lower the risk of Wilms tumor, with kidney transplantation planned once he reaches the required weight. At 18 months, diagnostic-therapeutic laparoscopy had revealed intra-abdominal atrophic testes despite apparently acceptable testicular function on biopsy, which showed prepubertal seminiferous tubules with minimal atrophy; unilateral orchiectomy and a one-stage Fowler-Stephens procedure on the opposite side were performed, since preserving atrophic testes carries malignant transformation risk without clear endocrine benefit.

The discussion places this variant in context. Classic Denys-Drash syndrome is rare, with fewer than 500 cases reported in the literature, and its prevalence is unknown. Across WT1-related disorders, proteinuria appears in more than 90 percent of cases, steroid-resistant nephrotic syndrome in 40 to 70 percent, and isolated proteinuria without other manifestations in 27 to 42 percent, mainly in patients with 46XX karyotypes. Complete gonadal dysgenesis occurs in 32 percent of affected females, while partial gonadal dysgenesis ranges down to subtle findings such as cryptorchidism alone, seen in up to 83 percent of cases. Cryptorchidism by itself is common, affecting 1 to 4.6 percent of term newborns and up to 30 percent of preterm infants, one third of them bilateral, so it cannot be considered a syndromic feature in isolation. The largest WT1 cohort, drawn from the PodoNet registry, included 61 patients screened across exons 8 and 9; those with exonic variants were younger at diagnosis, averaging 2.7 years, with heavier proteinuria, faster progression to end-stage kidney disease and diffuse mesangial sclerosis almost exclusively. A similar variant at position 474 has been described in an eight-year-old girl with steroid-resistant disease, focal segmental glomerulosclerosis, Wilms tumor and progression to end-stage kidney disease within one year.

By contrast, this patient’s phenotype was atypical on nearly every axis: early-onset steroid-resistant nephrotic syndrome with marked ascites and suspected intestinal obstruction at presentation, focal segmental glomerulosclerosis rather than diffuse mesangial sclerosis, progression to end-stage kidney disease in 14 months, partial rather than complete gonadal dysgenesis, and no Wilms tumor after two years of follow-up. The authors suggest this course may relate to the variant’s position within the fourth zinc finger. The report also carries a treatment message: in a cohort of 225 children with spontaneous nephrotic syndrome, Ruf and colleagues found zero steroid-sensitive patients among those with WT1 variants, and more than half of children with genetic nephrotic syndrome progress to end-stage kidney disease within five years, compared with 30 percent kidney survival at ten years among those with steroid-resistant disease overall. The authors argue that whole exome sequencing, including in low-resource settings, is preferable to invasive and imprecise procedures such as renal biopsy in primary infantile nephrotic syndrome, since a timely molecular diagnosis guides treatment withdrawal, Wilms tumor surveillance and long-term management. Limitations include the absence of electron microscopy, unavailable parental testing and eGFR estimates that must be interpreted cautiously given creatinine-only calculation in an undernourished child.

Subject of Research: A case report of infantile steroid-resistant nephrotic syndrome caused by an atypical WT1 gene variant

Article Title: A case report of WT1-associated infantile steroid-resistant nephrotic syndrome with atypical genotype–phenotype correlation

Article References: Rebolledo Zamora, A., González Rodríguez, L. E., Sierra Pineda, I. F., Lara Hernández, M. F. D. C., Pasquel Sentíes, S., & Ortega Solar, J. M. (2026). A case report of WT1-associated infantile steroid-resistant nephrotic syndrome with atypical genotype–phenotype correlation. Discover Pediatrics, 1(1), Article 4. https://doi.org/10.1007/s44571-026-00004-6

Image Credits: AI Generated

DOI: 10.1007/s44571-026-00004-6

Keywords: WT1, nephrotic syndrome, Denys-Drash syndrome, genetic testing, whole exome sequencing, focal segmental glomerulosclerosis, cryptorchidism, pediatric nephrology, kidney failure, case report, case, report