WT1-related disorders comprise a spectrum of conditions resulting from mutations or deletions of the WT1 gene. Alteration in this gene have been associated with many syndromes, including WAGR syndrome, Denys-Drash syndrome (DDS), Frasier syndrome (FS) and Meacham syndrome. We present the case of an 8-year-old phenotypically female child with symptoms of end-stage kidney disease (ESKD), hypertension and anasarca, requiring renal replacement therapy. This case is distinctive due to its unusual onset, the presence of thrombotic microangiopathy (TMA), and the detection of a heterozygous missense mutation in the WT1 gene (c.1298G>A, p.Cys433Tyr) located in exon 8, in association with a 46 XY karyotype. The kidney biopsy indicated advanced focal segmental glomerulosclerosis (FSGS) with characteristics of TMA, implying a possible alternative diagnosis. In light of the heightened malignancy risk, the patient had preventative laparoscopic gonadectomy, which revealed rudimentary testicular tissues. The identified genotype points toward a diagnosis of DDS. However, the clinical presentation is more consistent with features typically seen in FS. This discrepancy highlights the significant phenotypic and genotypic overlap between the two syndromes. As a result, there is ongoing discussion in the literature about whether DDS and FS should be considered distinct clinical entities or rather variable expressions along a shared disease spectrum. WT1 disorder is characterized by congenital/infantile or childhood onset of steroid-resistant nephrotic syndrome (SRNS), a progressive glomerulopathy that does not respond to standard steroid therapy. Additional common findings can include disorders of testicular development (with or without abnormalities of the external genitalia and/or müllerian structures) and Wilms tumor. Less common findings are congenital anomalies of the kidney and urinary tract (CAKUT), gonadoblastoma, and 46,XX gonadal dysgenesis. In adulthood, most individuals are affected by early gonadal insufficiency of variable severity with potential impact on puberty and fertility. While various combinations of renal and other findings associated with a WT1 pathogenic variant were designated as certain syndromes in the past (the most common being Denys-Drash and Frasier syndromes), those designations are now recognized to be part of a phenotypic continuum and are no longer clinically helpful. The diagnosis of WT1 disorder is established in a proband with suggestive clinical findings and a heterozygous pathogenic variant in WT1 identified by molecular genetic testing. Treatment of manifestations: SRNS: avoid immunosuppressants; consider renin-angiotensin-aldosterone system (RAAS) inhibition. Disorders of testicular development and 46,XX gonadal dysgenesis: management is often by a multidisciplinary team (clinical geneticist, endocrinologist, urologist, and psychologist). Treat Wilms tumor with standard oncology protocols and, when applicable, nephron-sparing surgery. Treat CAKUT per standard care. Prevent whenever possible gonadoblastoma by prophylactic gonadectomy in those with a disorder of testicular development. Diaphragmatic hernia repair prior to the start of peritoneal dialysis. Surveillance: Monitor for first appearance of the following: proteinuria every six months until age ten years, yearly thereafter; Wilms tumor every three months until age seven years; early gonadal insufficiency yearly after puberty. For ongoing issues with disorders of testicular development and 46,XX gonadal dysgenesis, monitor per treating multidisciplinary team, and for CAKUT, monitor per treating nephrologist and/or urologist. Agents/circumstances to avoid: Avoid treating glomerulopathy with immunosuppressants, as they are not effective and potentially toxic. Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an individual with WT1 disorder in order to identify as early as possible those who would benefit from prompt initiation of treatment and surveillance for glomerulopathy and Wilms tumor. WT1 disorder is inherited in an autosomal dominant manner. Most individuals diagnosed with WT1 disorder have the disorder as the result of an apparent de novo WT1 pathogenic variant; in rare instances, a parent of an individual with WT1 disorder is heterozygous for the pathogenic variant identified in the proband. If a parent of the proband is affected and/or is known to have the WT1 pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. If the WT1 pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental gonadal mosaicism. Once the WT1 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Historically, specific mutations in WT1 gene have been associated with distinct syndromes based on phenotypic characteristics, including Denys-Drash syndrome (DDS), Frasier syndrome (FS), Meacham syndrome, and WAGR syndrome. DDS is classically defined by the triad of steroid-resistant nephrotic syndrome (SRNS) onset in the first year of life, disorders of sex development (DSD), and a predisposition to Wilms tumor (WT). Currently, a paradigm shift acknowledges a diverse spectrum of presentations beyond traditional syndromic definitions. Consequently, the concept of WT1-related disorders becomes more precise. A genotype-phenotype correlation has been established, emphasizing that the location and type of WT1 mutations significantly influence the clinical presentation, the condition severity, and the chronology of patient manifestations. Individuals presenting with persistent proteinuria, with or without nephrotic syndrome, and varying degrees of kidney dysfunction accompanied by genital malformations should prompt suspicion of WT1 mutations. Recent genetic advances enable a more accurate estimation of malignancy risk in these patients, facilitating a conservative nephron-sparing surgery (NSS) approach in select cases, with a focus on preserving residual kidney function and delaying nephrectomies. Other key management strategies include kidney transplantation and addressing DSD and gonadoblastoma. In summary, recent genetic insights underscore the imperative to implement individualized, integrated, and multidisciplinary management strategies for WT1-related disorders. This approach is pivotal in optimizing patient outcomes and addressing the complexities associated with these diverse clinical manifestations.

Congenital mutations of the Wilms' tumor 1 (WT1) gene can lead to various abnormalities, including renal/gonadal developmental disorders and cardiac malformations. Although there have been many reports of somatic WT1 mutations in patients with acute myeloid leukemia and myelodysplastic syndrome, congenital WT1 mutations have not been reported in hematological disorders. We herein report a patient with early-onset clonal cytopenia of undetermined significance that was associated with a congenital mutation of WT1 and an acquired mutation of DNMT3A [encoding DNA (cytosine-5)-methyltransferase 3A].