WT1 Disorder

Excerpt

Clinical characteristics: 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) and gonadoblastoma. While various combinations of renal and other findings associated with a WT1 pathogenic variant were designated as certain syndromes in the past, those designations are now recognized to be part of a phenotypic continuum and are no longer clinically helpful.

Diagnosis/testing: The diagnosis of a WT1 disorder is established in a proband with suggestive clinical findings and a heterozygous pathogenic variant in WT1 identified by molecular genetic testing.

Management: Treatment of manifestations: SRNS: Avoid immunosuppressants; consider renin-angiotensin-aldosterone system (RAAS) inhibition. Disorder of testicular development: Management is often by a multidisciplinary team (medical geneticist, endocrinologist, urologist, and psychologist). Treat Wilms tumor with standard oncology protocols and, when applicable, nephron-sparing surgery. Treat CAKUT as per standard care. Prevent whenever possible gonadoblastoma by prophylactic gonadectomy.

Surveillance: Monitor for first appearance of the following: (1) proteinuria every six months until age ten years, yearly thereafter; (2) Wilms tumor every three months until age seven years. For ongoing issues with disorder of testicular development as per treating multidisciplinary team and for CAKUT as 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 a WT1 disorder in order to identify as early as possible those who would benefit from prompt initiation of treatment and surveillance.

Genetic counseling: 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 WT1 pathogenic variant. 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 WT1 pathogenic variant is 50%. If the proband's WT1 pathogenic variant 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 germline mosaicism. Once the WT1 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.