Clinical Guidance

Recent developments have allowed delineation of genotype-phenotype correlations for certain subgroups of WT1 pathogenic variants (see also Table 1 in ). Truncating pathogenic variants (all nonsense, frameshift, or splice-site variants that are not KTS [lysine, threonine, and serine] intron 9 variants; see ) are associated with the following [, , , ]:

Source: GeneReviews — "WT1 Disorder"

Penetrance

The penetrance of WT1 disorder is high. It is age dependent, reaching about 90% by the end of puberty. A few asymptomatic parents heterozygous for the same germline WT1 variant in their affected offspring have been reported [, , , , ]. The penetrance appears to depend on the sex of the affected parent, with higher penetrance associated with paternal origin of the WT1 variant . However, current data on penetrance are limited because the variable expressivity of WT1 pathogenic variants was not recognized until recently, and the asymptomatic parents of a child with a WT1 pathogenic variant were not routinely tested.

Source: GeneReviews — "WT1 Disorder"

Diagnostic Criteria

Formal diagnostic criteria for WT1 disorder have not been established. Note: This chapter on WT1 disorder excludes WAGR syndrome (Wilms tumor-aniridia-genital anomalies-range of developmental delays), caused by a contiguous gene deletion of PAX6 and WT1 (see PAX6-Related Aniridia).

Suggestive Findings

WT1 disorder should be suspected in an individual with the following clinical, imaging, and supportive laboratory findings.

Clinical Findings

Steroid-resistant nephrotic syndrome. A progressive glomerulopathy that does not respond to standard steroid therapy; see and for diagnostic clinical practice guidelines.

Source: GeneReviews — "WT1 Disorder"

Differential Diagnosis

For the differential diagnosis of:

• Steroid-resistant nephrotic syndrome, see Genetic Steroid-Resistant Nephrotic Syndrome Overview;

• Wilms tumor, see Wilms Tumor Predisposition;

• 46,XY disorders of testicular development, see Nonsyndromic Disorders of Testicular Development Overview;

• Diaphragmatic hernia, see

Source: GeneReviews — "WT1 Disorder"

Management Guidelines

See and for clinical practice recommendations for the management of children with steroid-resistant nephrotic syndrome.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with WT1 disorder, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 3.

WT1 Disorder: Recommended Evaluations Following Initial Diagnosis

System/Concern | Evaluation | Comment

Glomer-

ulopathy | Persistentproteinuria | Urine protein-to-creatinine ratio | For evidence of proteinuria

SRNSCKDCNS | • 24-hr urine protein test

• Serum protein, albumin, creatinine, cholesterol, IgG, C3

• Blood pressure measurements

| For evidence of proteinuria, hypertension, CKD1

Disorder of

testicular

development | Karyotype w/FISH for SRY or CMA (to determine chromosomal sex) | To be performed in all persons w/ambiguous genitalia all prepubertal phenotypic females

Pelvic US | Eval of gonadal localization character

Hormonal studies | For children who have not undergone gonadectomy: hormonal studies as directed by pediatric endocrinologist

Wilms tumor

| Abdominal US | Metachronous synchronous tumors may be unilateral or bilateral.

CAKUT

| Abdominal US | To identify duplex kidney, horseshoe kidney, kidney malrotation, /or signs of obstructive nephropathy due to vesicoureteral reflux ureteropelvic junction stenosis

Diaphragmatic

Source: GeneReviews — "WT1 Disorder"

Clinical Guidance

Avoid treating glomerulopathy with immunosuppressants, as they are not effective and potentially toxic.

Source: GeneReviews — "WT1 Disorder"

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Source: GeneReviews — "WT1 Disorder"

Surveillance Guidelines

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in are recommended. Table 5. WT1 Disorder: Recommended Surveillance

Source: GeneReviews — "WT1 Disorder"