Clinical Description
WT1 disorder is characterized by congenital/infantile or childhood onset of 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 (see Table 2). 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 have in the past been designated as certain syndromes, those combinations are now recognized to be part of a phenotypic continuum and their designations are no longer clinically helpful (see Nomenclature) [Chernin et al 2010, Lipska et al 2014, Lehnhardt et al 2015, Ahn et al 2017].
Table 2.
WT1 Disorder: Frequency of Select Features
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Feature | % of Persons w/Feature | Comment |
---|
Glomer-
ulopathy
| Persistent proteinuria | >95% | Renal hallmark of WT1 disorder; degree may vary over time |
SRNS | 80% | Criteria for diagnosis of SRNS 1 may not be met initially. |
CNS | 15% | Nephrotic syndrome within 1st 3 mos of life |
|
External genitalia
|
Müllerian structures
|
Gonadal findings
|
Disorder of
testicular
development
| 46,XX DSD or CGD | See footnote 2. | Range: microphallus, hypospadias & cryptorchidism, ambiguous, normal-appearing female | Range: absent to normal uterus & fallopian tubes | Range: ovotestis, dysgenetic testis, streak gonads, hypertrophic ovaries, or normal ovaries |
46,XY DSD | 63%-79% of 46,XY individuals 3 | Range: microphallus, hypospadias & cryptorchidism, ambiguous, normal-appearing female | Range: absent to normal uterus & fallopian tubes | Range: normal testis, ovotestis, dysgenetic testis, streak gonad |
46,XY CGD | 18%-33% of 46,XY individuals 3 | Normal female | Uterus & fallopian tubes present | Streak gonads or dysgenetic testes |
Early gonadal insufficiency
| 67% at 12.6 yrs (83% at 16.2 yrs) 4 | Spontaneous puberty in 94% of 46,XX & 60% of 46,XY persons ↑ FSH & LH; ↓ AMH or inhibin B plasma levels in majority of persons
|
Wilms tumor
| 38%-60% 3 |
|
CAKUT
| ~11% 3 |
|
Gonadoblastoma
| 5% |
|
AMH = anti-műllerian hormone; CAKUT = congenital anomalies of the kidney and urinary tract; CGD = complete gonadal dysgenesis; CNS = congenital nephrotic syndrome; DSD = disorder of sex development; FSH = follicle-stimulating hormone; LH = luteinizing hormone; SRNS = steroid-resistant nephrotic syndrome
- 1.
Nephrotic syndrome (proteinuria, hypoalbuminemia, edema, and hyperlipidemia) that does not respond to standard steroid therapy
- 2.
- 3.
- 4.
Progressive glomerulopathy. Persistent proteinuria is the most common initial finding of the glomerulopathy in WT1 disorder. While the degree of proteinuria may fluctuate at the onset of renal involvement, it becomes progressively worse over time. The severity of the proteinuria varies among affected individuals, even within the same family. Note: Individuals with end-stage kidney failure may be anuric, and thus will not have proteinuria.
Steroid-resistant nephrotic syndrome (SRNS) – proteinuria, hypoalbuminemia, edema, and hyperlipidemia that does not respond to standard steroid therapy – is the characteristic kidney finding in WT1 disorder. SRNS can precede Wilms tumor by as much as four years, present at the time of Wilms tumor diagnosis, or develop after Wilms tumor (as much as 10 years after completion of the oncology treatment) [Lipska et al 2014, Lehnhardt et al 2015].
SRNS results in irreversible and progressive decline of kidney function and inevitably leads to end-stage kidney failure. Congenital nephrotic syndrome (nephrotic syndrome that presents in the first 3 months of life) is more rapidly progressive, resulting in end stage kidney failure within weeks to months [Boyer et al 2021].
Typical findings of the glomerulopathy on kidney biopsy are diffuse mesangial sclerosis reported primarily in children younger than age two years and focal segmental glomerulosclerosis in older individuals, although other diagnoses, including membranoproliferative glomerulonephritis, have also been reported [Anderson et al 2022]. Note: Because the histologic findings do not correlate with the clinical findings and because remarkable histopathologic heterogeneity is observed even among individuals with the same WT1 pathogenic variant [Lipska et al 2014, Lehnhardt et al 2015, Trautmann et al 2017], kidney biopsy is no longer considered a first-tier diagnostic measure for individuals of any age.
Wilms tumor. Wilms tumor (nephroblastoma) is one of the most common pediatric malignant solid tumors. The estimated risk to heterozygotes who have an exonic WT1 pathogenic variant of developing Wilms tumor is one tumor per nine years at risk. Calculation of the exact penetrance is hampered because a significant number of individuals with a WT1 pathogenic variant undergo prophylactic nephrectomy at the time of kidney transplantation or placement of a peritoneal dialysis catheter.
The median age at Wilms tumor diagnosis in WT1 disorder is significantly younger (median age: 1.3-1.6 years; range: 0-4.5 years) compared to Wilms tumor of unknown cause.
Bilateral tumors are more frequent in individuals with a truncating WT1 variant compared to individuals with other variants (>50% vs <15%) [Lipska et al 2014, Lehnhardt et al 2015] (see Genotype-Phenotype Correlations).
The survival rates for individuals with Wilms tumor caused by WT1 disorder do not differ significantly from those of individuals with Wilms tumor of unknown cause.
Genital findings. 46,XY individuals with WT1 disorder typically have a disorder of testicular development that is either a disorder of sex development (DSD) or complete gonadal dysgenesis (CGD) (see Table 2). 46,XY individuals with normal testes, normal male external genitalia, and normal fertility have been reported anecdotally.
46,XX individuals with a WT1 pathogenic variant typically have normal ovaries, normal female external genitalia, and müllerian structures that are usually normal (however, on occasion bicornuate uterus has been observed [Lipska et al 2014]) (see Table 2). 46,XX CGD has been reported in two 46,XX individuals with a WT1 pathogenic variant with absent ovaries [Ahn et al 2017, Roca et al 2019]. 46,XX DSD (testicular DSD or ovotesticular DSD) has been reported in seven individuals with a pathogenic variant in exon 10 encoding the fourth zinc finger of WT1 or within splicing sites involved in intron 9 splicing [Eozenou et al 2020].
In adulthood, most individuals are affected by early gonadal insufficiency of variable severity with potential impact on puberty and fertility [Carré Lecoindre et al 2024]. Premature gonadal failure was observed in persons with all karyotypes and genotypes irrespective of the timing of renal insufficiency.
Congenital anomalies of the kidney and urinary tract (CAKUT). CAKUT are observed in about 10% of individuals with WT1 disorder. The most common kidney abnormalities are duplex kidney, horseshoe kidney, and kidney malrotation. The most commonly reported urinary tract anomalies are vesicoureteral reflux, ureteropelvic junction stenosis, and urogenital sinus (in a 46,XX individual in whom both the urethra and vagina open into a common channel).
Gonadoblastoma. Individuals with 46,XY disorder of testicular development (either 46,XY DSD or 46,XY CGD) are at increased risk for germ cell tumors, particularly gonadoblastoma. The observed incidence is one gonadal tumor per 30 years at risk [Lipska et al 2014].
Because of the lack of long-term follow-up data, exact penetrance and long-term outcome are unknown. The survival rates for gonadoblastoma are excellent; however, if not treated it may result in malignant transformation of germ cells. A few instances of Sertoli tumor or other malignant testicular germ cell tumors have been reported [Kitsiou-Tzeli et al 2012, van Peer et al 2024].
Other. Diaphragmatic defect or herniation is a rare finding in WT1 disorder, reported in fewer than ten infants [Denamur et al 2000, Suri et al 2007, Ahn et al 2017].
Post-transplant lymphoproliferative disorder (PTLD) was reported in 7%-17% of individuals with WT1 disorder following kidney transplantation [Lipska et al 2014, Ahn et al 2017]. In all children undergoing kidney transplantation, the 25-year cumulative incidence of PTLD, adjusted for the competing risk of death, is 3.6% (95% CI: 2.7-4.8). Because of small numbers and lack of standardized follow-up data, it is not yet possible to determine if the frequency of PTLD is higher for WT1 disorder than for other children undergoing kidney transplantation.
Genotype-Phenotype Correlations
Recent developments have allowed delineation of genotype-phenotype correlations for certain subgroups of WT1 pathogenic variants (see also Table 1 in Nagano & Nozu [2025]).
Truncating pathogenic variants (all nonsense, frameshift, or splice-site variants that are not KTS [lysine, threonine, and serine] intron 9 variants; see Molecular Genetics) are associated with the following [Lipska et al 2014, Lehnhardt et al 2015, van Peer et al 2024, Glénisson et al 2025]:
Wilms tumor is often the first clinical manifestation.
Glomerulopathy. Proteinuria is typically diagnosed in the second decade of life in individuals who underwent unilateral or partial nephrectomy for Wilms tumor. The course of SRNS is slower.
Genital anomalies secondary to a 46,XY DSD affect the vast majority of phenotypic males; 46,XY CGD is unlikely.
The risk for bilateral Wilms tumor is the highest (odds ratio = 18.4).
One in five individuals has CAKUT.
Missense
pathogenic variants affecting nucleotides coding for amino acid residues in the DNA-binding region in exons 8 and 9 (see Molecular Genetics) are associated with the following [Lipska et al 2014, Nagano et al 2021, Glénisson et al 2025]:
The risk for
congenital nephrotic syndrome or early-onset rapidly progressive SRNS is the highest. By age 2.5 years, 50% of affected children have end-stage kidney failure.
Of 46,XY individuals, approximately 80% have 46,XY DSD and 20% 46,XY CGD [BS Lipska-Ziętkiewicz, personal observation].
Missense pathogenic variants
in exons 8 and 9 outside the DNA-binding region are associated with an intermediate glomerulopathy phenotype that manifests before age five years and progresses to end-stage kidney failure by about age ten years [Lipska et al 2014, Nagano et al 2021].
Certain donor splice-site pathogenic variants
in intron 9 (see Molecular Genetics) are associated with the following [Chernin et al 2010, Lipska et al 2014, Lehnhardt et al 2015, Tsuji et al 2021]:
Later onset and relatively slow progression of glomerulopathy that typically leads to end-stage kidney failure in adolescence
46,XY CGD in the majority of (but not all) 46,XY individuals and 46,XY DSD in a few individuals
Highest risk for gonadoblastoma in CGD/DSD individuals, with risk of Wilms tumor significantly lower (≤3%)