Case report
WT1 gene mutation responsible for male sex reversal and renal failure: the Frasier syndrome

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Abstract

We report the case of a young woman with primary amenorrhea. In her childhood, she suffered from renal failure requesting kidney transplantation at the age of 11. The investigations for primary amenorrhea revealed a hypergonadotropic hypogonadism associated with 46 XY karyotype. The association of primary amenorrhea with renal failure suggested Frasier syndrome (FS) or Denys–Drash syndrome (DDS). Genetic analysis revealed a Wilms’ tumour (WT1) gene mutation characteristic of the Frasier syndrome. Dysgenetic ovaries were removed laparoscopically due to the risk of gonadal cancer.

Introduction

Development of the sexual organs is complex and depends on multiple hormonal and genetic factors. At 6 weeks of fetal life, the gonads are indifferent but bipotential; they are able to differentiate either to testis or ovaries. It is now well known that the sex-determining region (SRY) gene on the short arm of the Y chromosome is required for testicular differentiation [1]. It is expressed during the embryonic period in the genital ridge when testicular cords form. Mutation or deletion in SRY gene is responsible for XY female with streak ovaries [2]. The SRY gene can be found by translocation in the genome XX male [3].

More recently, Wilms’ tumour (WT1) gene has been implicated in sex determination. In fact, anomalies in the gene (deletion, mutation) and/or its product are responsible of genito-urinary anomalies, high frequency of Wilms’ tumour and pseudohermaphrodism like Denys–Drash syndrome (DDS) or Frasier syndrome (FS).

The association between chronic renal failure in female patient with XY gonadal dysgenesis has been initially described by Frasier et al. [4], Denys et al. [5] and Drash et al. [6]. The DDS and FS have similarities and have been confound for a long time. However, the two syndromes have clinical and genetic differences.

The triad of nephrotic syndrome, Wilms’ tumour, and intersex characterizes the DDS. Nephropathy is the key defining feature of the syndrome, which can exist in either complete form or in incomplete form in which nephropathy is present in association with either Wilms’ tumour or intersexual status. The nephropathy is defined by diffuse mesangial sclerosis and manifests generally in the first year of life. Patients with DDS have a high risk of Wilms’ tumour, which is bilateral in 20% of cases. The median age at presentation is 18 months. The majority of patients appears phenotypically female or has ambiguous genitalia. Only a few cases have normal male external genitalia [7], [8].

Frasier syndrome has the same clinical features but presents some important differences. The nephropathy appears later in life and is due to focal segmental glomerulosclerosis. Progression to renal failure is slower. There is no predisposition to Wilms’ tumour but Frasier syndrome patients have higher risk of gonadoblastoma, which can be the presenting feature [4], [8]. The exact frequency of gonadal neoplasm in this syndrome is not well known. However, in dysgenetic gonads, the overall incidence of ovarian neoplasia is about 20–30% [9]. Therefore, removal of those non-functional streak gonads is recommended.

Table 1 presents a comparison of clinical features in the two syndromes.

We report here a case of Frasier syndrome that illustrates the role of WT1 gene in sex determination. We discuss the molecular mechanism of sex reversal in DDS and FS.

Section snippets

Case report

We report the case of an Italian woman with a male pseudohermaphrodism. At the age of seven, she developed nephrotic syndrome that was resistant to corticosteroı̈d therapy. Renal failure appeared rapidly and she underwent haemodialysis at nine years of age. Kidney transplantation had been performed at age of 11.

At 17 years of age, the patient had primary amenorrhea. She had no pilosity and no mammary development. Absent puberty was then diagnosed. A small uterus was seen on pelvic

Discussion

Wilms’ tumour suppressor gene WT1 appears to have multiple roles in human physiology and pathology. Its function is more complex than only tumour suppression. WT1 is located on chromosome 11p13. Mutation or deletion of WT1 gene is associated with different pathologies of the urogenital tract including Wilms’ tumour, Denys–Drash and Frasier syndrome.

Heterozygous WT1 gene deletions are associated with mild genitourinary anomalies and a predisposition to Wilms’ tumour [10].

A wide variety of WT1

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    Therefore, NR5A1 was sequenced, but somewhat surprisingly (given the phenotypic normalcy of the affected siblings), no mutations were identified. Additional candidate genes such as WT1 (Saylam and Simon, 2003) or SOX9 (Wagner et al., 1994; Foster et al., 1994) also play a major role in the sex determination pathway., It was also apparent that many other genes (Ahmed et al., 2013) including GATA4 (Lourenco et al., 2011), DHH (Liao et al., 2011; Das et al., 2011), CBX2 (Biason-Lauber et al., 2009) and ATRX (Ion et al., 1996) should be considered and therefore, at this point in the investigation, an array CGH was used to screen the genome for CNVs. Having excluded a mutation in SRY, it was hypothesized (just as Benko et al. (2011) did) that the mutation must be maternally inherited with a male ‘permissive’ gene to have affected the children but spared the father.

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