Frasier Syndrome

A number sign (#) is used with this entry because of evidence that Frasier syndrome is caused by heterozygous mutation in the WT1 gene (607102) on chromosome 11p13.

Description

Frasier syndrome is a rare disorder defined by pseudohermaphroditism and progressive glomerulopathy (Frasier et al., 1964; Haning et al., 1985; Kinberg et al., 1987). Patients present with normal female external genitalia, streak gonads, and XY karyotype, and frequently develop gonadoblastoma (Blanchet et al., 1977). Glomerular symptoms consist of childhood proteinuria and nephrotic syndrome, characterized by nonspecific focal and segmental glomerular sclerosis, progressing to end-stage renal failure in adolescence or early adulthood. Wilms tumor is not a usual feature (Barbaux et al., 1997).

Clinical Features

Moorthy et al. (1987) suggested that some of the patients reported as cases of Denys-Drash syndrome (194080) in fact had a different disorder for which they suggested the designation Frasier syndrome (Frasier et al., 1964). Moorthy et al. (1987) discussed 6 previously reported patients with streak gonads, pseudohermaphroditism, and renal failure. In several of the patients the diagnosis was established only after successful kidney transplantation during evaluation for primary amenorrhea. Gonadoblastoma arising from the streak gonad was noted in 5 of the 6 patients.

Barbaux et al. (1997) described 3 unrelated patients with Frasier syndrome. All 3 presented with persistent proteinuria between the ages of 2 and 6 years and subsequently developed nephrotic syndrome that progressed to end-stage renal failure between 9 and 35 years of age. Renal biopsies performed before the onset of renal insufficiency showed minimal nonspecific glomerular changes in 1 patient and focal and segmental glomerular sclerosis in the other 2 patients. All 3 patients underwent successful kidney transplantation without recurrence of the nephrotic syndrome. Evaluation of primary amenorrhea in these 3 females with normal female phenotype led to a diagnosis of 46,XY gonadal dysgenesis. One of the 3 patients developed gonadoblastoma, which was diagnosed when she was 19; no recurrence was observed after surgical treatment. The other 2 patients underwent bilateral surgical gonadectomy.

Melo et al. (2002) reported a patient diagnosed with Frasier syndrome who had the external genitalia characteristic of Denys-Drash syndrome. They suggested that these 2 syndromes are not distinct diseases but may represent 2 ends of a spectrum of disorders caused by alterations in the WT1 gene.

Molecular Genetics

Because mutations in exons 8 or 9 of the WT1 gene had been identified in 10 unrelated patients with Denys-Drash syndrome by Pelletier et al. (1991), Poulat et al. (1993) screened exons 1 through 10 of WT1 in patients with Frasier syndrome, but identified no mutations. Because they screened for mutations with single-strand conformation polymorphism (SSCP) analysis, a method that detects only an estimated 80% of point mutations, the possibility of mutations elsewhere in the gene was not completely excluded.

Berta et al. (1992) found no large deletion in the sex-determining region of the Y chromosome or mutations in the SRY gene (480000) in 2 girls with XY gonadal dysgenesis and chronic renal failure.

In 3 patients with Frasier syndrome, Barbaux et al. (1997) identified mutations in the donor splice site of intron 9 of the WT1 gene (607102.0018; 607102.0019) with a predicted loss of the so-called +KTS isoform. Normally, an alternative splice site in intron 9 allows the addition of 3 amino acids (KTS) between the third and fourth zinc fingers of the WT1 protein. All 3 patients had male pseudohermaphroditism, nephrotic syndrome progressing to end-stage renal failure, and 46,XY gonadal dysgenesis. Renal biopsies performed before the onset of renal insufficiency showed minimal nonspecific glomerular changes in 1 patient and focal and segmental glomerular sclerosis in the other 2 patients. In 1 patient, gonadoblastoma was diagnosed at the age of 19.

Barbaux et al. (1997) suggested that the patient reported as having Denys-Drash syndrome and a mutation in intron 5 of the WT1 gene (607102.0009) in fact had Frasier syndrome.

Klamt et al. (1998) showed that no mutant protein is produced by the mutations in WT1 causing Frasier syndrome. Instead, the mutation results in an altered ratio of the 2 splice isoforms of the protein, those with and those without the extra 3 amino acids (KTS). In the Denys-Drash syndrome, the tumor risk is much greater than in Frasier syndrome. The dominant-negative mutant allele is defective and loss of the second allele (according to the 2-hit model) may be an important step in tumor formation. In contrast, Frasier patients have 1 normal copy of WT1 and 1 that can only produce a shorter isoform. Allele loss would thus lead to cells that cannot produce the +KTS isoform of WT1, but still have large amounts of the -KTS isoform. In this respect, it is interesting to note that tumorigenicity of the G401 Wilms tumor cell line in nude mice can be suppressed to the same extent by +KTS and -KTS isoforms. Gonadoblastoma is frequent in Frasier patients.

Melo et al. (2002) reported a 19-year-old male with Frasier syndrome who had the IVS9+4C-T mutation (607102.0018), which predicts a change in splice site utilization. He had an unusual phenotype. WT1 transcript analysis showed reversal of the normal positive/negative KTS isoform ratio, confirming the diagnosis of FS. The authors concluded that this patient had the external genitalia characteristic of Denys-Drash syndrome, suggesting that these 2 syndromes are not distinct diseases but may represent 2 ends of a spectrum of disorders caused by alterations in the WT1 gene.

Animal Model

Using immunofluorescence analysis, Bradford et al. (2009) found a significantly lower level of Sry (480000) protein per cell in XY Wt1(+KTS)-null mouse gonads. There were also a reduced number of Sry-expressing cells, correlating with a decrease in cell proliferation at and near the coelomic epithelium at 11.5 days postcoitum. No reduction in somatic cell numbers was seen in XX Wt1(+KTS)-null gonads, indicating that the effect of Wt1 on cell proliferation was mediated by Sry. Sertoli cell differentiation was blocked in XY Wt1(+KTS)-null mouse gonads, as indicated by the loss of Sox9 (608160) and Fgf9 (600921) expression, but the addition of recombinant Fgf9 to ex vivo gonad cultures rescued the mutant phenotype, as indicated by the induction of the Sertoli cell-specific marker anti-Mullerian hormone (AMH; 600957). The authors suggested that WT1(+KTS) may be involved in the cell-autonomous regulation of SRY expression, which in turn influences cell proliferation and Sertoli cell differentiation via FGF9. Thus, sex reversal in Wt1(+KTS)-null mice and Frasier syndrome patients may result from a failure of Sertoli cells both to fully differentiate and to reach sufficient numbers to direct testis development.