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The Journal of Clinical Endocrinology & Metabolism Vol. 87, No. 6 2500-2505
Copyright © 2002 by The Endocrine Society

The Impact of the Human Genome on Endocrinology: Original Articles

An Unusual Phenotype of Frasier Syndrome due to IVS9 +4C>T Mutation in the WT1 Gene: Predominantly Male Ambiguous Genitalia and Absence of Gonadal Dysgenesis

Karla F. S. Melo, Regina M. Martin, Elaine M. F. Costa, Filomena M. Carvalho, Alexander A. Jorge, Ivo J. P. Arnhold and Berenice B. Mendonca

Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular, LIM/42 (K.F.S.M., R.M.M., E.M.F.C., A.A.J., I.J.P.A., B.B.M.), Departamento de Anatomia Patológica, LIM/14 (F.M.C.), Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, 01060-970, Brazil

Address all correspondence and requests for reprints to: Berenice B Mendonca, M.D., Hospital das Clínicas, FMUSP, Divisão de Endocrinologia, Caixa Postal 3671, São Paulo, 01060-970, Brazil. E-mail: . beremen{at}usp.br

Abstract

The Wilms’ tumor gene (WT1) encodes a zinc-finger transcription factor involved in the development of the kidneys and gonads and their subsequent normal function. Mutations in the WT1 gene were identified in patients with WAGR (Wilms’ tumor, aniridria, genitourinary abnormalities, and mental retardation), Denys-Drash syndrome, and Frasier syndrome (FS). Constitutional heterozygous mutations of the WT1 gene, almost all located at intron 9, are found in patients with FS. This syndrome is characterized by female external genitalia in 46,XY patients, late renal failure, streak gonads, and high risk of gonadoblastoma development. We report a male with FS with an unusual phenotype characterized by normal penis size with perineal hypospadias, end-stage renal failure at the age of 19 yr, normal adult male serum T levels, extremely elevated gonadotropin levels, para-testicular leiomyoma, unilateral testicular germ cell tumor, bilateral gonadoblastoma, and absence of gonadal dysgenesis. Automatic sequencing identified the IVS9 +4C>T mutation in the WT1 gene, which predicts a change in splice site utilization. WT1 transcript analysis showed reversal of the normal positive/negative KTS (lysine, threonine, and serine) isoform ratio, confirming the diagnosis of FS. This patient with FS presents an external genitalia of Denys-Drash syndrome, suggesting that these two syndromes are not distinct diseases but may represent two ends of a spectrum of disorders caused by alterations in WT1 gene.

This case expands the spectrum of phenotypes associated with WT1 mutations, by including predominantly male ambiguous genitalia and absence of gonadal dysgenesis, extremely high gonadotropin levels, and delayed adrenarche, and presence of a para-testicular leiomyoma, bilateral gonadoblastoma, and germ cell neoplasia.

THE WT1 GENE WAS located at the short arm of chromosome 11, as the result of a positional cloning effort to identify a gene for Wilms’ tumor, in patients with sporadic Wilms’ tumor or with Wilms’ tumor associated with aniridria, genitourinary abnormalities, and mental retardation, known as the WAGR syndrome (1, 2).

Mutations in the WT1 gene leads to both Wilms’ tumors and urogenital abnormalities (3, 4). Constitutional heterozygous mutations in the WT1 gene were reported in most of the patients with Denys-Drash syndrome (DDS) and Frasier syndrome (FS) (5). The DDS phenotype consists of male pseudohermaphroditism, high risk of Wilms’ tumor development, and early renal failure. The molecular defect of DDS is the presence of heterozygous missense mutations in the zinc finger encoding exons (DNA-binding domain) of WT1 gene. These mutant forms of WT1 act as dominant negative, and effective WT1 levels in cells are probably reduced below 50% because WT1 protein is able to dimerize, resulting in nonfunctional homo- and heterodimers of mutant WT1 protein (6). Kidney function is severely impaired due to diffuse mesangial sclerosis, leading to nephrotic syndrome and kidney failure within the first 2 or 3 yr of life (7). Gonadal development is impaired in variable degrees, resulting in a spectrum of male pseudohermaphroditism (8, 9).

The FS phenotype in 46,XY patients consists of female external genitalia, gonadal dysgenesis, high risk of gonadoblastoma, and development of renal failure in the second decade of life (10). FS is caused by heterozygous mutations in intron 9 of the WT1 gene, leading to a change in splicing that results in deficiency of the usually more abundant lysine, threonine, and serine (KTS)-positive isoforms and reversal of the normal KTS positive to negative ratio from 2:1 to 1:2, suggesting that a precise balance between WT1 isoforms is necessary for WT1 normal function (5, 8, 11).

We report a patient presenting an overlapping of some typical characteristics of FS (end-stage renal failure in the second decade, gonadoblastoma, and IVS9 +4C>T mutation), but with the gonadal and external genitalia development usually found in DDS.

Case Report

The patient

The patient, now a 22-yr-old male, had nonconsanguineous parents and was born with ambiguous genitalia characterized by perineal hypospadias, urogenital sinus, bifid scrotum, and bilateral cryptorchidism. He was raised as male and underwent three surgeries for repair of hypospadias and the external genitalia in childhood, with good results. His karyotype was 46,XY. At 13 yr of age, proteinuria was noticed in a routine examination. He had developed spontaneous puberty without gynecomastia, and at the age of 17 yr had a Tanner stage V pubic hair development, a normal penis size (10 x 3 cm) with a topic urethra, and testes of soft consistency measuring 2.2 x 0.6 cm (right) and 1.7 x 0.6 cm (left) (Fig. 1Go).



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  		Figure 1. Patient showing normal male phenotype after surgical correction of hypospadias, bifid scrotum, and cryptorchidism.

 
Adrenal function. He had low basal levels of dehydroepiandrosterone sulfate (DHEA-S), and an acute ACTH test was performed at 17 yr. ACTH stimulation showed a normal cortisol response and an absent or decreased response of the steroids 17-hydroxyprogesterone, androstenedione, and DHEA (Table 1Go). At the age of 20 yr, his DHEA-S levels were normal and another acute ACTH test revealed a normal adrenal response, suggesting that this patient had a delayed adrenarche.


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  		Table 1. Adrenal function before and after acute ACTH stimulation tests in a patient with FS

 
Hypothalamic-pituitary-testicular axis. Between 13.8 and 14.1 yr of age, the patient had normal adult levels of T associated with slightly elevated levels of LH and FSH in basal condition (Table 2Go). At 17.2 yr, LH, FSH, and T were measured every 20 min for 4 h in the same day and confirmed elevated LH and FSH levels and normal T levels for an adult male. To rule out the hypothesis of partial androgen insensitivity, we sequenced the entire coding region of the AR gene using primers and protocols described previously (12), and no mutations were found.


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  		Table 2. Hypothalamic-pituitary-testicular function before and after orchidectomy in a patient with FS

 
At age 18 yr, a 2.5-cm left testicular nodule of hard consistency was palpable, and he was submitted to left testicular resection. At that time, LH and FSH levels increased further and blood tests identified elevated urea and creatinine levels compatible with end-stage renal failure raising the hypothesis of WT1 gene mutation. The left nodule was a paratesticular leiomyoma, and in the small left testis was identified an in situ gonadoblastoma at histological analysis.

To confirm the hypothesis of FS, PCR amplification of exon 9 and part of intron 9 of the WT1 gene was performed on 100 ng genomic DNA, with the primers WT9a sense (5'-TAGGGCCGAGGCTAGACCTTCTCTGT-3') and WT9b-antisense (5'-ATCCCTCTCATCACAATTTCATTCC-3') and previously described protocols (11). Samples were sequenced with the ABI Prism Dye Terminator sequencing kit (Perkin-Elmer Corp., Norwalk, CT) according to the manufacturer’s instructions, using the primer WT9a. Sequencing found the previously described cytosine (C) to thymidine (T) transition at position +4 of the splice donor site within intron 9, in heterozygous state, confirming a molecular diagnosis of FS. The analysis by the computer program for splice site prediction (http://www-hgc.lbl.gov/projects/splice.html) revealed that the C->T substitution at position +4 reduced the score for site 2 [including the three amino acids (KTS) in the end of exon 9] from 0.76 to 0.55. To confirm the splice site prediction, total RNA was extracted from the patient’s leiomyoma and left testicular tissues and from epidydimis tissue of a normal subject used as control. RT was performed according to standard methods. PCR amplification was performed on cDNA with primers WTRT1 (5'-CTTGTCAGCGAAAGTTCTCC-3') and WTRT2 (5'-CTTTTTCTGACAACTTGGCC-3') at 94 C for 40 sec, 55 C for 40 sec, and 72 C for 40 sec for 32 cycles. Both +KTS and -KTS WT1 alternative transcripts (113 and 104 bp, respectively) were amplified by RT-PCR and were separated by nondenaturing electrophoresis on a 12% polyacrylamide gel (11). The bands produced were quantified by Kodak Digital Science 1D (Kodak, Rochester, NY). The RT-PCR analysis of WT1 expression in the patient’s tissues (leiomyoma and left testis) demonstrated a predominance of the -KTS isoform, resulting in the inversion of the +/-KTS isoform ratio (0.25 ± 0.038) compared with the control tissue (2.2 ± 0.61) (Fig. 2Go).



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  		Figure 2. Quantification of WT1 +/-KTS isoforms in the patient’s tissues (leiomyoma and left testis) and in control. Both +KTS (113 bp) and -KTS (104 bp) isoforms were amplified by RT-PCR and quantified by Kodak Digital Science 1D to establish the +/-KTS ratio. The two additional bands probably correspond to DNA heterodimers (8 ).

 
Because of the high risk of gonadoblastoma development in patients with FS, the patient was submitted to a right testicular resection at age of 20 yr.

Histological analysis. Histological sections showed hypotrophic testes embedded in fibrous connective tissue without areas of gonadal dysgenesis. The degree of atrophy was more intense in the right testis compared with the left testis. The seminiferous tubules were numerous and showed a thick basal membrane. The germinative epithelium was flattened with a decreased number of spermatogonia, without signs of spermatogenesis. Many structures were hyalinized, particularly on the right. The stroma showed hyperplastic Leydig cells. Focally we identified a bilateral gonadoblastoma characterized by small nests with round or oval contours composed by germinative and sex cord cells with hyaline bodies and frequent calcifications (Fig. 3Go). The neoplasm was associated with the testicular tissue and was, in many areas, restricted to the lumen of the seminiferous tubules. In the right testis we also observed some tubules that were slightly distended and filled with atypical germinative cells that were stained for alkaline placental phosphatase characterizing an in situ germ cell neoplasia.



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  		Figure 3. A, Gonadoblastoma: nests of tumor with areas of calcification (hematoxylin and eosin, x100). B, Neoplasic germ cells in hypotrophic testis with seminiferous tubules showing thick basal membrane. Hyperplasic Leydig cells in the stroma. Hematoxylin and eosin, x100.

 
After bilateral gonadectomy, the patient was treated with 200 mg T enanthate injection every 14 d. There was an increase in T levels up to 1520 ng/dl 24 h after T injection with no effect on gonadotropin levels.

Discussion

The WT1 gene encodes a nuclear zinc finger protein that can bind to DNA, and acts as a transcriptional regulator in different ways. In certain contexts it binds DNA and acts as either a repressor or an activator, and, in others where DNA binding is not required, it may work as a coactivator (13). Knockout of this gene in mice resulted in the absence of renal and gonadal development (14).

The WT1 gene contains 10 exons, of which exons 1–6 encode a proline/glutamine-rich transcriptional-regulation region and exons 7–10 encode the four zinc fingers of the DNA-binding domain. There are four major species of RNA with conserved relative amounts, different binding specificities, and different subnuclear localizations, generated by two alternative splicing regions (13). Splicing at the first site results in either inclusion or exclusion of exon 5 (encoding 17 amino acids). The second alternative splicing site is in the 3' end of exon 9 and allows the inclusion or exclusion of three amino acids (KTS) between the third and fourth zinc fingers, resulting in either KTS-positive or -negative isoforms (15). The KTS motif in the WT1 protein is highly conserved during evolution whereas the alternative splice site in exon 5 is not. Isoforms that only differ by the presence or absence of the KTS amino acids have different affinities for DNA and, therefore, possibly different regulatory functions (16).

Frasier et al. (10) were the first to report a pair of 46,XY monozygotic twins with pure gonadal dysgenesis, streak gonads, and gonadoblastoma whose follow-up was complicated by the development of renal failure (10). Intronic mutations in the WT1 gene and consequent imbalance in +/-KTS isoforms were later demonstrated to be the cause of FS (8, 11, 17). Five different mutations were reported in intron 9 of the WT1 gene, which result in deficiency of the usually more abundant +KTS isoform: +2T>C, +4C>T, +5G>A, +5G>T, and +6T>A. The most frequent mutation identified in patients with FS is +4C>T, present in 52% of the patients. This mutation hot spot probably results from the potential to deaminate 5 methylcytosine at +4/+5 CpG dinucleotide (8). The +5G>A mutation was identified in 26% of the cases, and the +2T>C, +6T>A, and +5G>T mutations were identified in one patient each. More recently, two exonic mutations, R390X and F392L, which did not alter the normal balance of the +/-KTS isoforms, were identified in two Japanese patients with FS (18).

To our knowledge, 27 46,XY patients with FS have been reported, to date (Table 3Go). Molecular analysis of the WT1 gene were performed in 25 cases, and 23 patients had mutations in intron 9 that alter splicing and invert the normal +KTS/-KTS isoform ratio, whereas two Japanese patients presented mutations in exon 9 (18). Twenty-four cases had the following characteristics: complete female phenotype that led to female sex rearing, streak gonads, and late renal failure. Three patients presented atypical phenotypes. One prepubertal patient with IVS9 +4C>T mutation in the WT1 gene presented diaphragmatic hernia, hypospadias and unilateral cryptorchidism, and male sex rearing (28). The diaphragmatic hernia is also probably related to the WT1 mutation because WT1 is expressed in pleural and abdominal mesothelium, and mice lacking both WT1 alleles exhibit diaphragmatic hernia (14). The two Japanese patients, one with the exonic mutation R390X and the other with the F392L mutation, had a predominantly male phenotype characterized by penoscrotal hypospadias and cryptorchidism that led to male sex rearing, associated with dysgenetic gonads and gonadoblastoma in one of the patients (18). Our patient presented the IVS9 +4C>T mutation in the WT1 gene and had a predominantly male ambiguous external genitalia that led to a male sex rearing. After surgical interventions, he achieved a normal male external genitalia and normal sexual activity. Postnatal T secretion was within the normal adult range, and testes contained hyperplastic Leydig cells. The preservation of testicular function contrasts with that of most patients with FS carrying the same mutation, suggesting that epigenetic factors might influence the effect of WT1 on gonadal development.


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  		Table 3. Clinical and molecular characteristics of 46,XY patients with FS

 
Hormonal studies in FS are scarce in the literature, and there are no data on adrenal function in these patients. Adrenal function before and after an ACTH stimulation test performed in our patient demonstrated that he had a delayed adrenarche. Moore et al. (30) showed that human-derived WT1 transgenic construct completely rescue the cardiac defects and midgestation lethality in Wt1 null mice but did not prevent the severe renal, adrenal, and gonad maldevelopment. This finding, and the interaction of WT1 -KTS isoform with SF-1 in the embryological derivatives of intermediate mesoderm, allows us to consider that the delayed adrenarche in this patient might be caused by the mutation in the WT1 gene (31).

Only eight patients with FS have had gonadotropin levels reported (18, 20, 21, 26, 27, 29). The pubertal and adult patients with FS had extremely high gonadotropin levels ranging from 53–117 IU/liter for LH and from 66–254 lU/liter for FSH. All these patients had dysgenetic gonads. The patient described here had also extremely elevated LH and FSH levels associated with normal adult T levels in the presence of atrophic but not dysgenetic testes at histological analysis. After left gonadectomy the patient presented a further increase in LH and FSH levels and decrease in T levels, probably because the right testis was more atrophic than the left testis. After the second gonadectomy the marked increased LH and FSH levels were not suppressed by T enanthate replacement therapy, suggesting that the normal T-LH feedback is altered in FS. Considering these data, we speculate whether WT1 might also have a role in the hypothalamic-pituitary-gonadal feedback regulation.

The incidence of gonadal tumors in patients with FS is about 44%. Most of them are gonadoblastomas (37%), but dysgerminoma and T-secreting hilar cell tumors have also been reported (23, 24). It has been suggested that the gonadoblastoma might be the result of the obligatory presence of dysgenetic gonads, which carry a high risk of tumorigenesis or differences in the stage at which gonadal development is halted in FS and DDS (5). Our patient presented bilateral gonadoblastoma associated with germ cell neoplasia that was never described in FS patients before, despite the absence of gonadal dysgenesis, suggesting that the function of the WT1 gene as a tumor suppressor had a crucial role in the development of these tumors.

The report of ambiguous external genitalia in four patients, including the patient reported here (18, 28), the presence of Wilms’ tumor in one patient (23), and the description of exonic mutations in the DNA-binding domain of the WT1 gene (18) in patients with FS indicate an overlap of clinical and molecular features in DDS and FS. This suggests that DDS and FS are not distinct diseases but may represent two ends of a spectrum of disorders caused by alterations in the WT1 gene and that genotype-phenotype correlations are not always possible.

Our case provides new data concerning the heterogeneity of phenotypes associated with WT1 mutations by including predominantly male ambiguous genitalia and absence of gonadal dysgenesis, associated with the presence of a para-testicular leiomyoma, bilateral gonadoblastoma, germ cell neoplasia, and delayed adrenarche, thus expanding the spectrum of the phenotypes associated with this syndrome.

Acknowledgments

Footnotes

Abbreviations: DDS, Denys-Drash syndrome; DHEA-S, dehydroepiandrosterone sulfate; FS, Frasier syndrome; KTS, lysine, threonine, and serine.

Received June 4, 2001.

Accepted February 5, 2002.

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