| We report the identification of a novel wilms tumor suppressor gene mutation in a 5-month-old girl who presented with unilateral wilms tumor (WT) and renal diffuse mesangial sclerosis typical of denys-drash syndrome (DDS). The patient did not have ambiguous genitalia and the karyotype (by amniocentesis) was 46, XX. A de novo constitutional heterozygous mutation in WT1 gene exon 9 coding for the third zinc-finger (1163G-->A, C388Y) was identified. This mutation affects a cysteine residue involved in the coordination of the zinc atom, confirming the importance of these residues in the biological function of WT1 protein. ( info) |
2/22. A review of the phenotypic variation due to the denys-drash syndrome-associated germline WT1 mutation R362X. The gene WT1 is required for the normal development and function of the urogenital tract. Constitutional mutations are associated with familial wilms tumor and syndromes such as denys-drash syndrome (DDS) characterized by nephropathy, genital anomalies and often a predisposition to wilms tumor. We report a case of constitutional WT1 mutation in an XX female with multifocal wilms tumor but no genital anomalies or renal dysfunction and, for the first time, review patients previously reported with this germline mutation. The mutation (1084C>T) changes the amino acid arginine at position 362 to the translation stop codon TGA (R362X) resulting in a predicted truncated protein lacking three of the four zinc finger domains necessary for correct functioning of the gene. This constitutional mutation has been reported to cause a variety of phenotypes in eleven different patients, including the classical Denys-Drash phenotype of diffuse mesangial sclerosis which leads to early renal failure, genital anomalies in XY individuals and Wilms tumors. The absence of mesangial sclerosis and renal failure in our patient excludes DDS. Our case differs from those previously described as the normal kidney tissue shows some small subcapsular glomeruli indicating that the WT1 mutation has impaired nephron development. This patient extends the range and variation of phenotypes that may arise from a specific germline mutation in WT1. ( info) |
3/22. A girl with bilateral ovarian tumours: frasier syndrome. frasier syndrome (FS) is characterised by male pseudohermaphroditism, slowly progressing nephropathy and frequent development of gonadoblastoma. The Wilms' tumour suppressor gene (WT1 gene) plays an important role in the development of the urogenital system and the gonads. A splice mutation in intron 9 of the WT1 gene was recently described in patients with FS. We analysed the WT1 gene of a Japanese patient with male pseudohermaphroditism, steroid resistant-nephr-opathy and gonadoblastoma by the polymerase chain reaction and direct sequencing and detected a heterozygous point mutation in intron 9. CONCLUSION: analysis of the Wilms' tumour suppressor gene in a patient with frasier syndrome by the polymerase chain reaction and direct sequencing detected a 5G -->A transition at a position of the second alternative splice region of exon 9, important for predicting the risk of the occurrence of Wilms' tumour. ( info) |
4/22. 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. 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. ( info) |
| STUDY OBJECTIVES: To report a rare reason for primary amenorrhea, a frasier syndrome, XY gonadal dysgenesis associated with renal failure with eventual development of gonadoblastoma. To study immunohistochemical analysis of gonadoblastoma and dysgerminoma. To analyze the possibility of androgen receptor mutation in this rare syndrome. methods: We report a case of a 16-yr-old female with this syndrome. She underwent a laparoscopic bilateral gonadectomy and salpingectomy. A histopathological examination revealed gonadoblastoma with focal malignant dysgerminoma in the left dysgenetic gonad and an immunohistochemical of these fairly rare, malignant tumors. An androgen receptor was coded. Analysis was done. RESULTS: Immunohistochemical analysis showed that inhibin was strongly positive in gonadoblastoma but negative in dysgerminoma. No mutations of the androgen receptor gene were found. CONCLUSIONS: Inhibin positivity in gonadal stroma and in gonadoblastoma may indicate hormonal activity causing advanced puberty in patients with XY gonadal dysgenesis. ( info) |
6/22. Gonadal mosaicism of frasier syndrome in 3 Chinese siblings with donor splice site mutation of Wilms' tumour gene. frasier syndrome is a rare human developmental disorder classically affecting 46,XY females and leading to male pseudohermaphroditism and chronic renal failure. We describe a family with both 46,XX and 46,XY females affected by the syndrome due to WT1 splice site mutations. The diagnosis of frasier syndrome in 1 of the children led to the discovery of the syndrome in 2 other siblings, of whom 1 is asymptomatic. Since the mutation was not found in either parents, gonadal mosaicism was suggested. The implication of family screening for WT1 gene mutation in asymptomatic members is also discussed. ( info) |
7/22. Molecular analysis of frasier syndrome: mutation in the WT1 gene in a girl with gonadal dysgenesis and nephronophthisis. The Wilms' tumor gene (WT1) encodes a protein that is believed to exert transcriptional and tumor-suppressor activities. Mutations in this gene have occasionally been associated with Wilms' tumor (<15% patients) and, more consistently, with three syndromes characterized by urogenital abnormalities (WAGR, Denys-Drash and Frasier syndromes). We report 17 years follow-up of a 29 year-old phenotypic female with 46,XY karyotype, gonadal dysgenesis and nephronophthisis in order to identify possible germline alterations of the WT1 gene. frasier syndrome was suspected and confirmed by genetic analysis. Sequence analysis permitted the identification of an A40-->G mutation in position 5 in the donor splice site of intron 9. During surgery for streak gonads extirpation, a microscopic gonadoblastoma was found, a typical complication of frasier syndrome. ( info) |
| fraser syndrome (MIM 219000) is a rare disorder of autosomal recessive inheritance, characterized by the association of cryptophthalmos, syndactyly and genital abnormalities. Here we report on two cases of fraser syndrome (cryptophthalmos syndrome) in a non-consanguineous couple, with variable expression in echographic, clinical and autopsy findings. Furthermore, we highlight the difficulties in prenatal diagnosis of fraser syndrome. ( info) |
9/22. Embryonal hyperplasia of Bowman's capsular epithelium in patients with WT1 mutations. Embryonal hyperplasia of Bowman's capsular epithelium (EHBCE) is a rare condition, observed in patients with end-stage renal disease when treated with long-term dialysis. Immunohistochemical studies have suggested that EHBCE originates from the visceral epithelium of the Bowman's capsule. Here we report two patients with WT1 missense mutations in exon 7, who received continuous ambulatory peritoneal dialysis and developed EHBCE without wilms tumor. One patient showed manifestations of denys-drash syndrome (DDS), while the other patient exhibited rapid progress into end-stage renal disease, but no genitourinary anomaly. Recently, abnormal expression of WT1 and PAX2 was shown in the podocytes in diffuse mesangial sclerosis (DMS) associated with DDS and isolated DMS. We hypothesize that EHBCE is a reversion of Bowman's capsular epithelial cells to an earlier cell differentiation state, which has the characteristics of a progenitor cell of both Bowman's capsular epithelia and podocytes. Immunohistochemical analysis of WT1, PAX2, vimentin, cytokeratin, and epithelial membrane antigen was performed in the kidney specimens obtained at autopsy or surgery. Abnormal expression of WT1 and PAX2 in the EHBCE was observed in both patients, supporting our hypothesis. The nephropathy associated with constitutional WT1 mutations might therefore be associated with EHBCE. ( info) |
10/22. Alport syndrome-like basement membrane changes in frasier syndrome: an electron microscopy study. frasier syndrome (FS) is a rare disease characterized by male pseudohermaphroditism and slowly progressing nephropathy. FS originates from heterozygous mutation in the intron 9 splicing donor site of Wilms' tumor suppressor gene (WT1). Focal segmental glomerular sclerosis is common in FS, but there have not been so many detailed pathologic investigations. The authors examined the kidneys of 3 patients with FS. The results showed that nephropathy started as mesangial proliferative glomerulonephritis, and later a concomitant focal segmental lesion developed. In all cases, electron microscopy results showed widespread thinning, splitting, and lamellation of the glomerular basement membrane, which mimicked hereditary nephritis. Throughout adulthood, WT1 protein expresses on glomerular podocytes. Recent reports described that podocytes expressing WT1 play an important role in maintaining the glomerular basement membrane. Hereditary nephritis-like glomerular basement membrane findings in FS suggest that one of the important functions of podocytes is to form and maintain the glomerular basement membrane. ( info) |