Skip to main content
  • AACR Publications
    • Blood Cancer Discovery
    • Cancer Discovery
    • Cancer Epidemiology, Biomarkers & Prevention
    • Cancer Immunology Research
    • Cancer Prevention Research
    • Cancer Research
    • Clinical Cancer Research
    • Molecular Cancer Research
    • Molecular Cancer Therapeutics

AACR logo

  • Register
  • Log in
  • My Cart
Advertisement

Main menu

  • Home
  • About
    • The Journal
    • AACR Journals
    • Subscriptions
    • Permissions and Reprints
    • Reviewing
  • Articles
    • OnlineFirst
    • Current Issue
    • Past Issues
    • Meeting Abstracts
    • Collections
      • COVID-19 & Cancer Resource Center
      • "Best of" Collection
      • Editors' Picks
  • For Authors
    • Information for Authors
    • Author Services
    • Best of: Author Profiles
    • Submit
  • Alerts
    • Table of Contents
    • Editors' Picks
    • OnlineFirst
    • Citation
    • Author/Keyword
    • RSS Feeds
    • My Alert Summary & Preferences
  • News
    • Cancer Discovery News
  • COVID-19
  • Webinars
  • Search More

    Advanced Search

  • AACR Publications
    • Blood Cancer Discovery
    • Cancer Discovery
    • Cancer Epidemiology, Biomarkers & Prevention
    • Cancer Immunology Research
    • Cancer Prevention Research
    • Cancer Research
    • Clinical Cancer Research
    • Molecular Cancer Research
    • Molecular Cancer Therapeutics

User menu

  • Register
  • Log in
  • My Cart

Search

  • Advanced search
Cancer Prevention Research
Cancer Prevention Research
  • Home
  • About
    • The Journal
    • AACR Journals
    • Subscriptions
    • Permissions and Reprints
    • Reviewing
  • Articles
    • OnlineFirst
    • Current Issue
    • Past Issues
    • Meeting Abstracts
    • Collections
      • COVID-19 & Cancer Resource Center
      • "Best of" Collection
      • Editors' Picks
  • For Authors
    • Information for Authors
    • Author Services
    • Best of: Author Profiles
    • Submit
  • Alerts
    • Table of Contents
    • Editors' Picks
    • OnlineFirst
    • Citation
    • Author/Keyword
    • RSS Feeds
    • My Alert Summary & Preferences
  • News
    • Cancer Discovery News
  • COVID-19
  • Webinars
  • Search More

    Advanced Search

Review

Gonadal Tumor in Frasier Syndrome: A Review and Classification

Jiro Ezaki, Kazunori Hashimoto, Tatsuo Asano, Shoichiro Kanda, Yuko Akioka, Motoshi Hattori, Tomoko Yamamoto and Noriyuki Shibata
Jiro Ezaki
1The Medical Training Center for Graduates, Tokyo Women's Medical University, Tokyo, Japan.
2Department of Surgical Pathology, Tokyo Women's Medical University, Tokyo, Japan.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kazunori Hashimoto
3Department of Obstetrics and Gynecology, Tokyo Women's Medical University, Tokyo, Japan.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Tatsuo Asano
4Department of Pediatric Nephrology, Tokyo Women's Medical University, Tokyo, Japan.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Shoichiro Kanda
4Department of Pediatric Nephrology, Tokyo Women's Medical University, Tokyo, Japan.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yuko Akioka
4Department of Pediatric Nephrology, Tokyo Women's Medical University, Tokyo, Japan.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Motoshi Hattori
4Department of Pediatric Nephrology, Tokyo Women's Medical University, Tokyo, Japan.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Tomoko Yamamoto
2Department of Surgical Pathology, Tokyo Women's Medical University, Tokyo, Japan.
5Department of Pathology, Tokyo Women's Medical University, Tokyo, Japan.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Noriyuki Shibata
2Department of Surgical Pathology, Tokyo Women's Medical University, Tokyo, Japan.
5Department of Pathology, Tokyo Women's Medical University, Tokyo, Japan.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: shibatan@research.twmu.ac.jp
DOI: 10.1158/1940-6207.CAPR-14-0415 Published April 2015
  • Article
  • Figures & Data
  • Info & Metrics
  • PDF
Loading

Abstract

Frasier syndrome is a rare inherited disease characterized by steroid-resistant nephrotic syndrome, gonadal tumor, and male pseudohermaphroditism (female external genitalia with sex chromosomes XY), which is based on a splice site mutation of Wilms tumor-suppressor gene 1 (WT1). Several unusual Frasier syndrome cases have been reported in which male pseudohermaphroditism was absent. We reviewed 88 Frasier syndrome cases in the literature and classified them into three types (type 1–3) according to external genitalia and sex chromosomes, and described their clinical phenotypes. Type 1 Frasier syndrome is characterized by female external genitalia with 46,XY (n = 72); type 2 by male external genitalia with 46,XY (n = 8); and type 3 by female external genitalia with 46,XX (n = 8). Clinical course differs markedly among the types. Although type 1 is noticed at the mean age of 16 due to mainly primary amenorrhea, type 2 and 3 do not present delayed secondary sex characteristics, making diagnosis difficult. The prevalence of gonadal tumor is high in type 1 (67%) and also found in 3 of the 8 type 2 cases, but not in any type 3 cases, which emphasize that preventive gonadectomy is unnecessary in type 3. On the basis of our findings, we propose a new diagnostic algorithm for Frasier syndrome. Cancer Prev Res; 8(4); 271–6. ©2015 AACR.

Introduction

Frasier syndrome and Denys–Drash syndrome (DDS) are both rare inherited diseases characterized by steroid-resistant nephrotic syndrome, which leads to renal failure, gonadal tumor (most commonly gonadoblastoma or dysgerminoma), and male pseudohermaphroditism (female external genitalia with sex chromosomes XY; ref. 1). In comparison with other conditions in which male pseudohermaphroditism is present, the risk of gonadal tumor is particularly high in Frasier syndrome (60% compared with 40% for DDS and 15% for partial androgen insensitivity syndrome; ref. 2). Early diagnosis and early elective bilateral gonadectomy have, therefore, been recommended for patients with Frasier syndrome and DDS (3, 4).

Frasier syndrome and DDS are both caused by specific mutations in the Wilms tumor-suppressor gene (WT1), which is located in autosome 11p13 (3). In DDS, a dominant negative mutation in exons 8 or 9 of WT1 leads to the production of abnormal WT1 protein, which results in renal failure before 1 year of age and the development of Wilms tumor of the kidney (1). In contrast, in Frasier syndrome, a point mutation on the donor splice site on intron 9 [intervining sequence (IVS 9)] of WT1 leads to a slow progression of glomerulopathy, leading to proteinuria and nephrotic syndrome in childhood, followed by renal failure in adolescence or early adulthood. Only one case of Frasier syndrome associated with Wilms tumor has been reported (5). The presence of focal segmental glomerulosclerosis or diffuse mesangial sclerosis limits the utility of renal histopathology in distinguishing between these two syndromes (6).

WT1 is a regulator of early gonadal and renal development (7). Two major WT1 isoforms are produced by alternative splicing of the lysine–threonine–serine (KTS) domain, including an insertion (+KTS) or deletion (−KTS; ref. 3). The +KTS isoform of WT1 participates in RNA processing, and has been shown to play a crucial role in the regulation of sex-determining region Y (SRY) in vivo in mice (3, 7). Thus, it can be surmised that WT1 or SRY mutations can induce early errors in the processes of sex determination mediated by preventing proper formation of the testis. Furthermore, sex reversal is observed in male mice deficient in the +KTS isoform of WT1 (7). In human patients with Frasier syndrome, a point mutation on IVS9 brings about downregulation of the +KTS isoform of WT1, which in turn diminishes SRY expression levels (8), and thereby impairs testicular development (7). Thus, male to female sex reversal will occur in pediatric Frasier syndrome patients with 46,XY (9).

Because most patients with Frasier syndrome have external female genitalia and are raised as girls, Frasier syndrome is often suspected when these children with steroid-resistant nephrotic syndrome are evaluated for delayed puberty or primary amenorrhea. The diagnosis is confirmed by detecting WT1 mutations (3). Because of the high risk of gonadal tumor, early diagnosis of Frasier syndrome and early gonadectomy are very important for preventing tumorigenesis (3, 4). However, because most Frasier syndrome patients only present with slowly progressing renal failure, it is very difficult to distinguish it from primary amenorrhea associated with other disorders. A possible option for early diagnosis of Frasier syndrome might be the genetic screening of children with steroid-resistant nephrotic syndrome.

Over the past two decades, several cases of Frasier syndrome of unusual phenotype have been reported. These cases carry a Frasier syndrome–specific IVS 9 mutation in WT1 without the presence of male pseudohermaphroditism. These cases can be classified into two types: patients with male chromosomes (XY) and male external genitalia, and patients with female chromosomes (XX) and female external genitalia. Mother and daughter cases of Frasier syndrome with transmission of WT1 splice-site mutation have been reported (10). The clinical features of these “unusual” cases differ from classical Frasier syndrome.

Previous review articles concerning Frasier syndrome have not provided detailed descriptions of the clinical features and treatment of classical and unusual cases (7, 11). Here, we review the literature, focusing on clinical course, mutation patterns, and prevalence rates of gonadal tumor in classical and unusual cases of Frasier syndrome. We also propose a new classification system for Frasier syndrome, which may be applied to genetic diagnosis and therapeutic strategies.

Literature Review and Classification of Frasier Syndrome

Search strategy and selection criteria

A systematic search of the MEDLINE database up to February 2014 was performed to identify literature with the search term, “Frasier syndrome.” In addition, an extensive manual search was conducted using references from all retrieved reports and review articles. Initially, we found 99 cases that were classified as Frasier syndrome. However, for the purpose of the current analysis, 8 cases were excluded because they lacked descriptions about external genitalia and/or karyotype. Two cases with WT1 mutations (1168C→T and 1174T→C) in exon 9 but not IVS 9 mutation have been reported as unusual Frasier syndrome (12). Although these mutations are also consistent with DDS, both slow progression of steroid-resistant nephrotic syndrome and the absence of Wilms tumor indicate Frasier syndrome (12). However, the fact that these cases were not associated with abnormal KTS splice isoforms suggests an etiology similar to DDS rather than Frasier syndrome. We therefore excluded these two cases from our study. Another unusual Frasier syndrome case showed external genitalia of female phenotype, chronic renal failure, and primary hypogonadism as well as defects of the uterine cervix, body and tubes, and gonads on pelvic MRI (13, 14). However, the case was excluded from our study because genetic analysis of WT1 was not performed. The inclusion criteria for our review of the Frasier syndrome literature were as follows: (i) the presence of steroid-resistant nephrotic syndrome; and (ii) the presence of male pseudohermaphroditism or IVS 9 mutation. In total, 88 Frasier syndrome cases were selected for our review (Supplementary Table S1).

Classification of Frasier syndrome

Because Frasier syndrome is caused by a point mutation in the IVS9 of WT1 located on chromosome 11 (autosome), by which abnormal WT1 + KTS protein are produced (7), both males and females can suffer from Frasier syndrome. However, the interaction between SRY and abnormal WT1 + KTS protein means that the presence of SRY (male) affects phenotype in Frasier syndrome. Moreover, it is hypothesized that there is a gene on the Y chromosome that is involved in the development of gonadoblastoma (15). This is called the gene for testis-specific protein Y (TSPY), which has been referred to as the gonadoblastoma locus on the Y chromosome (GBY; ref. 16). However, the complete mechanism by which the TSPY product causes tumorigenesis remains to be elucidated (2). Therefore, we classified Frasier syndrome from viewpoints such as sex chromosome and external genitalia.

All of the selected cases were categorized into three types: type 1 cases with female external genitalia and 46,XY (n = 72); type 2 with male external genitalia and 46,XY (n = 8); and type 3 cases with female external genitalia and 46,XX (n = 8; Table 1). To our knowledge, there have been no cases of Frasier syndrome with male external genitalia and 46,XX.

View this table:
  • View inline
  • View popup
Table 1.

Classification of Frasier syndrome (n = 88)

Clinical course of Frasier syndrome

We extracted information on the “first complaint” and the “complaint that lead to diagnosis of Frasier syndrome” from each of the 88 cases, and compared their clinical course. Proteinuria, nephrotic syndrome, and hypertension, or edema due to renal failure were abbreviated as “renal disorder,” and primary amenorrhea and/or delayed puberty were abbreviated as “delayed secondary sex characteristics.” The number of cases, age of complaints, types of WT1 mutation and histopathologic type of gonadal tumor were described for each type of Frasier syndrome (Table 1). We diagnosed a case with coexisting gonadoblastoma and dysgerminoma as having dysgerminoma, which is more malignant than gonadoblastoma.

To elucidate the characteristics of gonadal tumor in type 1, we compared the age at gonadectomy and between three groups: cases without gonadal tumor, cases with gonadoblastoma and cases with dysgerminoma (Table 2). To explore the relationship between the types of WT1 mutation and the occurrence of gonadal tumor, we also compared the difference in the number of cases corresponding to each type of WT1 mutation (Table 2).

View this table:
  • View inline
  • View popup
Table 2.

Characteristics of gonadal tumor in type 1 Frasier syndrome (n = 45)a

Statistical analysis

Age was expressed as mean ± SD. One-way ANOVA was used for continuous variables, and the χ2 test was used for categorical variables. Statistical analyses were performed using the SPSS statistics software, version 20 (IBM). A P value of <0.05 was considered to be statistically significant.

Type 1 Frasier syndrome (female external genitals with sex chromosome XY)

The majority of cases reported in the literature (n = 72, 82%) were of type 1 Frasier syndrome (Table 1). In type 1, the most common “first complaint” (that which prompted parents of Frasier syndrome patients to first visit a clinic), was renal disorder in the infant period (n = 49, mean age at first visit: 5.4 ± 4.3 years). Only seven type 1 cases were diagnosed with Frasier syndrome at this point. Most other type 1 patients were diagnosed in adolescence due to delayed secondary sexual characteristics (n = 36, mean age at diagnosis: 16.3 ± 2.3 years). In the cases with descriptions of WT1 mutation, 90% of genetic mutations were restricted to IVS9 +4 and IVS9 +5 of WT1.

The characteristics of gonadal tumor (n = 45) in type 1 Frasier syndrome are summarized in Table 2. A previous study indicated that early diagnosis of Frasier syndrome and early gonadectomy prevented the occurrence of gonadal tumor (4). To verify this association, we compared the mean age at gonadectomy in cases without gonadal tumor, cases with gonadoblastoma, and cases with dysgerminoma. The tendency for cases with clinically aggressive gonadal tumor phenotypes to undergo early gonadectomy creates a reverse causal problem. We therefore conducted analyses separately: cases noticed because of renal disorder or delayed secondary sexual characteristics and cases noticed because of abdominal pain or mass. There was no statistically significant difference of age at gonadectomy and position of WT1 mutation among the three groups: cases without gonadal tumor, cases with gonadoblastoma and cases with dysgerminoma (P = 0.519 for age at gonadectomy and P = 0.779 for position of WT1 mutation, Table 2). Neoplastic transformations seem to occur in the period of adolescence. However, our study's cross-sectional design meant that we could not ascertain the rate of gonadal tumor occurrence.

Six Frasier syndrome cases were diagnosed by the presence of abdominal pain or mass, all of which had gonadal tumor [gonadoblastoma (refs. 17–19), or dysgerminoma (refs. 20–22)]. In some cases, metastasis (17), or recurrence (20) was observed. These cases underwent gonadectomy around the age of 11, which was earlier than in cases diagnosed by the presence of renal disorder and/or delayed secondary sexual characteristics. Among the 46,XY Frasier syndrome cases, 32 (67%) had gonadal tumor, suggesting that the risk of gonadal tumor is higher than that reported in previous studies [60%; (ref. 11) and 48% (ref. 7)].

Type 2 Frasier syndrome (male external genitals with sex chromosome XY)

Eight cases of type 2 Frasier syndrome have been reported (8, 12, 23–29). Although 5 of the cases initially visited clinics due to hypospadia or aplasia of testis (mean age at first visit: 1.0 ± 2.2 years), in most cases, these features did not lead to the diagnosis of Frasier syndrome. Three cases were diagnosed during investigation of renal disorder, and four cases were diagnosed because of other features (Table 1). Features that lead to the diagnosis of Frasier syndrome in these four cases include testicular nodule (gonadoblastoma; ref. 27), genetic investigation due to familial history of Frasier syndrome (28, 29), and severe hypertension due to renal failure (24).

Interestingly, both the distribution and pattern of WT1 mutation in type 2 Frasier syndrome were different from those in type 1 Frasier syndrome. The number of patients with IVS9 +5G→A (n = 27) was larger than patients with IVS9 +4C→T (n = 17) in type 1 Frasier syndrome, whereas the number of patients with IVS9 +5G→A (n = 2) was smaller than patients with IVS9 +4C→T (n = 5) in type 2 Frasier syndrome (P = 0.11 for the χ2 test of IVS9 +4C→T and IVS9 +5G→A; Table 1). The position of the altered base could influence the ratio of +KTS and −KTS isoforms of WT1 protein, by which external genitals were determined. However, it is also conceivable that other mutations may affect the phenotype of external genitalia. Whole-genome sequencing in types 1 and 2 Frasier syndrome patients may clarify the mechanism by which external genital phenotypes are determined.

Among the 8 cases of type 2 Frasier syndrome, three cases first presented because of gonadal tumors: Sertoli cell tumor and seminoma (23), intratubular germ cell neoplasia unclassified (ITGCN; ref. 8), and gonadoblastoma (27). There is no description concerning gonadectomy in cases without gonadal tumor (24, 26, 28–30). The rate of gonadal tumor in type 2 Frasier syndrome cases remains unclear. Because type 2 Frasier syndrome cases do not present primary amenorrhea, the presence of steroid-resistant nephrotic syndrome in children with male external genitalia may provide a chance to examine mutations in WT1. Clinicians should pay attention to the history of infantile hypospadias or aplasia of testis.

Type 3 Frasier syndrome (female external genitals with sex chromosome XX)

Eight cases of type 3 Frasier syndrome have been reported (10, 13, 14, 31–36). Few type 3 Frasier syndrome cases are diagnosed because patients exhibit normal secondary sexual characteristics by the XX chromosome and suffer from renal failure without gonadal impairment. In a previous case report on mother-to-child transmitted WT1 splice-site mutation (10), the mother (46,XX) had an IVS9+5G→A mutation of WT1 and renal failure without gonadal impairment, and her 46,XY daughter had the same mutation and renal failure. It is of interest that the mother and daughter seem to be of types 3 and 1, respectively. These cases point to the possibility that a 46,XY child who is born to a type 3 Frasier syndrome parent could have type 1 Frasier syndrome. In this regard, WT1 sequencing is useful not only in instances of sporadic steroid-resistant nephrotic syndrome, but also in familial cases. Thus, it should be considered with caveat that patients with type 3 Frasier syndrome, as well as those with types 1 and 2, might require careful genetic counseling.

It is noteworthy that there were no cases of type 3 Frasier syndrome with gonadal tumor (Table 1). The absence of gonadal tumor in type 3 Frasier syndrome, in contrast with the other types, suggests the possibility that a gonadoblastoma-related gene locus exists on the Y chromosome (15). On the basis of this finding, it would seem that gonadectomy should not be recommended in cases of type 3 Frasier syndrome. However, the existence of 8 non–Frasier syndrome cases with gonadoblastoma in pure 46,XX females suggests that there is a level of risk of gonadal tumor in type 3 Frasier syndrome that cannot be ignored (37, 38). The prudent recommendation in type 3 Frasier syndrome cases might, therefore, be that medical practitioners carry out careful follow-up examinations of gonadal (ovarian) tissues.

Discussion

On the basis of the results of our review of 88 Frasier syndrome cases, we classified Frasier syndrome into three types (types 1–3 Frasier syndrome). All genetic mutations were detected at the IVS9 region of WT1. However, the rates of occurrence of gonadal tumor and clinical features differed among the three types. Although gonadal tumor was frequently present in types 1 and 2, it was not present in any type 3 Frasier syndrome cases. In comparison with other studies, our study showed a higher risk of gonadal tumor (67%) in type 1 Frasier syndrome (7, 11). Six cases were diagnosed in response to abdominal pain or mass reflecting gonadal tumor (17–22), of which two showed metastasis or recurrence (17, 20). These six cases underwent gonadectomy at around 11 years of age—which was younger than in cases diagnosed in response to renal disorder, delayed secondary sexual characteristics, or both. These data suggest that diagnosis of Frasier syndrome before puberty requires sequencing analysis of WT1. Gonadal tumor is also a risk in type 2 Frasier syndrome cases. Thus, early diagnosis and early gonadectomy should be considered in cases of types 1 and 2. However, given that no cases of gonadal tumor have been reported from type 3 Frasier syndrome, gonadectomy should not be recommended in type 3—even if that necessitates the further follow-up examination of gonadal tissues.

A large number of genetic mutations have been identified in subjects with steroid-resistant nephrotic syndrome and focal segmental glomerulosclerosis. A genetic testing algorithm for steroid-resistant nephrotic syndrome based on age at onset and familial/sporadic status was recently reported (39). According to the algorithm for infantile and child onset steroid-resistant nephrotic syndrome, WT1 gene analysis should be performed only in patients with “sporadic steroid-resistant nephrotic syndrome” and “female external genitalia” who are negative for mutation in the gene for nephrosis 2, idiopathic, and steroid-resistant (podocin; NPHS2). NPHS2 mutation is the most common cause of infantile and child onset steroid-resistant nephrotic syndrome (39).

Cases of Frasier syndrome types 2 and 3 show steroid-resistant nephrotic syndrome but not primary amenorrhea. Although there is a lack detailed data concerning age of onset, the age at onset of renal disorder represented by proteinuria ranges from 1 to 18 years. In other words, these data point to the possibility that cases of steroid-resistant nephrotic syndrome in patients of 1 to 18 years of age could include cases of type 2 and 3 Frasier syndrome. The fact that there are Frasier syndrome cases displaying male external genitalia (type 2 Frasier syndrome according to our classification) or suspected familial steroid-resistant nephrotic syndrome (10), indicates that it is noteworthy to consider sequencing analysis of WT1 not only in patients with female external genitalia and sporadic steroid-resistant nephrotic syndrome, but also in those with male external genitalia or familial steroid-resistant nephrotic syndrome. Regarding these characteristics, we have proposed a new diagnostic algorithm for Frasier syndrome (Fig. 1).

Figure 1.
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 1.

Algorithm for diagnosis of Frasier syndrome. Diagnostic processes require the following criteria/data: clinical features, presence of steroid-resistant nephrotic syndrome, and gene analysis. FS, Frasier syndrome; NPHS2, nephrosis 2, idiopathic, steroid-resistant (podocin); WT1, Wilms tumor gene 1. *, in infantile- or child-onset steroid-resistant nephrotic syndrome cases, NPHS1 should be sequenced. PLCE1 should be sequenced in cases of AR familial history in the event that a patient is negative for NPHS1 mutation. In cases of adolescent-onset steroid-resistant nephrotic syndrome, TRPC6/INF2 and ACTN4 should be sequenced if the patient has AD familial history (see ref. 39 for details).

Taken together, we summarized and reviewed the clinical, genetic, and pathologic features of 88 Frasier syndrome cases. It is very important to perform early diagnosis and type classification on Frasier syndrome cases. Further investigations using epidemiologic, genetic, and molecular biologic approaches will be addressed to verify the ultimate significance of our new classification system, which is linked to clarifying the etiology of Frasier syndrome and therapeutic strategies.

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Prevention Research Online (http://cancerprevres.aacrjournals.org/).

  • Received November 19, 2014.
  • Revision received January 12, 2015.
  • Accepted January 16, 2015.
  • ©2015 American Association for Cancer Research.

References

  1. 1.↵
    1. Saylam K,
    2. Simon P
    . WT1 gene mutation responsible for male sex reversal and renal failure: the Frasier syndrome. Eur J Obstet Gynecol Reprod Biol 2003;110:111–3.
    OpenUrlCrossRefPubMed
  2. 2.↵
    1. Pleskacova J,
    2. Hersmus R,
    3. Oosterhuis JW,
    4. Setyawati BA,
    5. Faradz SM,
    6. Cools M,
    7. et al.
    Tumor risk in disorders of sex development. Sex Dev 2010;4:259–69.
    OpenUrlCrossRefPubMed
  3. 3.↵
    1. Guaragna MS,
    2. Lutaif AC,
    3. Bittencourt VB,
    4. Piveta CS,
    5. Soardi FC,
    6. Castro LC,
    7. et al.
    Frasier syndrome: four new cases with unusual presentations. Arq Bras Endocrinol Metabol 2012;56:525–32.
    OpenUrlCrossRefPubMed
  4. 4.↵
    1. Hughes IA,
    2. Houk C,
    3. Ahmed SF,
    4. Lee PA
    . Consensus statement on management of intersex disorders. J Pediatr Urol 2006;2:148–62.
    OpenUrlCrossRefPubMed
  5. 5.↵
    1. Jaubert F,
    2. Vasiliu V,
    3. Patey-Mariaud de Serre N,
    4. Auber F,
    5. Jeanpierre C,
    6. Gubler MC,
    7. et al.
    Gonad development in Drash and Frasier syndromes depends on WT1 mutations. Arkh Patol 2003;65:40–4.
    OpenUrlPubMed
  6. 6.↵
    1. Hausladen J,
    2. Granahan E,
    3. Bockenhauer D
    . Case report: teenage girl with proteinuria and amenorrhea. Curr Opin Pediatr 2001;13:150–3.
    OpenUrlCrossRefPubMed
  7. 7.↵
    1. Hersmus R,
    2. van der Zwan YG,
    3. Stoop H,
    4. Bernard P,
    5. Sreenivasan R,
    6. Oosterhuis JW,
    7. et al.
    A 46,XY female DSD patient with bilateral gonadoblastoma, a novel SRY missense mutation combined with a WT1 KTS splice-site mutation. PLoS ONE 2012;7:e40858.
    OpenUrlCrossRefPubMed
  8. 8.↵
    1. Schumacher V,
    2. Gueler B,
    3. Looijenga LH,
    4. Becker JU,
    5. Amann K,
    6. Engers R,
    7. et al.
    Characteristics of testicular dysgenesis syndrome and decreased expression of SRY and SOX9 in Frasier syndrome. Mol Reprod Dev 2008;75:1484–94.
    OpenUrlCrossRefPubMed
  9. 9.↵
    1. Love JD,
    2. DeMartini SD,
    3. Coppola CP
    . Prophylactic bilateral salpingo-oopherectomy in a 17-year-old with Frasier syndrome reveals gonadoblastoma and seminoma: a case report. J Pediatr Surg 2006;41:e1–4.
    OpenUrlPubMed
  10. 10.↵
    1. Denamur E,
    2. Bocquet N,
    3. Mougenot B,
    4. Da Silva F,
    5. Martinat L,
    6. Loirat C,
    7. et al.
    Mother-to-child transmitted WT1 splice-site mutation is responsible for distinct glomerular diseases. J Am Soc Nephrol 1999;10:2219–23.
    OpenUrlAbstract/FREE Full Text
  11. 11.↵
    1. Joki-Erkkila MM,
    2. Karikoski R,
    3. Rantala I,
    4. Lenko HL,
    5. Visakorpi T,
    6. Heinonen PK
    . Gonadoblastoma and dysgerminoma associated with XY gonadal dysgenesis in an adolescent with chronic renal failure: a case of Frasier syndrome. J Pediatr Adolesc Gynecol 2002;15:145–9.
    OpenUrlCrossRefPubMed
  12. 12.↵
    1. Kohsaka T,
    2. Tagawa M,
    3. Takekoshi Y,
    4. Yanagisawa H,
    5. Tadokoro K,
    6. Yamada M
    . Exon 9 mutations in the WT1 gene, without influencing KTS splice isoforms, are also responsible for Frasier syndrome. Hum Mutat 1999;14:466–70.
    OpenUrlCrossRefPubMed
  13. 13.↵
    1. Reznik VM,
    2. Mendoza SA,
    3. Freidenberg GR
    . Evaluation of delayed puberty in the female adolescent with chronic renal failure. Pediatr Nephrol 1993;7:551–3.
    OpenUrlCrossRefPubMed
  14. 14.↵
    1. Bailey WA,
    2. Zwingman TA,
    3. Reznik VM,
    4. Griswold WR,
    5. Mendoza SA,
    6. Jones KL,
    7. et al.
    End-stage renal disease and primary hypogonadism associated with a 46,XX karyotype. Am J Dis Child 1992;146:1218–23.
    OpenUrlCrossRefPubMed
  15. 15.↵
    1. Page DC
    . Hypothesis: a Y-chromosomal gene causes gonadoblastoma in dysgenetic gonads. Development 1987;101 Suppl:151–5.
    OpenUrlAbstract/FREE Full Text
  16. 16.↵
    1. Tsuchiya K,
    2. Reijo R,
    3. Page DC,
    4. Disteche CM
    . Gonadoblastoma: molecular definition of the susceptibility region on the Y chromosome. Am J Hum Genet 1995;57:1400–7.
    OpenUrlPubMed
  17. 17.↵
    1. Koziell A,
    2. Charmandari E,
    3. Hindmarsh PC,
    4. Rees L,
    5. Scambler P,
    6. Brook CG
    . Frasier syndrome, part of the Denys Drash continuum or simply a WT1 gene associated disorder of intersex and nephropathy? Clin Endocrinol 2000;52:519–24.
    OpenUrlCrossRefPubMed
  18. 18.↵
    1. Okuhara K,
    2. Tajima S,
    3. Nakae J,
    4. Sasaki S,
    5. Tochimaru H,
    6. Abe S,
    7. et al.
    A Japanese case with Frasier syndrome caused by the splice junction mutation of WT1 gene. Endocr J 1999;46:639–42.
    OpenUrlCrossRefPubMed
  19. 19.↵
    1. Frasier SD,
    2. Bashore RA,
    3. Mosier HD
    . Gonadoblastoma associated with pure gonadal dysgenesis in monozygous twins. J Pediatr 1964;64:740–5.
    OpenUrlCrossRefPubMed
  20. 20.↵
    1. Mestrallet G,
    2. Bertholet-Thomas A,
    3. Ranchin B,
    4. Bouvier R,
    5. Frappaz D,
    6. Cochat P
    . Recurrence of a dysgerminoma in Frasier syndrome. Pediatr Transplant 2011;15:e53–5.
    OpenUrlCrossRefPubMed
  21. 21.↵
    1. Subbiah V,
    2. Huff V,
    3. Wolff JE,
    4. Ketonen L,
    5. Lang FF Jr.,
    6. Stewart J,
    7. et al.
    Bilateral gonadoblastoma with dysgerminoma and pilocytic astrocytoma with WT1 GT-IVS9 mutation: a 46 XY phenotypic female with Frasier syndrome. Pediatr Blood Cancer 2009;53:1349–51.
    OpenUrlCrossRefPubMed
  22. 22.↵
    1. Shimoyama H,
    2. Nakajima M,
    3. Naka H,
    4. Park YD,
    5. Hori K,
    6. Morikawa H,
    7. et al.
    A girl with bilateral ovarian tumours: Frasier syndrome. Eur J Pediatr 2002;161:81–3.
    OpenUrlCrossRefPubMed
  23. 23.↵
    1. Kitsiou-Tzeli S,
    2. Deligiorgi M,
    3. Malaktari-Skarantavou S,
    4. Vlachopoulos C,
    5. Megremis S,
    6. Fylaktou I,
    7. et al.
    Sertoli cell tumor and gonadoblastoma in an untreated 29-year-old 46,XY phenotypic male with Frasier syndrome carrying a WT1 IVS9+4C>T mutation. Hormones 2012;11:361–7.
    OpenUrlCrossRefPubMed
  24. 24.↵
    1. Yang Y,
    2. Feng D,
    3. Huang J,
    4. Nie X,
    5. Yu Z
    . A child with isolated nephrotic syndrome and WT1 mutation presenting as a 46, XY phenotypic male. Eur J Pediatr 2013;172:127–9.
    OpenUrlCrossRefPubMed
  25. 25.↵
    1. Chan WK,
    2. To KF,
    3. But WM,
    4. Lee KW
    . Frasier syndrome: a rare cause of delayed puberty. Hong Kong Med J 2006;12:225–7.
    OpenUrlPubMed
  26. 26.↵
    1. Tajima T,
    2. Sasaki S,
    3. Tanaka Y,
    4. Kusunoki H,
    5. Nagashima T,
    6. Nonomura K,
    7. et al.
    46,XY phenotypic male with focal segmental glomerulosclerosis caused by the WT1 splice site mutation. Horm Res 2003;60:302–5.
    OpenUrlCrossRefPubMed
  27. 27.↵
    1. Melo KF,
    2. Martin RM,
    3. Costa EM,
    4. Carvalho FM,
    5. Jorge AA,
    6. Arnhold IJ,
    7. et al.
    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. J Clin Endocrinol Metab 2002;87:2500–5.
    OpenUrlCrossRefPubMed
  28. 28.↵
    1. Denamur E,
    2. Bocquet N,
    3. Baudouin V,
    4. Da Silva F,
    5. Veitia R,
    6. Peuchmaur M,
    7. et al.
    WT1 splice-site mutations are rarely associated with primary steroid-resistant focal and segmental glomerulosclerosis. Kidney Int 2000;57:1868–72.
    OpenUrlCrossRefPubMed
  29. 29.↵
    1. Demmer L,
    2. Primack W,
    3. Loik V,
    4. Brown R,
    5. Therville N,
    6. McElreavey K
    . Frasier syndrome: a cause of focal segmental glomerulosclerosis in a 46,XX female. J Am Soc Nephrol 1999;10:2215–8.
    OpenUrlAbstract/FREE Full Text
  30. 30.↵
    1. Kanemoto K,
    2. Ishikura K,
    3. Ariyasu D,
    4. Hamasaki Y,
    5. Hataya H,
    6. Hasegawa Y,
    7. et al.
    WT1 intron 9 splice acceptor site mutation in a 46,XY male with focal segmental glomerulosclerosis. Pediatr Nephrol 2007;22:454–8.
    OpenUrlCrossRefPubMed
  31. 31.↵
    1. Yang YH,
    2. Zhao F,
    3. Feng DN,
    4. Wang JJ,
    5. Wang CF,
    6. Huang J,
    7. et al.
    Wilms' tumor suppressor gene mutations in girls with sporadic isolated steroid-resistant nephrotic syndrome. Genet Mol Res 2013;12:6184–91.
    OpenUrlCrossRefPubMed
  32. 32.↵
    1. Fujita S,
    2. Sugimoto K,
    3. Miyazawa T,
    4. Yanagida H,
    5. Tabata N,
    6. Okada M,
    7. et al.
    A female infant with Frasier syndrome showing splice site mutation in Wilms' tumor gene (WT1) intron 9. Clin Nephrol 2010;73:487–91.
    OpenUrlCrossRefPubMed
  33. 33.↵
    1. Ismaili K,
    2. Verdure V,
    3. Vandenhoute K,
    4. Janssen F,
    5. Hall M
    . WT1 gene mutations in three girls with nephrotic syndrome. Eur J Pediatr 2008;167:579–81.
    OpenUrlCrossRefPubMed
  34. 34.↵
    1. Aucella F,
    2. Bisceglia L,
    3. De Bonis P,
    4. Gigante M,
    5. Caridi G,
    6. Barbano G,
    7. et al.
    WT1 mutations in nephrotic syndrome revisited. High prevalence in young girls, associations and renal phenotypes. Pediatr Nephrol 2006;21:1393–8.
    OpenUrlCrossRefPubMed
  35. 35.↵
    1. Chak WL,
    2. To KF,
    3. Cheng YL,
    4. Tsui KM,
    5. Lo KL,
    6. Tong HM,
    7. et al.
    Gonadal mosaicism of Frasier syndrome in 3 Chinese siblings with donor splice site mutation of Wilms' tumour gene. Nephron 2002;91:526–9.
    OpenUrlCrossRefPubMed
  36. 36.↵
    1. Jeanpierre C,
    2. Denamur E,
    3. Henry I,
    4. Cabanis MO,
    5. Luce S,
    6. Cecille A,
    7. et al.
    Identification of constitutional WT1 mutations, in patients with isolated diffuse mesangial sclerosis, and analysis of genotype/phenotype correlations by use of a computerized mutation database. Am J Hum Genet 1998;62:824–33.
    OpenUrlCrossRefPubMed
  37. 37.↵
    1. Esin S,
    2. Baser E,
    3. Kucukozkan T,
    4. Magden HA
    . Ovarian gonadoblastoma with dysgerminoma in a 15-year-old girl with 46, XX karyotype: case report and review of the literature. Arch Gynecol Obstet 2012;285:447–51.
    OpenUrlCrossRefPubMed
  38. 38.↵
    1. Kanagal DV,
    2. Prasad K,
    3. Rajesh A,
    4. Kumar RG,
    5. Cherian S,
    6. Shetty H,
    7. et al.
    Ovarian Gonadoblastoma with Dysgerminoma in a Young Girl with 46, XX Karyotype: a Case Report. J Clin Diagn Res 2013;7:2021–2.
    OpenUrlPubMed
  39. 39.↵
    1. Santin S,
    2. Bullich G,
    3. Tazon-Vega B,
    4. Garcia-Maset R,
    5. Gimenez I,
    6. Silva I,
    7. et al.
    Clinical utility of genetic testing in children and adults with steroid-resistant nephrotic syndrome. Clin J Am Soc Nephrol 2011;6:1139–48.
    OpenUrlAbstract/FREE Full Text
View Abstract
PreviousNext
Back to top
Cancer Prevention Research: 8 (4)
April 2015
Volume 8, Issue 4
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover

Sign up for alerts

View this article with LENS

Open full page PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Cancer Prevention Research article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
Gonadal Tumor in Frasier Syndrome: A Review and Classification
(Your Name) has forwarded a page to you from Cancer Prevention Research
(Your Name) thought you would be interested in this article in Cancer Prevention Research.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Gonadal Tumor in Frasier Syndrome: A Review and Classification
Jiro Ezaki, Kazunori Hashimoto, Tatsuo Asano, Shoichiro Kanda, Yuko Akioka, Motoshi Hattori, Tomoko Yamamoto and Noriyuki Shibata
Cancer Prev Res April 1 2015 (8) (4) 271-276; DOI: 10.1158/1940-6207.CAPR-14-0415

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
Gonadal Tumor in Frasier Syndrome: A Review and Classification
Jiro Ezaki, Kazunori Hashimoto, Tatsuo Asano, Shoichiro Kanda, Yuko Akioka, Motoshi Hattori, Tomoko Yamamoto and Noriyuki Shibata
Cancer Prev Res April 1 2015 (8) (4) 271-276; DOI: 10.1158/1940-6207.CAPR-14-0415
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Introduction
    • Literature Review and Classification of Frasier Syndrome
    • Discussion
    • Disclosure of Potential Conflicts of Interest
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • PDF
Advertisement

Related Articles

Cited By...

More in this TOC Section

  • Immune Responses and Triple-negative Breast Cancer
  • Anticancer Pharmacology of WA in Breast Cancer
  • OPSCC Is Now the Most Common HPV-associated Cancer
Show more Review
  • Home
  • Alerts
  • Feedback
  • Privacy Policy
Facebook   Twitter   LinkedIn   YouTube   RSS

Articles

  • Online First
  • Current Issue
  • Past Issues

Info for

  • Authors
  • Subscribers
  • Advertisers
  • Librarians

About Cancer Prevention Research

  • About the Journal
  • Editorial Board
  • Permissions
  • Submit a Manuscript
AACR logo

Copyright © 2021 by the American Association for Cancer Research.

Cancer Prevention Research
eISSN: 1940-6215
ISSN: 1940-6207

Advertisement