Atlas of Genetics and Cytogenetics in Oncology and Haematology


Home   Genes   Leukemias   Solid Tumours   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

X Y 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 NA
 

Frasier syndrome (FS)

Identity

Inheritance Sporadic occurrence, with possible cases of autosomal dominant inheritance

Clinics

Phenotype and clinics
  • Clinical presentation usually occurs between 2nd and 3rd decades; most cases at puberty.
    - Exceptional cases in younger children; youngest example at 6 months of age.
  • Male pseudohermaphroditism; phenotypically female patients presenting with amenorrhea.
    - XY karyotype:
    - Streak (dysgenetic) gonads with gonadoblastoma.
    - Normal external female genitalia; clitoris enlargement and ambiguous genitalia may be present.
    - Small uterus (often with an inactive/atrophic endometrium) and fallopian tubes.
  • Nephrotic syndrome with slowly progressing renal disease, resulting in end-stage renal failure.
    - Focal and segmental glomerulosclerosis; in later stages of renal disease, only chronic, nonspecific findings may be present in kidney biopsy.
  • XX karyotype: patients with less severe phenotype, frequently not clinically identified as FS.
    - Normal and functioning female genitalia.
    - Clinically present only with renal disease.
  •  
     
      Figure 1. Surgical appearance of the internal genitalia in a patient with Frasier syndrome. A) Small but normally shaped uterus. B) A streak gonad is seen at the tip of the surgical instrument (courtesy of Dr. Masoud Azodi, Yale University School of Medicine). Figure 2. A-B: Kidney biopsy showing focal and segmental glomerulosclerosis (FSGS). A: Masson trichrome stain (400X). B: Semi-thin section stained with toluidine blue (400X). C-D: Gonadectomy specimens. C: Streak gonad with gonadoblastoma (H&E 40X). D: Gonadoblastoma nodule displaying Call-Exner body-like structures, surrounded by Leydig-like cells (H&E 200X). E-F: Histological aspect of dysgerminoma arising in gonadoblastoma. E: Gonadectomy specimen showing both, gonadoblastoma and dysgerminoma (H&E 100X). F: Peritoneal metastasis of dysgerminoma (H&E 200X).
    Neoplastic risk Gonadoblastomas are present in virtually all XY patients; usually bilateral.
    Germ cell tumors (dysgerminomas) may arise from gonadoblastoma within dysgenetic gonads.
    Wilms tumors are exceptional, and in these cases the diagnosis of FS is controversial (differential diagnosis with Denys-Drash syndrome; vide infra).
    Treatment Prophylactic bilateral gonadectomy (may be laparoscopic if there is no evidence of overgrowth by a germ cell tumor); hysterectomy is not necessary.
    The renal disease is usually steroid-resistant, requiring dialysis and renal transplantation.
    Chemotherapy may be needed in cases with germ cell tumors.
    In XY patients, menstruation can be induced with cyclic hormone replacement therapy; there are reported cases of successful pregnancy following in vitro fertilization procedures in these patients.
    Evolution The end-stage renal disease is usually the major cause of morbidity in FS patients. The focal and segmental glomerulosclerosis progresses slowly (often for more than 10 years) and leads to terminal renal failure, requiring dialysis therapy and renal transplantation which can result in complications and increased morbidity. There are limited data regarding the clinical outcome after renal transplantation in these patients. The occurrence of germ cell neoplasia in FS patients can affect their prognosis. However, there is no evidence that FS-associated germ cell tumors have a different clinical outcome in comparison with sporadic tumors.

    Genes involved and Proteins

     
    Gene NameWT1 (Wilms Tumor 1)
    Location 11p13
    DNA/RNA
    Description 10 exons; spans approximately 50 kb. Encodes 4 zinc finger domains.
    Transcription Alternative splicing in two different sites (exons 5 and 9) leads to variable insertion of exon 5 and/or insertion of 9 nucleotides in exon 9, resulting in transcription of four different isoforms.
    Protein
    Description Transcription factor: contains 4 zinc finger domains.
    Four different isoforms, ranging from 52 to 54 kDa (429-449 aminoacids).
    Alternative splicing in exon 9: variable insertion of aminoacids lysine (K), threonine (T) and serine (S) between 3rd and 4th zinc fingers results in either +KTS or -KTS isoforms.
    Expression During embryonal life, the WT1 protein is mainly expressed in the metanephros and developing kidney, gonadal ridges, coelomic surfaces, heart, spleen, liver, thymus, uterus and muscles of the abdominal wall.
    An adequate ratio of +KTS/-KTS expression is essential for the wild type function of WT1.
    Localisation Nuclear (transcription factor function).
    Function WT1 functions mainly as a transcription factor, with many different downstream target genes; a post-transcriptional regulatory function of some target mRNAs has been also proposed.
    In mammalian embryos, expression of the -KTS isoform induces gonadal ridge formation through proliferation of the coelomic epithelium, resulting in the bipotential gonad.
    In XY individuals, expression of the +KTS isoform will activate the transcription of the SRY gene located on Y chromosome, which induces the expression of anti-mYllerian hormone by the developing Sertoli cells. Expression of the anti-mYllerian hormone in the developing testis results in formation of seminiferous cords, allowing sex-specific gonadal development, and regression of mYllerian structures (which give rise to the female genitalia).
    During early kidney development in mammal embryos, the -KTS isoform promotes proliferation of the primordial mesenchyme, epithelial-mesenchymal interactions and ureteric bud branching. In later phases of kidney development, expression of +KTS leads to differentiation of podocytes and glomerular capillaries.
    Mutations
    Note Most of the WT1 gene mutations in FS are located in positions 2, 4, 5 or 6 of the second splice donor site in intron 9.
    These mutations lead to a decrease in the +KTS isoform, affecting the zinc fingers' DNA binding affinity.
    A decrease in +KTS is in keeping with the phenotype observed in FS, in which there seems to be a defect in antimüllerian hormone expression resulting in abnormal genital development in XY individuals. Also, defective expression of this isoform could explain the glomerular lesion observed in FS.

    To be noted

    The classical clinical picture of FS is that of a phenotypically female adolescent patient presenting with either amenorrhea or nephrotic syndrome, or both. However, the clinical presentation may be atypical, with cases occurring at earlier ages or in XX patients, resulting in the presence of only renal disease. These atypical cases must be differentiated from sporadic forms of nephrotic syndrome, and from other entities such as Denys-Drash syndrome (DDS), which is also related to WT1 mutations but features rapidly progressive renal disease at earlier ages. It is important to establish a differential diagnosis between FS and DDS, since they carry different tumor risks requiring specific clinical management: while in FS there is an increased risk for the development of gonadal neoplasms, in DDS there is an increased risk for the development of Wilms tumors; while FS mutations affect a splice site in intron 9, DDS results from missense mutations in exons 8 and 9 of WT1. In these atypical cases, molecular analysis may be of extreme importance to reveal the specific genetic defect in the WT1 gene, allowing an accurate diagnosis.

    External links

    OrphanetFrasier syndrome

    Bibliography

    GONADOBLASTOMA ASSOCIATED WITH PURE GONADAL DYSGENESIS IN MONOZYGOUS TWINS.
    FRASIER SD, BASHORE RA, MOSIER HD
    The Journal of pediatrics. 1964 ; 64 : 740-745.
    PMID 14149008
     
    Chronic renal failure and XY gonadal dysgenesis: Frasier syndrome--a commentary on reported cases.
    Moorthy AV, Chesney RW, Lubinsky M
    American journal of medical genetics. Supplement. 1987 ; 3 : 297-302.
    PMID 3130865
     
    Alternative splicing and genomic structure of the Wilms tumor gene WT1.
    Haber DA, Sohn RL, Buckler AJ, Pelletier J, Call KM, Housman DE
    Proceedings of the National Academy of Sciences of the United States of America. 1991 ; 88 (21) : 9618-9622.
    PMID 1658787
     
    Donor splice-site mutations in WT1 are responsible for Frasier syndrome.
    Barbaux S, Niaudet P, Gubler MC, Grł║nfeld JP, Jaubert F, Kuttenn F, Fłękłętłę CN, Souleyreau-Therville N, Thibaud E, Fellous M, McElreavey K
    Nature genetics. 1997 ; 17 (4) : 467-470.
    PMID 9398852
     
    Frasier syndrome is caused by defective alternative splicing of WT1 leading to an altered ratio of WT1 +/-KTS splice isoforms.
    Klamt B, Koziell A, Poulat F, Wieacker P, Scambler P, Berta P, Gessler M
    Human molecular genetics. 1998 ; 7 (4) : 709-714.
    PMID 9499425
     
    Frasier syndrome: a cause of focal segmental glomerulosclerosis in a 46,XX female.
    Demmer L, Primack W, Loik V, Brown R, Therville N, McElreavey K
    Journal of the American Society of Nephrology : JASN. 1999 ; 10 (10) : 2215-2218.
    PMID 10505699
     
    Wilms' tumor suppressor gene WT1: from structure to renal pathophysiologic features.
    Mrowka C, Schedl A
    Journal of the American Society of Nephrology : JASN. 2000 ; 11 Suppl 16 : S106-S115.
    PMID 11065340
     
    WT1 proteins: functions in growth and differentiation.
    Scharnhorst V, van der Eb AJ, Jochemsen AG
    Gene. 2001 ; 273 (2) : 141-161.
    PMID 11595161
     
    Surgical management and genotype/phenotype correlations in WT1 gene-related diseases (Drash, Frasier syndromes).
    Auber F, Lortat-Jacob S, Sarnacki S, Jaubert F, Salomon R, Thibaud E, Jeanpierre C, Nihoul-Fłękłętłę C
    Journal of pediatric surgery. 2003 ; 38 (1) : 124-129.
    PMID 12592634
     
    One tissue, two fates: molecular genetic events that underlie testis versus ovary development.
    Brennan J, Capel B
    Nature reviews. Genetics. 2004 ; 5 (7) : 509-521.
    PMID 15211353
     
    Successful pregnancy in a gonadectomized woman with 46,XY gonadal dysgenesis and gonadoblastoma.
    Chen MJ, Yang JH, Mao TL, Ho HN, Yang YS
    Fertility and sterility. 2005 ; 84 (1) : page 217.
    PMID 16009184
     
    Wilms' tumour: connecting tumorigenesis and organ development in the kidney.
    Rivera MN, Haber DA
    Nature reviews. Cancer. 2005 ; 5 (9) : 699-712.
    PMID 16110318
     
    Frasier syndrome comes full circle: genetic studies performed in an original patient.
    Wang NJ, Song HR, Schanen NC, Litman NL, Frasier SD
    The Journal of pediatrics. 2005 ; 146 (6) : 843-844.
    PMID 15973330
     
    EXPANDING THE CLINICAL SPECTRUM OF FRASIER SYNDROME.
    Gwin K, Cajaiba M, Caminoa-Lizarralde A, Picazo M, Nistal M, Reyes-Młćgica M
    Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society. 2007 : page 1.
    PMID 17378674
     
    REVIEW articlesautomatic search in PubMed
    Last year articlesautomatic search in PubMed

    Contributor(s)

    Written05-2007Mariana M Cajaiba, Miguel Reyes-Múgica
    Program of Pediatric and Developmental Pathology, Yale University School of Medicine, 430 Congress Avenue, New Haven, CT 06520-8023, USA (MR-M)

    Citation

    This paper should be referenced as such :
    Cajaiba, MM ; Reyes-Múgica, M
    Frasier syndrome (FS)
    Atlas Genet Cytogenet Oncol Haematol. 2008;12(1):81-84.
    Free online version   Free pdf version   [Bibliographic record ]
    URL : http://AtlasGeneticsOncology.org/Kprones/FrasierID10035.html

    © Atlas of Genetics and Cytogenetics in Oncology and Haematology
    indexed on : Tue Aug 26 15:56:11 CEST 2014


    Home   Genes   Leukemias   Solid Tumours   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

    For comments and suggestions or contributions, please contact us

    jlhuret@AtlasGeneticsOncology.org.