Frasier syndrome

Definition: Frasier syndrome is a rare disorder defined by gonadal dysgenesis, male pseudohermaphroditism and progressive glomerulopathy. It is caused by mutations in the donor splice site in intron 9 of the WT1 gene.

The occurrence of symptoms is associated with a decrease in the ratio of the lysine-threonine-serine (+/- KTS) isoform of the WT1 protein.

Mutations in the WT1 gene are present in children with Frasier syndrome, Denys-Drash syndrome, WAGR syndrome, and some cases of Wilms tumor.

WT1 is necessary for normal urogenital development.

Frasier syndrome is an association between focal segmental glomerulosclerosis, beginning in the second and third decade, male to female sex reversal, and dysgenetic gonads.

Early prophylactic resection of dysgenetic gonads is indicated in children with Frasier syndrome to prevent the development of germ cell malignancy.

Synopsis

 46,XY male to female sex reversal (46,XY phenotypic female)

• male pseudohermaphroditism with retentio testis
• hypoplastic uterus
• cord-like gonadal structures
• gonadal dysgenesis (dysgenetic gonads)
• foci of gonadoblastoma in dysgenetic gonads
• hypospadias
• cryptorchidism

 in females

• atrophic ovaries

 nephrotic syndrome

• diffuse mesangial sclerosis
• nonspecific focal and segmental glomerulosclerosis (FSGS)

 tumoral predisposition

• gonadoblastoma in situ
• early gonadoblastoma (17101338, 20419325, 19653292)
• bilateraal gonadoblastoma (19653292)
• seminoma/dysgerminoma (17101338, 20408995, 19653292)

Etiology

 constitutional mutations in the WT1 gene

• donor splice site heterozygous mutations in intron 9
• donor site mutation IVS9+5G>A of the splice site in the intron 9
• The ratio of +/-KTS splice variants of the Wilms’ tumour suppressor protein WT1 mRNA is determined by an intronic enhancer. (18756326)

See also

 Denys-Drash syndrome

References

 A female infant with Frasier syndrome showing splice site mutation in Wilms’ tumor gene (WT1) intron 9. Fujita S, Sugimoto K, Miyazawa T, Yanagida H, Tabata N, Okada M, Takemura T. Clin Nephrol. 2010 Jun;73(6):487-91.PMID: 20497763

 Frasier syndrome: early gonadoblastoma and cyclosporine responsiveness. Sinha A, Sharma S, Gulati A, Sharma A, Agarwala S, Hari P, Bagga A. Pediatr Nephrol. 2010 Oct;25(10):2171-4. PMID: 20419325

 Recurrence of a dysgerminoma in Frasier syndrome. Mestrallet G, Bertholet-Thomas A, Ranchin B, Bouvier R, Frappaz D, Cochat P. Pediatr Transplant. 2010 Apr 8. PMID: 20408995

 Bilateral gonadoblastoma with dysgerminoma and pilocytic astrocytoma with WT1 GT-IVS9 mutation: A 46 XY phenotypic female with Frasier syndrome. Subbiah V, Huff V, Wolff JE, Ketonen L, Lang FF Jr, Stewart J, Langford L, Herzog CE. Pediatr Blood Cancer. 2009 Dec 15;53(7):1349-51. PMID: 19653292

 Characteristics of testicular dysgenesis syndrome and decreased expression of SRY and SOX9 in Frasier syndrome. Schumacher V, Gueler B, Looijenga LH, Becker JU, Amann K, Engers R, Dotsch J, Stoop H, Schulz W, Royer-Pokora B. Mol Reprod Dev. 2008 Sep;75(9):1484-94.PMID: 18271004

 Management of Wilms tumors in Drash and Frasier syndromes. Auber F, Jeanpierre C, Denamur E, Jaubert F, Schleiermacher G, Patte C, Cabrol S, Leverger G, Nihoul-Fékété C, Sarnacki S. Pediatr Blood Cancer. 2009 Jan;52(1):55-9. PMID: 18816692

 The ratio of +/-KTS splice variants of the Wilms’ tumour suppressor protein WT1 mRNA is determined by an intronic enhancer. Yang C, Romaniuk PJ. Biochem Cell Biol. 2008 Aug;86(4):312-21. PMID: 18756326

 Expanding the clinical spectrum of Frasier syndrome. Gwin K, Cajaiba M, Caminoa-Lizarralde A, Picazo M, Nistal M, Reyes-Mugica M. Pediatr Dev Pathol. 2007 Mar 22:1 PMID: 17378674

 Prophylactic bilateral salpingo-oopherectomy in a 17-year-old with Frasier syndrome reveals gonadoblastoma and seminoma: a case report. Love JD, DeMartini SD, Coppola CP. J Pediatr Surg. 2006 Nov;41(11):e1-4. PMID: 17101338

 The same mutation affecting the splicing of WT1 gene is present on Frasier syndrome patients with or without Wilms’ tumor. Barbosa AS, Hadjiathanasiou CG, Theodoridis C, Papathanasiou A, Tar A, Merksz M, Gyorvari B, Sultan C, Dumas R, Jaubert F, Niaudet P, Moreira-Filho CA, Cotinot C, Fellous M. Hum Mutat. 1999;13(2):146-53. PMID: #10094551

 Donor splice-site mutations in WT1 are responsible for Frasier syndrome. Barbaux S, Niaudet P, Gubler MC, Grunfeld JP, Jaubert F, Kuttenn F, Fekete CN, Souleyreau-Therville N, Thibaud E, Fellous M, McElreavey K. Nat Genet. 1997 Dec;17(4):467-70. PMID: 9398852