Frasier syndrome: four new cases with unusual presentations

Abstract

SUMMARYFrasier syndrome (FS) is characterized by gonadal dysgenesis and nephropathy. It is caused by specific mutations in the Wilms' tumor suppressor gene (WT1) located in 11p23. Patients with the 46,XY karyotype present normal female genitalia with streak gonads, and have higher risk of gonadal tumor, mainly, gonadoblastoma. Therefore, elective bilateral gonadectomy is indicated. Nephropathy in FS consists in nephrotic syndrome (NS) with proteinuria that begins early in childhood and progressively increases with age, mainly due to nonspecific focal and segmental glomerular sclerosis (FSGS). Patients are generally unresponsive to steroid and immunosuppressive therapies, and will develop end-stage renal failure (ESRF) during the second or third decade of life. We report here four cases of FS diagnosis after identification of WT1 mutations. Case 1 was part of a large cohort of patients diagnosed with steroid-resistant nephrotic syndrome, in whom the screening for mutations within WT1 8-9 hotspot fragment identified the IVS9+5G>A mutation. Beside FS, this patient showed unusual characteristics, such as urinary malformation (horseshoe kidney), and bilateral dysgerminoma. Cases 2 and 3, also bearing the IVS9+5G>A mutation, and case 4, with IVS9+1G>A mutation, were studied due to FSGS and/or delayed puberty; additionally, patients 2 and 4 developed bilateral gonadal tumors. Since the great majority of FS patients have normal female external genitalia, sex reversal is not suspected before they present delayed puberty and/or primary amenorrhea. Therefore, molecular screening of WT1 gene is very important to confirm the FS diagnosis. Arq Bras Endocrinol Metab. 2012;56(8):525-32 SUMÁRIO A síndrome de Frasier (SF), caracterizada por disgenesia gonadal e nefropatia, é causada por mutações específicas no gene supressor do tumor de Wilms (WT1) localizado em 11p23. Pacientes com cariótipo 46,XY apresentam genitália feminina normal com gônadas disgenéticas e alto risco de tumor gonadal, principalmente o gonadoblastoma. Por isso, a gonadectomia bilateral eletiva está indicada. A nefropatia na SF consiste de síndrome nefrótica com proteinúria que se inicia na infância e aumenta progressivamente com a idade, principalmente devido à glomeruloesclerose focal e segmentar (GESF). Esses pacientes não respondem ao tratamento com esteroides e imunossupressores e desenvolverão insuficiência renal crônica durante a segunda ou terceira década de vida. Neste trabalho, são relatados quatro casos de SF cujo diagnóstico foi definido após o rastreamento molecular do gene WT1. O caso 1 faz parte de um grande grupo de pacientes que tiveram diagnóstico de síndrome nefrótica corticorresistente e no qual o rastreamento de mutações no fragmento 8-9 do gene WT1 identificou a mutação IVS9+5G>A. Além da SF, essa paciente apresentou características incomuns, tais como malformação urinária (rins em ferradura) e disgerminoma bilateral. Os casos 2 e 3 também apresentaram a mutação IVS9+5G>A, e, no caso 4, foi identificada a mutação IVS9+1G>A, sendo que esse...

Gonadal Tumor in Frasier Syndrome: A Review and Classification

“…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).…”

“…Two major WT1 isoforms are produced by alternative splicing of the lysine-threonine-serine (KTS) domain, including an insertion (þKTS) or deletion (ÀKTS; ref. 3). The þKTS 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).…”

“…3). The þKTS 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.…”

“…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.…”