Lack of Puberty Despite Elevated Estradiol in a 46,XY Phenotypic Female with Frasier Syndrome

Miyoshi, Yoko; Santo, Yoko; Tachikawa, Kanako; Namba, Noriyuki; Hirai, Haruhiko; Mushiake, Sotaro; Nakajima, Shigeo; Michigami, Toshimi; Ozono, Keiichi

doi:10.1507/endocrj.k05-180

Cited by 9 publications

(10 citation statements)

References 18 publications

(17 reference statements)

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“…The IVS9+1G>A mutation, identified in case 4, was described for the first time in a FS patient by Myioshi and cols. (12). Intron 9 splice mutations affect the KTS(+) isoform production and impair the 2:1 ratio for KTS(+) and KTS(-) isoforms, respectively, which are important for the normal development of the glomerular podocytes and for male sex determination (13).…”

Section: Discussionmentioning

confidence: 99%

Frasier syndrome: four new cases with unusual presentations

Guaragna

Lutaif

Bittencourt

et al. 2012

Arq Bras Endocrinol Metab

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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...

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Section: Discussionmentioning

confidence: 99%

Frasier syndrome: four new cases with unusual presentations

Guaragna

Lutaif

Bittencourt

et al. 2012

Arq Bras Endocrinol Metab

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“…Here, we applied a massively parallel splicing assay to systematically test the effects of every single-nucleotide variant in and near WT1 exon 9, a hotspot of pathogenic variants for multiple genetic forms of nephrotic syndrome including Frasier Syndrome. The resulting splicing effect map correctly identified all seven known FS variants [8][9][10][11]13 as associated with reduced KTS+/KTS-ratio, along with another variant reported to cause isolated steroid resistant NS and FSGS. 12 By contrast, all but one of the 36 tested variants which appear in the ClinVar database with a Likely benign interpretation, or the general healthy population database gnomAD, scored as splice-neutral, indicating this assay is highly sensitive and specific for identification of pathogenic WT1 exon 9 splice disruption.…”

Section: Discussionmentioning

confidence: 91%

“…We focused first on the eight known FS/FSGS variants as described in the ClinVar database or published case reports. [8][9][10][11][12][13] All eight dramatically lowered the KTS+:KTS-balance, as quantified by log2(KTS+/KTS-) scores of -2.21 or lower (Figure 1D, E; Table 1). By contrast, our assay scored as neutral in all but one of the 19 variants listed in ClinVar with an interpretation of Likely Benign, as well as an additional 17 variants observed in the population database gnomAD (log2 ratio scores between -0.11 and 0.53; Figure 1E, Supplemental Table 2).…”

Section: Identification Of Known and Novel Variants Disrupting Kts+ U...mentioning

confidence: 98%

“…[7][8][9] Currently, eight variants downstream of the KTS+ splice donor are known to cause FS or focal segmental glomerulosclerosis (FSGS). [8][9][10][11][12][13] It remains unclear if other nearby variants are similarly splice disruptive. Accurate computational prediction of variants' splicing effects remains challenging, so we devised a massively parallel splice assay 14 to measure the splicing effects of every possible single nucleotide variant (SNV) in or near WT1 exon 9 and the flanking introns (N=519 variants).…”

Section: Introductionmentioning

confidence: 99%

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High-throughput splicing assays identify known and novelWT1exon 9 variants in nephrotic syndrome

Smith

Burugula

Dunn

et al. 2023

Preprint

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Frasier Syndrome (FS) is a rare Mendelian form of nephrotic syndrome caused by variants which disrupt the proper splicing of WT1. This key transcription factor gene is alternatively spliced at exon 9 to produce two isoforms ("KTS+" and "KTS-"), which are normally expressed in the kidney at a ~2:1 (KTS+:KTS-) ratio. FS results from variants that reduce this ratio by disrupting the splice donor of the KTS+ isoform. FS is extremely rare, and it is unclear whether any variants beyond the eight already known could cause FS. To prospectively identify other splicing-disruptive variants, we leveraged a massively parallel splicing assay. We tested every possible single nucleotide variant (n=519) in and around WT1 exon 9 for effects upon exon inclusion and KTS+/- ratio. Splice disruptive variants made up 11% of the tested point variants overall, and were tightly concentrated near the canonical acceptor and the KTS+/- alternate donors. Our map successfully identified all eight known FS or focal segmental glomerulosclerosis variants and 16 additional novel variants which were comparably disruptive to these known pathogenic variants. We also identified 19 variants that, conversely, increased the KTS+/KTS- ratio, of which two are observed in unrelated individuals with 46,XX ovotesticular disorder of sex development (46,XX OTDSD). This splicing effect map can serve as functional evidence to guide the clinical interpretation of newly observed variants in and around WT1 exon 9.

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“…It is caused by splice donor site variants in intron 9 of the Wilms’ tumor 1 ( WT1 [NM_024426.6]) gene, with 6 variants identified thus far (c.1432+1 G>A, c.1432+2 T>C, c.1432+4 C>T, c.1432+5 G>A, c.1432+5 G>T, and c.1432+6 T>A). 1 , 2 , 3 , 4 WT1 is composed of 10 exons and encodes a transcription factor with 4 zinc finger motifs; this transcription factor plays an important role in early gonadal and renal development by regulating the sex-determining region Y. 5 , 6 Two active splice donor sites of intron 9 result in a mixture of 2 transcripts with or without 3 amino acids (+KTS or −KTS) between zinc fingers 3 and 4.…”

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confidence: 99%

Systematic Review of Genotype-Phenotype Correlations in Frasier Syndrome

Tsuji

Yamamura

Nagano

et al. 2021

Kidney International Reports

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Lack of Puberty Despite Elevated Estradiol in a 46,XY Phenotypic Female with Frasier Syndrome

Cited by 9 publications

References 18 publications

Frasier syndrome: four new cases with unusual presentations

Frasier syndrome: four new cases with unusual presentations

High-throughput splicing assays identify known and novelWT1exon 9 variants in nephrotic syndrome

Systematic Review of Genotype-Phenotype Correlations in Frasier Syndrome

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