Frasier syndrome: four new cases with unusual presentations

Frasier 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

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Frasier syndrome: A rare syndrome with WT-1 gene mutation

International Journal of Contemporary Pediatrics ◽

10.18203/2349-3291.ijcp20171736 ◽

2017 ◽

Vol 4 (3) ◽

pp. 1101

Author(s):

Vindhiya Kadambavana Sundaram ◽

Sundari Subramanian ◽

Lakshmi Charan Chinumuthu ◽

Aishwarya Dharmanathan

Keyword(s):

Nephrotic Syndrome ◽

Wilms Tumor ◽

Immunosuppressive Agents ◽

External Genitalia ◽

Female Child ◽

Suppressor Gene ◽

Glomerular Sclerosis ◽

Frasier Syndrome ◽

Sex Development ◽

Focal Segmental Glomerular Sclerosis

Frasier syndrome is a rare disorder of sex development. It is caused by mutation in Wilms’ tumor suppressor gene (WT-1) located in 11p23. This gene encodes a transcription factor involved in the development of kidney and gonads. The syndrome is characterized by female external genitalia in 46, XY patients, streak gonads with a higher risk of gonadal tumors, mainly gonadoblastoma. Nephropathy consists of nephrotic syndrome (NS) mainly due to focal segmental glomerular sclerosis (FSGS). NS presents early in childhood and responds poorly to steroid and immunosuppressive agents. Progression to End Stage Renal Disease (ESRD) usually occurs by second or third decade of life. We present a 6 years old female child with insignificant past medical history diagnosed as steroid resistant nephrotic syndrome. Renal biopsy showed FSGS. CT Abdomen showed streak gonads with rudimentary uterus. Further genotype showed WT-1 mutation with Karyotype of 46XY. Elective bilateral gonadectomy was done and histopathology showed bilateral dysgerminoma. After a year, her disease progressed to ESRD and she succumbed to the illness.

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Frasier Syndrome: A Rare Cause of Refractory Steroid-Resistant Nephrotic Syndrome

Children ◽

10.3390/children8080617 ◽

2021 ◽

Vol 8 (8) ◽

pp. 617

Author(s):

Yung-Chieh Huang ◽

Ming-Chin Tsai ◽

Chi-Ren Tsai ◽

Lin-Shien Fu

Keyword(s):

Nephrotic Syndrome ◽

Wilms Tumor ◽

Donor Site ◽

External Genitalia ◽

Protein Isoforms ◽

Splice Donor Site ◽

Frasier Syndrome ◽

Mixed Germ Cell Tumor ◽

Male Patients

Frasier syndrome is a rare disease that affects the kidneys and genitalia. Patients who have Frasier syndrome develop nephrotic syndrome (NS) featuring focal segmental glomerulosclerosis (FSGS) that is resistant to steroid treatment in early childhood. Male patients can have female external genitalia (pseudo-hermaphroditism) at birth and develop gonado-blastoma in their adolescence. Frasier syndrome is caused by mutations in the splice donor site at intron 9 of the Wilms’ tumor WT1 gene; these mutations result in an imbalanced ratio of WT1 protein isoforms and affect the development of the urogenital tract, podocyte function, and tumor suppression. Here, we report on a patient with long-term refractory NS who developed a malignant mixed germ cell tumor arising in a gonado-blastoma of the ovary 8 years after the onset of proteinuria.

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WT1 Pathogenic Variants are Associated with a Broad Spectrum of Differences in Sex Development Phenotypes and Heterogeneous Progression of Renal Disease

Sexual Development ◽

10.1159/000517373 ◽

2021 ◽

pp. 1-9

Author(s):

Maria T.M. Ferrari ◽

Andreia Watanabe ◽

Thatiane E. da Silva ◽

Nathalia L. Gomes ◽

Rafael L. Batista ◽

...

Keyword(s):

Kidney Development ◽

Wilms Tumor ◽

Genetic Diagnosis ◽

Germ Cell Tumors ◽

Disorders Of Sex Development ◽

Medical Attention ◽

Primary Amenorrhea ◽

Normal Female ◽

Sex Development ◽

Pathogenic Variants

Wilms’ tumor suppressor gene 1 (WT1) plays an essential role in urogenital and kidney development. Heterozygous germline pathogenic allelic variants of WT1 have been classically associated with Denys–Drash syndrome (DDS) and Frasier syndrome (FS). Usually, exonic pathogenic missense variants in the zinc finger region are the cause of DDS, whereas pathogenic variants affecting the canonic donor lysine-threonine-serine splice site in intron 9 cause FS. Phenotypic overlap between WT1 disorders has been frequently observed. New WT1 variant-associated phenotypes, such as 46,XX testicular/ovarian-testicular disorders of sex development (DSD) and primary ovarian insufficiency, have been reported. In this report, we describe the phenotypes and genotypes of 7 Brazilian patients with pathogenic WT1 variants. The molecular study involved Sanger sequencing and massively parallel targeted sequencing using a DSD-associated gene panel. Six patients (5 with a 46,XY karyotype and 1 with a 46,XX karyotype) were initially evaluated for atypical genitalia, and a 46,XY patient with normal female genitalia sought medical attention for primary amenorrhea. Germ cell tumors were identified in 2 patients, both with variants affecting alternative splicing of WT1 between exons 9 and 10. Two pathogenic missense WT1 variants were identified in two 46,XY individuals with Wilms’ tumors; both patients were <1 year of age at the time of diagnosis. A novel WT1 variant, c.1453_1456 (p.Arg485Glyfs*14), was identified in a 46,XX patient with testicular DSD. Nephrotic proteinuria was diagnosed in all patients, including 3 who underwent renal transplantation after progressing to end-stage kidney disease. The expanding phenotypic spectrum associated with WT1 variants in XY and XX individuals confirms their pivotal role in gonadal and renal development as well as in tumorigenesis, emphasizing the clinical implications of these variants in genetic diagnosis.

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Pure gonadal dysgenesis (Swyer syndrome) due to microdeletion in the SRY gene: a case report

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2014-0071 ◽

2015 ◽

Vol 28 (1-2) ◽

Cited By ~ 2

Author(s):

Gül Yesiltepe Mutlu ◽

Heves Kırmızıbekmez ◽

Hatip Aydın ◽

Handan Çetiner ◽

Serdar Moralıoğlu ◽

...

Keyword(s):

Gonadal Dysgenesis ◽

External Genitalia ◽

Delayed Puberty ◽

Sex Characteristics ◽

Primary Amenorrhea ◽

Laboratory Findings ◽

Secondary Sex Characteristics ◽

Disorder Of Sexual Development ◽

Swyer Syndrome

Abstract46,XY complete gonadal dysgenesis (Swyer syndrome) is a rare cause of disorder of sexual development. This syndrome is caused by a defect in the determination of sex during embryogenesis and is characterised with female external genitalia, normal or rudimentary uterus, and streak gonads, despite the presence of the 46,XY karyotype. Most of the studied cases presented with leak of secondary sex characteristics and primary amenorrhea during adolescence. Laboratory findings reveal hypergonadotropic hypogonadism. Herein we present the case of a female with a 46,XY karyotype who was admitted with delayed puberty and detected to have a microdeletion in the

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XY female with complete androgen insensitivity syndrome with bilateral inguinal hernia

International Surgery Journal ◽

10.18203/2349-2902.isj20211325 ◽

2021 ◽

Vol 8 (4) ◽

pp. 1353

Author(s):

Aafrin Shabbir Baldiwala ◽

Vipul C. Lad

Keyword(s):

Inguinal Hernia ◽

External Genitalia ◽

Androgen Insensitivity Syndrome ◽

Primary Amenorrhea ◽

Normal Female ◽

Bilateral Inguinal Hernia ◽

Complete Androgen Insensitivity Syndrome ◽

Androgen Insensitivity ◽

Primary Amenorrhoea ◽

The Individual

The complete androgen insensitivity syndrome (AIS), previously called testicular feminization syndrome, is an X-linked recessive rare disorder. AIS is the most common male pseudohermaphrodite. Patient has 46, XY chromosome and testis. The individual is phenotypically female and genotypically male. Antimullerian hormone is produced by the testis. So, uterus and fallopian tubes do not develop in fetus. The fault lies with androgen receptors which are mutated. Male differentiation of external genitals does not occur. The individuals are reared as girls and the condition is suspected when the individual is evaluated for primary amenorrhea, infertility or when unilateral/bilateral inguinal hernia is diagnosed in girls. This disorder includes a spectrum of changes ranging from male infertility to completely normal female external genitalia in a chromosomally male individual. These cases need proper diagnosis and appropriate management. We report this case for its interesting presentation. The patient is a 23 year old female, presented with bilateral labial swellings and primary amenorrhoea. Subsequent investigations were done which revealed that the patient is a genetically male with absence of female internal genitalia but presence of testes. Proper psychological support was also given to her, which is more important.

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Mother-to-Child Transmitted WT1 Splice-Site Mutation Is Responsible for Distinct Glomerular Diseases

Journal of the American Society of Nephrology ◽

10.1681/asn.v10102219 ◽

1999 ◽

Vol 10 (10) ◽

pp. 2219-2223

Author(s):

ERICK DENAMUR ◽

NATHALIE BOCQUET ◽

BEATRICE MOUGENOT ◽

FRANCIS DA SILVA ◽

LAURENCE MARTINAT ◽

...

Keyword(s):

Splice Site ◽

Early Onset ◽

Index Case ◽

Wilms Tumor ◽

Splice Site Mutation ◽

Normal Female ◽

Diffuse Mesangial Sclerosis ◽

Frasier Syndrome ◽

Site Mutation ◽

Glomerular Diseases

Abstract. Mutations in the Wilms' tumor suppressor gene (WT1) are linked with Denys-Drash syndrome (DDS), a rare childhood disease characterized by diffuse mesangial sclerosis and renal failure of early onset, XY pseudohermaphroditism, and high risk of Wilms' tumor. KTS (lysine-threonine-serine) splice site mutations in WT1 intron 9 have been described in patients with Frasier syndrome, another rare syndrome defined by focal and segmental glomerulosclerosis (FSGS), XY pseudohermaphroditism, and frequent occurrence of gonadoblastoma. Cases of Frasier syndrome raise the question whether splice site mutations may also be found in XX females with isolated FSGS. A girl (index case) presented with the nephrotic syndrome at 9 mo of age. The diagnosis of DDS was based on the finding of diffuse mesangial sclerosis in the kidney biopsy and of a XY karyotype. The index case's mother had had proteinuria since she was 6 years of age. A renal biopsy was performed when she was 28 and disclosed FSGS. The same splice site mutation in intron 9 (WT1 1228+5 G→A) involving one allele was found in the child and in her mother, but not in other members of the kindred (including the parents, the two brothers, and the two sisters of the index case's mother) who were free of renal symptoms. Quantification of WT1 +KTS/-KTS isoforms in the index case's father and one index case's maternal uncle showed a normal +KTS/-KTS ratio of 1.50. In contrast, the index case and her mother had a low ratio (0.40 and 0.34, respectively), within the range reported in Frasier syndrome. In conclusion, this study shows that the KTS splice site mutation is not specific for Frasier syndrome, but that it can also be found in DDS and in a normal female (XX) with FSGS, a woman who achieved normal pregnancy. It is suggested that WT1 splice site mutations should be sought in phenotypically normal females who present with FSGS or with related glomerulopathies of early onset.

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Role of Imaging in the Diagnosis and Management of Complete Androgen Insensitivity Syndrome in Adults

Case Reports in Radiology ◽

10.1155/2013/158484 ◽

2013 ◽

Vol 2013 ◽

pp. 1-6 ◽

Cited By ~ 2

Author(s):

Marco Nezzo ◽

Pieter De Visschere ◽

Guy T'Sjoen ◽

Steven Weyers ◽

Geert Villeirs

Keyword(s):

External Genitalia ◽

Proximal Part ◽

Androgen Insensitivity Syndrome ◽

Primary Amenorrhea ◽

Normal Female ◽

Adult Women ◽

Complete Androgen Insensitivity Syndrome ◽

Androgen Insensitivity ◽

Female External Genitalia

Complete androgen insensitivity syndrome is an X-linked recessive androgen receptor disorder characterized by a female phenotype with an XY karyotype. Individuals affected by this syndrome have normal female external genitalia but agenesis of the Müllerian duct derivatives, that is, absence of the Fallopian tubes, uterus, cervix, and the proximal part of the vagina, with presence of endoabdominal, labial, or inguinal testes. The estimated prevalence is between 1 and 5 in 100,000 genetic males. Complete androgen insensitivity syndrome can be diagnosed as a result of mismatch between the prenatal sex prediction and the phenotype at birth, can be detected by chance, or remain undetected until investigations for primary amenorrhea. Imaging can be important both to diagnose the pathology and to localize gonads prior to surgical treatment. In this paper, we present three cases of complete androgen insensitivity syndrome in adult women of 34, 22, and 38 years old.

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Cytogenetics and sex determination in man and mammals

Journal of Biosocial Science ◽

10.1017/s0021932000023427 ◽

1970 ◽

Vol 2 (S2) ◽

pp. 7-30 ◽

Cited By ~ 26

Author(s):

C. E. Ford

Keyword(s):

Y Chromosome ◽

External Genitalia ◽

Mutant Gene ◽

Normal Female ◽

Human Female ◽

Present Evidence ◽

Male Development ◽

Sex Development ◽

Internal Genitalia ◽

Male External Genitalia

SummarySex in man and probably throughout the class mammalia is normally determined by the presence of a Y chromosome (male) or its absence (female). The presence of genetic loci on both the long and the short arm of the X chromosome in double dose appears to be essential for the development of mature functional ovaries in the human female though a single X suffices in the female mouse.The development of masculine genital anatomy and phenotype is a consequence of prior formation of testes. In the absence of gonads of either kind, female internal and external genitalia are formed but secondary sex development fails. In rare human families a mutant gene suppresses the development of male external genitalia in 46, XY embryos but permits the development of testes and male internal genitalia. The external phenotype is normal female (syndrome of testicular feminization). A sex-linked mutant gene in the mouse has a similar effect.The locus or loci directly concerned with male development might lie wholly on the Y chromosome or might be located on another chromosome or chromosomes. In the latter case it (or they) must be repressed in the female and normally activated by a locus or loci on the Y chromosome in the male. Present evidence does not permit the exclusion of either possibility.

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