46,XX Male - Testicular Disorder of Sexual Differentiation (DSD): hormonal, molecular and cytogenetic studies

Alves, Crésio de Aragão Dantas; Braid, Zilda; Coeli, Fernanda Borchers; Mello, Maricilda Palandi de

doi:10.1590/s0004-27302010000800004

Cited by 19 publications

(13 citation statements)

References 23 publications

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“…The free softwares Chromas Pro v.1.5 and CLC Sequence Viewer v.6.6.2 were used to analyze and compare sequences with the published WT1 (ENSG00000184937) sequence at Ensembl database (www.ensembl.org). Y-chromosome sequence analysis was conducted by PCR and nested-PCR with primers for SRY gene, TSPY gene and Y-centromeric region DYZ3, as described elsewhere (10). After PCR amplification, reaction products (10 µl) were submitted to 2% agarose gel electrophoresis stained with ethidium bromide and using a molecular weight marker.…”

Section: Methodsmentioning

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: Methodsmentioning

confidence: 99%

Frasier syndrome: four new cases with unusual presentations

Guaragna

Lutaif

Bittencourt

et al. 2012

Arq Bras Endocrinol Metab

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“…Clinical phenotypes about 46, XX DSD have been identified to three groups, including males with normal phenotype, males with genital ambiguities and males with true hermaphrodites [3]. Ovotesticular DSD, which is characterized by the presence of both testicular and ovarian tissue in the gonads of the same individual, and testicular DSD characterized by a full development of both gonads as testes without any evidence of ovarian tissue [4]. Approximately 80% of individuals with 46,XX testicular DSD present after puberty with normal pubic hair and normal penile size, but small testes, and sterility resulting from azoospermia [5].…”

Section: Introductionmentioning

confidence: 99%

Clinical, molecular and cytogenetic analysis of 46, XX testicular disorder of sex development with SRY-positive

et al. 2014

BMC Urol

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BackgroundTo review the possible mechanisms proposed to explain the etiology of 46, XX sex reversal by investigating the clinical characteristics and their relationships with chromosomal karyotype and the SRY(sex-determining region Y)gene.MethodsFive untreated 46, XX patients with SRY-positive were referred for infertility. Clinical data were collected, and Karyotype analysis of G-banding in lymphocytes and Fluorescence in situ hybridization (FISH) were performed. Genomic DNA from peripheral blood of the patients using QIAamp DNA Blood Kits was extracted. The three discrete regions, AZFa, AZFb and AZFc, located on the long arm of the Y chromosome, were performed by multiplex PCRs(Polymerase Chain Reaction) amplification. The set of PCR primers for the diagnosis of microdeletion of the AZFa, AZFb and AZFc region included: sY84, sY86, sY127, sY134, sY254, sY255, SRY and ZFX/ZFY.ResultsOur five patients had a lower body height. Physical examination revealed that their testes were small in volume, soft in texture and normal penis. Semen analyses showed azoospermia. All patients had a higher follicle-stimulating hormone(FSH), Luteinizing Hormone(LH) level, lower free testosterone, testosterone level and normal Estradiol, Prolactin level. Karyotype analysis of all patients confirmed 46, XX karyotype, and FISH analysis showed that SRY gene were positive and translocated to Xp. Molecular analysis revealed that the SRY gene were present, and the AZFa, AZFb and AZFc region were absent.ConclusionsThis study adds cases on the five new 46, XX male individuals with SRY-positive and further verifies the view that the presence of SRY gene and the absence of major regions in Y chromosome should lead to the expectance of a completely masculinised phenotype, abnormal hormone levels and infertility.

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“…SRY -negative XX males usually have a phenotype similar to Y-positive males but differ in showing genital ambiguity, which is the case in our patient. Alves et al [2010] suggested that negative XX testicular DSD may result due to gain-of-function mutations in one or more genes downstream to the SRY gene pathway or due to a loss of function in some genes associated with the inhibition of male development. It has been postulated that Y-negative XX testicular DSD and XX OT-DSD have a common origin [Toublanc et al, 1993;Kolon et al, 1998], which is supported by many reports of sibship among XX males and XX OT-DSD [Abbas et al, 1990;Ramos et al, 1996;Slaney et al, 1998;Maciel-Guerra et al, 2008].…”

Section: Discussionmentioning

confidence: 99%

Sex Chromosome Mosaicism in the Gonads of DSD Patients: A Karyotype/Phenotype Correlation

Kamel

El-Ghany²,

Mekkawy³

et al. 2015

Sex Dev

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Sex chromosome mosaicism results in a large clinical spectrum of disorders of sexual development (DSD). The percentage of 45,X cells in the developing gonad plays a major role in sex determination. However, few reports on the gonadal mosaic status have been published, and the phenotype is usually correlated with peripheral lymphocyte karyotypes, which makes the phenotype prediction imprecise. This study was conducted on 7 Egyptian DSD patients to demonstrate the effect of sex chromosome constitution of both blood lymphocytes and gonadal tissues on the phenotypic manifestations. Conventional cytogenetic and FISH analyses of blood lymphocytes were conducted, and laparoscopy with gonadal biopsy was performed for histopathologic examination and FISH analysis. Gonosomal mosaicism was detected in 3 patients who had a non-mosaic chromosome pattern in blood lymphocytes. Two patients showed the same type of sex chromosome mosaicism in both the blood and gonadal tissues but with different distributions. Two other patients revealed a non-mosaic pattern in both tissues. The present study elucidates the importance of examining sex chromosome mosaicism in gonadal tissues of DSD patients and highlights the critical role of 45,X mosaicism which can lead to serious effects during early gonadal organogenesis.

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46,XX Male - Testicular Disorder of Sexual Differentiation (DSD): hormonal, molecular and cytogenetic studies

Cited by 19 publications

References 23 publications

Frasier syndrome: four new cases with unusual presentations

Frasier syndrome: four new cases with unusual presentations

Clinical, molecular and cytogenetic analysis of 46, XX testicular disorder of sex development with SRY-positive

Sex Chromosome Mosaicism in the Gonads of DSD Patients: A Karyotype/Phenotype Correlation

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