Disease relevance of Gonadal Dysgenesis

• The triad of nephropathy, partial gonadal dysgenesis and Wilms' tumour (WT) is known as Denys-Drash syndrome (DDS) [1].
• Here we show that a related disease, Frasier syndrome, characterized by focal glomerular sclerosis, delayed kidney failure and complete gonadal dysgenesis, is probably caused by specific intronic point mutations of WT1 that preferentially affect a CpG dinucleotide [2].
• Mutations of the Wilms' tumour-1 (WT1) gene in humans can lead to childhood kidney cancer, life-threatening glomerular nephropathy and gonadal dysgenesis [3].
• Denys-Drash syndrome is a rare disorder of urogenital development characterized by the association of early onset glomerulopathy caused by diffuse mesangial sclerosis, gonadal dysgenesis leading to pseudohermaphroditism in males, and a high risk of developing Wilms' tumor [4].
• We describe a new point mutation in the SRY gene of a Chinese XY female with gonadal dysgenesis (Swyer syndrome) [5].

High impact information on Gonadal Dysgenesis

• Thus, LHX9 mutations may underlie certain forms of isolated gonadal agenesis in humans [6].
• We have now identified a mutation in SRY in one out of 12 sex-inversed XY females with gonadal dysgenesis who do not lack large segments of the short arm of the Y chromosome [7].
• We have analysed the biochemical properties of the DNA binding domains (HMG-boxes) of mutant SRY proteins from five patients with complete gonadal dysgenesis [8].
• In conclusion, secretion of AMH is a constitutive feature of the immature Sertoli cell and its expression is altered only by mutations of the AMH gene, but not by gonadal dysgenesis [9].
• We now describe a novel 8-bp microdeletion of SF-1, isolated from a 46, XY patient who presented with gonadal agenesis but normal adrenal function, which causes premature termination upstream of sequences encoding the activation function 2 domain [10].

Chemical compound and disease context of Gonadal Dysgenesis

• Chronic estrogen deficiency, as in untreated patients with gonadal dysgenesis, is associated with failure to manifest the elevation of Sm-C that occurs during normal puberty [11].
• (c) Administration of estrogen to patients with gonadal agenesis did not affect their levels of DHA and DHAS although those patients given androgen developed higher DHAS, but not DHA, levels [12].
• Intersex states result either from gonadal dysgenesis, in which both Leydig and Sertoli cell populations are affected, or from impaired secretion or action of either testosterone or AMH [13].
• Similarly, in the patient with gonadal dysgenesis FSH isoforms in the basic range were more abundant during the DES treatment period than in the pre- or posttreatment serum pools [14].
• Plasma glycoprotein hormone alpha-subunit in the syndrome of gonadal dysgenesis: the effect of estrogen replacement in hypergonadotropic hypogonadism [15].

Biological context of Gonadal Dysgenesis

• These data indicate that the majority of XY females with pure gonadal dysgenesis owe their sex-reversed phenotype to mutations in as yet uncharacterised segments of the SRY gene, or, at other loci acting early in the sex-determining pathway [16].
• Based on the high incidence of gonadoblastoma in females with XY gonadal dysgenesis or 45,X/46,XY mosaicism, the existence of a susceptibility locus on the Y chromosome (GBY) has been postulated [17].
• We describe here two novel missense mutations in the SRY gene after the screening of 17 patients, including 3 siblings, with 46,XY gonadal dysgenesis and 4 true hermaphrodites [18].
• Here we describe an XY sex-reversed female with pure gonadal dysgenesis who harbors a de novo nonsense mutation in the SRY open reading frame (SRY-orf) [19].
• Four patients with 46,XX true hermaphroditism and one patient with 46,XY pure gonadal dysgenesis (Swyer syndrome) were analyzed with a Y chromosome-derived probe that detects a specific fragment on the short arm of the Y chromosome in the putative testicle-determining region and also a fragment on the short arm of the X chromosome [20].

Anatomical context of Gonadal Dysgenesis

• To date germ-line mutations in SRY have been reported in approximately 20% of subjects with 46,XY complete gonadal dysgenesis [21].
• An unusual phenotype of Frasier syndrome due to IVS9 +4C>T mutation in the WT1 gene: predominantly male ambiguous genitalia and absence of gonadal dysgenesis [22].
• In order to evaluate the role of SRY in the determination of the testis, we sequenced the conserved domain of the SRY gene in 8 patients with 46,XY gonadal dysgenesis and 3 patients with related disorders, and compared our data with those obtained in 6 other similar studies [23].
• On the basis of clinical findings, familial tendency, and androgen secretion from the streak gonads in these patients, it is proposed that the XY gonadal dysgenesis represents a severe form of male pseudohermaphroditism [24].
• A study was made of the endometria of 16 patients with gonadal dysgenesis who had been give cyclic replacement treatment with conjugated estrogens for 2 to 10 years, and of 9 other patients who had received medroxyprogesterone in addition to the conjugated estrogens for 2 to 5 years [25].

Gene context of Gonadal Dysgenesis

• Absence of mutations involving the LIM homeobox domain gene LHX9 in 46,XY gonadal agenesis and dysgenesis [26].
• Therefore, we screened the coding region and the 5' and 3' flanking region of the SOX3 gene for mutations by means of single-stranded conformation polymorphism and heteroduplex analysis in eight subjects with 46, XX sex reversal (SRY negative) and 25 subjects with 46, XY gonadal dysgenesis [27].
• We performed this test in order to evaluate its applicability in 16 patients with intersexual genital status: eleven with 46,XY gonadal dysgenesis and three with true hermaphroditism (group I), and in two patients with androgen insensitivity syndrome (AIS, group II) [28].
• Four XY gonadal dysgenesis patients with mutations in SRY NLS regions showed reduced nuclear import accompanied in some cases by reduced importin beta recognition [29].
• Gonadal dysgenesis may be isolated, as in the case of SRY mutations, or associated with abnormal development of other organs, such as bone or adrenals, consistent with the spatial expression profile of the disrupted genes (SOX9 or SF1) [30].

Analytical, diagnostic and therapeutic context of Gonadal Dysgenesis

• Curettage carried out during the third week of treatment of ethinyl oestradiol in 14 patients with gonadal dysgenesis showed cystic glandular hyperplasia in seven patients developed a large endometrial polyp and in one atypical changes were found in the hyperplastic endometrium [31].
• Six out of the 13 patients (49.5 +/- 4.8 y were peri- and postmenopausal = group A. Seven patients (21.5 +/- 2.2 y) suffered from primary and secondary amenorrhea, in 4 out of them due to gonadal dysgenesis = group B. Estradiol was measured by commercial radioimmunoassay [32].
• Southern-blotting studies and PCR analyses of SRY, androgen receptor and CYP21B genes can be routinely used for the direct diagnosis of gonadal dysgenesis, androgen insensitivity syndromes and congenital adrenal hyperplasia, respectively [33].
• Mares with gonadal dysgenesis treated with progesterone can establish and maintain pregnancy after embryo transfer, but there may be differences in this capability among mares, possibly related to the cause of the gonadal dysgenesis [34].
• Y chromosome analysis and laparoscopic surgery in XY pure gonadal dysgenesis: a case report and a review of literature [35].

References