Disease relevance of Pseudohermaphroditism

• Naturally occurring mutations in the gene encoding 5 alpha-reductase type 2 cause male pseudohermaphroditism, indicating that this isozyme is responsible for the synthesis of dihydrotestosterone required for virilization of the embryonic male urogenital tract [1].
• WT1 mutants associated with Denys-Drash syndrome (DDS), which is characterized by Wilms' tumor, pseudohermaphroditism, and nephropathy, fail to interact with SRY [2].
• In a nationwide study on male pseudohermaphroditism among all pediatric endocrinologists and clinical geneticists in The Netherlands, 18 17betaHSD3-deficient index cases were identified, 12 of whom initially had received the tentative diagnosis androgen insensitivity syndrome (AIS) [3].
• Gynecomastia as a familial incomplete male pseudohermaphroditism type 1: a limited androgen resistance syndrome [4].
• We describe here a new phenotype, female pseudohermaphroditism and severe hypokalemia, caused by a homozygous inactivating mutation of the GR gene [5].

High impact information on Pseudohermaphroditism

• Male pseudohermaphroditism caused by mutations of testicular 17 beta-hydroxysteroid dehydrogenase 3 [6].
• 17-Ketosteroid reductase deficiency results in male pseudohermaphroditism because conversion of the weak androgen androstenedione to the more potent androgen testosterone is impaired [7].
• The male pseudohermaphroditism resulted from deficient testosterone synthesis due to deficiency of 17 alpha-hydroxylase and 17,20 desmolase [8].
• Deletion of steroid 5 alpha-reductase 2 gene in male pseudohermaphroditism [9].
• The enzyme steroid 5 alpha-reductase catalyzes the conversion of testosterone into the more potent androgen, dihydrotestosterone, and impairment of this reaction causes a form of male pseudohermaphroditism in which genetic males differentiate predominantly as phenotypic females [10].

Chemical compound and disease context of Pseudohermaphroditism

• Dihydrotestosterone binding was measured in culture fibroblasts from 14 control subjects and from 12 patients with five different types of hereditary male pseudohermaphroditism [11].
• Thus, this study identified a second community with inherited male pseudohermaphroditism due to 5-alpha-reductase deficiency, confirming the autosomal recessive inheritance of this condition and the generalized abnormality in both C19 and C21 steroid 5-alpha metabolism [12].
• 17Beta-hydroxysteroid dehydrogenase-3 (17betaHSD3) deficiency is an autosomal recessive form of male pseudohermaphroditism caused by mutations in the HSD17B3 gene [3].
• Deficient 17 alpha-hydroxylation of pregnenolone and progesterone and subsequent deficiency of the cleavage of the C-17,20 carbon bond result in the absence of sex hormone formation in both the adrenal glands and the gonads, causing hypogonadism and male pseudohermaphroditism [13].
• Testicular function was evaluated in forty-one prepubertal patients with male pseudohermaphroditism by determining serum concentrations of progesterone, 17-hydroxyprogesterone, dehydroepiandrosterone, androstenedione, testosterone and dihydrotestosterone before and after stimulation with hCG and, in some instances, ACTH [14].

Biological context of Pseudohermaphroditism

• Inactivating mutations of the hLHR lead to Leydig cell hypoplasia (LCH), a form of male pseudohermaphroditism resulting from the failure of fetal testicular Leydig cell differentiation [15].
• In 46,XX patients with a normal male phenotype or ambiguous genitalia, in whom the diagnosis of female pseudohermaphroditism had been excluded, serum AMH levels higher than 75 pmol/L were indicative of the presence of testicular tissue and correlated with the mass of functional testicular parenchyma [16].
• A patient with male pseudohermaphroditism is presented whose testicular biopsy showed marked paucity of the Leydig cell populations to which is attributed testosterone deficiency and impaired spermatogenesis [17].
• We analysed the WT1 gene of a Japanese patient with male pseudohermaphroditism, steroid resistant-nephr-opathy and gonadoblastoma by the polymerase chain reaction and direct sequencing and detected a heterozygous point mutation in intron 9 [18].
• This is caused by mutations that inactivate the LHR resulting in subnormal male sexual development or male pseudohermaphroditism [19].

Anatomical context of Pseudohermaphroditism

• Familial incomplete male pseudohermaphroditism associated with impaired nuclear androgen retention. Studies in cultured skin fibroblasts [20].
• In genetic males, mutation of the 17beta-hydroxysteroid dehydrogenase 3 (17HSD3)gene that is normally expressed in the testes impairs testosterone formation and causes development of male pseudohermaphroditism [21].
• The incidence of 17betaHSD3 deficiency is 0.65 times the incidence of AIS, which is thought to be the most frequent known cause of male pseudohermaphroditism without dysgenic gonads [3].
• Four fetuses were diagnosed with male pseudohermaphroditism (1 with steroid sulfatase deficiency, 1 with presumed camptomelic dysplasia, and 2 undetermined) [22].
• Phenotypically normal girl with male pseudohermaphroditism, hypoplastic left ventricle, lung aplasia, horseshoe kidney, and diaphragmatic hernia [23].

Gene context of Pseudohermaphroditism

• The recent description of a 46,XY patient bearing a mutation in the NR5A1 gene, causing male pseudohermaphroditism and adrenal failure, demonstrated the crucial role of SF-1 in male gonadal differentiation [24].
• Steroid 5alpha-reductase 2 deficiency is an autosomal recessive form of male pseudohermaphroditism caused by mutations in the SRD5A2 gene [25].
• The current findings boost to 16 the number of mutations in the HSD17B3 gene that impair testosterone synthesis and cause male pseudohermaphroditism, and add 1 apparently silent polymorphism to this tally [26].
• Androgen-insensitivity syndrome (AIS) is a major cause of male pseudohermaphroditism (MPH) [27].
• Homozygous mutation within the conserved Ala-Phe-Asn-Glu-Thr motif of exon 7 of the LH receptor causes male pseudohermaphroditism [28].

Analytical, diagnostic and therapeutic context of Pseudohermaphroditism

• Three adult patients with male pseudohermaphroditism were given 15 microgram/kg body weight of 17 beta-estradiol im daily (at 08:00 hours) for 12-15 days and circulating levels of gonadotropins, prolactin and estradiol were determined by radioimmunoassay before and during the steriod course [29].

References