SRVX, FORMERLY, INCLUDED
TESTIS-DETERMINING FACTOR, X-CHROMOSOMAL, FORMERLY, INCLUDED
46,XY GONADAL DYSGENESIS, COMPLETE, SRY-RELATED 46,XY TRUE HERMAPHRODITISM, SRY-RELATED, INCLUDED
SEX-REVERSING LOCUS ON X, FORMERLY, INCLUDED
TDFX, FORMERLY, INCLUDED
46,XY SEX REVERSAL, SRY-RELATED
SRXY1
Individuals with 46,XY complete gonadal dysgenesis are phenotypically female; however, they do not develop secondary sexual characteristics at puberty and do not menstruate. They have bilateral 'streak gonads,' which typically consist of fibrous tissue and variable amounts of ... Individuals with 46,XY complete gonadal dysgenesis are phenotypically female; however, they do not develop secondary sexual characteristics at puberty and do not menstruate. They have bilateral 'streak gonads,' which typically consist of fibrous tissue and variable amounts of wavy ovarian stroma. A uterus and fallopian tube are present and external genitalia are female (reviewed by Berkovitz et al., 1991). - Genetic Heterogeneity of 46,XY Sex Reversal Male sexual determination is initiated by Y-chromosomal SRY, which activates a cascade of genes that lead the embryonic gonad to develop into a testis. Fetal testicular Sertoli cells then produce mullerian inhibitory substance (600957), which is responsible for the involution of the mullerian ducts, which would otherwise develop into the uterus, fallopian tubes, and cervix. Fetal testicular Leydig cells produce testosterone from cholesterol by the sequential action of a series of enzymes. Subsequent differentiation of male external genitalia also requires the action of dihydrotestosterone, produced from testicular testosterone. Perturbations in the enzymes in this classic pathway or in an alternative pathway of testicular androgen biosynthesis can result in genetic males with disordered sexual development and incompletely developed ('ambiguous') external genitalia (summary by Fluck et al., 2011). Disorders of male development for which a genetic cause has been found include 46,XY sex reversal-2 (SRXY2; 300018), which is caused by duplication of the NR0B1 gene (300473) on chromosome Xp21.3-p21.2; SRXY3 (612965), caused by mutation in the NR5A1 gene (184757) on chromosome 9q33; SRXY4 (154230), caused by deletion on chromosome 9p24.3; SRXY5 (613080), caused by mutation in the CBX2 gene (602770) on chromosome 17q25; SRXY6 (613762), caused by mutation in the MAP3K1 gene (600982) on chromosome 5q11.2; SRXY7 (233420), caused by mutation in the DHH gene (605423) on chromosome 12q13; and SRXY8 (614279), caused by mutation in the AKR1C2 gene (600450) on chromosome 10p15, with a possible contribution from the closely linked AKR1C4 gene (600451).
Swyer (1955) described 2 46,XY women with primary amenorrhea, tall stature, female external genitalia (one with enlarged clitoris), and normal, but hypoestrogenized, vagina and cervix.
Affected sisters were reported by Cohen and Shaw (1965), and affected ... Swyer (1955) described 2 46,XY women with primary amenorrhea, tall stature, female external genitalia (one with enlarged clitoris), and normal, but hypoestrogenized, vagina and cervix. Affected sisters were reported by Cohen and Shaw (1965), and affected twins by Frasier et al. (1964). The sisters reported by Cohen and Shaw (1965) had a marker autosome, which was present also in the mother. They referred to another instance of XY 'sisters' with an abnormal autosome. One of their 2 patients had gonadoblastoma. Taylor et al. (1966) stated there is a high incidence of neoplasia (gonadoblastomas and germinomas) in streak gonads of patients with Swyer syndrome. Two sisters reported by Fine et al. (1962) were of normal stature but were chromatin negative. One of these cases and 1 of those reported by Baron et al. (1962) had gonadoblastoma. In the last family, 2 'females' and a male were affected, the male showing no testes. All 3 sibs were sex-chromatin negative. Barr et al. (1967) reported on a sibship containing 2 genetic males. The first, who had male pseudohermaphroditism, was reared as a female; he developed signs of masculinization at puberty and had undescended but otherwise normal testes and small fallopian tubes. The second genetic male (180 cm tall) had pure gonadal dysgenesis with small uterus and streak gonads. This patient was at first thought to have the testicular feminization syndrome (300068). An unaffected sister had a son with perineal hypospadias (urethral orifice at the base of the penis). The sibship reported by Chemke et al. (1970) was similar to that of Barr et al. (1967). Rushton (1979) pointed out that the streak gonads of this disorder differ from those of the 45,X Turner syndrome in the presence of calcification and the increased hazard of gonadoblastoma. Comparative studies of the frequency of gonadoblastoma in Turner mosaics with normal or rearranged Y chromosomes have suggested that the integrity of the Y chromosome, and in particular the presence of the distal fluorescent band Yqh, is required in these mosaics for the tumor to develop; no cases with distal deletions of the fluorescent band on Yq had been reported (Lukusa et al., 1986). Dumic et al. (2008) reported a fertile woman with normal ovaries and a predominantly 46,XY ovarian karyotype who gave birth to a 46,XY female with complete gonadal dysgenesis. The karyotype of the phenotypically normal mother was 100% 46,XY in blood, 80% 46,XY and 20% 45,X in cultured skin fibroblasts, and 93% 46,XY, 6% 45,X, and less than 1% 46,XX in the ovary. The 52-year-old mother had normal pubertal development with spontaneous menarche at 11 years of age. She had 2 unassisted pregnancies, the first of which ended in miscarriage. She had regular menses until menopause at age 49 years. Physical examination revealed a feminine-appearing woman with a normal body habitus; there was no receding hairline or balding of the scalp and no acne or facial hair. Breasts and pubic hair were Tanner stage V, and external genitalia were normal with no clitoromegaly or labial fusion. The vaginal introitus was normal, and pelvic examination revealed a uterus in retroverted position with no adnexal masses; hormonal findings were compatible with a normal menopausal woman. The daughter born of her second pregnancy presented at 17 years of age due to lack of breast development and primary amenorrhea. Examination showed mild facial acne but no facial hair, with Tanner stage I breasts and stage IV pubic hair. External female genitalia were normal, without clitoromegaly or labial fusion, and the vaginal introitus was normal. Pelvic examination revealed a hypoplastic uterus with no palpable gonads; ultrasound showed a small left gonad, but no gonad was seen on the right. On karyotyping, the daughter was 100% 46,XY in blood, 100% 46,XY in skin, and 99.25% 46,XY and 0.75% 45,X in gonadal tissue. The family pedigree on the mother's side was notable for the presence of 7 individuals over 4 generations, both phenotypic males and females, who had sexual ambiguity, infertility, or failure to menstruate, including 1 individual with documented 45,X/46,XY mixed gonadal dysgenesis. The mode of inheritance in the family was strongly suggestive of X-linkage. Dumic et al. (2008) stated that this was the first report of fertility in a woman with a predominantly 46,XY karyotype in the ovary, and suggested that perhaps all mothers of 46,XY(SRY+) females with complete gonadal dysgenesis should be carefully examined for an XY karyotype as well. - 46,XY True Hermaphroditism A 'true hermaphrodite' must have both mature ovarian and mature testicular tissue with histologic evidence of follicles and tubules, respectively (van Niekerk and Retief, 1981). It is a genetically heterogeneous condition. Van Niekerk and Retief (1981) found that the ovotestis was the most common gonad of the true hermaphrodite, found in 44.3% of 406 cases. The genotype of most affected individuals was 46,XX (see 400045), but many had 46,XY or a mosaic of 46,XX/46,XY. Milner et al. (1958) reported 2 brothers who had hypospadias and both testicular and ovarian tissue bilaterally. Lowry et al. (1975) determined that the brothers reported by Milner et al. (1958) lacked Barr bodies (were 'chromatin negative'), indicating an XY genotype. Lowry et al. (1975) described affected first cousins whose fathers were brothers. Both had a normal male (XY) karyotype.
Page et al. (1987) cloned a 230-kb segment of the human Y chromosome thought to contain some or all of the TDF (SRY) gene. The cloned region spanned the deletion in ... - 46,XY Gonadal Dysgenesis, Complete Page et al. (1987) cloned a 230-kb segment of the human Y chromosome thought to contain some or all of the TDF (SRY) gene. The cloned region spanned the deletion in a female who carried all but 160 kb of the Y. Homologous sequences were found within the sex-determining region of the mouse Y chromosome. Jager et al. (1990) demonstrated a mutation in SRY in 1 out of 12 sex-reversed XY females with gonadal dysgenesis who had no large deletions of the short arm of the Y chromosome. They found a 4-nucleotide deletion in the part of the SRY gene that encodes a conserved DNA-binding motif. A frameshift presumably led to a nonfunctional protein. Mutation occurred de novo, because the father had a normal SRY sequence. This is strong evidence that SRY is TDF. The de novo G-to-A mutation led to a change from methionine to isoleucine at a residue that lies within the putative DNA-binding motif of SRY and is identical in all SRY and SRY-related genes. Vilain et al. (1992) described a family in which all 5 XY individuals in 2 generations had a single basepair substitution resulting in an amino acid change in the conserved domain of the SRY open reading frame (480000.0004). A G-to-C change at nucleotide 588 resulted in substitution of leucine for valine. Three of the individuals were XY sex-reversed females and 2 were XY males. One of the males had 8 children; all were phenotypic females, 2 of whom were sex-reversed XY females carrying the mutation mentioned. Several models were proposed to explain association between a sequence variant in SRY and 2 alternative sex phenotypes. These included the existence of alleles at an unlinked locus. McElreavey et al. (1992) described an XY sex-reversed female with pure gonadal dysgenesis who harbored a de novo nonsense mutation in SRY, which resulted directly in the formation of a stop codon in the putative DNA-binding motif. A C-to-T transition at nucleotide 687 changed a glutamine codon (CAG) to a termination codon (TAG); see 480000.0005. The patient, referred to as the 'propositus,' was a phenotypic female who presented at age 20 years for primary amenorrhea. Treatment with estrogen induced menstruation and slight enlargement of the breasts which were underdeveloped. Laparotomy showed 2 streak gonads without germ cells or remnants of tubes. Harley et al. (1992) found point mutations in the region of the SRY gene encoding the high mobility group (HMG) box in 5 XY females. (The HMG box is related to that present in the T-cell-specific, DNA binding protein TCF1 (142410).) In 4 cases, the binding activity of mutant SRY protein for the AACAAAG core sequence was negligible; in the fifth case, DNA binding was reduced. In the SRY gene in a 46,XY female, Muller et al. (1992) demonstrated an A-to-T transversion of nucleotide 684 in the open reading frame, resulting in a change of lysine (AAG) to a stop codon (UAG). The patient had gonadoblastoma. - 46,XY True Hermaphroditism Maier et al. (2003) reported a 46,XY true hermaphrodite who had a mutation in the SRY gene (480000.0006). The father, his 3 brothers, and his first-born son carried the identical mutation without phenotypic effects. Maier et al. (2003) concluded that the mutated protein retained enough activity to allow normal development in some individuals. - Associations Pending Confirmation Norling et al. (2013) performed array CGH in 9 unrelated patients with 46,XY gonadal dysgenesis in whom sequence analysis of known gonadal dysgenesis-associated genes was negative, and identified 3 candidate regions: in a pair of affected sibs, a 217-kb interstitial duplication of exons 5 to 12 of the SUPT3H gene (602947) on chromosome 6p21, and a 22-kb deletion involving 8 of the 9 exons of the C2ORF80 gene (615536) on 2q34, both inherited from their unaffected mother; and in another patient, a 454-kb duplication at chromosome 9q21.11 involving the candidate genes PIP5K1B (602745), PRKACG (176893), and FAM189A2 (607710). Norling et al. (2013) noted that all 5 candidate genes are expressed in testicular tissues, but that detailed functional information was lacking. - Exclusion Studies Dumic et al. (2008) evaluated the Y chromosome in a 46,XY girl and her 46,XY mother and normal father, and confirmed that the girl inherited her Y chromosome from her father. Analysis of multiple candidate genes, including SOX9 (608160), SF1 (184757), DMRT1 (602424), DMRT3 (614754), TSPYL (604714), BPESC1, DHH (605423), WNT4 (603490), SRY (480000), and DAX1 (300473), revealed normal male coding sequences in both the mother and daughter.