Swyer syndrome

GONADAL DYSGENESIS, XY FEMALE TYPE; GDXY

Alternative titles; symbols

SWYER SYNDROMETESTIS-DETERMINING FACTOR, X-CHROMOSOMAL, INCLUDED; TDFX, INCLUDEDSEX-REVERSING LOCUS ON X, INCLUDED; SRVX, INCLUDED

Gene map locus Xp22.11-p21.2

TEXT

DESCRIPTION

Gonadal dysgenesis, XY female type, is associated with point mutations or deletions of the SRY gene (480000), but also in some cases with changes in the X chromosome.

At birth the patients with the XY female type of gonadal dysgenesis (Swyer syndrome) appear to be normal females; however, they do not develop secondary sexual characteristics at puberty, do not menstruate, and have 'streak gonads.' They are chromatin negative and have a 46,XY karyotype.

CLINICAL FEATURES

Affected sisters were reported by Cohen and Shaw (1965), and twins by Frasier et al. (1964). Sternberg et al. (1968) observed 3 cases, each in a different sibship of a family connected through normal females (proposita, maternal cousin, and maternal aunt). A high incidence of neoplasia (gonadoblastomas and germinomas) in streak gonads of patients with the XY karyotype was claimed by Taylor et al. (1966).

Patients are of normal stature and have no somatic stigmata of Turner syndrome except, of course, the lack of secondary sexual characteristics and streak gonads. In this condition, as in the testicular feminization syndrome (300068), it was at first unclear whether the gene that was responsible was on the X chromosome or on an autosome and expressed only in chromosomal males. Whether the abnormal gene directly suppresses testis-determining loci on the chromosome or blocks some early stage of testicular morphogenesis was also unknown. 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.

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. 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). Espiner et al. (1970) described 5 XY females in 3 sibships of 2 generations. They emphasized that the affected persons were unusually tall for females. The height of patients with XY gonadal dysgenesis (unusually great for females) is probably explained by androgen production in the streak gonad (Rose et al., 1974). Clitoromegaly is present in some cases.

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).

Moreira-Filho et al. (1979) suggested that there are 3 forms of Swyer syndrome (defined as streak gonads without other somatic features of the Turner syndrome and with a normal 46,XY karyotype). (1) Sporadic testicular agenesis syndrome (STAS) corresponds to H-Y negative Swyer syndrome. (2) Familial testicular agenesis syndrome (FTAS) is H-Y negative Swyer syndrome showing an X-linked recessive pedigree pattern. The mutation is probably homologous to that of the wood lemming. The phenotype of STAS and FTAS is identical even though the mutation is probably on the Y in STAS and on the X in FTAS. (3) In familial testicular dysgenesis syndrome (FTDS), the patients are H-Y positive and have a female phenotype and streak gonads; the streak gonads may contain testis-like tumoral structures. (See report of 3 sisters by Moreira-Filho et al. (1979) and cases of Wolf (1979).) The XY gonadal agenesis syndrome is a separate disorder (see 273250).

Passarge and Wolf (1981) pointed out that there are 2 groups of patients with XY gonadal dysgenesis (Swyer syndrome) and that each of these may be heterogeneous. One group is the H-Y antigen-positive form, which may represent a 'receptor disease.' The second is the H-Y antigen-negative form, which may be due to mutation in the H-Y generating system, either of the structural gene (presumably autosomal) or of a controlling gene (on the sex chromosomes). It may be only the H-Y antigen-positive cases that are at risk for gonadoblastoma or dysgerminoma.
See 233300 for discussion of the XX type of gonadal dysgenesis.

INHERITANCE

Simpson et al. (1981) reported 3 pedigrees of XY gonadal dysgenesis consistent with X-linked inheritance.
German et al. (1978) suggested that there is a gene on the X chromosome that blocks the testis-determining function of H-Y (which was then a leading candidate for TDF, testis-determining factor). However, it was later shown that TDF and H-Y antigen map to different parts of the Y chromosome with TDF being absent and H-Y antigen being present in XY females with Y short arm deletions (Simpson et al., 1987). See 278850. It appeared that 46,XY women had premature ovarian involution, with resulting 'streak gonads.' Families such as that of Barr et al. (1967) described above may indicate that the mutation is 'leaky.' The pedigree pattern was equally consistent with X-linked recessive or autosomal dominant inheritance. Indeed, Allard et al. (1972) observed transmission through a normal male, arguing for autosomal inheritance.
Nazareth et al. (1979) found H-Y positivity in a sporadic case occurring in an offspring of first-cousin parents. They favored recessive inheritance; see 233420.

CYTOGENETICS

De Arce et al. (1992) contributed further support of this hypothesis by demonstrating lack of gonadoblastoma in a 14-year-old girl who was a mosaic for 45X/46X-isodicentric Y. The anomalous Y chromosome showed no fluorescent distal Yq. In another patient, an 8-year-old girl with 45X/46XY karyotype, bilateral gonadoblastoma developed in her rudimentary ovaries at the age of 8.

Her normal Y chromosome showed the characteristic distal fluorescence seen in her father's Y chromosome. Using Y chromosome probes, De Arce et al. (1992) demonstrated the Y chromosome in the paraffin blocks of the ovarian tissue of both girls.

Wachtel (1979) and Wachtel et al. (1980) suggested the existence of 4 'causes' of XY gonadal dysgenesis: (1) mutational suppression of H-Y structural genes by regulatory elements of the X chromosome or failure of an X-linked structural gene (in association with H-Y negative somatic cell phenotype); (2) failure of H-Y antigen to engage its gonadal receptor (in association with the H-Y positive somatic cell phenotype); (3) loss of the critical moiety of H-Y genes in deleted or translocated Y chromosome (in association with H-Y negative or intermediate somatic cell phenotype); and (4) presence of XY-XO mosaicism.

(Small deletions in the short arm of the Y chromosome can result in 46,XY females (Disteche et al., 1986). The 2 patients reported by Disteche et al. (1986) had some signs of Turner syndrome, including congenital lymphedema and primary amenorrhea with streak gonads, but were of normal height. One of the patients had bilateral gonadoblastoma. Several Y-chromosome-specific DNA probes were found to be deleted in the 2 patients. DNA analysis showed that the 2 deletions were different, but included a common overlapping region likely to contain the testis-determining factor (TDF) gene.)

Bernstein et al. (1980) observed an abnormal band on Xp in a 46,XY female and her 46,XY female fetal sib. Despite the presence of an intact Y chromosome, neither had testicular differentiation and both were H-Y negative. Giemsa banding suggested duplication of p21 and p22. The maternal grandmother, mother and a younger sister, all phenotypically normal, had a karyotype 46,XXp+. The proband had profound psychomotor retardation, and both sibs had multiple congenital malformations. (The second sib was ascertained by amniocentesis for prenatal diagnosis followed by elective abortion.) Multiple congenital anomalies in the proband included ventricular septal defect, cleft palate, asymmetric skull and facies, prognathic jaw, low-set ears, and clinodactyly V. When the girl died at 5 year of age, postmortem studies showed hypoplastic uterus and fallopian tubes. Histologic examination of the uterine adnexa revealed an area of ovarian stroma with scattered degenerative follicles. There was no testicular morphology, and the external genitalia were those of a normal 5-year-old female. The second affected sib, the product of a pregnancy terminated at 20 weeks, showed ovaries containing numerous follicles and germ cells.

As in the proband, there was no evidence of testicular morphology. Wachtel (1998) referred to other cases of XY sex reversal in subjects with Xp duplication and chromosomal abnormalities resembling those in the family reported by Bernstein et al. (1980). This suggested occurrence of a gene on Xp, duplication of which can block development of the testis in an XY fetus. The gonads begin to develop as ovaries, but in the absence of the second X chromosome, the germ cells die, the follicles become atretic, and the ovaries degenerate.
Cytogenetic duplication of the X chromosome in males is a rare event usually characterized by a significant degree of phenotypic abnormality, which can include sex reversal despite an apparently normal Y chromosome. Arn et al. (1994) reported 2 half brothers with maternally inherited cytogenetic duplications of Xp and sex reversal; the absence of dysmorphic features in mother and children was thought to be because of the relatively small extent of the duplication. Comparison with previous reports allowed the putative sex reversing locus (SRVX) to be assigned to a 5- to 10-Mb segment between Xp22.11 and Xp21.2, which includes the DMD locus. The regional assignment may help in the isolation of SRVX mutations that may cause sex reversal in the 90% of sex-reversed women with XY gonadal dysgenesis who do not have detectable mutations of the SRY gene.

MAPPING

Mapping studies by hybridization to DNA from somatic cell hybrids containing various fragments of the X chromosome suggested that the sequence on the X chromosome maps to region Xp22.3-p21 (Page et al., 1987). Arn et al. (1994) mapped the SRVX gene to a 5- to 10-Mb segment between Xp22.11 and Xp21.2, which includes the DMD locus.

MOLECULAR GENETICS

Page et al. (1987) cloned a 230-kb segment of the human Y chromosome thought to contain some or all of the TDF 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. (TDF and SRY are written Tdy and Sry in the mouse.)

HETEROGENEITY

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 TCF-1 (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.

PATHOGENESIS

Page et al. (1987) advanced several hypotheses to explain the existence of the X-linked locus. One hypothesis was inconsistent with the prevailing notion of a dominantly acting sex-determining factor unique to the Y chromosome and suggested that the X and Y loci are functionally interchangeable, that both are testis determining, and that the X locus is subject to X-chromosome inactivation. According to this model, sex is determined by the total number of expressed X and Y loci: a single dose is female determining, while a double (or greater) dose is male determining. The addition of an X-derived transgene to the genome of an XX embryo should result in testis differentiation, as long as that transgene is not subject to X inactivation. Increased expression of the X-chromosomal locus could explain the presence of testicular tissue in XX hermaphrodites and the rare Y-negative XX males, who lack the TDF locus of the Y chromosome. Although some XY females lack TDF as judged by Y-DNA analysis, others do not have discernible deletions. These unexplained XY females may have point mutations in TDF or in genes that function in conjunction with or downstream of TDF. The model mentioned above suggests that mutation in the X-chromosomal locus (at Xp22.3-p21) could cause XY embryos to develop as females.

However, Berta et al. (1990) and Jager et al. (1990) presented compelling evidence that the mutation in one type of XY female gonadal dysgenesis is not on the X but on the Y chromosome. In the human sex-determining region in a 35-kb interval near the pseudoautosomal boundary of the Y chromosome, there is a candidate gene for testis-determining factor, termed SRY ('sex-reversed, Y,' from mouse terminology), which is conserved and specific to the Y chromosome in all mammals tested (Sinclair et al., 1990); see 480000. (Cherfas (1991) stated that SRY stands for 'sex-determining region Y.' This is a nice presumption and perhaps in its present usage should be so considered, but it does not indicate the true historical derivation.)

CLINICAL MANAGEMENT

Moreira-Filho et al. (1979) suggested that the H-Y antigen status in the Swyer syndrome may be a useful indicator of whether removal of the gonads is necessary to avoid malignancy.

SEE ALSO

Boczkowski (1976); Ghosh et al. (1978); Herbst et al. (1978); Judd et al. (1970); Koopman et al. (1991); Koopman et al. (1990); Mann et al. (1983); Wolf et al. (1980)