1071
XY Female
XY females are completely sex-reversed individuals who are phenotypically females with 46,XY karyotype, failure to develop secondary sex characteristics, amenorrhea, and “streak gonads”.
GENETICS/BASIC DEFECTS
1. SRY gene and its mouse homologue, Sry
a. The sex-determining region on the Y chromosome i. Mapped to the short arm of the Y chromosome ii. Encodes for a testis-determining factor (TDF) iii. Candidate gene narrowed down to a 35-kb inter-
val on the Y chromosome adjacent to the pseudoautosomal boundary which contains a Y chromosomal-specific sequence, named SRY (sex-determining region Y gene)
iv. Demonstration that mice transgenic for Sry developed into sex-reversed males despite an XX karyotype provided the confirmation of SRY being the TDF that directs the undifferen- tiated gonad into a testis
b. Deletions or mutations occurring in the SRY i. Result in failure of testis development ii. Sex differentiation along the female pathway 2. Mechanism of male to female sex reversal (abnormalities
of XY sex determination)
a. Mutations in the SRY gene resulting in XY females with gonadal dysgenesis (vs translocation of this gene sequence to X chromosome giving rise to XX males) i. Increasing variety of unique mutations within SRY gene reported in patients with gonadal dys- genesis/XY reversal. These patients are, in gen- eral, normal 46,XY females with complete gonadal dysgenesis
ii. SRY gene mutations noted in 15–20% of cases with complete gonadal dysgenesis
a) Most mutations are located in the High Mobility Group (HMG) box
b) De novo mutations affect only one individ- ual in a family in the majority of cases c) Phenotypic variability is associated with dif-
ferent mutations
iii. About one third of the SRY mutations reported are inherited.
a) No apparent explanation available to explain why an inherited SRY mutation which results in sex reversal in the offspring is associated with a normal male phenotype in the father and sometime in brothers and uncles.
b) Paternal mosaicism for the mutant SRY pro- vides an explanation for the other familial cases of XY gonadal dysgenesis.
iv. 80% of patients with sporadic or familial 46,XY gonadal dysgenesis lack a mutation or deletion of the SRY gene, indicating that other autosomal or X-linked genes have a role in sex determination.
b. Sox9
i. Another gene involved in sex determination identified by positional cloning of a chromoso- mal breakpoint has been identified in the XY female with campomelic dysplasia, a condition in which three-quarters of XY patients show genital and gonadal malformations.
ii. Belongs to a family of SRY-box related (SOX) genes which encode proteins with at least 60%
amino acid homology to the HMG box of the SRY protein
c. Atrx
i. The gene responsible for the ATR-X syndrome causes α-thalassemia, severe mental retardation and multiple congenital anomalies which may include 46,XY gonadal dysgenesis and under- masculinization.
ii. The C-terminal region of the protein has been lost in most cases where there has been gonadal dysgenesis associated with ATR-X syndrome.
d. Deletions of variable portions of the short arm of chromosome 9 (DMRT-1 identified as a candidate gene) result in partial or complete gonadal dysgenesis in XY females
e. Sex-reversing Xp duplication (Xp21)
CLINICAL FEATURES
1. 46,XY females (individuals with 46,XY complete gonadal dysgenesis) (Swyer Syndrome)
a. Diagnosed usually not made until puberty when the patient presents with delayed pubertal development b. Unambiguous female phenotype with completely
female external genitalia
c. Gonadal dysgenesis (streak gonads) d. Well developed Mullerian structures e. Absence of testicular development
f. Absence of Wolffian structures
g. Absence of other somatic abnormalities h. Absence of secondary sexual characteristics
i. Amenorrhea
j. High risk of developing gonadal tumors i. Gonadoblastoma
ii. Dysgerminoma 2. Differential diagnosis
a. Individuals with 46,XY partial gonadal dysgenesis
(also called 46,XY mixed gonadal dysgenesis or dys-
genetic male pseudohermaphroditism)
1072 XY FEMALE
i. Majority of patients present in the newborn period for evaluation of ambiguous genitalia ii. Partial testicular determination. The extent of
masculinization of the external genitalia depends on the extent of testicular differentiation.
iii. Dysgenetic gonads
iv. Presence of Mullerian and Wolffian structures v. Regarded as the clinical spectrum of 46,XY
gonadal dysgenesis
b. Individuals with 46,XY embryonic testicular regres- sion syndrome (also called true agonadism or gonadal agenesis)
i. A term used to describe the spectrum of genital anomalies resulting from regression of testis development from 8–14 weeks of gestation ii. Regression of the fetal testes between the 8–10
weeks of gestation
a) Complete absence of gonads
b) Rudimentary Mullerian and/or Wolffian ductal structure
c) Hypoplastic uterus
d) Female genitalia with/or without ambiguity iii. Regression of the testes after the critical period
of male differentiation (around 12–14 weeks) a) Anorchia
b) Partial testicular regression resulting in a male phenotype as in anorchia but with small rudimentary testes
DIAGNOSTIC INVESTIGATIONS
1. Karyotype analysis
a. 46,XY in phenotypic females
b. To exclude 45,X/46,XY and other forms of mosaicism, served to exclude the more common forms of gonadal dysgenesis
2. Molecular analysis for SRY gene
a. Nucleotide substitutions (missense/nonsense) b. Deletions
c. Insertions
3. Ultrasonography/laparotomy a. Complete gonadal dysgenesis
i. Streak gonads
ii. Presence of Mullerian ducts iii. Absence of Wolffian ducts b. Partial gonadal dysgenesis
i. Dysgenetic gonads
ii. Presence of Mullerian and Wolffian structures 4. Gonadal histology
a. Streak gonads
i. Absence of primordial follicles
ii. Wavy ovarian stroma intermixed with fibrous tissue b. Gonadal tumors observed in about 30% of cases
i. Gonadoblastomas: usually benign ii. Dysgerminoma
iii. Embryonal carcinoma: more life-threatening 5. Biochemical findings
a. Elevated levels of FSH and LH b. Low levels of estradiol
c. No elevation of androgen levels
GENETIC COUNSELING
1. Recurrence risk
a. Patient’s sib: recurrence risk depending on whether the inheritance is X-linked recessive, male-limited autosomal dominant, or autosomal recessive
b. Patient’s offspring: Patients are nonreproductive c. To rule out the disease in siblings because of the pres-
ence of familial aggregation.
2. Prenatal diagnosis: demonstration of the sexual discrep- ancy between fetal karyotype (XY) and ultrasonographic fetal phenotype
a. To exclude sample error and placental mosaicism b. Detailed fetal ultrasound examination to check for
syndromic gender discrepancy such as:
i. Campomelic dysplasia (skeletal malformation) ii. Denys-Drash syndrome
iii. Smith-Lemli-Opitz syndrome a) Microcephaly
b) Abnormal cholesterol metabolism iv. Alfi syndrome
a) Craniostenosis b) Trigonocephaly
c) Multiple congenital anomalies
c. Prenatal diagnosis possible by SRY analysis for XY gonadal dysgenesis (SRY-negative XY female and SRY-positive XY female)
i. FISH using SRY probe on metaphase chromo- somes
ii. Sequencing of entire coding region 3. Management
a. Removal of gonads to avoid malignancy
b. Initiate cyclic hormonal therapy with estrogen and progesterone at puberty
c. Psychological counseling i. Raise as a female
ii. Increase patient’s knowledge about medical and surgical history and karyotype
iii. Counseling for sexual function
iv. Achievement of pregnancy in some patients fol- lowing in vitro fertilization with a donor egg
REFERENCES
Ahmed SF, Hughes IA: The genetics of male undermasculinization. Clin Endocr 56:1–18, 2002.
Arn P, Chen H, Tuck-Muller CM, et al.: SRVX, a sex reversing locus in Xp21.2-p22.11. Hum Genet 93:389–393, 1994.
Bardoni B, Zanaria E, Guioli S, et al.: A dosage sensitive locus at chromo- some Xp21 is involved in male to female sex reversal. Nature Genet 7:497–501, 1994.
Barr ML, Carr DH, Plunkett E R, et al.: Male pseudohermaphroditism and pure gonadal dysgenesis in sisters. Am J Obstet Gynec 99:1047–1055, 1967.
Berkovitz GD: Abnormalities of gonad determination and differentiation.
Semin Perinatol 16:289–298, 1992.
Berta P, Hawkins JR, Sinclair AH, et al.: Genetic evidence equating SRY and the testis-determining factor. Nature 348:448–450, 1990.
Bretelle F, Salomon L, Senat M-V, et al.: Fetal gender: antenatal discrepancy between phenotype and genotype. Ultrasound Obstet Gynecol 20:286–289, 2002.
Calvan V, Bertini V, De Grandi A, et al.: A new submicroscopic deletion that refines the 9p region for sex reversal. Genomics 65:203–212, 2000.
XY FEMALE 1073
Cameron F, Sinclair AH: Mutations in SRY and SOX9: testis-determining genes. Hum Mutat 9:388–395, 1997.
Davis RM: Localization of male-determining factors in man: A thorough review of structural anomalies of the Y chromosome. J Med Genet 18:161–195, 1981.
Goodfellow PN, Lovell-Badge R: SRY and sex determination in mammals.
Annu Rev Genet 27:71–92, 1993.
Graves PE, Davis D, Erickson RP, et al.: Ascertainment and mutational studies of SRY in nine XY females. Am J Med Genet 83:138–139, 1999.
Harley VR, Goodfellow PN: The biochemical role of SRY in sex determina- tion. Mol Reprod Dev 39:184–193, 1994.
Hawkins JR: Genetics of XY sex reversal. J Endocrinol 147:183–187, 1995.
Hawkins JR, Taylor A, Berta P, et al.: Mutational analysis of SRY: nonsense and missense mutations in XY sex reversal. Hum Genet 88:471–475, 1992.
Hawkins JR, Taylor A, Goodfellow PN, et al.: Evidence for increased preva- lence of SRY mutations in XY females with complete rather than partial gonadal dysgenesis. Am J Hum Genet 51:979–984, 1992.
Hines RS, Tho SPT, Zhang YY, et al.: Paternal somatic and germ-line mosaicism for a sex-determining region on Y (SRY) missense mutation leading to recurrent 46,XY sex reversal. Fertil Steril 67:675–679, 1997.
Jacob PA, Ross A: Structural abnormalities of the Y chromosome in man.
Nature 210:352–354, 1966.
Jäger RJ, Anvret M, Hall K, et al.: A human XY female with a frame shift mutation in the candidate testis-determining gene SRY. Nature 348:452–454, 1990.
Jordan BK, Jain M, Natarajan S, et al.: Familial mutation in the testis-determin- ing gene SRY shared by an XY female and her normal father. J Clin Endocrinol Metab 87:3428–3432, 2002.
Koopman P, Gubay J, Vivian N, et al.: Male development of chromosomally female mice transgenic for Sry. Nature 351:117–121, 1991.
Kwok C, Weller PA, Guioli S, et al.: Mutations in SOX9, the gene responsible for campomelic dysplasia and autosomal sex reversal. Am J Hum Genet 57:1028–1036, 1995.
Kwok C, Tyler-Smith C, Mendonca BB, et al.: Mutation analysis of the 2 kb 5' to SRY in XY females and XY Intersex subjects. J Med Genet 33:465–468, 1996.
McDonald MT, Flejter W, Sheldon S, et al.: XY sex reversal and gonadal dys- genesis due to 9p24 monosomy. Am J Med Genet 73:321–326, 1997.
McElreavey K, Fellous M: Sex determination and the Y chromosome. Am J Med Genet (Semin Med Genet) 89:176–185, 1999.
McElreavey K, Vilain E, Abbas N, et al.: XY sex reversal associated with a deletion 5’ to the SRY “HMG box” in the testis-determining region. Proc Natl Acad Sci USA 89:11016–11020, 1992.
McElreavey K, Vilain E, Barbauxz S, et al.: Loss of sequences 3’ to the testis- determining gene, SRY, including the Y pseudoautosomal boundary asso- ciated with partial testicular determination. Proc Natl Acad Sci USA 93:8590–8594, 1996.
Morerio C, Calvari V, Rosanda C, et al.: XY female with a dysgerminoma and no mutation in the coding sequence of the SRY gene. Cancer Genet Cytogenet 136:58–61, 2002.
Nazareth HRS, Moreira-Filho CA, Cunha AJB, et al. antigens in 46,XY pure testicular dysgenesis. Am J Med Genet 3:149–154, 1979.
Portuondo JA, Neyro JL, Barral A, et al.: management of phenotypic female patients with an XY karyotype. J Reprod Med 31:611–615, 1986.
Sarafoglou K, Ostrer H: Familial sex reversal: a review. J Clin Endocrinol Metab 85:483–493, 2000.
Sauer MV, Lobo RA, Paulson RJ: Successful twin pregnancy after embryo donation to a patient with 46,XY gonadal dysgenesis. Am J Obstet Gynecol 161:380–381, 1989.
Schäffler A, Barth N, Winkler K, et al.: Identification of a new missense muta- tion (Gly95Glu) in a highly conserved codon within the high-mobility group box of the sex-determining region Y gene: report on a 46,XY female with gonadal dysgenesis and yolk-sac tumor. J Clin Endocrinol Metab 85:2287–2292, 2000.
Simpson JL, Blgowidow N, Martin AO: XY gonadal dysgenesis: genetic het- erogeneity based upon clinical observations, H-Y antigen status, and seg- regation analysis. Hum Genet 58:91–97, 1981.
Sinclair AH, Berta P, Palmer MS, et al.: A gene from the human sex-determin- ing region encodes a protein with homology to a conserved DNA-binding motif. Nature 346:240–245, 1990.
Swain A, Zanaria E, Hacker A, et al.: Mouse Dax1 expression is consistent with a role in sex determination as well as in adrenal and hypothalamus func- tion. Nature Genet 12:404–409, 1996.
Veitia R, Ion A, Barbaux S, et al.: Mutations and sequence variants in the testis- determining region of the Y chromosome in individuals with a 46,XY female phenotype. Hum Genet 99:648–652, 1997.
Vilain E, Jaubert F, Fellous M, et al.: Pathology of 46,XY pure gonadal dysge- nesis: absence of testis differentiation associated with mutations in the testis-determining factor. Differentiation 52:151–159, 1993.
1074 XY FEMALE
Fig. 1. A patient with 46,XY female with gonadal dysgenesis at 42 years of age. Patient has short stature (4’6”), primary amenorrhea, lack of secondary sex characteristics (absent axillary hair, poor breast development), but normal female external genitalia. Laparotomy revealed absent Wolffian structures and presence of uterus and streak gonads which were excised.
