SEX REVERSAL SYNDROME (XX Male) GEORGE ZAKHARIA, M.D. DENNIS J. KRAUSS, M.D. From the Department of Veterans Affairs Medical Center, Health Science Center, State University of New York, Syracuse, New York
ABSTRACT--Men who appear normal and live a normal life, may have a 46,XX karyotype and present with the typical features of infertility and end organ (testicular) failure. They are azoospermic and their small testicles show specific patterns on light and electron microscopy. Recent advances in genetics (I) favor the "X-Y interchange" theory to explain this phenomenon; (2) hypothesize about the roles of the H-Y antigen and testis determining factor (TDF) in determining "maleness'} and (3) allow mapping of the relative positions of H-Y and TDF loci on the Y chromo' 8ome.
In mammals, genetic sex is determined by the presence or absence of the Y chromosome. People with 45,XO chromosome constitution (Turner syndrome) are phenotypically female with short stature and gonadal dysgenesis. Those with 47,XXY are usually tall and phenotypically male with hypogonadism (Klinefelter syndrome). Mosaieism of 45,XO and 46,XY is associated with a spectrum of phenotypes from the Turner syndrome through ambiguous genitalia and mixed gonadal dysgenesis to normal male. Exceptions to this are the normal-appearing females with 46,XY (testicular feminization) and normal-appearing males with 46,XX chromosomes (sex reversed males). More than 150 males with a 46,XX chromosome constitution have been reported since the first by de la Chapelle in 1964.1 Most cases occur sporadically, at an estimated frequency of 1 per 20,000 males. 2
CYTOGEN£1ICS LABORATORY ,JostaCe Medical Center 5yrncuse, New York
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Case Report
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The patient is a twenty-eight-year-old white man who presented to our urology clinic because of infertility and "shrinking testicles." He claimed to have a satisfying sexual life and no
322
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FIGURE 1. Karyotype of "sex reversed" (XX) real6,
UROLOGY
/
OCTOBER 1990
/
VOLUME XXXVI, NUMBER 4
"~4
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hyperplasia, no germ cells present. (Original magnification x 180.)
Q
Comment The XX male is a phenotypieally and psychosexually normal male. He will have small testes and a small-to-normal-sized penis. Affected adults are shorter in height than average. One third of adults have gynecomastia. All are infertilea; hypospadias occurs in 10 percent and eryptorehism in 15 percent. 4 Testosterone may be at a low normal level. li;~FSH and LH are usually inereasedS; the prolae• tin level is normal. Semen analysis shows no spermatozoa Light microscopic examination of :~ the testes usually reveals hyalinized seminifer/
,,
~
history of erection problems. He had mumps as a ehild but no orchitis. He was intelligent, with a height of 165 em, and weight of 65 kg, mild gyneeomastia bilaterally and a small eervieodorsal hump. He had a normal male hair pattern and normal penis. His left testicle measured 2.0 em x 1.5 em and the right testiele was 1.5 em x 1.5 em. Semen analysis (done twice) revealed no sperm. There was normal fructose, viscosity, pH, and volume. Serum hormone levels ineluded: testosterone 240 ng/dL (300-1,000); follicle-stimulating hormone (FSH) 72 mIU/dL (5-25); luteinizing hormone (LH) 61 mIU/dL (6-30); proiactin 16.3 ng/dL (7-18). Tests of adrenal function were normal. Chromosome analysis done on the peripheral blood lymphocytes and on skin fibroblasts revealed 46,XX (Fig. 1). There was no evidence of mosaicism. Testieular biopsy revealed both Leydig cell and Sertoli cell hyperplasia; no germ cells were seen in the tubules (Fig. 2).
:~:UROLOGY
#
FIGURE 2. XX male testicular biopsy: (A) Leydig cell hyperplasia; (B) seminiferous tubules with Sertoli cell
;.
OCTOBER 1990
/
ous tubules which contain only Sertoli cells. There is frequently Leydig cell hyperplasia. 6,7 Electron microscopically, the Sertoli eells show a large number of lipid droplets and microfflaments. Leydig cells ean be immature, also having cytoplasm vacuolated with large lipid droplets and/or containing abundant microfilament bundles and microcrystalline inelusions; or even may be normal. This subpopulation of ultrastructurally normal Leydig cells is probably responsible for most of the testosterone biosynthesis, s There are several theories to try to explain the etiology of this condition. Aeeording to the "autosomal gene theory," the male sex determining factors are loeated on chromsomes other than the Y. A gonad, under the influence of this autosomal gene for maleness, would develop into a testis. For this testis to be normal the Y chromosome would have to exert some effect. The "mosaieism theory" postulates the existence of a eell line containing a Y ehromosome that was present during an early stage of development but was subsequently lost. The presence of Y material in the genome of XX males (described below) speaks against this theory. The transloeation ("X-Y Interehange") of a portion of the Y chromosome to the X, is the most compelling theory. XX maleness is the result of a transloeation during paternal meiosis, such that some of the Y's ehromosome material is transferred to the X chromosome2 The first evidenee in support of this is that some XX males with the blood group Xg(a - ) had fathers who are Xg(a + ).1° Since the Xg(a) inheritance is X-linked dominant, there must have been
VOLUME XXXVI, NUMBER 4
323
some interchange of genetic material so that the X carried by the sperm has Y material and not the Xg(a) material. The next evidence for the X to be containing Y DNA is through the use of chromosome banding procedures. Madan and Walked 1,12reported that the terminal pale band (p22) of the short arm of one X chromosome (of an XX male subjeer) is longer than the p22 band of the other X chromosome of the pair. This occurred in 80 percent of the cells they analyzed. T M Third, using several Y-specific, single copy "probes" that have been isolated, it has been shown that there is Y chromosome material in the genome of XX males. 13,14 Still further evidence comes from in situ hybridization of Y-specific probes showing that the Y DNA for testis differentiation ("testis determining factor" or TDF) is located on the tip of the short arm of the Y chromosome. ~5 This is borne out by the finding of normal-appearing females who have an XY chromosome constitution with a deletion of the Y short arm.~6,~7 "Maleness" in XX males seems to be determined by the testis determining factor (TDF) rather than the H-Y antigen. Earlier evidence suggested that the H-Y antigen plays a role in testicular differentiation~S.19; others have proposed that H-Y antigen is the TDF. 2° More recently it has been shown, by DNA hybridization studies using Y-specific probes on a series of sex reversed humans (XX males and XY females), that the gene for H-Y antigen is located on the long arm or perieentromerie region of the human Y chromosome, away from the TDF locus (which is on the distal short arm). Since some XX males are H - Y ( - ) and some XY females are H-Y( + ), the H-Y antigen does not seem to function in the process of sex determination of the undifferentiated gonad. It may well influence the later development and normal hormonal and sperm-producing function of the testis. In addition, since some XX males have been found to be H-Y antigen positive, then these particular people probably have their H-Y determining genetic material in a position so that it translocates along with the rest of the Y short arm (and the TDF).2~ Summary
Syracuse, New York 13210 (DR. ZAKHARIA) References 1. de la Chapelle A, Hortling H, Niemi N, and Wennestrom J: : XX sex chromosomes in a human male. First ease, Acta Med Stand (suppl 412) 175:25 (1964). 2. de la Chapelle A: Etiology of malenesss in XX men, Hum Genet 58:105 (1981). 3. Minowada S, et al: Two XX male brothers, Clin Goner 15:
399 (1979). 4. Raspa RW, Burbige KA, and Hensle TW: The sex reversal syndrome (the XX male patient), J Urol 134:152 (1985). 5. Borghi A, et al: La sindrome del masehio XX, Ree Progr Med 64:152 (1978). 6. de la Chapelle A: Analytic review: nature and origin of males with XX sex chromosomes, Am J Genet 24:71 (1972). 7. Pals VM, and Vasudevan P: Infertility in an XX male, J Urol 110:690 (1977). 8. Nistal M, and Paniagua R: Ultrastrueture of testieular biopsy from an XX male, Virehows Arch B Cell Pathol 31:45
(1979). 9. Ferguson-Smith MA: X-Y chromosomal interchange in the aetiology of true hermaphroditism and of XX Klinefelter's syndrome, Lancet 2:475 (1966). 10. de la Chapelle A, Tippett PA, Wetterstrand G, and Page D: Genetic evidence of X-Y interchange in a human XX male, Nature 307:170 (1984). 11. Madan K, and Walker S: Possible evidence for Xp + in an XX male, Lancet 1:1223 (1974). 12. Madan K: Chromosome measurements of an XXp + male, Hum Genet 32:141 (1976). 13. Guellaen G, et al: Human XX males with Y single-copy DNA fragments, Nature 307:172 (1984). 14. Magenis RE, et al: Further cytologic evidence for Xp-Yp : transloeation in XX males using in situ hybridization with Y-derived probe, Hum Genet 75:228 (1987). 15. Anderson M, Page DC, and de la Chapelle A: Chromosome Y-specific DNA is transferred to the short arm of X chromosome in human XX males, Science 233:786 (1986). ;' 16. Rosenfeld RG, et al: Sexual and somatic determinants o f the human Y chromosome: studies in a 46,XYP-phenotypie female, Am J Hum Genet 31:458 (1979). 17. Magenis RE, et al: Turner syndrome resulting from partial deletion of Y chromosome short arm: localization of male determinants, J Pediatr 105:916 (1984). 18. Wachtel SS: Immunogenetie aspects of abnormal sexual differentiation, Cell 16:691 (1979). 19. Magenis RE, et al: Translocation (X;Y) (p 22.33; p 11.2)ir~ XX males: etiology of male phenotype, Hum Genet 62:271
(1982).
The "sex reversed" (46,XX) males have Y chromosome material present on one of the X chromosomes. It is there probably because of an exchange of genetic material between the X and 324
Y chromosomes during paternal sperm produe. tion. Many of these XX men are H-Y antigen negative; the rest are X-Y positive. All should have the testis determining factor. The site of the break in the Y chromosome determines whether or not both loci will be present on the X. Development of the undifferentiated gonad into a testis is controlled by the TDF. The H-Y antigen may play its role at a later stage of d e velopment.
20. Wachtel SS, Ohno S, Koo GC, and Boyse EA: Possible role for H-Y antigen in the primary determination of sex, Nature 257~ 235 (1975). 21. Simpson E, et al: Separation of the genetic loci for the H-Y : antigen and for testis determination on human Y chromosome, Nature 326:876 (1987).
UROLOGY
/
OCTOBER 1990
/
VOLUME XXXVI, NUMBER 4
ill
ABSTRACT--Men who appear normal and live a normal life, may have a 46,XX karyotype and present with the typical features of infertility and end organ (testicular) failure. They are azoospermic and their small testicles show specific patterns on light and electron microscopy. Recent advances in genetics (I) favor the "X-Y interchange" theory to explain this phenomenon; (2) hypothesize about the roles of the H-Y antigen and testis determining factor (TDF) in determining "maleness'} and (3) allow mapping of the relative positions of H-Y and TDF loci on the Y chromo' 8ome.
In mammals, genetic sex is determined by the presence or absence of the Y chromosome. People with 45,XO chromosome constitution (Turner syndrome) are phenotypically female with short stature and gonadal dysgenesis. Those with 47,XXY are usually tall and phenotypically male with hypogonadism (Klinefelter syndrome). Mosaieism of 45,XO and 46,XY is associated with a spectrum of phenotypes from the Turner syndrome through ambiguous genitalia and mixed gonadal dysgenesis to normal male. Exceptions to this are the normal-appearing females with 46,XY (testicular feminization) and normal-appearing males with 46,XX chromosomes (sex reversed males). More than 150 males with a 46,XX chromosome constitution have been reported since the first by de la Chapelle in 1964.1 Most cases occur sporadically, at an estimated frequency of 1 per 20,000 males. 2
CYTOGEN£1ICS LABORATORY ,JostaCe Medical Center 5yrncuse, New York
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i ~'ab 13
14
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Case Report
-7
The patient is a twenty-eight-year-old white man who presented to our urology clinic because of infertility and "shrinking testicles." He claimed to have a satisfying sexual life and no
322
~EX C HROMC~SOIa[ 5
FIGURE 1. Karyotype of "sex reversed" (XX) real6,
UROLOGY
/
OCTOBER 1990
/
VOLUME XXXVI, NUMBER 4
"~4
•
m
Jo
~ ~, lt ~,
,,%
•
"1
_
hyperplasia, no germ cells present. (Original magnification x 180.)
Q
Comment The XX male is a phenotypieally and psychosexually normal male. He will have small testes and a small-to-normal-sized penis. Affected adults are shorter in height than average. One third of adults have gynecomastia. All are infertilea; hypospadias occurs in 10 percent and eryptorehism in 15 percent. 4 Testosterone may be at a low normal level. li;~FSH and LH are usually inereasedS; the prolae• tin level is normal. Semen analysis shows no spermatozoa Light microscopic examination of :~ the testes usually reveals hyalinized seminifer/
,,
~
history of erection problems. He had mumps as a ehild but no orchitis. He was intelligent, with a height of 165 em, and weight of 65 kg, mild gyneeomastia bilaterally and a small eervieodorsal hump. He had a normal male hair pattern and normal penis. His left testicle measured 2.0 em x 1.5 em and the right testiele was 1.5 em x 1.5 em. Semen analysis (done twice) revealed no sperm. There was normal fructose, viscosity, pH, and volume. Serum hormone levels ineluded: testosterone 240 ng/dL (300-1,000); follicle-stimulating hormone (FSH) 72 mIU/dL (5-25); luteinizing hormone (LH) 61 mIU/dL (6-30); proiactin 16.3 ng/dL (7-18). Tests of adrenal function were normal. Chromosome analysis done on the peripheral blood lymphocytes and on skin fibroblasts revealed 46,XX (Fig. 1). There was no evidence of mosaicism. Testieular biopsy revealed both Leydig cell and Sertoli cell hyperplasia; no germ cells were seen in the tubules (Fig. 2).
:~:UROLOGY
#
FIGURE 2. XX male testicular biopsy: (A) Leydig cell hyperplasia; (B) seminiferous tubules with Sertoli cell
;.
OCTOBER 1990
/
ous tubules which contain only Sertoli cells. There is frequently Leydig cell hyperplasia. 6,7 Electron microscopically, the Sertoli eells show a large number of lipid droplets and microfflaments. Leydig cells ean be immature, also having cytoplasm vacuolated with large lipid droplets and/or containing abundant microfilament bundles and microcrystalline inelusions; or even may be normal. This subpopulation of ultrastructurally normal Leydig cells is probably responsible for most of the testosterone biosynthesis, s There are several theories to try to explain the etiology of this condition. Aeeording to the "autosomal gene theory," the male sex determining factors are loeated on chromsomes other than the Y. A gonad, under the influence of this autosomal gene for maleness, would develop into a testis. For this testis to be normal the Y chromosome would have to exert some effect. The "mosaieism theory" postulates the existence of a eell line containing a Y ehromosome that was present during an early stage of development but was subsequently lost. The presence of Y material in the genome of XX males (described below) speaks against this theory. The transloeation ("X-Y Interehange") of a portion of the Y chromosome to the X, is the most compelling theory. XX maleness is the result of a transloeation during paternal meiosis, such that some of the Y's ehromosome material is transferred to the X chromosome2 The first evidenee in support of this is that some XX males with the blood group Xg(a - ) had fathers who are Xg(a + ).1° Since the Xg(a) inheritance is X-linked dominant, there must have been
VOLUME XXXVI, NUMBER 4
323
some interchange of genetic material so that the X carried by the sperm has Y material and not the Xg(a) material. The next evidence for the X to be containing Y DNA is through the use of chromosome banding procedures. Madan and Walked 1,12reported that the terminal pale band (p22) of the short arm of one X chromosome (of an XX male subjeer) is longer than the p22 band of the other X chromosome of the pair. This occurred in 80 percent of the cells they analyzed. T M Third, using several Y-specific, single copy "probes" that have been isolated, it has been shown that there is Y chromosome material in the genome of XX males. 13,14 Still further evidence comes from in situ hybridization of Y-specific probes showing that the Y DNA for testis differentiation ("testis determining factor" or TDF) is located on the tip of the short arm of the Y chromosome. ~5 This is borne out by the finding of normal-appearing females who have an XY chromosome constitution with a deletion of the Y short arm.~6,~7 "Maleness" in XX males seems to be determined by the testis determining factor (TDF) rather than the H-Y antigen. Earlier evidence suggested that the H-Y antigen plays a role in testicular differentiation~S.19; others have proposed that H-Y antigen is the TDF. 2° More recently it has been shown, by DNA hybridization studies using Y-specific probes on a series of sex reversed humans (XX males and XY females), that the gene for H-Y antigen is located on the long arm or perieentromerie region of the human Y chromosome, away from the TDF locus (which is on the distal short arm). Since some XX males are H - Y ( - ) and some XY females are H-Y( + ), the H-Y antigen does not seem to function in the process of sex determination of the undifferentiated gonad. It may well influence the later development and normal hormonal and sperm-producing function of the testis. In addition, since some XX males have been found to be H-Y antigen positive, then these particular people probably have their H-Y determining genetic material in a position so that it translocates along with the rest of the Y short arm (and the TDF).2~ Summary
Syracuse, New York 13210 (DR. ZAKHARIA) References 1. de la Chapelle A, Hortling H, Niemi N, and Wennestrom J: : XX sex chromosomes in a human male. First ease, Acta Med Stand (suppl 412) 175:25 (1964). 2. de la Chapelle A: Etiology of malenesss in XX men, Hum Genet 58:105 (1981). 3. Minowada S, et al: Two XX male brothers, Clin Goner 15:
399 (1979). 4. Raspa RW, Burbige KA, and Hensle TW: The sex reversal syndrome (the XX male patient), J Urol 134:152 (1985). 5. Borghi A, et al: La sindrome del masehio XX, Ree Progr Med 64:152 (1978). 6. de la Chapelle A: Analytic review: nature and origin of males with XX sex chromosomes, Am J Genet 24:71 (1972). 7. Pals VM, and Vasudevan P: Infertility in an XX male, J Urol 110:690 (1977). 8. Nistal M, and Paniagua R: Ultrastrueture of testieular biopsy from an XX male, Virehows Arch B Cell Pathol 31:45
(1979). 9. Ferguson-Smith MA: X-Y chromosomal interchange in the aetiology of true hermaphroditism and of XX Klinefelter's syndrome, Lancet 2:475 (1966). 10. de la Chapelle A, Tippett PA, Wetterstrand G, and Page D: Genetic evidence of X-Y interchange in a human XX male, Nature 307:170 (1984). 11. Madan K, and Walker S: Possible evidence for Xp + in an XX male, Lancet 1:1223 (1974). 12. Madan K: Chromosome measurements of an XXp + male, Hum Genet 32:141 (1976). 13. Guellaen G, et al: Human XX males with Y single-copy DNA fragments, Nature 307:172 (1984). 14. Magenis RE, et al: Further cytologic evidence for Xp-Yp : transloeation in XX males using in situ hybridization with Y-derived probe, Hum Genet 75:228 (1987). 15. Anderson M, Page DC, and de la Chapelle A: Chromosome Y-specific DNA is transferred to the short arm of X chromosome in human XX males, Science 233:786 (1986). ;' 16. Rosenfeld RG, et al: Sexual and somatic determinants o f the human Y chromosome: studies in a 46,XYP-phenotypie female, Am J Hum Genet 31:458 (1979). 17. Magenis RE, et al: Turner syndrome resulting from partial deletion of Y chromosome short arm: localization of male determinants, J Pediatr 105:916 (1984). 18. Wachtel SS: Immunogenetie aspects of abnormal sexual differentiation, Cell 16:691 (1979). 19. Magenis RE, et al: Translocation (X;Y) (p 22.33; p 11.2)ir~ XX males: etiology of male phenotype, Hum Genet 62:271
(1982).
The "sex reversed" (46,XX) males have Y chromosome material present on one of the X chromosomes. It is there probably because of an exchange of genetic material between the X and 324
Y chromosomes during paternal sperm produe. tion. Many of these XX men are H-Y antigen negative; the rest are X-Y positive. All should have the testis determining factor. The site of the break in the Y chromosome determines whether or not both loci will be present on the X. Development of the undifferentiated gonad into a testis is controlled by the TDF. The H-Y antigen may play its role at a later stage of d e velopment.
20. Wachtel SS, Ohno S, Koo GC, and Boyse EA: Possible role for H-Y antigen in the primary determination of sex, Nature 257~ 235 (1975). 21. Simpson E, et al: Separation of the genetic loci for the H-Y : antigen and for testis determination on human Y chromosome, Nature 326:876 (1987).
UROLOGY
/
OCTOBER 1990
/
VOLUME XXXVI, NUMBER 4
ill
