Human Genetics

, Volume 84, Issue 2, pp 198–202 | Cite as

Genotype-phenotype correlations in XX males and their bearing on current theories of sex determination

  • M. A. Ferguson-Smith
  • A. Cooke
  • N. A. Affara
  • E. Boyd
  • J. L. Tolmie
Short Communications


Clinical, chromosomal and molecular studies of a group of 15 XX males confirm the presence of two main groups. A Y+ve group of ten patients exhibit sex reversal as the result of transfer of the distal end of the short arm of the Y chromosome, including testis determining factors, to the short arm of one X-chromosome, presumably by accidental crossing-over in paternal meiosis. The ten patients have Klinefelter's syndrome but differ from XXY cases in that they are short and shown no impairment of intelligence. The four Y-ve XX males have no demonstrable Y sequences and differ from Y+ve cases in abnormality of the external genitalia and invariable gynaecomastia; in this, they more closely resemble XX true hermaphrodites than XY males. These observations on Y-ve XX males and an additional exceptional Y+ patient suggest that the ZFY locus is not essential for male differentiation and is not the primary testis determining factor. Male sex determination in sporadic, and familial Y-ve XX males and true hermaphrodites is likely to be the result of mutation in an X-linked TDF gene and its consequent escape from the constraints of X-inactivation. It seems premature to abandon the dosage model of sex determination on the recent evidence that ZFX does not show dosage compensation.


Dosage Compensation External Genitalia Primary Testis Dosage Model Male Differentiation 
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  1. Abbas N, Boucekkine C, Moreira-Filho CA, Ternes-Pereira E, Cabralde-Almeida JC, Fellous M (1989) Familial cases of XX males: argument for a common origin of Y negative 46 XX males and true hermaphrodites (abstract). (10th International Workshop on Human Gene Mapping) Cytogenet Cell Genet 51:948Google Scholar
  2. Affara NA, Ferguson-Smith MA, Tolmie J, Kwok K, Mitchell M, Jamieson D, Cooke A, Florentin L (1986) Variable transfer of Y-specific sequences in XX males. Nucleic Acids Res 14:5375–5387Google Scholar
  3. Affara N, Chambers D, O'Brien J, Habeebu SSM, Kalaitsidaki M, Bishop CE, Ferguson-Smith MA (1989) Evidence for distinguishable transcripts of the putative testis determining gene (ZFY) and mapping of homologous cDNAs sequences to chromosomes X, Y and 9. Nucleic Acids Res 17:2987–2999Google Scholar
  4. Andersson M, Page DC, Chapelle A de la (1986) Chromosome Y- specific DNA is transferred to the short arm of X chromosome in human XX males. Science 233:786–788Google Scholar
  5. Bain AD, Scott JS (1965) Mixed gonadal dysgenesis with XX/XY mosaicism. Lancet I:1035–1039Google Scholar
  6. Buckle VJ, Boyd Y, Fraser N, Goodfellow PN, Goodfellow PJ, Wolfe J, Craig IW (1987) Localisation of Y chromosome sequences in normal and XX males. J Med Genet 24:197–203Google Scholar
  7. Bull JJ, Hillis DM, O'Steen S (1988) Mammalian ZFY sequences exist in reptiles regardless of sex determining mechanism. Science 242:567–569Google Scholar
  8. Chandra HS (1985) Is human X chromosome inactivation a sex determining device? Proc Natl Acad Sci USA 82:6947–6949Google Scholar
  9. Chapelle A de la, Hortling H, Niemi M, Wennstrom J (1964) XX sex chromosomes in a human male; first case. Acta Med Scand 412 [Suppl]:25–38Google Scholar
  10. Chapelle A de la, Tipett PA, Wetterstrand G, Page DC (1984) Genetic evidence of X-Y interchange in a human XX male. Nature 307:170–171Google Scholar
  11. Court-Brown WM, Harnden DG, Jacobs PA, Maclean N, Mantle DJ (1964) Abnormality of sex chromosome complement in man. (Medical research council special report series, no 305) Her Majesty's Stationary Office, London, pp 108–109Google Scholar
  12. Evans HJ, Buckton KE, Spowart G, Carruthers AD (1979) Heteromorphic X chromosomes in 46 XX males: evidence for the involvement of X-Y interchange. Hum Genet 49:11–31Google Scholar
  13. Ferguson-Smith MA (1966) X-Y chromosomal interchange in the aetiology of true hermaphroditism and of XX Klinefelter's syndrome. Lancet II:475–476Google Scholar
  14. Ferguson-Smith MA (1988a) Progress in the molecular cytogenetics in man. Philos Trans R Soc Lond [Biol] 319:239–248Google Scholar
  15. Ferguson-Smith MA (1988b) Genes on the X and Y chromosomes controlling sex. Br Med J 297:635–636Google Scholar
  16. Ferguson-Smith MA, Affara NA (1988) Accidental X-Y recombination and the aetiology of XX males and true hermaphrodites. Philos Trans R Soc Lond [Biol] 322:133–144Google Scholar
  17. Ferguson-Smtih MA, Affara NA, Boyd E, Cooke A, Aitken DA, Florentin L, Tolmie J (1985) Analysis of variable X-Y interchange in XX males (abstract). Am J Hum Genet 37:153Google Scholar
  18. Ferguson-Smith MA, Affara NA, Magenis RE (1987) Ordering of Y specific sequences by deletion mapping and analysis of X-Y interchange males and females. Development 101 [Suppl]:41–50Google Scholar
  19. Gartler SM, Waxman SH, Giblett E (1962) An XX/XY human hermaphrodite resulting from double fertilisation. Proc Natl Acad Sci USA 48:332–335Google Scholar
  20. German J (1988) Gonadal dimorphism explained as a dosage effect of a locus on the sex chromosomes, the gonad differentiation locus (GDL). Am J Hum Genet 42:414–421Google Scholar
  21. Guellaen G, Casanova M, Bishop C, Geldwerth D, Andre E, Fellous M, Weissenbach J (1984) Human XX males with Y single copy DNA fragments. Nature 307:172–173Google Scholar
  22. Jacobs PA, Ross A (1966) Structural abnormalities of the Y chromosome in man. Nature 210:352–354Google Scholar
  23. Kalaizidakis M, Theriault A, Boyd E, Affara NA, Cooke A, Ferguson-Smith MA (1987) The destination of Y-specific sequences in X-Y interchange males (abstract). Development 101 [Suppl]:195Google Scholar
  24. Madan K (1976) Chromosome measurements on an XXp+ male. Hum Genet 32:141–142Google Scholar
  25. Magenis RE, Webb MJ, McKean RS, Tomar D, Allen LJ, Kammer H, Van Dyke DL, Lovrien E (1982) Translocation (X;Y) (p22. 33;p11. 2) in XX males: etiology of male phenotype. Hum Genet 62:271–276Google Scholar
  26. Magenis RE, Tomar D, Sheehy R, Fellous M, Bishop C, Casanova M (1984) Y short arm material translocated to distal X short arm in XX males: evidence from in situ hybridisation of a Y specific single copy DNA probe (abstract). Am J Hum Genet 36:1025Google Scholar
  27. Mardon G, Page DC (1989) The sex determining region of the mouse Y chromosome encodes a protein with a highly acidic domain and 13 genic fingers. Cell 56:765–770Google Scholar
  28. Muller U, Lalande M, Donlon T, Latt SA (1986) Moderately repeated DNA sequences specific for the short arm of the human Y chromosomes are present in XX males and reduced in copy number in an XY female. Nucleic Acids Res 14:1325–1340Google Scholar
  29. Page DC, Chapelle A de la, Weissenbach J (1985) Chromosome Y-specific DNA in related human XX males. Nature 315:224–226Google Scholar
  30. Page DC, Mosher R, Simpson EM, Fisher EMC, Mardon G, Pollack J, McGillivray B, Chapelle A de la, Brown LG (1987) The sex determining region of the human Y chromosome encodes a finger protein. Cell 51:1091–1104Google Scholar
  31. Ramsay M, Bernstein R, Zwane E, Page DC, Jenkins T (1988) XX true hermaphroditism in Southern African Blacks: an enigma of primary sexual differentiation. Am J Hum Genet 43:4–13Google Scholar
  32. Schneider-Gädicke A, Beer-Romero P, Brown LG, Nussbaum R, Page DC (1989) ZFX has a gene structure similar to ZFY, the putative human sex determinant, and escapes X-inactivation. Cell 57:1247–1258Google Scholar
  33. Sinclair AH, Foster JW, Spencer JA, Page DC, Palmer M, Good-fellow PN, Graves JAM (1988) Sequences homologous to ZFY, a candidate human sex determining gene, are autosomal in marsupials. Nature 336:780–783Google Scholar
  34. Skordis NA, Stetka DG, MacGillivray MH, Greenfield SP (1987) Familial 46,XX males coexisting with familial 46,XX true hermaphrodites in same pedigree. J Pediatr 110:244–248Google Scholar
  35. Tarkowski AJ (1964) True hermaphroditism in chimaeric mice. J Embryol Exp Morphol 12:735–757Google Scholar
  36. Therkelsen AJ (1964) Sterile male with the chromosome constitution 46,XX. Cytogenetics 3:207–218Google Scholar
  37. Wachtel SS, Koos GC, Breg WR, Thaler HT, Dillard GM, Rosenthal IM, Dosik H, Gerald PS, Saenger P, New M, Lieber E, Miller OJ (1976) Serologic detection of a Y-linked gene in XX males and XX true hermaphrodites. N Engl J Med 295:750–754Google Scholar
  38. Waibel F, Scherer G, Fraccaro M, Hustinx TWJ, Weissenbach J, Wieland J, Mayerova A, Back E, Wolf U (1987) Absence of Y specific DNA sequences in human 46,XX true hermaphrodites and in 45,X mixed gonadal dysgenesis. Hum Genet 76:332–336Google Scholar

Copyright information

© Springer-Verlag 1990

Authors and Affiliations

  • M. A. Ferguson-Smith
    • 1
  • A. Cooke
    • 2
  • N. A. Affara
    • 1
  • E. Boyd
    • 2
  • J. L. Tolmie
    • 2
  1. 1.Department of PathologyCambridge UniversityCambridgeUK
  2. 2.Duncan Guthrie Institute of Medical Genetics, University of GlasgowYorkhillUK

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