Human Genetics

, Volume 58, Issue 1, pp 105–116 | Cite as

The etiology of maleness in XX men

  • Albert de la Chapelle


Information relating to the etiology of human XX males is reviewed. The lesser body height and smaller tooth size in comparison with control males and first-degree male relatives could imply that the patients never had any Y chromosome. Neither reports of occasional mitoses with a Y chromosome, nor of the occurrence of Y chromatin in Sertoli cells are convincing enough to support the idea that low-grade or circumscribed mosaicism is a common etiologic factor. Reports of an increase in length of one of the X chromosomes in XX males are few and some are conflicting. Nor is there any evidence to support the idea of loss of material. However, absence of visible cytogenetic alteration does not rule out the possibility of translocations, exchanges or deletions.

A few familial cases are known. Mendelian gene mutations may account for a number of instances of XX males, similar genes being well known in several animal species. The existing geographical differences in the prevalence of human XX males could be explained by differences in gene frequency. But if gene mutation were a common cause of XX maleness there would be more familial cases.

Any hypothesis explaining the etiology of XX males should take into account the following facts. There are at least 4 examples of XX males who have inherited the Xg allele carried by their fathers, and at least 9 of such males who have not. The frequency of the Xg phenotype among XX males is far closer to that of males than to that of females, while the absence of any color-blind XX males (among 40 tested) resembles the distribution in females. Furthermore, H-Y antigen is present in XX males, often at a strength intermediate between that in normal males and females. Finally, in a pedigree comprising three independently ascertained XX males, the mothers of all three are H-Y antigen-positive, and the pattern of inheritance of the antigen in two of them precludes X-chromosomal transmission.

Many of the data are consistent with the hypothesis that XX males arise through interchange of the testic-determining gene on the Y chromosome and a portion of the X chromosome containing the Xg gene. However, actual evidence in favor of this hypothesis is still lacking, and the H-Y antigen data are not easy to explain. In contrast, if recent hypotheses on the mechanisms controlling the expression of H-Y antigen are confirmed, a gene exerting negative control on testis determination would be located near the end of of the short arm of the X chromosome. This putative gene is believed not to be inactivated in normal females, for at least two other genes located in the same region, i.e. Xg and steroid sulfatase, are not. Deletion or inactivation of these loci would explain how XX males arise and would be consistent with most, but not all, the facts.

There is yet no single hypothesis that by itself can explain all the facts accumulated about XX males. While mosaicism appears very unlikely in most cases, Mendelian gene mutation, translocation, X-Y interchange, a minute deletion or preferential inactivation of an X chromosome, or part thereof, remain possible. The etiology of XX maleness may well be heterogeneous.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Alvesalo L, Kari M (1977) Sizes of deciduous teeth in 47,XYY males. Am J Hum Genet 29:486–489Google Scholar
  2. Alvesalo L, de la Chapelle A (1979) Permanent tooth sizes in 46,XX males. Ann Hum Genet Lond 43:97–102Google Scholar
  3. Alvesalo L, de la Chapelle A (1981) Tooth sizes in two males with deletions of the long arm of the Y chromosome. Ann Hum Genet Lond 45:49–54Google Scholar
  4. Alvesalo L, Osborne RH, Kari M (1975) The 47,XYY male, Y chromosome, and tooth size. Am J Hum Genet 27:53–61Google Scholar
  5. Bartsch-Sandhoff M (1974) Erweiterte Mosaikhypothese als Erklärung für XX-Männer. Humangenetik 23:161–162Google Scholar
  6. Bartsch-Sandhoff M, Schade H, Wiegelmann W, Solbach HG, Scholz W (1974) Eir Beitrag zur Genese von XX-Männern. Humangenetik 21:245–253Google Scholar
  7. Berg K, Bearn AG (1966) An inherited X-linked serum system in man: the Xm system. J Exp Med 123:379–397Google Scholar
  8. Berg K, Bearn AG (1968) Human serum protein polymorphisms: a selected review. Ann Rev Genet 2:341–362Google Scholar
  9. Bernstein R, Wagner J, Isdale J, Nurse GT, Lane AB, Jenkins T (1978) X-Y translocation in a retarded phenotypic male. Clinical, cytogenetic, biochemical and serogenetic studies. J Med Genet 15: 466–474Google Scholar
  10. Bernstein R, Jenkins T, Dawson B, Wagner J, Dewald G, Koo GC, Wachtel SS (1980) Female phenotype and multiple abnormalities in sibs with a Y chromosome and partial X chromosome duplication: H-Y antigen and Xg blood group findings. J Med Genet 17: 291–300Google Scholar
  11. Bühler EM (1980) A synopsis of the human Y chromosome. Hum Genet 55:145–175Google Scholar
  12. Caspersson T, Zech L, Johansson C, Modest EJ (1970) Identification of human chromosomes by DNA-binding fluorescing agents. Chromosoma 30:215–227Google Scholar
  13. Cattanach BM, Pollard CE, Hawkes SG (1971) Sex-reversed mice: XX and X0 males. Cytogenetics 10:318–337Google Scholar
  14. de la Chapelle A, Hortling H, Niemi M, Wennström J (1964) XX sex chromosomes in a human male. First case. Acta Med Scand [Suppl] 412:25–38Google Scholar
  15. de la Chapelle A (1972) Analytic review nature and origin of males with XX sex chromosomes. Am J Hum Genet 24:71–105Google Scholar
  16. de la Chapelle A, Miller OJ (1979) Report of the Committee on the Genetic Constitution of Chromosomes 10, 11, 12, X, and Y. Cytogenet Cell Genet 25:47–58Google Scholar
  17. de la Chapelle A, Schröder J, Murros J, Tallqvist G (1977) Two XX males in one family and additional observations bearing on the etiology of XX males. Clin Genet 11:91–106Google Scholar
  18. de la Chapelle A, Koo GC, Wachtel SS (1978) Recessive sex-determining genes in human XX male syndrome. Cell 15:837–842Google Scholar
  19. de la Chapelle A, Simola K, Simola P, Knuutila S, Gahmberg N, Pajunen L, Lundqvist C, Sarna S, Murros J (1979) Heteromorphic X chromosomes in 46,XX males? Hum Genet 52:157–167Google Scholar
  20. Cullen M, Greally M, Greally J (1976) The XX male syndrome — a case report. Clin Genet 10:73–76Google Scholar
  21. Dosik H, Wachtel SS, Khan F, Spergel G, Koo GC (1976) Y-chromosomal genes in a phenotypic male with a 46,XX karyotype. J Am Med Assoc 236:2505–2508Google Scholar
  22. Evans HJ, Buckton KE, Spowart G, Carothers AD (1979) Heteromorphic X chromosomes in 46,XX males: evidence for the involvement of X-Y interchange. Hum Genet 49:11–31Google Scholar
  23. Forabosco A, Carratu A, Assuma M, de Pol A, Dutrillaux B, Cheli E (1977) Male with 45,X karyotype. Clin Genet 12:97–100Google Scholar
  24. Ford CE (1961) Die Zytogenese der Intersexualität des Menschen. In: Overzier C (Hrsg) Die Intersexualität. Georg Theime Verlag, Stuttgart, pp 90–121Google Scholar
  25. Fraccaro M, Tiepolo L, Zuffardi O, Chiumello G, Di Natale E, Gargantini G, Wolf U (1979) Familial XX true hermaphroditism and the H-Y antigen. Hum Genet 48:45–52Google Scholar
  26. Fromantin M, Gautier D, Dienot B, Boisselier P, Thabaut A (1973) Le sujet masculin au caryotype XX — variété chromosomique du syndrome de Klinefelter? (A propos de 2 nouvelles observations). Lyon Médical 230:781–784Google Scholar
  27. Ghosh SN, Shah PN, Gharupe HM (1978) Absence of H-Y antigen in XY females with dysgenetic gonads. Nature 276:180Google Scholar
  28. Giammarini A, Rocchi M, Zennaro W, Filippi G (1980) XX male with breast cancer. Clin Genet 18:103–108Google Scholar
  29. Iinuma K, Ohzeki T, Ohtaguro K, Higashihara E, Tanae A, Nakagome Y (1975) Y-chromatin positive cells in the smear preparations of the gonad from an XX male. Humangenetik 30:193–196Google Scholar
  30. Kaiser P, Gerhard-Ratschow K, Zabel B, Gey W (1977) A new case of XX-male (XX/XXY mosaic). Hum Genet 39:131–137Google Scholar
  31. Kasdan R, Nankin HR, Troen P, Wald N, Pan S, Yanaihara T (1973) Paternal transmission of maleness in XX human beings. N Engl J Med 288:539–545Google Scholar
  32. Lo Curto F, Pucci E, Scappaticci S, Scotta S, Severi F, Burgio GB, Fraccaro M (1974) X0 and male phenotype. Am J Dis Child 128: 90–91Google Scholar
  33. Lubetzki J, de Grouchy J, Duprey J, Lenormand M-E (1972) Caryotype 46,XX chez un sujet à phénotype mâle. Ann Méd Interne Paris 123: 635–639Google Scholar
  34. Madan K (1976) Chromosome measurements on an XXp+ male. Hum Genet 32:141–142Google Scholar
  35. Madan K, Walker S (1974) Possible evidence for Xp+ in an XX male. Lancet I:1223Google Scholar
  36. Malka J, Dieterlen M, Hadjian A-J, Jonnard A, Bost M, Jalbert P (1975) Pédiatrie 30:73–76Google Scholar
  37. Minowada S, Kobayashi K, Isurugi K, Fukutani K, Ikeuchi H, Hasegawa T, Yamada K (1979) Two XX male brothers. Clin Genet 15:399–405Google Scholar
  38. Miro R, Caballin MR, Marina S, Egozcue J (1978) Mosaicism in XX males. Hum Genet 45:103–106Google Scholar
  39. Mohandas T, Shapiro LJ, Sparkes RS, Sparkes MC (1979) Regional assignment of the steroid sulfatase-X-linked ichthyosis locus: implications for a noninactivated region on the short arm of human X-chromosome. Proc Natl Acad Sci USA 76:5779–5783Google Scholar
  40. Moorrees CFA, Fanning EA, Hunt EE Jr (1963) Age variation of formation stages for ten permanent teeth. J Dent Res 42:1450–1502Google Scholar
  41. Mori Y, Mizutani S, Sonoda T, Furuyama J (1969) XX male: a case report. Jpn J Urol 60:279–285Google Scholar
  42. Müller CR, Migl B, Traupe H, Ropers HH (1980a) X-linked steroid sulfatase: evidence for different gene-dosage in males and females. Hum Genet 54:197–199Google Scholar
  43. Müller CR, Westerveld A, Migl B, Franke W, Ropers HH (1980b) Regional assignment of the gene locus for steroid sulfatase. Hum Genet 54:201–224Google Scholar
  44. Nicolis GL, Hsu LY, Sabetghadam R, Kardon NB, Chernay PR, Mathur DP, Rose HG, Hirschhorn K, Gabrilove JL (1972) Klinefelter's syndrome in identical twins with the 46,XX chromosome constitution. Am J Med 52:482–491Google Scholar
  45. Nielsen J, Sillesen I (1975) Incidence of chromosome aberrations among 11,148 newborn children. Humangenetik 30:1–12Google Scholar
  46. Noel B, Tous J (1978) Sexual determination of XX men. J Génét Hum 26:287–288Google Scholar
  47. Paluke WA, Chen Y, Chen H (1973) Presence of brightly fluorescent material in testes of XX males. J Med Genet 10:170–174Google Scholar
  48. Pawlowitzki IH, Holzgreve W, Kövary M, Niermann H, Scholz W (1978) Testing mosaicism hypothesis in an XX male. Ann Génét Paris 21:152–156Google Scholar
  49. Pietriga J-J (1977) Les hommes XX. Thèse, Faculté de Médecine de Dijon, pp 1–86Google Scholar
  50. Polani PE, Angell R, Giannelli F, de la Chapelle A, Race RR, Sanger R (1970) Evidence that the Xg locus is inactivated in structurally abnormal X chromosomes. Nature 227:613–616Google Scholar
  51. Powers HO, Neu RL, Smulyan H, Gardner LI (1970) An adult phenotypic male with a 46,XX chromosome complement. J Clin Endocrinol 31:576–579Google Scholar
  52. Race RR, Sanger R (1975) Blood groups in man, 6th edn. Blackwell Scientific Publ, Oxford London Edinburgh MelbourneGoogle Scholar
  53. Rehder H, Brühl P, Seth PK (1975) Das XX-Mann-Syndrom. Pathogenese und Beitrag zu den Fehlermöglichkeiten der Diagnose. Urologie A 14:182–186Google Scholar
  54. Rios ME, Kaufman RL, Sekhorn GS, Bucy JG, Bauman JE, Jacobs LS (1975) An XX male: Cytogenetic and endocrine studies. Clin Genet 7:155–162Google Scholar
  55. Roe TF, Alfi OS (1977) Ambiguous genitalia in XX male children: report of two infants. Pediatrics 60:55–59Google Scholar
  56. Rubio GR, Weiss L, Nunez JF, Saeed uz Zafar M (1974) Phenotypic males with 46,XX karyotype. Henry Ford Hosp Med J 22:120Google Scholar
  57. Selden JR, Wachtel SS, Koo GC, Haskins ME, Patterson DF (1978) Genetic basis of XX male syndrome and XX true hermaphroditsim: evidence in the dog. Science 201:644–646Google Scholar
  58. Sellyei M, Wass L, Krausz T (1975) Non-random appearance of Y-chromatin-like fluorescence in the nuclei of thyroid and brain and its chromosomal background. Humangenetik 27:339–342Google Scholar
  59. Soller M, Padeh B, Wysoki M, Ayalon N (1969) Cytogenetics of Saanen goats showing abnormal development of the reproductive tract associated with the dominat gene for polledness. Cytogenetics 8: 51–62Google Scholar
  60. Steffensen DM, Gosden JR (1979) Report of the Committee on Molecular Cytogenetics. Cytogenet Cell Genet 25:77–81Google Scholar
  61. Sutherland GR, Wiener S, Bartholomew AA (1972) A male with karyotype 46,XX. Ann Génét Paris 15:187–189Google Scholar
  62. Takayasu H, Kinoshita K, Isurugi K, Matsumoto Y, Komine Y, Tonomura A (1973) Male hermaphrodite with 46,XX chromosome constitution. Acta Endocrinol 73:396–406Google Scholar
  63. Tiepolo L, Zuffardi O, Fraccaro M, di Natale D, Gargantini L, Müller CR, Ropers HH (1980) Assignment by deletion mapping of the steroid suflatase X-linked ichthyosis locus to Xp223. Hum Genet 54:205–206Google Scholar
  64. Wachtel SS (1979) Immunogenetic aspects of abnormal sexual differentiation. Cell 16:691–695Google Scholar
  65. Wachtel SS, Ohno S, Koo GC, Boyse EA (1975) Possible role for H-Y antigen in the primary determination of sex. Nature 257:235–236Google Scholar
  66. Wachtel SS, Koo GC, Breg WR, Thaler HT, Dilard GM, Rosenthal IM, Dosik G, 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
  67. Wachtel SS, Basrur P, Koo GC (1978) Recessive male-determining genes. Cell 15:279–281Google Scholar
  68. Wolf U (1979) XY gonadal dysgenesis and the H-Y antigen. Report on 12 cases. Hum Genet 47:269–277Google Scholar
  69. Wolf U, Fraccaro M, Mayerová A, Hecht T, Maraschio P, Hameister H (1980a) A gene controlling H-Y antigen on the X chromosome. Tentative assignment by deletion mapping to Xp223. Hum Genet 54:149–154Google Scholar
  70. Wolf U, Fraccaro M, Mayerová A, Hecht T, Zuffardi O, Hameister H (1980b) Turner syndrome patients are H-Y positive. Hum Genet 54:315–318Google Scholar
  71. Yunis E, de la Cruz E, Nossa MA, Gutierrez G (1975) XX males: two new cases. Clin Genet 7:394–399Google Scholar

Copyright information

© Springer-Verlag GmbH & Co. KG 1981

Authors and Affiliations

  • Albert de la Chapelle
    • 1
  1. 1.Department of Medical GeneticsUniversity of HelsinkiHelsinki 29Finland

Personalised recommendations