Indmedica Home | About Indmedica | Medical Jobs | Advertise On Indmedica
Search Indmedica Web
Indmedica - India's premier medical portal

Journal of the Anatomical Society of India

46,XX/46, XY Chimerism – A Case Report

Author(s): Aruna N; Purushottam Rao M; Sayee Rajangam

Vol. 55, No. 1 (2006-01 - 2006-07)


T46,XY/46,XX mosaic is an individual in whom some cells have the male chromosomal complement (XY) and some cells have the female chromosomal complement (XX). This kind of condition, where there is more than one set of cell lines with different sets of chromosomes making up the body is known as chimerism. The natural incidence of chimerism is unknown. Cases of true 46,XX/46,XY chimerism are usually ascertained in early childhood during investigation of ambiguous genitalia and is also associated with normal fertile males and females and fertile females with true hermaphroditism. In the present study one (3.45%) individual out of 29 patients referred for ambiguous genitalia reared as male, presented with 46,XX/46,XY karyotype. Male sex was ascertained to the present case with information gonadal biopsy, regarding risk of gonadoblastomas, cosmetic surgery for external genitalia and regular follow up by a team of experts.

Key words: Chimerism, ambiguous genitalia, phenotype, 46,XX/46,XY.


46, XY/46,XX mosaic is an individual in whom some cells have the male chromosomal complement (XY) and some cells have the female chromosomal complement (XX). This kind of condition, where there is more than one set of cell lines with different sets of chromosomes making up the body is known as chimerism a chimera is an individual, with (at least) two different populations of cells, which are genetically distinct and originate in different zygotes (fertilised eggs). Chimeras are named after the mythological creature Chimera.

Chimerism may occur during in-vitro fertilization or naturally during pregnancy, when two non-identical zygotes combine, at a very early stage of development, to form a single fetus. Such an individual is called a tetragametic chimera as it is formed from four gametes—two eggs and two sperm. As the result, the resulting chimera may possess organs that have different sets of chromosomes.

Chimerism can be classified as artificial chimerism, tetragametic chimerism and twin chimerism. Artificial chimerism results from transfused blood stem cells either by intrauterine transfusion or by allogenic bone marrow transplantation as well as other organ transplantations. Tetragametic chimerism is induced by the fertilization of two oocytes by two spermatozoa and the fusion of these products into one body. Tetragametic chimerism seems to be very rare in humans as reported by Tippett (1983). Such a chimerism can be a cause of true hermaphroditism.

Twin chimerism or blood chimerism confined to blood cells has been thought to be an exception in humans, while it is reported frequently in cattle. Blood chimeas result from and exchange or blood cells, via the placenta, between non-identical twins is utero. However, using a sensitive fluorescence technique, blood group chimerism was detected in 8% of twin pairs and 21% of triplets (Van Dijk et al 1996).

Chimeras should not be confused with mosaics, who are individuals with genetically different cell types, but originate from a single zygote.

Chimeras should also be differentiated from hybrids, who are individuals formed from two gametes (each from a different species), forming a single zygote. All cells in a hybrid originate from this single zygote. For example, a mule is a hybrid created from the sperm of a donkey and the egg of a horse.

Natural incidence of chimerism is unknown. Because of its rarity it is being reported. In this report, we describe an infant with 46, XX/46, XY karyotype in lymphocytes accounting for 20% true hermaphroditism, which is a rare condition and makes up less than 10% of all intersex cases.

Case Report:

A four year old proband, born to nonconsanguinous couple was referred to Division of Human Genetics for chromosomal analysis and Karyotyping with the chief complaint of ambiguous genitalia. The patient was subjected to the following scheme of examination: a detailed clinical history, family history, physical examination with photographs, chromosomal analysis and Karyotyping, reference for relevant special investigations and treatment. Chromosomal analysis was done using method of Arakkaki and Sparkes (1963) for peripheral lymphocyte culture and GTG banding. For the above case 30 metaphase spreads were counted and analyzed and 4 of them were photographed. For confirmation the culture was repeated by redrawing the fresh blood and another 30 metaphase spreads were counted and analyzed.

Fig.1a: Ambiguous genitalia with small penis
Fig.1b: Perineoscrotal hypospadias

Ambiguous genitalia with small penis, Perineoscrotal hypospadias

The proband was second born and was reared as male. He was moderately nourished, Presenting complaint was abnormal urethral opening and absence of gonads since birth. Developmental milestones and intelligence was normal. Family history was not significant.

On examination of the external genitalia the following features were noticed: Penis was 2 cms long with a conical glans, unfused urethral groove was seen on the ventral aspect with perineoscrotal hypospadias. Labioscrotal fold were not prominent, however minimal pigmentation and rugosity was noticed along with a palpable swelling in the right inguinal region (Fig. I). Investigations: Ultrasonogram showed doubtful testicular tissue in the inguinal region on the right side measuring 1.16X0.41cms and uterus was not visualized.

Fig.2 a: Metaphase spreads 46, XX/46,XY (32%)
Fig.2 b: Metaphase spreads 46, XX/46,XY ( 68%)

Metaphase spreads 46, XX/46,XY

Excision of the tissue and histopathological examination revealed Mullerian duct derivatives. Karyotype was 46,XX/46,XY


Whole body chimerism is assumed if two or more genotypes exist in non-hematogenous tissue (skin, gonads) or they persist for a long period of time in hematogenous tissue. Whole body chimerism is due to the fusion of two zygotes or early embryos, which otherwise would develop separately (as in twins). The mechanism for chimerism is uncertain, but possibilities include: fertilization of:

  1. The secondary oocyte and first polar body;
  2. The ovum and first polar body;
  3. The ovum and second polar body;
  4. Fusion of two embryos each derived from an independently ovulated and separately fertilized ovum.
  5. Fertilization of oocyte by two different sperms or
  6. Possibly other undiscovered ways.

Two recent studies (Strain et al 1998, Uehara et al 1995) using DNA fingerprinting techniques have shown the tetragametic origin of cases of XX/XY hermaphroditism, proving that these cases of chimerism originated by the fusion of two fertilised gametes.

Cases of true 46,XX/46,XY chimerism are usually ascertained in early childhood during investigation of the abnormal appearance of external genitalia. 46,XX/ 46,XY chimerism is known to have a variety of presentations, including ambiguous genitalia, hypospadias, gynaecomastia, and inguinal herniae, (Freiberg et al 1988) and is responsible for about 13% of cases of true hermaphroditism, Danon and Friedman (1996). The natural incidence of chimerism is unknown.

Review of literature revealed in one study of intersexual individuals that 6.06% (2/33) of patients both reared as males showed 46,XX/46,XY karyotype Zhen-Guo et al (2000) and in other study is reported 0.1% (1/916) patients, referred for Karyotyping reared as male presented with 46,XX/46,XY karyotype, Duarte et al (2004). In the present study only one (3.45%) individual out of 29 consecutively referral for ambiguous genitalia over a period of three years presented with 46,XX/46,XY karyotype. The true frequency of the genotype, however, is unknown because of the bias in ascertainment.

Rare cases with normal male and normal female phenotype have also been ascertained as an incidental finding by Bromilow and Duguid (1989). Also reported are Normal fertile males by Watkins et al. (1981); Schoenle et al. (1983); fertile female hermaphrodites by Verp et al. (1992) to phenotypically normal, fertile females by Bromilow and Duguid (1989). This sparse literature is undoubtedly biased toward cases with sexual ambiguity or other gonadal problems, and many XX/XY chimeras may go unnoticed. Same-sex chimeras should be almost invariably phenotypically normal and can be diagnosed only with DNA analysis.

In infancy, genetic counseling and determination of the dominant phenotype are crucial to gender assignment and rearing. Late diagnosis, poses additional dilemmas for the patient in that the malignant potential of undescended or a dysmorphic gonad is greater and issues of fertility may become significant. Male sex was ascertained to the present case. Surgical exploration and biopsy of the gonadal tissue was suggested to rule out true hermaphroditism and possibility of gonadoblastomas was explained. It was emphasized that the external characteristics can be altered by means of cosmetic surgery. Emphasis was laid on regular follow up by a team of experts.


Any patient with hypospadias and one or more undescended testre before ascertaining cryptorchidism may be advised to undergo karyotyping and exploration and biopsy of gonadal tissue early in life. True histology of the gonad should be determined in order to properly manage patients. Because of the complexities surrounding gender assignment / reassignment, use of an experienced team is the best approach including specialists from pediatrics, gynecology, urology endocrinology and psychiatry. All should be comfortable with the gender assignment decision, which depends on the diagnostic evaluation results. Gender assignment may be made as early as possible prior to age 18 months, when children develop gender identity, so as to minimize psychosocial trauma. Aside from the physical and emotional consequences associated with genital ambiguity, patients usually do not possess other developmental malformations. These individuals generally are of average intelligence and have a normal life expectancy.


  1. Arakaki DT, Sparkes RS. Microtechnique for culturing leucocyte from whole blood. Cytogenetics 1963; 2: 57-60.
  2. Bromilow IM, Duguid J. The Liverpool chimaera. Vox Sang 1989; 57: 147-149. (Medline)
  3. Danon M, Friedman SC: Pediatric endocrinology: a clinical guide. Ambiguous genitalia, micropenis, hypospadias, and cryptorchidism. 3rd ed; Marcel Dekker; New York; 1996, 281-304.
  4. Duarte AC, Cunha E, Roth JM, et al. Cytogenetics of Genetic Counseling Patients in Pelotas, Rio Grande do Sul, Brazil. Genet. Mol. Res 2004. 3(3): 303-308. (Medline)
  5. Freiberg AS, Blumberg B, et al. XX/XY chimerism encountered during prenatal diagnosis. Prenat Diagn 1988; 8: 423-426.
  6. Schoenle E, Schmid W, et al. 46,XX/46,XY Chimerism in a phenotypically normal man. Hum Genet 1983; 64: 86-89.
  7. Strain L, Dean JC, et al. A true hermaphrodite chimera resulting from embryo amalgamation after in vitro fertilization. N Engl J Med 1998; 338: 166- 169.
  8. Tippett, P. Blood group chimaeras. Vox Sang 1983; 44: 333–359. (Medline)
  9. Uehara S, Nata M, et al. Molecular biologic analyses of tetragametic chimerism in a true hermaphrodite with 46,XX/46,XY. Fertil Steril 1995; 63: 189-192.
  10. Van Dijk BA, Boomsma DI et al. Blood group chimerism in human multiple births is not rare. Am. J. Med. Genet 1996; 61: 264–268.
  11. Verp MS, Harrison HH, et al. Chimerism as the etiology of a 46,XX/46,XY fertile true hermaphrodite. Fertil Steril 1992; 57: 346-349.
  12. Watkins WM, Yates AD, et al. A human dispermic chimaera first suspected from analyses of the blood group gene-specified glycosyltransferases. J Immunogenet 1981; 8: 113-128.
  13. Zuffardi O, Gargantini L, et al. Presumptive mosaic origin of an XX/XY female with ambiguous genitalia. J Med Genet 1987; 24: 177-180
  14. Zhen-Guo MI, Xiao-Feng Y, et al. Karyotypic analysis of intersexuality in Chinese from Taiyuan Asian. J Androl 2000; 2: 155-157.
Access free medical resources from Wiley-Blackwell now!

About Indmedica - Conditions of Usage - Advertise On Indmedica - Contact Us

Copyright © 2005 Indmedica