46,XX/46,XY chimerism in a phenotypically normal man

Schoenle, Eugen J.; Schmid, Werner; Schinzel, Albert; Mahler, Margaret S.; Ritter, Malte; Schenker, Thomas; Metaxas, M. N.; Froesch, P; Froesch, E. R.

doi:10.1007/bf00289485

Cited by 39 publications

(26 citation statements)

References 10 publications

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“…Nonetheless, several cases of proven tetragametic chimeras arising from two independent fertilization events have been described based initially on chromosome heteromorphisms, and more recently on genotyping, 9,18,26,27 including Case 1 in the present study. More intriguingly, many cases have been described that are compatible with a single maternal contribution, but two distinct paternal contributions with the more recent papers providing compelling molecular data 10,17 , 28–32 …”

Section: Discussionmentioning

confidence: 99%

Chimerism in Black Southern African Patients with True Hermaphroditism 46,XX/47XY,+21 and 46,XX/46,XY

Ramsay

Pfaffenzeller

Kotze

et al. 2008

Annals of the New York Academy of Sciences

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True hermaphroditism is defined by the presence of both testicular and ovarian tissue in an individual. True hermaphrodites usually present at birth with ambiguous genitalia, and subsequent invasive investigations are needed to confirm the diagnosis. Several large cohorts of black South Africans with true hermaphroditism have been described, and by far the majority of those investigated had a 46,XX karyotype, with absence of the SRY sequence. This paper represents the first report of the molecular investigation of mosiacism/chimerism as the cause of hermaphroditism in black southern African patients. It is the second report worldwide of a 46,XX/47,XY,+21 chimera, with the first described in a Japanese infant in 1994. Case 1 in the present study is a child who is a 46,XX/47,XY,+21 tetragametic chimera. Molecular studies revealed two paternal and two maternal alleles at four of ten STR loci investigated and three alleles at four of these loci. The young boy exhibited no features of Down syndrome, other than a unilateral single palmar crease. Cases 2 and 3 both have a 46,XX/46,XY karyotype. Chimerism is supported by molecular analysis in Case 2, and molecular studies were not done for Case 3.

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Section: Discussionmentioning

confidence: 99%

Chimerism in Black Southern African Patients with True Hermaphroditism 46,XX/47XY,+21 and 46,XX/46,XY

Ramsay

Pfaffenzeller

Kotze

et al. 2008

Annals of the New York Academy of Sciences

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“…Examples of chimerism and tetragametism, have been found in mice [58][59][60], and other mammals [61] including humans [62][63][64][65][66]. Affected persons are identified by the production of two populations of cells in all tissues, or/and ambiguous genitalia and hermaphroditism alone or in combination [67].…”

Section: Fusion Of Embryosmentioning

confidence: 97%

Chimerism and tetragametic chimerism in humans: implications in autoimmunity, allorecognition and tolerance

et al. 2007

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The presence of cells or tissues from two individuals, chimeras, or the presence of cells and tissues that include the gonads, tetragametic chimerism can be detected by the analysis of cytogenetics and analysis of polymorphic genetic markers, using patterns of pedigree inheritance. These methodologies include determination of sex chromosomes, major histocompatibility complex (MHC) polymorphisms and panels of short tandem repeats (STRs) that include mitochondrial DNA markers. Studies routinely involve cases of temporal chimerism in blood transfusion, or following allotransplantation to measure the outcome of the organ, lymphopoietic tissues or bone marrow grafts. Demonstration of persistent chimerism is usually discovered in cases of inter-sexuality due to fusion of fraternal twins or in cases of fusion of embryos with demonstrable allogeneic monoclonality of blood which, excluded maternity or paternity when blood alone is used as the source of DNA. In single pregnancies it is possible to produce two kinds of microchimerism: feto-maternal and materno-fetal, but in cases of fraternal twin pregnancies it is possible to identify three different kinds which are related to cases of vanishing twins that can be identified during pregnancy by imaging procedures; (1) hematopoietic, (2) gonadal, and (3) freemartins when the twins have different sex and the individual born is a female with either gonadal or both gonadal and hematopoietic tissues. Fraternal twin pregnancies can also produce fusion of embryos. Such cases could be of different sex presenting with inter-sexuality or in same sex twins. One of such cases, the best studied, showed evidence of chimerism and tetragametism. In this regard, the case was studied because of disputed maternity of two of her three children. All tissues studied, except for the blood, demonstrated four genetic components but only two in her blood of four possible showed allogeneic monoclonality consistent with the interpretation that her blood originated from one hematopoietic stem cell. Also, microchimerism, due to traffic of cells via materno-fetal or feto-maternal has been prompted by reports of their potential association with the development of autoimmune disorders including systemic lupus erythematosus (SLE) and systemic sclerosis, and in allotransplantation. In addition, their relevance of chimerism in the positive and negative selection of T cells in the thymus has not been addressed. T lymphocytes play a central role in controlling the acquired immune response and furthermore serve as crucial effector cells through antigen specific cytotoxic activity and the production of soluble mediators. Central tolerance is established by the repertoire selection of immature T lymphocytes in the thymus, avoiding the generation of autoreactive T cells. Expression of chimeric antigens in the thymus could modify the generation of specific T cell clones in chimeric subjects and these mechanisms could be important in the induction of central tolerance against foreign antigens important in allo-transp...

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“…46,XY/46,XX mosaics are more common in Caucasians and present in ∼ 10% of all DSD patients considered 'true hermaphrodites' [Niu et al, 2002;Alonso et al, 2007]. These DSD patients have common morphological traits, such as a prostatic utricle (pseudovagina) and/or a vagina, cryptorchidism (mostly unilateral) and, generally, a testis on one side and an ovary on the other [Giltay et al, 1998;Repas-Humpe et al, 1999;Yaron et al, 1999] as well as early or late (puberty-onset) defects of the central nervous system [Schoenle et al, 1983;Lieber et al, 1986;Alonso et al, 2007;Souter et al, 2007].…”

Section: Discussionmentioning

confidence: 99%

“…Accordingly, to assess and define the gender of a child based simply on the phenotype of the internal and external genitalia is insufficient, which warrants a thorough investigation of the genetic background of the affected child and parents in every DSD case [Schoenle et al, 1983].…”

Section: Discussionmentioning

confidence: 99%

Uniparental Disomy in Somatic Mosaicism 45,X/46,XY/46,XX Associated with Ambiguous Genitalia

Serra

Denzer²,

Hiort³

et al. 2015

Sex Dev

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Disorders of sex development (DSD) affect the development of chromosomal, gonadal and/or anatomical sex. We analyzed a patient with ambiguous genitalia aiming to correlate the genetic findings with the phenotype. Blood and tissue samples from a male patient with penoscrotal hypospadias were analyzed by immunohistochemistry, karyotyping and FISH. DNA was sequenced for the AR, SRY and DHH genes, and further 26 loci in different sex chromosomes were analyzed by MLPA. The gonosomal origin was evaluated by simple tandem repeat (STR) analysis and SNP array. Histopathology revealed a streak gonad, a fallopian tube and a rudimentary uterus, positive for placental alkaline phosphatase, cytokeratin-7 and c-kit, and negative for estrogen, androgen and progesterone receptors, alpha-inhibin, alpha-1-fetoprotein, β-hCG, and oct-4. Karyotyping showed a 45,X/46,XY mosaicism, yet FISH showed both 46,XX/46,XY mosaicism (gonad and urethral plate), 46,XX (uterus and tube) and 46,XY karyotypes (rudimentary testicular tissue). DNA sequencing revealed intact sequences in SOX9, WNT4, NR0B1, NR5A1, CYP21A2, SRY, AR, and DHH. STR analysis showed only one maternal allele for all X chromosome markers (uniparental isodisomy, UPD), with a weaker SRY signal and a 4:1 ratio in the X:Y signal. Our findings suggest that the observed complex DSD phenotype is the result of somatic gonosomal mosaicism and UPD despite a normal blood karyotype. The presence of UPD warrants adequate genetic counseling for the family and frequent, lifelong, preventive follow-up controls in the patient.

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46,XX/46,XY chimerism in a phenotypically normal man

Cited by 39 publications

References 10 publications

Chimerism in Black Southern African Patients with True Hermaphroditism 46,XX/47XY,+21 and 46,XX/46,XY

Chimerism in Black Southern African Patients with True Hermaphroditism 46,XX/47XY,+21 and 46,XX/46,XY

Chimerism and tetragametic chimerism in humans: implications in autoimmunity, allorecognition and tolerance

Uniparental Disomy in Somatic Mosaicism 45,X/46,XY/46,XX Associated with Ambiguous Genitalia

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