J Pediatr Surg 2001 Feb;36(2):397-399

Management of the African child with true hermaphroditism.
Wiersma R.
Department of Paediatric Surgery, University of Natal, Durban, South Africa.

BACKGROUND/PURPOSE: A disproportionally high incidence of true hermaphroditism is seen among the South African black people, constituting 51% of children in local study on all intersex types. These patients were different from the commonly reported patients with true hermaphroditism in that the common gonad was a mixed type of ovotestis, making the management of such patients problematic. The aim of this study was to establish a protocol for the management for children with true hermaphroditism in Southern Africa. METHODS: Seventy-one children, over a 16-year period, were diagnosed with true hermaphroditism. After a decision on the child gender status, part of the management consisted of excision of all discordant and ovotesticular gonadal tissue. The histology of these gonads was then compared with the initial biopsy results. RESULTS: The histology of the initial gonadal biopsies showed that 55% of all gonads were ovotestes, 26% were ovaries, and 19% testes. Thirty-five patients had 44 gonads excised. Comparing the 2 sets of histology showed that the initial histology of the discordant gonads was insufficient to show all the ovotesticular tissue in 22% of gonads. Initial biopsies that showed testicular tissue only were misdiagnosed in 82% of cases. CONCLUSION: It is suggested that, in Southern African true hermaphrodites, all ovotestes, discordant gonads, and all gonads that show only testicular tissue be excised as part of the initial corrective management.
PMID: 11172444 [PubMed - indexed for MEDLINE]

Am J Med Genet 2000 Aug 28;93(5):417-420

Partially deleted SRY gene confined to testicular tissue in a 46,XX true hermaphrodite without SRY in leukocytic DNA.
Jimenez AL, Kofman-Alfaro S, Berumen J, Hernandez E, Canto P, Mendez JP, Zenteno JC.
Departamento de Genetica, Hospital General de Mexico-Facultad de Medicina, UNAM, Mexico, D.F., Mexico.

True hermaphroditism is an uncommon form of intersexuality in which testicular and ovarian tissue develop in the same individual. Most true hermaphrodites are 46,XX and lack SRY, the testis-determining gene. We describe results of molecular studies performed in a 46,XX true hermaphrodite SRY-negative in DNA from blood leukocytes but SRY-positive in DNA obtained from the testicular portion of the ovotestis. Surprisingly, the SRY identified in gonadal DNA carries a partial deletion at the 5' end of the gene. Our patient is the first case of a naturally occurring deletion within the SRY ORF (with a normal HMG box) and provides a new explanation for the abnormal gonadal development observed in 46,XX true hermaphrodites. Copyright 2000 Wiley-Liss, Inc.
PMID: 10951467 [PubMed - indexed for MEDLINE]

J Pediatr Endocrinol Metab 1998 Jul;11(4):519-524

True hermaphrodites in the southeastern region of Brazil: a different cytogenetic and gonadal profile.
Guerra Junior G, de Mello MP, Assumpcao JG, Morcillo AM, Marini SH, Baptista MT, Paiva e Silva RB, Marques-de-Faria AP, Maciel-Guerra AT.
Department of Pediatrics, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Sao Paulo, Brazil.

Sex ambiguity may be due to several disorders of gonadal differentiation, including true hermaphroditism (TH), as well as male and female pseudohermaphroditism. Although TH is a rare cause of intersex in Europe and North America, in Africa it presents one of the highest frequencies. The 46,XX karyotype has been found in the majority of the reported patients (70.6%), and aberrations in the sex chromosomes have been observed in about 22% of the cases. The 46,XY karyotype has been described as less frequent. Herein we describe ten cases of TH which have been diagnosed over the last 7 years, six lateral TH, two unilateral TH, and two cases of ovotestes with absent contralateral gonad. From a total of 18 gonads analyzed, there were 8 testes, 6 ovaries and 4 ovotestes. Nine subjects had originally a male sex assignment, and in three cases this was reverted to female. Four cases had a 46,XY karyotype. Additional sex chromosome aberrations had been found in four different cases [two 46,XX/46,XY, one 45,X/47,XYY, one 46,X,del(Yq)]. A 46,XX karyotype was found in only two individuals, and both were SRY negative. Our preliminary data, especially on the constitution of chromosomes and gonads, indicate marked differences from those in the literature.
PMID: 9777572 [PubMed - indexed for MEDLINE]

Am J Hum Genet 1998 Apr;62(4):937-940

Polymorphic detection of a parthenogenetic maternal and double paternal contribution to a 46,XX/46,XY hermaphrodite.
Giltay JC, Brunt T, Beemer FA, Wit JM, van Amstel HK, Pearson PL, Wijmenga C.
Department of Human Genetics, Utrecht University, Utrecht, The Netherlands. Giltay@pobox.ruu.nl

True hermaphroditism in humans usually is associated with a 46,XX karyotype or with mosaicism in which admixtures of cells with an XX and an XY karyotype are seen. However, the mechanisms that cause such mosaicisms are poorly understood. To date, with rare exceptions, analyses of hermaphrodites have been limited mostly to cytogenetic investigations. In this report, we describe a 5-year-old patient with true hermaphroditism and a 46,XX/46,XY karyotype (ratio 38:12) in lymphocytes, suggesting involvement of two fertilization events. Microsatellite DNA polymorphisms distributed throughout the genome were analyzed, to investigate the origin of the cell lines concerned. The results are consistent with double paternal and single maternal genetic contributions. Possible mechanisms that would explain these findings are discussed. The most likely mechanism involves a single haploid ovum dividing parthenogenetically into two haploid ova, followed by double fertilization and fusion of the two zygotes into a single individual, at the early embryonic stage.
PMID: 9529354 [PubMed - indexed for MEDLINE]

J Med Genet 1998 Jan;35(1):17-22

An autosomal or X linked mutation results in true hermaphrodites and 46,XX males in the same family.
Slaney SF, Chalmers IJ, Affara NA, Chitty LS.
Mothercare Unit of Clinical Genetics and Fetal Medicine, Institute of Child Health, London, UK.

It is now well established that the differentiation of the primitive gonad into the testis during early human embryonic development depends on the presence of the SRY gene. However, the existence of total or partial sex reversal in 46,XX males with genetic mutations not linked to the Y chromosome suggests that several autosomal genes acting in association with SRY may contribute to normal development of the male phenotype. We report a family in which four related 46,XX subjects with no evidence of Y chromosome DNA sequences underwent variable degrees of male sexual differentiation. One 46,XX male had apparently normal male external genitalia whereas his brother and two cousins had various degrees of sexual ambiguity and were found to be 46,XX true hermaphrodites. The presence of male sexual development in genetic females with transmission through normal male and female parents indicates that the critical genetic defect is most likely to be an autosomal dominant mutation, the different phenotypic effects arising from variable penetrance. Other autosomal loci have been implicated in male sexual development but the genetic mechanisms involved are unknown. In this family there may be an "activating" mutation which mimics the initiating role of the SRY gene in 46,XX subjects.
PMID: 9475089 [PubMed - indexed for MEDLINE]

Braz J Med Biol Res 1996 Jun;29(6):743-748

Molecular analysis of sex determination in sex-reversed and true hermaphroditism.
Copelli SB, Bergada C, Billerbeck AE, Goldberg AC, Kalil J, Damiani D, Targovnik HM.
Catedra de Genetica y Biologia Molecular, Facultad de Farmacia y Bioquimica, Universidad de Buenos Aires, Argentina.

The SRY (sex region of Y) gene determines testis formation but not all cases of sex reversal in humans can be explained by alterations in this gene. We studied one 46,XY female, four 46,XX males, and nine true hermaphrodites (TH): three with an XY and six with an XX chromosomal constitution. The SRY gene was identified in the XX males and the TH with a Y chromosome but was not demonstrated in the XY female and the six XX TH. The Y-heterochromatin region was also identified in one 46,XX male, indicating a low grade mosaicism undetected by cytogenetics. The amplification of the amelogenin gene showed the presence of a 977-bp band that belongs to the short arm of chromosome X in all patients but the absence of a 780-bp band of the short arm of chromosome Y in three 46,XX males and in all the 46,XX TH. These studies demonstrate that the molecular study of sex-reversed patients and TH will help to understand the complex mechanisms of sex determination. The SRY gene is involved but other genes on the X chromosome and autosomes still remain to be studied.
PMID: 9070386 [PubMed - indexed for MEDLINE]

Am J Med Genet 1996 May 17;63(2):348-355

Molecular analysis in true hermaphrodites with different karyotypes and similar phenotypes.
Torres L, Lopez M, Mendez JP, Canto P, Cervantes A, Alfaro G, Perez-Palacios G, Erickson RP, Kofman-Alfaro S.
Servicio Genetica, H.G.M. Ssa. Facultad de Medicina, U.N.A.M., Mexico, D.F., Mexico.

True hermaphroditism is characterized by the development of ovarian and testicular tissue in the same individual. Mullerian and Wolffian structures are usually present, and external genitalia are often ambiguous. The most frequent karyotype in these patients is 46,XX or various forms of mosaicism, whereas 46,XY is very rarely found. The phenotype in all these subjects is similar. We studied 10 true hermaphrodites. Six of them had a 46,XX chromosomal complement: 3 had been reared as males and 3 as females. The other 4 patients were mosaics: 3 were 46,XX/46,XY and one had a 46,XX/47,XXY karyotype. One of the 46,XX/46,XY mosaics was reared as a female, whereas the other 3 mosaics were reared as males. The sex of assignment in the 10 patients depended only on labio-scrotal differentiation. Molecular studies in 46,XX subjects documented the absence of Y centromeric sequences in all cases, arguing against hidden mosaicism. One patient presented Yp sequences (ZFY+, SRY+), which contrast with South African black 46,XX true hermaphrodites in whom no Y sequences were found. Molecular analysis in the subjects with mosaicism demonstrated the presence of Y centromeric and Yp sequences confirming the presence of a Y chromosome. Gonadal development, endocrine function, and phenotype in the 10 patients did not correlate with the presence of a Y chromosome or Y-derived sequences in the genome, confirming that true hermaphroditism is a heterogeneous condition.
PMID: 8725784 [PubMed - indexed for MEDLINE]

Hum Genet 1996 May;97(5):596-598

SRY-negative true hermaphrodites and an XX male in two generations of the same family.
Ramos ES, Moreira-Filho CA, Vicente YA, Llorach-Velludo MA, Tucci S Jr, Duarte MH, Araujo AG, Martelli L.
Departamento de Genetica, Faculdade de Medicina de Ribeirao Preto, Universidade de Sao Paulo, Brazil.

Two 46,XX true hermaphrodites and one XX male without genital ambiguities are reported. They coexist in two generations of the same pedigree, with paternal transmission and in the absence of SRY (sex-determining region, Y chromosome). These familial cases provide evidence to support the hypothesis that these disorders are alternative manifestations of the same genetic defect, probably an autosomal dominant mutation (with incomplete penetrance) or an X-linked mutation (limited by the presence of the Y chromosome).
PMID: 8655137 [PubMed - indexed for MEDLINE]

Am J Med Genet 1995 Jan 2;55(1):53-56

XX true hermaphroditism in southern African blacks: exclusion of SRY sequences and uniparental disomy of the X chromosome.
Spurdle AB, Shankman S, Ramsay M.
Department of Human Genetics, South African Institute for Medical Research, Johannesburg.

A molecular investigation of 16 Bantu-speaking Black XX true hermaphrodites was undertaken in an attempt to determine the cause of the disorder. Y-specific sequences, including sequences mapping to the sex-determining region of the Y, were shown to be absent from lymphocyte tissue of all 16 patients tested. Y chromosome sequences were also absent from the ovarian and testicular components of both ovotestes of a single XX true hermaphrodite, thus excluding gonadal mosaicism involving Y chromosome sequences. Since there is evidence for Xp genes involved in testis determination/differentiation, uniparental disomy of the X chromosome was investigated in 14 XXTH families. Uniparental disomy was excluded in 12 of the 14 families, and isodisomy was excluded in the remaining two cases.
PMID: 7702097 [PubMed - indexed for MEDLINE]