True hermaphroditism with XX/XY sex chromosome mosaicism: report of a case

A case of true hermaphroditism with 46, XX/46, XY karyotype is reported. The propositus, reared as a male, showed ambiguous external genitalia with perineoscrotal hypospadias, and internal genitalia represented by bilateral ovotestes, normal uterus and tubes. Periodic menstrual bleedings appeared at puberty. The endocrinologic data demonstrated the secretory activity of both the ovarian and the testicular tissue. The analysis of red cell, lymphocyte and serum markers, done on the propositus and on his parents, failed to show any evidence of double fertilization. On this basis, the origin of the XX/XY condition (mosaicism versus chimerism) and its developmental consequences are discussed.     

Pathogenetics of 45,X/46,XY gonadal mosaicism

Five patients with 45,X/46,XY mosaicism ranging from 8% to 66% of 46, XY lymphocytes in the peripheral blood were studied. Their age when chromosome studies were performed ranged from a few days to 37 yr. The phenotypic presentations were two females with gonadal dysgenesis and Turner syndrome features (cases 1 and 2), two males with ambiguous genitalia and mixed gonadal dysgenesis (cases 3 and 4), and an infertile male with an atrophic testis (case 5). Fluorescence in situ hybridization (FISH) using dual-color X and Y probes on paraffin-embedded sections of the gonads was performed to assess mosaicism. A mosaic cell line with a Y chromosome was present in the streak ovary, dysgenetic gonad, and testis. In the mixed gonadal dysgenesis cases (cases 3 and 4), the testis had a higher percentage (greater than two fold) of XY cells than the ovary had. However, the highest ratio of cells with a Y chromosome was in the atrophic testis of the infertile male (case 5). The distribution of mosaic clones in the different gonadal cell types was examined. Both females (cases 1 and 2) with dysgenetic gonads had scant ovarian stroma and nests of Leydig or hilus cells. In FISH studies, the coelomic epithelial cells were predominantly 46,XY; in comparison, the Leydig and hilus cells had a lower percentage and the ovarian stroma the least number of cells with a Y signal. A mixed gonadal dysgenesis case (case 3) possessed a right testis with an XY complement in approximately 21% of Sertoli cells and approximately 14% of Leydig cells. The infertile male had an atrophic testis with interstitial hyperplasia (case 5). His testis contained Sertoli cells but no evidence of spermatogenesis. FISH detected a Y signal in about 50-60% of the Sertoli and Leydig cells.     

Preoperative and intraoperative radioimmunodetection of cancer pretargeted by biotinylated monoclonal antibodies

OBJECTIVES: Two cases of 46,XX true hermaphroditism were analyzed for two Y-DNA sequences, including the recently cloned gene for male testis determination, the sex-determining region of the Y chromosome (SRY). METHODS: Polymerase chain reaction was performed to amplify the SRY. DNA was prepared from peripheral blood lymphocytes as well as from gonadal tissue preserved in a paraffin block. RESULTS: One hermaphrodite contained the SRY sequences in peripheral blood lymphocytes and the testicular part of ovotestis tissue preserved in a paraffin block, while in the second patient these sequences were not detected. CONCLUSIONS: The SRY positive subject resulted from occult Y mosaicism rather than from X-Y translocation. Testis differentiation in the SRY negative subject may have been caused by mutation of a gene on the X chromosome or, alternatively, on an autosome.     

A case of true hermaphroditism with 45X/46XY mosaicism

The authors describe a case of true hermaphroditism of mainly female phenotype, ambiguous genitalia, and ovotestis. The cytogenetic revealed 45X/46XY mosaicism and an absence of Barr bodies.     

Improved preparation of Xenopus oocytes for patch-clamp recording

The testis-determining gene SRY (sex determining region, Y) is located on the short arm of the Y chromosome and consists of a single exon, the central third of which is predicted to encode a conserved motif with DNA binding/bending properties. We describe the screening of 26 patients who presented with 46,XY partial or complete gonadal dysgenesis for mutations in both the SRY open reading frame (ORF) and in 3.8 kb of Y-specific flanking sequences. DNA samples were screened by using the fluorescence-assisted mismatch analysis (FAMA) method. In two patients, de novo mutations causing complete gonadal dysgenesis were detected in the SRY ORF. One was a nonsense mutation 5' to the HMG box, whereas the other was a missense substitution located at the C terminus of the conserved motif and identical to one previously detected in an unrelated patient. In addition, two Y-specific polymorphisms were found 5' to the SRY gene, and a sequence variant was identified 3' to the SRY polyadenylation site. No duplications of the DSS region in 20 of these patients were detected.     

Molecular, cytogenetic, and clinical characterisation of six XX males including one prenatal diagnosis

Cytogenetic analysis, fluorescent in situ hybridisation (FISH), and molecular amplification have been used to characterise the transfer of Yp fragments to Xp22.3 in six XX males. PCR amplification of the genes SRY, RPS4Y, ZFY, AMELY, KALY, and DAZ and of several other markers along the Y chromosome short and long arms indicated the presence of two different breakpoints in the Y fragment. However, the clinical features were very similar in five of the cases, showing a male phenotype with small testes, testicular atrophy, and azoospermia. All these patients have normal intelligence and a stature within the normal male range. In the remaining case, the diagnosis was made prenatally in a fetus with male genitalia detected by ultrasound and a 46,XX karyotype in amniocytes and fetal blood. Molecular analysis of fetal DNA showed the presence of the SRY gene. FISH techniques also showed Y chromosomal DNA on Xp22.3 in metaphases of placental cells. To our knowledge, this is the second molecular prenatal diagnosis reported of an XX male.     

A sex reversal infant with XX karyotype and complete male external genitalia

The unusual case of a Japanese newborn XX male is presented. Examination of chromosomes in amniotic fluid cells had shown a normal female karyotype (46,XX), but ultrasonography revealed a penis and a scrotum. The neonate had normal male external genitalia, and serum levels of luteinizing hormone, follicle stimulating hormone, and testosterone were all within the normal range. High resonance chromosome analysis revealed an excess portion on the short arm of one of the X chromosomes. We examined his genomic DNA by polymerase chain reaction (PCR) and detected two Y specific regions in his genomic DNA, the sex-determining region Y (SRY) and pseudoautosomal boundary Y. Nucleotide sequencing of the PCR products of SRY indicated no mutation. These findings suggested that the translocation or insertion of an SRY region on the X chromosome led to the development of testicles and a male phenotype.     

Three novel SRY mutations in XY gonadal dysgenesis and the enigma of XY gonadal dysgenesis cases without SRY mutations

Mutations in the Y-located testis-determining gene SRY are one cause for XY sex reversal. We have previously identified four SRY mutations in a total of 45 sex-reversed females with XY gonadal dysgenesis (XY GD). In a new sample of 16 XY GD cases, three previously undescribed SRY mutations were identified. Two are point mutations that lead to amino acid substitutions in the HMG domain of SRY, M64R, and F67V. The third SRY mutation is a single base insertion 5' to the HMG box within codon 43, converting this lysine codon to a stop codon (K43X). A total of 33 SRY mutations have so far been described that account for only 10-15% of XY GD females. A further 10-15% of these cases result from deletion of SRY due to aberrant X/Y interchange. The etiology of the remaining 70-80% of XY GD cases is still enigmatic. Possible explanations for these XY sex-reversal cases are discussed.     

Zfx mutation results in small animal size and reduced germ cell number in male and female mice

The zinc-finger proteins ZFX and ZFY, encoded by genes on the mammalian X and Y chromosomes, have been speculated to function in sex differentiation, spermatogenesis, and Turner syndrome. We derived Zfx mutant mice by targeted mutagenesis. Mutant mice (both males and females) were smaller, less viable, and had fewer germ cells than wild-type mice, features also found in human females with an XO karyotype (Turner syndrome). Mutant XY animals were fully masculinized, with testes and male genitalia, and were fertile, but sperm counts were reduced by one half. Homozygous mutant XX animals were fully feminized, with ovaries and female genitalia, but showed a shortage of oocytes resulting in diminished fertility and shortened reproductive lifespan, as in premature ovarian failure in humans. The number of primordial germ cells was reduced in both XX and XY mutant animals at embryonic day 11.5, prior to gonadal sex differentiation. Zfx mutant animals exhibited a growth deficit evident at embryonic day 12.5, which persisted throughout postnatal life and was not complemented by the Zfy genes. These phenotypes provide the first direct evidence for a role of Zfx in growth and reproductive development.     

Development in a 46 XX boy with positive SRY gene

We present the case of an 11 year-old boy, who asked for medical attention due to obesity and assumed underdeveloped external genitalia. He did not have genital anomalies, penile length was 5.3 cm, testicular volume 2 ml and pubic hair Tanner stage 1. His bone age was normal for chronological age. Endocrinological study showed normal results for his age. Karyotype revealed a 46 XX pattern. MRI of external genitalia showed bilateral scrotal testes which were normal in diameter for his age. The check of his historical growth chart and follow-up revealed normal growth with spontaneous pubertal development. However, hormonal studies showed progressive increase of FSH levels, indicative of failure of germinal epithelium. The presence of Y sequences, including SRY gene, was demonstrated by PCR. Our observation is in agreement with the view that 46 XX male subjects diagnosed at peripubertal age with the SRY gene in the genome have a good prognosis regarding growth and development, but the principal problem of these patients is infertility.     

ANNOUNCEMENT

We report on a 19-week-old fetus with a 46,XX karyotype, normal female external genitalia, complete gonadal agenesis, large encephalocele, spina bifida, and omphalocele. We postulate a new syndrome. Hitherto no consistent malformation patterns have been observed in agonadism patients. True agonadism, including even the unusual finding of an XX gonosomal status, is obviously not as rare as suggested.     

Abnormal female reproductive function

Sex differentiation may be seen as a sequence of gonadal determination, gonadal differentiation, genital differentiation. Malfunction of this causes abnormal female reproductive function. SRY (sex-determining region Y) has been show to induce testis which is needed to bring about development of the other male sex organs. Absence or point or frame shift mutation in the SRY causes XY females. Secondary sex determination depends on testosterone produced by Leydig cells. Testicular feminization syndrome typically lack the normal androgen receptor protein and therefore, they are distinctly female phenotype. Rokitansky syndrome is a type of aplasia vaginae and is a malformation of the Mullerian duct. They all present primary amenorrhea. Secondary amenorrhea is a common type of abnormal female reproductive function and differential diagnosis depends on hormonal analysis. One of the topics includes polycystic ovarian syndrome which is recently treated by laparoscopic surgery.     

Complete and partial XY sex reversal associated with terminal deletion of 10q: report of 2 cases and literature review

We describe 2 karyotypically male infants with terminal deletion of 10q and mental retardation, multiple phenotypic anomalies and abnormal genitalia. One [karyotype 46,XY, del(10)(q26.1)] had female external genitalia; the other [karyotype 46,XY,-10,+der(10)t (10;16)(q26.2;q21)] had an intersex phenotype. Of 8 males previously reported with terminal 10q deletion as the major or only cytogenetic abnormality, 2 had an intersex phenotype, and the others all had combinations of cryptorchidism, micropenis, and hypospadias. Terminal 10q deletions appear to be strongly associated with abnormal male genital development, and should be specifically searched for in the cytogenetic workup of such cases.     

Testicular intratubular germ cell neoplasia in children and adolescents with intersex

In a review of 102 cases with various intersex states, the frequency of intratubular germ cell neoplasia (IGCN) unclassified in testes of children and adolescents was 6%. It was seen in 2 of 87 cases in the prepubertal age group and 4 of 23 cases in the pubertal age group. The frequency of IGCN was 0 of 23 in androgen insensitivity syndrome (testicular feminization), 3 of 38 in gonadal dysgenesis, 1 of 12 in true hermaphroditism, 1 of 22 in male pseudohermaphroditism, and 1 of 7 in the group with multiple congenital anomalies and ambiguous genitalia. Five cases showed unilateral and one showed bilateral IGCN. Three pubertal cases had unilateral gonadoblastoma associated with IGCN. Invasive germ cell tumor was absent in all six cases. The atypical germ cells in all testes with IGCN showed immunoreactivity with placental alkaline phosphatase. Review of the literature revealed 30 prepubertal and pubertal cases with IGCN. The median age of the combined series of 36 cases with IGCN was 13 years (range 1 month to 19 years). Concomitant invasive tumor was present in 3 of 14 cases with gonadal dysgenesis and IGCN and 2 of 18 cases with androgen insensitivity and IGCN.     

Abnormal XY interchange between a novel isolated protein kinase gene, PRKY, and its homologue, PRKX, accounts for one third of all (Y+)XX males and (Y-)XY females

XX males and XY females have a sex reversal disorder which can be caused by an abnormal interchange between the X and the Y chromosomes. We have isolated and characterized a novel gene on the Y chromosome, PRKY. This gene is highly homologous to a previously isolated gene from Xp22.3, PRKX, and represents a member of the cAMP-dependent serine threonine protein kinase gene family. Abnormal interchange can occur anywhere on Xp/Yp proximal to SRY. We can show that abnormal interchange happens particularly frequently between PRKX and PRKY. In a collection of 26 XX males and four XY females, between 27 and 35% of the interchanges take place between PRK homologues but at different sites within the gene. PRKY and PRKX are located far from the pseudoautosomal region where XY exchange normally takes place. The unprecedented high sequence identity and identical orientation of PRKY to its homologous partner on the X chromosome, PRKX, explains the high frequency of abnormal pairing and subsequent ectopic recombination, leading to XX males and XY females and to the highest rate of recombination outside the pseudoautosomal region.     

Left ovarian cyst and right streak ovary in a neonate with a normal karyotype. Report of a case of neonatal Slotnick-Goldfarb syndrome or recessive gonadal dysgenesis

A female neonate with a streak ovary on one side and huge ovarian cyst on the other side is presented. Her karyotype was 46,XX. Adnexectomy was mandatory, leaving the patient with a single streak gonad. Whether this infant has the recessive form of gonadal dysgenesis with one ovary, streak or hypoplastic, replaced by a cyst or the Slotnick-Goldfarb syndrome is impossible to elucidate at present. The potential implications of a streak gonad, either related to gonadal dysgenesis or as a possible source of neoplasia, are reviewed. Current approaches to an ovarian cyst and streak ovary in the neonatal period are discussed.     

Testicular juvenile granulosa cell tumor in an infant with X/XY mosaicism clinically diagnosed as true hermaphroditism

We report a testicular juvenile granulosa cell tumor (T-JGCT) with characteristic clinical and histopathological features. The tumor was present in the left abdominal testis of a 7-month-old infant with a 45,X/46,XY karyotype and ambiguous genitalia. Preoperatively, the infant was diagnosed as having functional testicular and ovarian elements based on elevated levels of serum testosterone and estradiol following human chorionic gonadotropin and human menopausal gonadotropin administration, respectively. Histologically, the left gonad contained a tumorous lesion composed of an admixture of cellular areas and multiple cystic follicles that had some continuity with the adjacent testicular tubules. Some tumor cells showed immunoreactivity for estradiol. The right gonad was a streak gonad containing small irregular nests of sex cord-type cells. No maturing ovarian follicle was present in either gonad. To our knowledge, this is the fifth reported case of T-JGCT with abnormal sex chromosomes, and the first case of T-JGCT confirmed to have not only the morphological but also the functional characteristics of granulosa cells.     

SRY and karyotypic status of one abnormal and two intersexual marsupials

An intersexual agile wallaby (Macropus agilis) with a penis, a pouch and four teats had a sex-chromosome constitution of XXY in lymphocytes and cultured fibroblasts; the sex-determining region Y (SRY) gene was present, consistent with the presence of a testis. An intersexual eastern grey kangaroo (Macropus giganteus) with a small empty scrotum and no penis, and an abnormal red kangaroo (Macropus rufus) with no penis, pouch or teats, both had XX sex-chromosome complements; the SRY gene was not present, consistent with testis absence. The agile wallaby and grey kangaroo described here provide further evidence that scrotal development in marsupials is independent of the Y chromosome. The cause of the abnormalities in the XX individuals cannot be determined until candidate genes are identified. These animals provide a basis for further genetic studies into marsupial intersexuality and sex differentiation.     

Ultrastructure of an ovotestis in a case of true hermaphroditism

A case of true hermaphroditism with bilateral ovotestes is reported. The karyotype was 46, XX. At laparotomy done at the age of 21 months a uterus, bilateral fallopian tubes, and bilateral gonads were observed. On frozen section examination, each gonad was shown to be an ovotestis. By light and electron microscopy, the only cellular abnormality observed in the ovotestes was the absence of primitive germ cells in the seminiferous tubules. The ovarian portion showed primordial follicles and normal follicular development.     

Two cases of true hermaphrodite: the usefulness of laparoscopic gonadectomy in childhood. A case report

Laparoscopic operation has been an alternative method in not only adults but children. We presented two children with true hermaphroditism who were performed by open gonadectomy and laparoscopic gonadectomy respectively. Both patients at the age of 4, and 2 years showed karyotypes of 46, XX, and were raised as girls. In the first case left ovary and right ovotestis were revealed by open gonadal biopsy and right ovotestis was removed by open surgery. In another case bilateral ovotestes were revealed by laparoscopic gonadal biopsy and resected by laparoscopic procedure. Laparoscopy was very useful for detecting the gonadal structures to confirm the diagnosis in intersex patients. True hermaphrodite is one of uncommon intersex anomalies, therefore the diagnosis should be made to demonstrate the coexistence of both ovarian and testicular tissues definitely. We estimated laparoscopic gonadectomy in pediatric true hermaphrodite and concluded that laparoscopic gonadectomy was as profitable as open gonadectomy.