H-Y antigen in 46,XY gonadal dysgenesis

Summary Presence of H-Y antigen has been correlated with testicular differentiation, and absence of H-Y with failure of testicular differentiation, in a variety of mammalian species. To determine more precisely the relationship between expression of H-Y antigen and development of the testis, we studied the cells of phenotypic females with the 46,XY male karyotype. Blood leukocytes were typed H-Y⁺ in five XY females with gonadal dysgenesis, although in other studies blood leukocytes from XY females with gonadal dysgenesis were typed H-Y^-. Thus mere presence of H-Y antigen is not sufficient to guarantee normal differentiation of the testis. In the present paper we review evidence for an additional factor in gonadal organogenesis, the H-Y antigen receptor. We infer that testicular development requires engagement of H-Y and its receptor. It follows that XY gonadal dysgenesis is the consequence of functional absence of the H-Y testis inducer as in the following conditions: failure of synthesis of H-Y or failure of specific binding of H-Y.     

XY female mice express H-Y antigen

Karyotypically XY individuals of the C57BL/6J-Y^POS mouse stock develop as females or hermaphrodites, but never as normal males. The aberrant sexual development results from the interaction of the C57BL/6J genetic background with the M. poschiavinus-derived Y chromosome. XY females from this stock were assayed for H-Y antigen. By the criteria of skin-grafting, the cell-mediated lympholysis test, and the popliteal lymph node assay, these XY females are antigenically indistinguishable from normal C57BL/6 males. Implications for the hypothesis that H-Y antigen induces formation of the mammalian testis are discussed.     

XY gonadal dysgenesis and the H-Y antigen

Summary H-Y antigen was determined in 12 patients affected by XY gonadal dysgenesis. Of these, three proved to be H-Y negative, and nine, including two sisters, were H-Y positive; two of the unrelated positive cases exhibited a reduced antigen titer. Therefore, this clinical condition must be genetically heterogeneous. It is assumed that in the negative cases and possibly in those with reduced antigen titer, the H-Y generating system is affected by mutation, while in the regular positive cases the target cells are unable to respond due to a defect of the gonad-specific H-Y antigen receptor.I dedicate this article to the memory of Ilse Aschmoneit     

Sex-reversed XY females with campomelic dysplasia are H-Y negative

Summary Three families with infants affected with campomelic dysplasia, a genetically determined mesenchymal disease frequently associated with sex reversal were studied. Two XY famales with ovarian gonadal differentiation and typical clinical features of campomelic dysplasia could be tested for H-Y antigen and were found to be H-Y negative.     

Clinical and endocrine spectrum in patients with the 45,X/46,XY karyotype

Summary Cytogenetic and endocrine studies were performed in five unrelated 45,X/46,XY individuals in an attempt to correlate them with their clinical expression and gonadal morphology. A lack of a consistent pattern between cytogenetic findings and phenotype was observed.Endocrine studies revealed a wide spectrum of hypothalamic, pituitary, and gonadal hormone production as assessed by the base line levels of LH, FSH, T, and ⁴-A and their responses to appropriate exogenous stimulation (LH-RH and HCG). An adequate correlation between endocrine findings with gonadal morphology and phenotype could be established; thus demonstrating that patients with this particular chromosome complement have a functional integrity of the gonadotropin hypothalamic pituitary activity modulated accordingly with the gonadal function of each particular case.     

Absence of H-Y antigen in an XY female with campomelic dysplasia

Summary We have studied a stillborn infant who had the clinical and radiographic characteristics of campomelic dysplasia. External and internal genitalia were those of a normal female, except for slight enlargement of the clitoris. Microscopic examination of the ovaries revealed some areas resembling immature dysgenetic testicular tissue. Karyotypes from lymphocyte and fibroblast cultures were 46,XY with a structurally normal Y chromosome and no evidence of mosaicism. H-Y antigen was not detected on the fibroblasts in repeated assays using Raji cells as target cells after absorption. The sexreversal (chromosomal malephenotypic female) previously noted in patients with autosomal recessive campomelic dysplasia thus may be mediated through lack of detectable H-Y antigen on the cell surface. It appears that the mutation leading to campomelic dysplasia interferes with normal H-Y antigen expression.     

Follow-up 20 years later of 34 Klinefelter males with karyotype 47,XXY and 16 hypogonadal males with karyotype 46,XY

Summary A 20-year follow-up study of 50 hypogonadal males has been made. Of these 34 had Klinefelter's syndrome with the karyotype 47,XXY and 16 had the karyotype 46,XY. These males have been examined at mean ages of 27 and 37 and in the present study at a mean age of 47. At the first examination the following conditions were found in the Klinefelter males to a significantly higher degree than in the hypogonadal males with 46,XY: immaturity, below average school performance, few or no friends, previous mental illness, little energy and initiative, few or no spare time interests, occupation as an unskilled labourer. Psychological testing showed a full scale IQ of 103 in the Klinefelter males and 115 in the hypogonadal males. The follow-up studies have shown that in spite of these findings the Klinefelter males have managed far better than could have been expected at the time of the first investigation. The improvement in a number of conditions such as mental health, working capacity, social adjustment, relations with other people, and activity level was considerable between the ages of 27 and 37. The present examination shows a further improvement at the age of 47 with the only significant difference between the Klinefelter males and the hypogonadal males with 46,XY being a higher frequency of single Klinefelter males. The present examination also showed that there was no significant difference between the two groups in occupation, working capacity, social adjustment, mental and physical disorders or criminality. The results of the examination at the mean age of 27 would probably have been considerably more favourable for the Klinefelter males if diagnosis had been made in childhood, and information, counselling, support and hormone treatment had been given from an early age. The fact that the great majority of the Klinefelter males have managed quite well in spite of this and that no remarkable differences were found between them and a control group is of great importance for genetic counsellers, especially for prenatal counsellers. Up until now, in 75% of cases in which sex chromosome abnormalities, including Klinefelter's syndrome, have been diagnosed prenatally in Denmark abortion has been induced. We believe this is mainly due to insufficient information about the many positive aspects of the development of individuals with sex chromosome abnormalities.     

Complete (classic) hydatidiform mole with 46,XY karyotype of paternal origin

Summary A pachytene chromomere map of bivalent 10 is presented. Recent results from high-resolution metaphase banding document a similar pattern of intrachromosomal differentiation.     

A successful second delivery outcome using refrozen thawed testicular sperm from an infertile male true hermaphrodite with a 46, XX/46, XY karyotype: case report

We report a successful second delivery of a healthy infant fathered using refrozen thawed testicular sperm from an infertile male chimera. We also examined sex chromosome distribution of the seminiferous tubule. Intracytoplasmic sperm injection (ICSI) was performed using the remaining refrozen testicular sperm, which had been stored during the first treatment. Biopsied testicular cells were examined by fluorescence in situ hybridization (FISH) and the peripheral lymphocyte karyotype was tested using a G-band. Following ICSI, a second pregnancy was established, and a healthy girl was successfully delivered at 40 gestational weeks without complications. Although the husband’s lymphocyte chromosomal analysis revealed a 46, XX [28]/46, XY [2] karyotype, the seminiferous tubule cells on histological examination by FISH were chimeric sex chromosome type XX [18]/XY [82]. In conclusion, this is a very rare case report of a successful subsequent delivery of a healthy infant (46, XX) from an infertile true hermaphrodite (46, XX/46, XY) using refrozen thawed testicular sperm. The seminiferous tubule cells’ karyotype ratio differed from that of the lymphocytes.     

H-Y antigen in Swyer syndrome and the genetics of XY gonadal dysgenesis

Summary The H-Y antigen is a plasma membrane antigen involved in the organogenesis of the mammalian testis. Its expression on human cells is determined by a Y-linked gene. Phenotypic females affected by 46,XY gonadal dysgenesis (Swyer's syndrome) can be either H-Y-positive or H-Y-negative. In this paper we report H-Y antigen and endocrine studies in a sibship with three affected sisters. Immunological studies were performed on two of the patients, and a clearly positive expression was detected in both cases. Endocrine studies consisted in the investigation of the hypothalamic-pituitary-gonadal axis, which revealed that gonadal hormone insufficiency is the only endocrine abnormality associated with the syndrome. A new genetic interpretation and classification of XY gonadal dysgenesis is proposed.     

Aberrant testicular differentiation in 46,XY gonadal dysgenesis: Morphology,endocrinology, serology

Summary In an infant with gonadal dysgenesis and somatic anomalies, the internal and external genitalia were female but the gonads contained tubular structures suggesting male differentiation. The karyotype was 46,XY with no evidence of structural aberration or mosaicism. Hormonal metabolism and H-Y antigen expression were assayed in cultured gonadal cells. Although unable to synthesize testosterone, the cultured cells were able to convert it to dihydrotestosterone. H-Y antigen was present, perhaps at a level lower than that in cells from normal XY males. Our observations indicate that a modicum of testicular organogenesis may precede the involution that results in a streak gonad in some cases of gonadal dysgenesis.