A dosage sensitive locus at chromosome Xp21 is involved in male to female sex reversal.

Male to female sex reversal has been observed in individuals with duplications of the short arm of the X chromosome. Here we demonstrate that sex reversal results from the presence of two active copies of an Xp locus rather than from its rearrangement and that alterations at this locus constitute one of the causes of sex reversal in individuals with a normal 46,XY karyotype. We have named this locus DSS (Dosage Sensitive Sex reversal) and localized it to a 160 kilobase region of chromosome Xp21, adjacent to the adrenal hypoplasia congenita locus. The identification of male individuals deleted for DSS suggests that this locus is not required for testis differentiation. We propose that DSS has a role in ovarian development and/or functions as a link between ovary and testis formation.

A syndrome of primary gonadal failure, short stature, mitral valve prolapse, and mental retardation.

Two brothers referred for hypogonadism presented with short stature, mild mental retardation, and minor anomalies. In addition, both patients had hypogonadism due to primary gonadal failure and mitral valve prolapse, in the absence of other heart defects. A complete hormonal evaluation in one of the patients showed abnormal growth hormone (GH) and gonadotropin responses to different stimuli, findings suggestive of a disorder of hypothalamic-pituitary regulation. Both patients had normal chromosomes (46,XY) as did their mother (46,XX), who had some of the clinical manifestations found in her sons but in a milder form. We propose that this is a new syndrome.

Presence of H-Y antigen in female patients with sex-chromosome mosaics and absence of testicular tissue.

H-Y antigen was tested in five women with sex chromosome mosaicism and gonadal streaks. Three patients had a 45,X/46,XY or 46,X,der(Y) and two a 45,X/46,X, der(X) chromosome constitution. All patients were H-Y antigen positive. Lack of testis differentiation in these women may be explained by subthreshold expression of H-Y antigen, different H-Y antigen molecules, and/or different tissue distribution of the chromosome mosaicism.

Clonal chromosome abnormalities with preferential involvement of chromosome 3 in patients with porokeratosis of Mibelli.

Clonal chromosome abnormalities were found in cultured fibroblasts from three sibs and one sporadic case with porokeratosis of Mibelli. Chromosome 3 especially involved region p12-14. This region includes the most common fragile site in humans, and the proximal region of chromosome 3 short arm is involved in a variety of neoplastic conditions. We conclude that porokeratosis of Mibelli, an autosomal dominant disorder, is associated with chromosomal instability. Porokeratosis of Mibelli is known to also be associated with increased susceptibility to malignant disease. The chromosome instability may well predispose to malignancy.

Cytogenetics of multiple endocrine neoplasia syndromes. I. Two different, unique clonal chromosome changes in a medullary thyroid carcinoma and in a C-cell thyroid hyperplasia.

In short-term cultures of tumor tissue from a medullary thyroid carcinoma (MTC), we found a large clone of cells with a balanced translocation t(9;12)(p24;q22). A large clone with a balanced translocation t(10;16)(p11;q24) was also found in cultures from a C-cell thyroid hyperplasia. No clearcut evidence for chromosome instability was observed in the lymphocytes of the two patients. The mother of the first patient died of MTC; two relatives of the second patient had MTC and one of them had pheochromocytoma. These findings classify the two subjects as MEN 2A patients with different phenotypic expression but with the same type of chromosomal abnormality.

Cytogenetic studies in venous tissue from patients with varicose veins.

Cytogenetic investigation of primary cell cultures from fragments of varicose veins of seven patients with familial varicosity and seven patients with the sporadic type revealed the presence of metaphases with structural abnormalities, clonal trisomies of chromosomes 7, 12, and 18, and monosomy of chromosome 14 only in cases with the familial type, while the sporadic cases had no similar chromosome aberrations. The immunophenotypical results are consistent with fibroblast lineage of the cultured cells. These results suggest that karyotypic variations in familial varicose vein tissue cultures could in some way be associated either with the genotypic constitution responsible for the familial type or a longer duration of disease on average than those with sporadic varicosities.

Cytogenetics of multiple endocrine neoplasia syndrome. II. Chromosome abnormalities in an insulinoma and a glucagonoma from two subjects with MEN1.

Cytogenetic analysis of two pancreatic islet tumors, an insulinoma and a glucagonoma was ascertained in two subjects with multiple endocrine neoplasia type 1 (MEN1). The insulinoma had a modal peak at 84 chromosomes. Most cells were pseudotetraploid, and in all cells the normal chromosomes were represented in varied numbers, i.e., from 1 to 7 copies. The tumor had 5 characteristic and consistent marker chromosomes which were identified as deletions of chromosomes 1, 2, 7, 16, and 17. All metaphases had several double minute chromosomes (dmin) of variable size and possible intermediate structures between dmin and homogeneously staining chromosomal regions. The glucagonoma had a nearly equal proportion of normal metaphases and metaphases with structural and numerical abnormalities with no consistent trend.

Chromosome abnormalities in lymphocytes and fibroblasts of subjects with multiple endocrine neoplasia type 1.

A consistent degree of chromosome instability was found in cultured lymphocytes and in fibroblasts derived from skin biopsies of three patients with multiple endocrine neoplasia type 1 (MEN1). In both tissues, there was a significant increase in chromosomal breakage. Dicentrics and tricentrics, rings, translocations, deletions, acentric fragments, and presumptive double minutes were the most frequent abnormalities in lymphocytes. The fibroblasts of two patients had large clones consisting of trisomy 7 and trisomy 18 cells, respectively.

Cytogenetics of multiple endocrine neoplasia syndromes. III. Analysis of an insulinoma from a subject with MEN 1 by chromosome painting.

The cytogenetics of an insulinoma from a subject with MEN 1 characterized by the consistent presence of double minute chromosomes (dmins) and by five characteristic marker chromosomes was investigated with fluorescence in situ hybridization after labeling with a chromosome 11 library. The dmins were consistently negative for 11q material, with the exception of one metaphase which had two positive dmins. This indicated that the dmins are not derived massively from chromosome 11 and that they can be heterogeneous in their origin. One of the marker chromosomes, tentatively identified as a del (7), turned out to be the product of a 7;11 translocation.

Chromosome abnormalities and gamete production in man.

The averaged incidence of chromosome abnormalities from samples of infertile males has been estimated to be approximately 5%, of which 4% are sex chromosome abnormalities and 1% autosomal abnormalities. Variations in the frequencies among different samples are probably due to ascertainment bias. The autosomal abnormalities consist mainly of balanced translocations which are found with a frequency of nine per thousand. Most translocations are Robertsonian ones and most of them are familial. The reasons why a balanced translocation interferes with the normal meiotic process are discussed. The effects on female fertility of numerical and structural aberrations of the X chromosome are discussed with special attention to the deficiencies of the short and long arm of the X chromosome. Several of these deficiencies are secondary to X/autosome translocations transmitted by the mother of the probands. It is concluded that the function of the abnormal X chromosome rather than the loss of specific segments is probably correlated with the lack of gamete production.

Gene mapping and serendipity. The locus for torticollis, keloids, cryptorchidism and renal dysplasia (31430, Mckusick) is at Xq28, distal to the G6PD locus.

The syndrome of torticollis, keloids, cryptorchidism and renal dysplasia was described by Goeminne (1968) in a large family, and listed as X-linked incomplete dominant by McKusick (1978; No. 31430). We mapped the locus on the long arm of the X chromosome at band q28 and distal to the G6PD locus. This was achieved by the chance discovery in the literature that two females, each with a balanced X/autosome translocation involving Xq28, had partial manifestation of the syndrome as was the case with the females in the larger family of Goeminne (1968).

Clonal structural chromosomal rearrangements in primary fibroblast cultures and in lymphocytes of patients with Werner's Syndrome.

The cytogenetics of six cases of adult progeria (Werner's syndrome) from three Sardinian families were investigated. The overall increased incidence of chromosome breakage found in cultured lymphocytes and fibroblasts seems to be age-dependent. The occurrence of clonal variegated translocation mosaicism, previously found by other authors in fibroblast cell lines derived from Werner patients was demonstrated also in fibroblasts analyzed in situ on the outgrowth halos from primary skin explants; a strong indication that these aberrations are present in the in vivo precursors. The same type of clonal structural aberration was found for the first time also in 72h-cultured lymphocytes. These findings demonstrate that Werner's syndrome is indeed a further example of a chromosome rearrangement syndrome.