Das XO/XY-Geschlechtschromosomenmosaik

Zusammenfassung Ein Kleinkind mit intersexuellem Genitale, descendierter linker Gonade und einem Uterus zeigte bei der chromosomalen Untersuchung ein XO/XY-Mosaik. Diese Chromosomenmutation stellt eine relativ häufige Intersexform dar, deren Phänotyp erfahrungsgemäß sehr variabel ist. An Hand von 43 Beobachtungen in der Literatur werden Krankheitsbild und Differentialdiagnose des XO/XY-Mosaiks sowie seine Prognose hinsichtlich Pubertät, Fertilität, Körperwachstum und tumoröser Entartung der Gonaden zusammengestellt und Richtlinien für die Therapie vorgeschlagen. Eine frühzeitige Abgrenzung des XO/XY-Mosaiks gegen die inkomplete Form der testiculären Feminisierung ist in prognostischer und therapeutischer Hinsicht notwendig. Die Ätiologie des XO/XY-Mosaiks wird kurz besprochen.

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The XO/XY sex chromosome mosaicism

Summary A child with ambiguous external genitals, descended right gonad and uterus is described. The investigation of the chromosomes showed a XO/XY mosaicism. This chromosomal abnormality is a common type of intersexuality. The phenotype is quite variable. Based on 43 cases in the literature clinical picture and differential diagnosis of XO/XY mosaicism are presented. The prognosis with regard to puberty, fertility, growth and tumors of the gonads is discussed. Headlines for the therapy are given. An early differential diagnosis between XO/XY mosaicism and the incomplete form of testicular feminisation is important because of different prognosis and therapy. The etiology of XO/XY mosaicism is discussed.

     

XO/XY mosaicism and non-fluorescing Y chromosome in a male

Summary An adult male of short stature and with underdeveloped external genitalia is described, who carried out a number of sexual assaults on young women. He proved to have XO/XY mosaicism and a non-fluorescing Y chromosome. It was considered to be a terminal deletion on morphological grounds. It is suggested, on the evidence of the small number of XO/XY mosaics examined by appropriate staining methods, that an abnormal Y chromosome, whether terminally deleted or non-fluorescing owing to an altered chemical state, predisposes to anaphase lagging and non-disjunction.Of eleven reported cases of XO/XY mosaicism with a non-fluorescing Y chromosome, this is the fifth of male phenotype. The severe behaviour disturbance of early onset is considered to be probably causally associated with the chromosome anomaly.     

Males with chronic myeloid leukemia and the 45, XO,Ph1 chromosome pattern

Two cases of chronic myeloid leukemia in which the cytogenetic clone was 45, XO, Ph¹ are described and compared with 20 cases recorded in the literature. The 45, XO line is peculiar to the leukemic cells and is not a manifestation of constitutional mosaicism. It probably arises from a 46, XY, Ph¹ line by loss of the Y chromosome. Because of the few cases reported, one cannot be certain that these men have a better prognosis, although the median survival time suggests that this is so. Infertility is not part of this disorder.     

The fate of XO germ cells in the testes of XO/XY and XO/XY/XYY mouse mosaics: evidence for a spermatogenesis gene on the mouse Y chromosome

A cytogenetic and histological study of nine XO/XY or XO/XY/XYY mosaic mice revealed that XO germ cells were selectively eliminated from the spermatogenic epithelium. Although the XO contribution to the bone marrow in seven mice exceeded 50%, in only two cases were significant numbers of dividing XO spermatogonia present. These XO germ cells only occasionally progressed to meiosis and then degenerated prior to first meiotic metaphase. It was concluded that the mouse Y chromosome carries a "spermatogenesis gene" (or genes) which acts autonomously in the germ cells.     

XY follicle cells in the ovaries of XO/XY and XO/XY/XYY mosaic mice

XO/XY and XO/XY/XYY mosaic hermaphrodites were generated from crosses involving BALB/cWt males. The distribution of Y-bearing cells in the gonads of these mice was studied by in situ hybridisation using the Y-specific probe pY353B. XY cells were found to contribute to all cell lineages of the ovary including follicle cells. The proportion of XY follicle cells was not significantly different from the XY contribution to other gonadal or non-gonadal cell lineages. However, this proportion was consistently low, all the hermaphrodites having a low XY contribution to the animal as a whole. Because the XO- and Y-bearing cell lineages are developmentally balanced, the XY follicle cells cannot have formed as a result of a 'mismatch' in which the Y-directed testis determination process is pre-empted by an early acting programme of ovarian development. These results are discussed with respect to the hypothesis that Tdy acts in the supporting cell lineage, the lineage from which Sertoli cells and follicle cells are believed to be derived.     

True hermaphroditism in 45,X/46,XY mosaicism.

This report discusses the clinical findings on two patients with 45,X/46,XY mosaicism, two boys presented with penile hypospadias and cryptorchidism. A dysgenetic ovary and a testis were found in one boy, and a dysgenetic ovary in the other. Both patients can be considered to be true hermaphrodites on the basis of histology and clinical and hormonal observations. 45,X/46,XY mosaics have a wide range of phenotypic appearances and their gonadal morphology can also show great differences. However, the incidence of true hermaphroditism in individuals with 45,X/46,XY mosaicism is low and the reports in the literature rare. It is likely that males with 45,X/46,XY who suffer only mild maldevelopment of the external genitalia will not be recognized. In all patients with penoscrotal hypospadias and cryptorchidism with 45,X/46,XY mosaicism, the possibility of true hermaphroditism should be considered.     

Rare case of XX/XY mosaicism and trisomy 13 in early prenatal diagnosis

Coexistence of XX/XY sex mosaicism and autosomal trisomy in prenatal diagnosis is particularly rare. Herein, we report the first, to our knowledge, case of a fetus with cyclopia, ambiguous genitalia and a 47,XX,+13,inv9[47]/47,XY,+13[13] karyotype detected at 13 weeks of gestation after chorionic villus sampling. Molecular analysis after prenatal diagnosis suggests that this is a case of sex mosaicism coexisting with trisomy 13, rather than chimera.     

Klinefelter's syndrome, mosaic 46,XX/46,XY/47,XXY/48,XXXY/48,XXYY: a case report

A 35-year-old male was investigated for primary infertility. Clinical examination showed an intelligent man with normal facial appearance and moustache and small firm testes. Testicular histopathology revealed marked atrophy of the testes with no spermatogenesis and absence of germ cells. Hormonal profile showed elevated levels of FSH,LH and low levels of testosterone. Chromosome analysis from whole blood culture showed cells with 46,XX/46,XY/47,XXY/48,XXXY/48,XXYY mosaicism. The predominant cell line was 47,XXY (87.86%). 46,XY/47,XXY mosaicism is not uncommon. However, mosaicism of multiple sex chromosome aneuploidy is rarely observed. This is the first report of mosaicism in Klinefelter's syndrome variant with five cell lines.     

Satellite associations and the identification of the Y chromosome in man

In a sample of cells from a leucocyte culture of an XY/XO mosaic the number of satellite associations between two acrocentric chromosomes (groups 13–15 and 21–22) was determined. Three different types of associations were distinguished. A comparison of the numerical frequencies of the different types in XO and XY cells suggests that the Y chromosome does not take part in the associations and is therefore unsatellited.     

X0 Karyotype in a phenotypic male

Summary A 24-year-old male with ambiguous genitalia was found to have a predominantly 45,X chromosomal constitution. The clinical and cytological findings in this patient are presented in the report. The possible mode of origin of this aberrant phenotype due to chromosome mosaicism of 45,X/46,XY type during early embryogenesis and subsequent elimination of 46,XY cell line is discussed.     

The phenotype of 45,X/46,XY mosaicism: an analysis of 92 prenatally diagnosed cases.

We undertook an international survey of prenatally diagnosed 45,X/46,XY mosaicism to ascertain the phenotypic spectrum of this condition. Ninety-two cases were obtained by means of a questionnaire sent to over 730 cytogenetic laboratories. Seventy-six cases (75 males and 1 female) had physical examinations after delivery or termination of pregnancy. Among these, there were four significant genital anomalies: three hypospadias and one female with clitoromegaly. Gonadal histology was abnormal in three (27%) of 11 cases, all of whom had normal male external genitalia. Other anomalies were noted in five cases: one cystic hygroma in a male, two cardiac anomalies, one spina bifida with multiple other defects, and one intrauterine growth retardation. There was no relationship between the percent mosaicism and the presence or degree of abnormalities. We conclude that 95% of 45,X/46,XY fetuses will have normal male genitalia, although there will also be a significant risk (27%) for abnormal gonadal histology. Long-term follow-up studies of prenatally diagnosed cases of 45,X/46,XY mosaicism are needed to study, without ascertainment bias, stature, pubertal development, tumor risk, and fertility.     

Chromosomal Abnormalities and Their Relation to Disease

When human chromosome anomalies were first described in 1959, it appeared that specific abnormalities might be correlated with specific syndromes. Mongolism and the D and E syndromes are examples of specific syndromes associated with the presence of an extra autosome. Klinefelter''s syndrome may be associated with a variety of different sex chromosome anomalies including XXY, XXYY, XXXY and XXXXY. The lastnamed variant is the only one that frequently presents features distinguishing it from the others. An XO sex chromosome complex is found in many women with gonadal dysgenesis. However, a variety of mosaicisms have been described in association with this condition, including XO/XX, XO/XXX, XO/XX/XXX, XO/XY and XO/XYY. Extra X chromosomes in phenotypical females do not seem to impair fertility or be consistently associated with congenital anomalies. Two families are described in which chromosome anomalies were found, but the association with defects was irregular. In one family the abnormality involved one of the number 16 chromosomes and in the other it involved one of the small acrocentric chromosomes.     

New cytogenetic variant of Orbeli's syndrome (46,XY/45,XY,-D/46,XY,Dq+)

Summary A newborn child with multiple congenital abnormalities, including severe hypoplastic thumb and atresia recti, is described. The cytogenetic analysis revealed a mosaicism 46,XY/45,XY,-D/46,XY,Dq+. The combination of mosaic D-monosomy and two cardinal features of 13q-syndrome give the possibility to consider this case as new cytogenetical variant of the Orbeli's syndrome.

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Zusammenfassung Ein Neugeborenes mit multiplen kongenitalen Abnormitäten einschließ-lich erheblicher Hypoplasie der Daumen und Atresia recti wird beschrieben. Die cytogenetische Analyse ergab ein Mosaik 46,XY/45,XY,-D/46,XY,Dq+ Die Kombination von Mosaik D-Monosomie und den zwei Hauptsymptomen des 13q-Syndroms läßt in diesem Falle eine neue cytogenetische Variante des Orbeli-Syndroms vermuten.

     

Aberrant chromosomal sex-determining mechanisms in mammals, with special reference to species with XY females

Both mouse and man have the common XX/XY sex chromosome mechanism. The X chromosome is of original size (5-6% of female haploid set) and the Y is one of the smallest chromosomes of the complement. But there are species, belonging to a variety of orders, with composite sex chromosomes and multiple sex chromosome systems: XX/XY1Y2 and X1X1X2X2/X1X2Y. The original X or the Y, respectively, have been translocated on to an autosome. The sex chromosomes of these species segregate regularly at meiosis; two kinds of sperm and one kind of egg are produced and the sex ratio is the normal 1:1. Individuals with deviating sex chromosome constitutions (XXY, XYY, XO or XXX) have been found in at least 16 mammalian species other than man. The phenotypic manifestations of these deviating constitutions are briefly discussed. In the dog, pig, goat and mouse exceptional XX males and in the horse XY females attract attention. Certain rodents have complicated mechanisms for sex determination: Ellobius lutescens and Tokudaia osimensis have XO males and females. Both sexes of Microtus oregoni are gonosomic mosaics (male OY/XY, female XX/XO). The wood lemming, Myopus schisticolor, the collared lemming, Dirostonyx torquatus, and perhaps also one or two species of the genus Akodon have XX and XY females and XY males. The XX, X*X and X*Y females of Myopus and Dicrostonyx are discussed in some detail. The wood lemming has proved to be a favourable natural model for studies in sex determination, because a large variety of sex chromosome aneuploids are born relatively frequently. The dosage model for sex determination is not supported by the wood lemming data. For male development, genes on both the X and the Y chromosomes are necessary.     

Turner's syndrome in the male with chromosomal mosaicism

A chromosomal mosaic XO/XY (+estra chromosome) with unequal distribution of the cells lines in blood cells and in fibroblasts is described in a boy with typical traits of Turner's syndrome.     

XX/XO-Mosaik bei einem männlichen Individuum mit Kleinwuchs und Hypospadie

Zusammenfassung Bei einem normal intelligenten, kleinwüchsigen, 219/12 jährigen Mann mit Hypospadie, fraglicher rudimentärer Vagina und hypergonadotropem Hypogonadismus findet man bei der Biopsie des nur 7 ml großen linken Hodens eine gleichförmige tubuläre Atrophie mit Fehlen des Keimepithels und eine diffuse, kleinherdige Leydigzellwucherung. Sex-Chromatin in den Leydigzellen, im Mundabstrich und Drumsticks negativ. Karyotyp in den Lymphocyten und im Knochenmark normal weiblich (46,XX), in den Fibroblasten jedoch 45,XO.Somit weist dieser Patient Testesgewebe auf, das Y-Chromosom ist aber unauffindbar. Zur Klärung dieser Diskrepanz scheint das Vorhandensein einer dritten, zahlenmäßig stark in den Hintergrund tretenden, ein Y enthaltenden Zellpopulation die naheliegendste Hypothese zu sein.Eine Zwillingsschwester kam im Neugeborenenalter ad exitum; die Blutgruppenuntersuchungen beim Patienten und seiner Familie machen aber einen Blutchimärismus sehr unwahrscheinlich.Das klinische Bild unseres Patienten ist vollkommen verschieden von demjenigen, das beim XX/XO-Mosaik üblicherweise beobachtet wird und läßt sich auch vom klassischen Klinefelter-Syndrom deutlich abgrenzen. Es zeigt Ähnlichkeiten mit einigen Fällen von XO/XY-Mosaik.

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Summary In a normally intelligent man of 219/12 years the following main physical findings were present: short stature, hypospadias, possibly a rudimentary vagina, hypergonadotropic hypogonadism, small testis (7 ml) with tubular dystrophy consisting in absence of germinal epithelium and localized proliferation of Leydig's cells. Sex chromatin in buccal mucosa cells was negative; no drumsticks were found in neutrophils. The karyotype in lymphocyte cultures and bone-marrow preparations was 46,XX; in several independent fibroblast cultures 45,XO.The most likely explanation for the presence of testicular tissue seems to be the existence of an undiscovered cell population containing a Y-chromosome.A twin sister of the patient died in early infancy; blood group investigations gave no indications for the presence of blood chimerism.The clinical picture of this patient is entirely different from that of the usual XX/XO mosaics, it also clearly differs from Klinefelter's syndrome but shows some similarities to cases of XO/XY mosaicism.

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Direktor: Prof. Chr. Hedinger     

Ring chromosome 4 mosaicism and Potter sequence

A 46,XY/46,XY,r(4) mosaicism is described in a malformed male newborn with bilateral renal agenesis. A review of the phenotypic findings in the previously reported ring chromosome 4 patients is made and the importance of the detection of chromosomal abnormalities towards the nosology of malformation sequences is discussed.     

Meiotic studies in mice carrying the sex reversal (Sxr) factor

A sex reversal factor (Sxr) that causes mice having apparently normal X chromosomes to become phenotypically male is transmitted in an autosomal pattern. The origin of the Sxr factor is still unknown. It seems most likely that it has originated from an autosomal gene mutation or is the result of a translocation of part of the Y chromosome to one of the autosomes. Chromosomes from four XY and six XO mice carrying this sex reversal factor were examined in the diakinesis stage of meiosis. The following unusual observations were noted: (1) in XY males carrying the Sxr factor, the X and Y chromosomes were separated more often than in controls. (2) The Y chromosome tends to be closer to an autosome when the X and Y are separate than when the X and Y are attached. (3) A chromosome fragment was present in 4/226 cells from two XO males and a single cell from an XY, Sxr carrier. Although there is no direct evidence, these observations seem to favor the possibility that the Sxr factor involves a chromosomal rearrangement rather than a single gene mutation.