Use of probes for ZFY, SRY, and the Y pseudoautosomal boundary in XX males, XX true hermaphrodites, and an XY female.

Three XX males, two XX true hermaphrodites, and an XY female were studied for possible deletions using probes for the recently characterised SRY gene and the pseudoautosomal boundary. The XX males and true hermaphrodites were negative for all three probes, while the XY female was positive. One XX male and one XX true hermaphrodite were sibs. A previous sib pair of an XX male and an XX true hermaphrodite have been shown to be positive for Y chromosomal material near the pseudoautosomal boundary. Thus, both phenotypes can be produced from different mutations, some involving the SRY gene and others not.     

New X linked spondyloepimetaphyseal dysplasia: report on eight affected males in the same family.

We report on a probably new form of spondyloepimetaphyseal dysplasia (SEMD) with an X linked inheritance pattern. Eight males were affected in the same family. We were able to examine three adult patients and we studied the skeletal radiological aspect of one of these patients at 2 years 6 months and at 9 years of age. The main clinical features are severe short trunked dwarfism, brachydactyly, normal facies, and normal intelligence. Radiologically, the diaphyses of all the long bones are short and broad. The epiphyses of the distal portion of the femora and those of the proximal and distal portions of the tibia are embedded in their metaphyses and there is marked narrowing of the intercondylar groove. There is moderate platyspondyly. Several vertebrae show an anterior tongue in infancy and severe irregularities of the upper and lower surfaces are present in adulthood. The 11th or 12th thoracic vertebra is wedge shaped. The pelvis is narrow. The distal ulnae and fibulae are disproportionately long. The hands show radial deviation and brachydactyly is present in the hands and feet. This X linked SEMD was not detectable at birth.     

Unilateral true hermaphrodite with 46,XX/46,XY dispermic chimerism.

A 13 year old female presented with ambiguous external genitalia, right inguinal ovotestis, left ovary, apparently normal Mullerian system, and absent Wolffian system. Cultured lymphocytes showed a 46,XX/46,XY karyotype. Histopathology of the gonads confirmed true hermaphroditism. The presence of two genetically different erythrocyte populations was observed. The findings suggested that the patient is a true hermaphrodite dispermic chimera.     

46,XX男性和46,XX/45,X病例分析

目的探讨SRY基因在性分化和发育中的作用.方法细胞遗传学核型分析以及PCR技术检测外周血SYR基因.结果病例1的核型为46,XX,SRY( ).诊断为46,XX男性性反转综合征.病例2的核型为46,XX/45,X,SRY(-).诊断为Turner嵌合型.结论SRY基因检测比Y染色体更能预示睾丸组织的存在,是诊断性别发育异常患者的重要手段.性腺的病理取决于性腺组织的染色体核型和SRY基因.除SRY基因外,还存在多个参与性别决定和分化的基因,性分化异常表现现高度遗传异常性.     

Clinical traits and molecular findings in 46,XX males

46,XX maleness is characterized by the presence of testicular development in subjects who lack a Y chromosome. The majority of affected persons have normal external genitalia, but 10–15% show various degrees of hypospadias. Several hypotheses have been proposed to explain the etiology of this constitution: translocation of the testis-determining factor ( TDF ) from the Y to the X chromosome, mutation in an autosomal or X chromosomal gene which permits testicular determination in the absence of TDF , and undetected mosaicism with a Y-bearing cell line. We report the pheno-typic data and results of molecular analyses performed in six sporadic Mexican males with 46,XX karyotype. Molecular studies revealed Yp sequences in two individuals ( ZFY + SRY +) with different phenotypes, a third one presented with a smaller segment of Yp ( ZFY – SRY +) and complete virilization, while the remaining three were Y-negative and showed hypospadias. In all subjects a hidden mosaicism with a Y-bearing cell line was ruled out due to the absence of Y-centromeric sequences. Our data demonstrate that the phenotype does not always correlate with the presence or absence of Y-sequences in the genome, and confirm that 46,XX maleness is a genetically heterogeneous condition.     

A true hermaphrodite dispermic chimera with 46, XX and 46, XY karyotypes

A 16-year-old male with hypospadias and gynaecomastia had a rudimentary uterus with a right Fallopian tube and ovary; the left gonad was a functioning testis. Cytogenetic studies showed cells with 46 , XX and 46 , XY sex chromosomes in cultured blood, skin and gonadal tissues. Cells with the 46 , XX constitution predominated in all tissues. Extensive investigations failed to demonstrate blood cell and serum chimerism, but there was little genetic variation of these characters between family members. Cytogenetic studies demonstrated that the father had contributed different marker chromosomes to the 46 , XY and 46 , XX cell lines of the propositus, whereas the mother had contributed the same two informative markers to both cell lines. The patient was a chimera with two diploid cell lines of different sex that had developed from the products of two separate acts of syn-gamy. Dispermy was demonstrated, and, whereas there was no evidence of different maternal contributions to the chimeric cell lines, uncertainty remains that these were identical.     

Two XX males in one family and additional observations bearing on the etiology of XX males

Two XX males who were second cousins are reported. A genetic mechanism producing maleness is suggested. The putative factor had been transmitted solely through males, which excludes the possibility of a heritable X-Y interchange.
Recent reports on fluorescent Y chromatin in Sertoli cells of XX males prompted investigations into the fluorescence patterns of testicular cells. Sertoli cells from three XX males displayed brightly fluorescent spots, but it was concluded that they did not represent Y chromosomes. Evidence for this conclusion was obtained from the study of testicular fluorescence in XX, XXY and XY males.
No visually detectable cytogenetic evidence for an increase in length or altered banding pattern of one of the X chromosomes was found in three XX males.
We conclude that an autosomal gene is the most likely explanation of the male differentiation in the two XX males presented here.     

X chromosome inactivation patterns in 45,X/46,XX mosaics

To investigate X chromosome inactivation (XCI) patterns in 45,X/46,XX mosaics, genomic DNA was extracted from peripheral blood samples of 15 female subjects who showed different proportions of 45,X cell clones. XCI patterns were analyzed using two assays. The first assay was the BstXI restriction endonuclease detection of an X-linked phosphoglycerate kinase (PGK) gene polymorphism following digestion of the DNA with methylation-sensitive HpaII, or with methylation-insensitive AfaI as a control. The second assay was the detection of a CAG triplet repeat polymorphism in the X-linked androgen receptor (AR) gene after sodium bisulfite treatment. Of the 15 subjects, 11 were informative due to heterozygosity for at least one of the polymorphisms (6 were heterozygous for the PGK polymorphism and 9 were heterozygous for the AR polymorphism). Four of the 11 informative subjects (36%) showed extremely skewed XCI for at least one of the polymorphisms, which was a much higher incidence than previously reported for normal females. Moreover, 3 of these 4 women had proportions of 45,X cell clones greater than 20%. Although our results may be due to several possible cytogenetic or molecular mechanisms, the most likely explanation is that cases of 45,X/46,XX that contain relatively high levels of 45,X cell clones probably arose due to structural aberrations of the X chromosome undetectable by conventional karyotyping. Received: November 6, 2000 / Accepted: December 18, 2000     

H-Y antigen mosaicism in the gonad of a 46,XX true hermaphrodite

To clarify the mechanism for the coexistence of ovarian and testicular tissue in the 46,XX true hermaphrodite, we studied a 20-year-old phenotypic male with gynecomastia and elevated serum concentrations of estradiol in whom an ovotestis was discovered upon scrotal exploration. Y chromosomal material could not be detected by fluorescent Y-body analysis or Giemsa-banding technics in cells cultured from peripheral blood, breast or forearm skin or the ovarian or testicular portions of the ovotestis. However, serologic testing, using the sperm cytotoxicity assay, revealed that cells cultured from the testicular portion of the ovotestis were H-Y antigen positive whereas cells cultured from the ovarian portion were H-Y antigen negative. These observations indicate that the ovotestis arises from an H-Y+/H-Y- mosaic primordium.     

Body size and shape in 46, XX males: an anthropometric investigation

Anthropometric measurements of four 46, XX males are compared with those of their first degree male relatives, control males, and a sample of 47, XXY males. Most dimensions of 46, XX males are smaller than those of normal males. 46, XX males are also shorter and smaller than 47, XXY males.
The present results support the earlier suggestion that there is a gene(s) in the Y chromosome with a general size-increasing effect and that the Y chromosome has an active role in the development of sex dimorphism in many body dimensions. These four 46, XX males may possess the Y chromosomal gene which sets the later timing of development in males.     

X linked or autosomal recessive? A new approach to an old problem.

Families in which a single male is affected with a disease which might be either X linked recessive or autosomal recessive present problems in counselling. Before female relatives can be counselled, the probabilities of each mode of inheritance must be assessed, taking into account the prior probabilities, the pedigree structure, any DNA probe data, and any carrier testing data. The widely used linkage analysis package LINKAGE can be used to do the calculation, which is much simpler than the conventional Bayesian method.     

六例Y染色体短臂片段易位所致46,XX男性综合征患者的细胞和分子遗传学研究

目的 明确6例46,XX男性综合征患者细胞遗传和分子遗传水平的异常,探讨X-Y短臂易位所致46,XX男性综合征的临床特点和发病机制.方法 临床收集6例46,XX男性患者的表型数据,采用染色体核型分析、聚合酶链反应、荧光原位杂交对SRY基因进行检测和定位.结果 6例患者均为SRY阳性XX男性,携带一条由包含SRY区域的Y染色体短臂片段易位至X染色体短臂而构成的异常X染色体.3例患者通过550～700条带染色体核型分析确定了X-Y易位的断裂位点,均位于Xp22.33和Yp11.2;另外3例患者推测其断裂点位于Xp22.32和Yp11.31,或是Xp22.31和Yp11.2,其中Xp22.32、Xp22.31和Yp11.31的断裂位点既往报道较少.不同年龄段SRY阳性46,XX男性临床表现各有特点.4例成年男性患者均因不育而就诊,表现为无精及性发育不良;1例青少年患者以身材矮小和第二性征发育不良为主要特征;1例儿童患者以身材矮小为唯一表现.结论 染色体核型分析、聚合酶链反应和荧光原位杂交等方法的综合运用在46,XX男性综合征的诊断中具有重要意义.高分辨染色体核型分析对于易位导致的XX男性综合征的断裂点机制研究,以及基因型表型关联的深入分析有指导作用.     

A heterozygous mutation in RPGR associated with X‐linked retinitis pigmentosa in a patient with Turner syndrome mosaicism (45,X/46,XX)

Turner syndrome with retinitis pigmentosa (RP) is rare, with only three cases reported based on clinical examination alone. We summarized the 4‐year follow‐up and molecular findings in a 28‐year‐old patient with Turner syndrome and the typical features of short stature and neck webbing, who also had X‐linked RP. Her main complaints were night blindness and progressive loss of vision since the age of 9 years. Ophthalmologic examination, optical coherent tomographic imaging, and visual electrophysiology tests showed classic manifestations of RP. The karyotype of peripheral blood showed mosaicism (45,X [72%]/46,XX[28%]). A novel heterozygous frameshift mutation (c.2403_2406delAGAG, p.T801fsX812) in the RP GTPase regulator (RPGR) gene was detected using next generation sequencing and validated by Sanger sequencing. We believe that this is the first report of X‐linked RP in a patient with Turner syndrome associated with mosaicism, and an RPGR heterozygous mutation. We hypothesize that X‐linked RP in this woman is not related to Turner syndrome, but may be a manifestation of the lack of a normal paternal X chromosome with intact but mutated RPGR.     

A phenotypic male with true hermaphroditism and a 46,XX/46,XY/ 47,XXY karyotype

A phenotypic boy presenting with gynaecomastia showed a mixed karyotype of 46,XX/46,XY/47,XXY. The left gonad was normally descended into the scrotum, but proved to be an ovary without any testicular structures. After left gonadectomy, plasma androgen and estrogen levels showed that the right gonad only contained testicular tissue. Seven patients with this form of triple mosaicism have been described but the clinical features are strikingly different among the described cases.     

Screening for mutations in the WNT-4 gene in patients with 46,XX true hermaphroditism

We investigated if eight SRY-negative 46,XX true hermaphrodites presented mutations in WNT-4, in blood leukocytes and/or gonadal tissue, as the cause of their disorder. We designed the sequences of the reverse primer of exon 1 and the primers of exons 2-5. Direct sequencing of all five exons demonstrated no mutant alleles in any of the patients. The possibility of the existence of causative mutations in the untranslated regions of WNT-4, or within introns cannot be ruled out.