Familial 46,XX males coexisting with familial 46,XX true hermaphrodites in same pedigree

Reported here is a family with which 46,XX males and 46,XX true hermaphrodites coexist. The propositus was a paternal uncle with 46,XX true hermaphroditism. One of his brothers fathered a 46,XX daughter with true hermaphroditism; a second brother fathered two 46,XX males. Both fathers have normal male karyotypes and phenotypes. No evidence for chromosomal mosaicism or any additional chromosomal abnormalities was obtained. We conclude that inheritance of the abnormality is most likely via paternal transmission of an autosomal testis-determining factor. This family provides evidence to support the hypothesis that 46,XX true hermaphrodites and 46,XX males represent alternative manifestations of the same genetic defect.     

Monozygotic twin discordant for Down syndrome: mos 47,XX,+21/46,XX and 46,XX

Monozygotic twins, developed from a single zygote, are almost identical in clinical phenotype and concordant karyotypes. Monozygotic twins with discordant karyotypes are thought to be quite rare. Here, we report monochorionic-diamniotic twins discordant for Down syndrome. On findings of prenatal ultrasonography, nuchal translucency thickness was different between twins, and suggested that one of the twins was at high risk for having chromosomal abnormalities including Down syndrome. The twins were monochorionic-diamniotic; therefore, chorionic villi sampling of the common placenta was performed. The karyotype of the chorionic villi cells was 46,XX, and pregnancy was maintained. After delivery, dysmorphic clinical features suggesting Down syndrome were found in one of the twins, while the other twin showed a morphologically normal appearance. Karyotypes of peripheral blood leukocytes were repeatedly normal in the dysmorphic twin; however, the karyotype of skin fibroblasts from the dysmorphic twin indicated Down syndrome mosaicism; 47,XX,+21[99]/46,XX[2]. The karyotype of skin fibroblasts from the morphologically normal twin was 46,XX. Monozygosity of the twins was confirmed by a short tandem repeat analysis using 16 polymorphic markers. A mitotic nondisjunction followed by the twinning would explain the discordant karyotypes between monozygotic twins.     

46,XX真两性畸形的基因诊断

睾丸决定因子（Ｔｅｓｔｉｓ－ｄｅｔｅｒｍｉｎｉｎｇｆａｃｔｏｒ，ＴＤＦ）位于Ｙ染色体短臂上，它的表达产物诱导睾丸组织的发生。ＳＲＹ基因（Ｓｅｘ－ｄｅｔｅｒｍｉｎｉｎｇｒｅｇｉｏｎｏｆｔｈｅＹ）位于Ｙ染色体的性别决定区内，许多特征显示ＳＲＹ可能就是ＴＤＦ。采用多聚酶链反应（ＰＣＲ）结合斑点杂交对３例４６，ＸＸ真两性畸形性腺组织的石蜡切片中ＳＲＹ基因进行检测，２例检测到ＳＲＹ基因，１例未检测到。性腺组织病理检查均为卵睾组织。为探讨两性畸形的发病机理提供了资料。     

Clinical, hormonal and cytogenetic evaluation of 46,XX males and review of the literature

The main factor influencing the sex determination of an embryo is the genetic sex determined by the presence or absence of the Y chromosome. However, some individuals carry a Y chromosome but are phenotypically female (46,XY females) or have a female karyotype but are phenotypically male (46,XX males). 46,XX maleness is a rare sex reversal syndrome affecting 1 in 20,000 newborn males. Molecular analysis of sex-reversed patients led to the discovery of the SRY gene (sex-determining region on Y). The presence of SRY causes the bipotential gonad to develop into a testis. The majority of 46, SRY-positive XX males have normal genitalia; in contrast SRY-negative XX males usually have genital ambiguity. A small number of SRY-positive XX males also present with ambiguous genitalia. Phenotypic variability observed in 46,XX sex reversed patients cannot be explained only by the presence or absence of SRY despite the fact that SRY is considered to be the major regulatory factor for testis determination. There must be some other genes either in the Y or other autosomal chromosomes involved in the definition of phenotype. In this article, we evaluate four patients with 46,XX male syndrome with various phenotypes. Two of these cases are among the first reported to be diagnosed prenatally.     

Pseudohermaphroditis, with testes and a 46, XX karyotype.

A 14 4/12-year-old white girl, evaluated for progressive virilization and clitormegaly, was found to have the unusual combination of a 46, XX karyotype, well-developed Mullerian structures, and dysgenetic testes with Leydig cell hyperplasia. Although there have been previous case reports of 46, XX males, in all of these patients development of the Mullerian ducts had been suppressed. When contemporary classifications of human disorders of sexual differentation were reviewed, no report of a similar patient was found. We speculate that the genotype and phenotype in our patient correspond to the genetic intersexuality of the hornless goat, thereby raising the possibility that the human autosome may play a role in the control of sexual development.     

Trisomy 21 q: 46,XX,21s+/47,XX,+21q−(q22→qter) mosaicism (de novo) in a down syndrome child

A three year old girl with clinical features of Down syndrome and mental retardation is reported. Karyotype of the proband was 46,XX,21s⁺/47,XX,21q→(q22−qter), resulting in partial trisomy for chromosome 21. Her father, phenotypically normal, was a carrier for 21s+variant chromosome (46,XX,21s⁺). The maternal age was 32 years. This case further confirms that the Down phenotype is due to the trisomy of the distal segment of the band q22 of chromosome 21.     

45,X/46,XX mosaicism in turner’s syndrome

Summary A short-statured phenotypic female with primary amenorrhoea, infantilism, shield chest and 9% sex chromatin bodies in buccal smears had 2 cell lines, 45/46, in cultured leucocytes. She was diagnosed as a case of Turner's syndrome with X/XX chromosomal mosaicism. This patient is another example of modification of the Turner phenotype by the presence of a normal XX cell line. The report highlights the importance of cytogenetic investigations in short-statured females who do not possess all the clinical features of the classical form of Turner’s syndrome. From the Chaudhuri Centre for Medical Genetics, Calcutta-14.     

Three new 46,XX male patients: a clinical, cytogenetic and molecular analysis

BACKGROUND: XX males range phenotypically from completely masculinised individuals to true hermaphrodites and include a subset of SRY negative patients. The correlation between genotype (SRY+/-) and phenotype is still unclear. AIM: To report three new patients with this rare condition, one of whom was diagnosed prenatally and another was SRY negative, and to verify in our patients whether the presence of SRY results in a more masculinised phenotype. PATIENTS AND METHODS: We present two phenotypically normal XX male patients (10 and 13.5 years) and one 3.1 years old XX male with ambiguous external male genitalia Prader IV. The patients were diagnosed by clinical, hormonal, sonographic, genetic and histological criteria. RESULTS: Basal hormonal status was normal for phenotype but an excessive response to GnRH testing was noticed in the second patient together with insufficient hCG stimulation in all three patients. Pelvic ultrasound displayed male structures without Müllerian ducts; testicular biopsy, performed only in the intersex patient, showed Sertoli and Leydig cell hypoplasia. Chromosome analysis confirmed 46,XX karyotype. FISH analysis and molecular analysis by PCR were positive for Yp fragments/SRY gene on Xp in two patients and negative in the patient with ambiguous external genitalia. CONCLUSIONS: In our observation Y chromosome-specific material containing the SRY gene translocated to the X chromosome results in a completely masculinised phenotype. In the intersex patient, incomplete masculinisation without SRY suggests a mutation of one or more downstream non-Y testis-determining genes.     

Prepubertal XX male with profound physical and mental deficiency, retinitis pigmentosa and multiple congenital anomalies

A unique case of a prepubertal XX male with profound mental and physical retardation, retinitis pigmentosa, ambiguous genitalia and multiple congenital anomalies is reported. His clinical, genetic, dermatoglyphic and histological findings are presented. This case could represent a new multiple congenital malformation syndrome. Theories on XX male aetiology are briefly discussed.     

74例46,XX性发育异常患儿性腺探查结果及分析

目的 分析总结我院46,XX性发育异常患儿性腺探查结果并分析.方法 回顾性分析2006年1月至2015年12月期间就诊我科染色体核型为46,XX的性发育异常患儿98例,其中24例因内分泌科明确诊断CAH无需行性腺探查.另74例46,XX DSD为明确诊断行手术探查性腺,并取病理活检.根据术中探查所见内生殖器分布情况以及术后患儿的病理结果汇报归纳总结74例46,XX患儿性腺探查情况并分析.结果 除CAH外余74例46,XX DSD患儿中社会性别为:男48例,女26例.为明确诊断均行性腺探查术.其中单纯腹腔镜手术49例,腹腔镜联合开放手术12例,开放手术13例.性腺探查病理结果如下:双侧性腺均为卵睾25例(33.78％);一侧性腺为卵巢,一侧为睾丸13例(17.57％);一侧卵睾,一侧睾丸12例(16.22％);一侧卵睾,一侧卵巢18例(24.32％);双侧均为原始性腺2例(2.7％);一侧原始性腺,一侧卵巢2例(2.7％);一侧原始性腺,一侧睾丸2例(2.7％).31例含有卵巢性腺患儿中14例卵巢分布在左侧,占45.16％.25例含有睾丸性腺的患儿中11例睾丸位于右侧,占44％.结论 性腺探查及病理活检是46,XX DSD中除CAH外明确性发育障碍患儿的诊断及治疗方案重要的评估手段,对早期明确诊断、合理的选择性别及手术重建治疗具有重要的意义.     

End-stage renal disease and primary hypogonadism associated with a 46,XX karyotype.

OBJECTIVE--To determine the cause of absent sexual development in a 17-year-old girl with end-stage renal disease. DESIGN--Case study. PARTICIPANT--Seventeen-year-old girl with end-stage renal failure. INTERVENTIONS--None. MEASUREMENTS/MAIN RESULTS--The patient had phenotypically normal external female genitalia, müllerian duct hypoplasia, and no ovaries. Her serum gonadotropin levels were in the castrate range at baseline and after gonadotropin-releasing hormone stimulation. Her karyotype, in lymphocytes and cultured fibroblasts, was 46,XX. Analysis of genomic DNA, following polymerase chain reaction-amplication with oligonucleotide primers corresponding to the Y-encoded zinc finger protein ZFY and the testis-determining SRY gene, showed Y chromosome material in a male control but none in the patient. CONCLUSIONS--The results suggest a diagnosis of Frasier syndrome, a disorder characterized by true gonadal dysgenesis and end-stage renal disease occurring in normal phenotypic girls. Although previously reported only in individuals with a 46,XX karyotype, our studies indicate that Frasier syndrome may also occur in 46,XX girls. Delayed puberty is not uncommon in renal failure. This case illustrates the importance of measuring gonadotropin levels in teenage girls with delayed puberty and renal failure, particularly if the origin of the renal disease is obscure.     

Clinical, cytogenetic and molecular analysis of three 46,XX males

Cytogenetic analysis, fluorescent in situ hybridization (FISH) and polymerase chain reaction (PCR) were applied to characterize the Y-chromosomal breakpoints of three XX male patients. Two of these patients show a breakpoint within a protein kinase gene, PRKY, previously described as a hotspot of ectopic recombination between homologous regions on X and Y chromosomes during male meiosis. The slightly different clinical phenotypes of the three patients cannot be correlated with the localization of the breakpoints.     

An unusal case of hermaphroditism--a 46,XX/69,XXY chimera

A diploid/triploid karyotype is an uncommon but important cause of true hermaphroditism and ambiguous genitalia. Individuals have a recognisable phenotype and characteristic hydatidiform placental changes. We report a 46,XX/69,XXY chimeric hermaphrodite. This case highlights the typical features (large placenta, intrauterine growth retardation, asymmetric growth, cranio-facial anomalies, syndactyly and pigmentary dysplasia). It illustrates the importance of obtaining skin and gonadal karyotypes in the case of genital ambiguity, as the venous lymphocytic karyotype is usually diploid.     

Down syndrome with XO/XX mosaicism.

A 2-month-old girl with Down syndrome was found to have 47, XX, +21/46, X, +21 mosaicism. No symptoms indicative of infantile Turner syndrome were observed.     

Absence of Y specific DNA sequences in two siblings with 46XX hermaphroditism.

We report two siblings with 46XX hermaphroditism in whom we were unable to show the presence of Y specific DNA sequences using the DNA probes Y-190, GMGY-7, pHY2.1, pDP34, and 27a. We conclude that an autosomal or X chromosome gene mutation is the most likely mechanism of inheritance in this family with 46XX hermaphroditism.     

尿生殖窦部分游离术在雄性化46,XX性别发育异常治疗中的应用

目的 探讨尿生殖窦部分游离术在雄性化46,XX性别发育异常(disorders of sex development,DSD)女性化手术中的应用,并对其疗效进行评估.方法 2010年5月到2015年2月,我院收治15例过度雄性化的46,XX DSD患儿,采用尿生殖窦部分游离(partial urogenital mobilization,PUM)术结合Poppas阴蒂整形术和阴唇成形术一期完成生殖器女性化手术.年龄5个月～13岁,中位年龄28.7个月.通过膀胱镜下测量尿生殖窦共同通道的长度,来决定是否实施PUM术.术后随访尿控情况、阴道口大小和位置及外阴外观等来判断PUM的疗效.结果 15例均获随访.随访时间1～5年,平均31.5个月.尿生殖窦共同通道长度1.2～3.0cm,平均1.7cm.外生殖器外观评估:12例(80％)为好,前庭部可见阴道开口,阴道内可进入8～15 mm的阴道扩张器(平均10mm).2例(13.3％)为一般,其中1例小阴唇偏短;另1例术后阴道口位置较深.不满意1例(6.7％),为尿生殖窦共同通道长度近3 cm的Prader V级患儿,术后阴道口较深,大阴唇外观皮肤冗多似阴囊,小阴唇偏短.但无一例出现阴道口狭窄.无一例出现尿失禁及尿频、排尿困难等下尿路症状;13例在术后1年以上做了尿流动力学检查,除3例有部分逼尿肌不稳定收缩外,余均无明显异常.结论 尿生殖窦共同通道长度小于2 cm的雄性化46,XX DSD,PUM术是治疗该畸形的有效方法,术后可获得开口于前庭的无狭窄的阴道、良好的尿控和满意的外生殖器外观.     

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 chromosoms. 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.     

46,XX patients with congenital adrenal hyperplasia: initial assignment as male, reassigned female

Six 46,XX patients with congenital adrenal hyperplasia (CAH) presented with genital ambiguity, five so severe that initial gender assignment was male. Once diagnosis was realized, parents were involved in evaluation and chose sex re-assignment as female. To date, these girls and their parents all indicate satisfaction with their decision for a female sex of rearing. The girls have a female gender identity with behavior characteristics known for females with CAH. Thus, while outcome is satisfactory, it is realized that for most, expression of sexual orientation and adult life adjustments have not yet occurred.     

De novo terminal deletion of chromosome 7 [46, XX, del(7)(q35)]

Objective : To report a new case of de novo 7q deletion distal to q35.
Methodology : Developmental, cytogenetic and audiological investigations were carried out in the assessment of this rare chromosomal condition.
Results : Moderate developmental delay, mild congenital microcephaly, growth retardation and conductive hearing impairment were found for this case of 46, XX, del(7)(q35).
Conclusions : The phenotype of 7q terminal deletion is highly variable.