儿童真两性畸形诊断与治疗:附9例报告

目的 探讨儿童真两性畸形的诊断、合理的性别选择及恰当的治疗方式。方法 回顾性分析1994年至2002年9例儿童真两性畸性的临床资料。结果 社会性别：男6例，女3例；染色体组型：46XX4例，46XY1例，45XO1例，45XO／46XY嵌合型3例。性腺畸形为：双侧型2例，单侧型3例，片侧型4例。按男性抚育者，行卵巢组织及子宫附件切除，睾丸固定，同期或二期尿道下裂修复；按女性抚育者，切除睾丸组织或卵睾，同期行阴蒂会阴成形术。近期2例用腹腔镜行盆腔探查和性腺切除。5例获得6个月～3年的随访。结论 早期诊断、根据外生殖器及性腺优势作出合理的性别选择至关重要，儿童期应完成对与确定性别相抵触性腺的切除和外生殖器矫形，腹腔镜在诊断与治疗上有很好的价值。     

True hermaphroditism

OBJECTIVE: True hermaphroditism is a rare cause of atypical genitalia which presents significant diagnostic and management challenges. We present the clinical and laboratory findings and management of four patients with true hermaphroditism. METHODOLOGY: Case studies from a teaching hospital and literature review. RESULTS: All four patients had atypical genitalia identified at birth. All had a palpable gonad, only one of which was palpable at birth. Three patients were 46XX (SRY -ve) and one 46XY (SRY +ve). Three patients were raised as females (two 46XX and one 46XY) and one as a male. All four patients were found to have an ovotestis present. CONCLUSIONS: The management of true hermaphroditism is controversial and requires a multidisciplinary approach. It has many implications for both the parent and child. We discuss the issues involved for the patients and their parents.     

A Case Series of Five Sri Lankan Patients with Ovotesticular Disorder of Sex Development

Ovotesticular disorder of sex development (OT-DSD) is a rare disorder of sexual differentiation in which the gonads of an individual are characterized by the presence of both mature ovarian and testicular tissues. The objective of this paper is to report the clinical, cytogenetic and histopathological findings in Sri Lankan patients diagnosed with OT-DSD who were referred to the Human Genetics Unit for cytogenetic evaluation during 2005 to 2011. Five patients had histopathologically confirmed OT-DSD. Their ages at presentation ranged from 2 mo to 47 yr. Clinical symptoms varied from ambiguous genitalia and inguinal hernias at birth to a lower abdominal mass presenting in adulthood. All 5 were reared as phenotypic males. An ovotestis was detected in all cases except one, and the predominant karyotype was 46,XY. The findings in this series of predominantly 46,XY karyotype are in contrast to previously published reports that have reported 46,XX as being the predominant karyotype. It is therefore recommended that individuals with ambiguous genitalia who have the 46,XY karyotype should be thoroughly investigated by ultrasonographic or laparoscopic assessment to determine the exact nature of their internal genital organs. OT-DSD should also be considered in the differential diagnosis of patients with cryptorchidism and inguinal hernia.     

True hermaphroditism with characteristics of Klinefelter's syndrome: a rare presentation

True hermaphroditism, a very rare cause of intersex, is usually diagnosed during the newborn period in the course of evaluating ambiguous genitalia. As an exception we report an unusual case of a 14.5 year-old boy with phenotypically near-normal male genitalia and bilaterally descended gonads, who was seen for evaluation of gynecomastia and hematuria. His eunuchoid body habitus and mild mental retardation were compatible with Klinefelter's syndrome. He had a low level of free testosterone (15.2 pmol/l), and high level of estradiol (264.3 pmol/l) for his age. The patient was diagnosed as true hermaphroditism with 46,XX /47,XXY karyotype causing an ovotestis with inguinal uterus hernia in the left scrotum and a dysgenetic testis in the right scrotum.     

True hermaphroditism: Geographical distribution,clinical findings,chromosomes and gonadal histology

We reviewed 283 cases of human true hermaphroditism published from 1980 to 1992. Of the 96 cases described in Africa 96.9% showed a 46,XX karyotype. In Europe 40.5% of 74 cases and 21.0% of the patients in North America had chromosomal mosaicism. The 46,XY karyotype is extremely rare (7%) and equally distributed through Asia, Europe and North America. Of 283 cases 87 were of black or black mixed origin with a 46,XX chromosomal constellation. The most common gonad in patients with true hermaphroditism, an ovotestis, was found in 44.4% of 568 gonads. Gonads with testicular tissue were more frequent on the right side of the body, while pure ovarian tissue was more common on the left. Histologically the testicular tissue was described to be immature and only twice was spermatogenesis reported while the ovarian portion often appeared normal. This coincides with 21 pregnancies reported in ten true hermaphrodites while only one true hermaphrodite apparently has fathered a child. Of the patients 4.6% were reported to have gonadal tumours. Position and type of the genital ducts, frequency of clinical findings such as genital abnormalities and gynaecomastia, correlations between assigned sex and karyotype as well as the age at diagnosis are reported.     

Is true hermaphroditism a primary germ cell disorder?

Eleven cases of true hermaphroditism, 6 raised as female and 5 as male, were seen in the 20-year period from 1965 to 1985. External genitalia varied from Prader types II to IV. The ovotestis (11/22) was the most common gonad, and a marked variation in macroscopic and microscopic appearances with five patterns of distribution of gonadal tissue was noted. Ovulation was observed in ovarian tissue, and spermatogonia, but no spermatozoa, in testicular tubules. A hypothesis is developed suggesting abnormal testicular differentiation, and a model is presented to explain observed patterns of gonadal tissue distribution. A uterus was present in all cases, but a hemiuterus or lateralized uterus was noted in the 5 cases in which only testicular or predominantly testicular tissue was observed on the contralateral side. Karyotype analysis showed 46 XX in 5 cases (1 with an H-Y antigen) and a mosaic involving 46 XY in the remaining 5. Spontaneous puberty was achieved in 3 of the females, and of the 4 males with residual testicular tissue, all are prepubertal.     

Impact of laparoscopy for diagnosis and treatment in patients with disorders of sex development

ObjectiveTo review laparoscopy in patients with disorders of sex development (DSD) in order to clarify its usefulness in diagnosis, devising subsequent therapeutic strategies and managing patients with various conditions.Patients and methodsBetween April 1992 and December 2012, 29 laparoscopic surgeries were performed in 25 DSD patients. Among them, ten were diagnostic laparoscopy including gonadal biopsy, and 19 were therapeutic laparoscopy. Surgical procedures and complications were evaluated.ResultsFor diagnostic laparoscopy, laparoscopic gonadal biopsy was performed in three patients. Inspection, with or without open gonadal biopsy, was performed on four out of seven patients with 46XY DSD or mixed gonadal dysgenesis (MGD). Additional surgery was planned and performed based on diagnostic laparoscopic findings in six out of seven patients. In the three patients with ovotesticular DSD, the gonadal pathology was diagnosed as: testis/ovary in one, testis/ovotestis in one and ovary/ovotestis in one – this was from the laparoscopic inspection and/or gonadal biopsy. However, the final diagnoses were bilateral ovotestis in two patients and ovary/ovotestis in one patient.For therapeutic laparoscopy, surgical procedures were: gonadectomy in 17 patients (bilateral in 13, unilateral in three, partial in two); hysterectomy in two patients; orchiopexy in one; and sigmoid vaginoplasty in one patient (included multiple procedures). There were no severe perioperative complications. In the four patients with a history of diagnostic laparoscopy, no severe intra-abdominal adhesions that would disturb therapeutic laparoscopic surgery were observed.ConclusionWhile diagnostic laparoscopy was helpful in devising a therapeutic surgical strategy in most of the patients with DSD who were suspected as having complex gonadal status or Müllerian duct derivatives, attention must be paid to precisely diagnosing the gonadal status in ovotesticular DSD. On the other hand, therapeutic laparoscopic surgeries were valuable procedures in treating DSD patients, even with a history of previous diagnostic laparoscopy.     

Presence of Turner stigmata in a case of dysgenetic male pseudohermaphroditism with 45,X/46,X+mar karyotype

A case is reported of dysgenetic male pseudohermaphroditism (DMPH) having Turner stigmata and 45,X/46,X+mar karyotype. The marker chromosome of this patient consisted of most if not all of the short arm, including the sex determining region of the Y chromosome. Although this karyotype is relatively common in Turner's syndrome and occasionally observed in mixed gonadal dysgenesis, DMPH is usually exemplified by a 46,XY karyotype except for one patient reported with 45,X/46,XY mosaicism. Turner stigmata have not previously been reported in DMPH. The present patient is an intermediate case between mixed gonodal dysgenesis and typical DMPH, and this indicates that 45,X/ 46,X +mar karyotype abnormality can result in a wide range of phenotype such as DMPH, mixed gonodal dysgenesis and Turner's syndrome.     

True hermaphroditism: 10 years' experience

True hermaphroditism (TH) is the rarest variant of intersex malformations. By definition, these patients have both ovarian and testicular tissue. Most present due to ambiguous genitalia and/or gynecomastia. From 1986 to 1996, we treated 97 patients with intersex disorders; there were 4 with TH. In all cases testicular and ovarian tissue was separate. In 3 patients the external genitalia were ambiguous and 1 had hypoplastic male genitalia. Three patients had a 46, XY and 1 a 46, XX karyotype. Three patients had been listed as males and 1 as a female. The number of operations required varied from 3 to 9 (mean 5.7 per patient). Two patients who had been raised as males finished puberty with hypogenitalism and hypoplastic testes. One married and could have erections, but no ejaculation. Two male patients have been on supplementary androgen therapy. The only patient who had been raised as a female after clitorovaginoplasty had a 6-cm-deep, blind-ending vagina that was deepened to 12 cm with bougienage, so that she was capable of having normal intercourse. It is felt at present that most patients with TH should be raised as females. This was confirmed in our patients as well, which underlines the significance of early diagnosis. Accepted: 11 January 2000     

卵睾型性发育异常单中心临床诊治分析

目的 总结卵睾型性发育异常的临床特点及诊治经验.方法 回顾性分析1993年1月至2015年12月就诊于医院并通过病理确诊卵睾型性发育异常的32例患儿临床资料和随访资料.社会性别:男30例,女2例.12.5％呈女性外貌,生殖器类别模糊,阴蒂1～3 cm,小阴唇发育差,有乳房发育;87.5％呈男性外貌,阴茎发育极差,重度下弯,尿道开口异常(位于阴囊处或会阴部),阴囊不同程度女性化,外形近阴唇貌,其中46.9％(15/32)伴有隐睾.染色体核型分析:46,XX卵睾型DSD 11例;46,XY卵睾型DSD 1例;性染色体异常DSD中的卵睾型性发育异常20例(嵌合性46,XY/46,XX6例;混合型14例).结果 11例行泌尿生殖系彩超和排泄性尿道阴道造影,二者结合检出率为100％(11/11).5例行SYR基因筛查,1例45,X卵睾型DSD及1例45,X/46,XY卵睾型DSD为SYR阳性,1例45,X/46,XY SYR基因为阴性,余2例46,XX卵睾型DSD中,50％SYR基因为阴性.64个性腺中16个卵睾,25个睾丸,23个卵巢.性腺畸形:双侧型5例,单侧型6例,片侧型21例.30例按男性抚养者均完成阴茎矫直术和尿道重建术.对29例患儿进行8个月～9年的随访,其中3例术后反复发生尿瘘,多次行尿瘘修补术,阴茎及睾丸发育极差,生活质量差;4例术后尿道开口位于冠状沟部或阴茎体部,排尿可;3例进入青春期后有乳房发育;2例阴茎、睾丸发育稍差;余阴茎形态可,长2.5～4.0 cm,睾丸测值较同龄人稍小.2例按女性抚养者均完成阴蒂矫形术,均获得满意的外观,1例处于青春期发育阶段,另1例予雌激素替代治疗后获得青春期发育,外阴形态可,有乳房发育.结论 早期诊断,确诊后是否立刻性别选择行手术治疗仍有争议,我们认为应将患儿的心理性别、社会性别作为参考的首要标准结合激素水平评估、优势性腺评估最后选择性腺切除或重建手术并辅以激素治疗.对于维持患儿正常的性生理、性心理及社会生活具有重要的意义.     

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.     

Presence of Turner stigmata in a case of dysgenetic male pseudohermaphroditism with 45,X/46,X+mar karyotype

Accepted 19 November 1996
A case is reported of dysgenetic male pseudohermaphroditism (DMPH) having Turner stigmata and 45,X/46,X+mar karyotype. The marker chromosome of this patient consisted of most if not all of the short arm, including the sex determining region of the Y chromosome. Although this karyotype is relatively common in Turner''s syndrome and occasionally observed in mixed gonadal dysgenesis, DMPH is usually exemplified by a 46,XY karyotype except for one patient reported with 45,X/46,XY mosaicism. Turner stigmata have not previously been reported in DMPH. The present patient is an intermediate case between mixed gonodal dysgenesis and typical DMPH, and this indicates that 45,X/46,X+mar karyotype abnormality can result in a wide range of phenotype such as DMPH, mixed gonodal dysgenesis and Turner''s syndrome.

     

The clinical and genetic heterogeneity of mixed gonadal dysgenesis: does “disorders of sexual development (DSD)” classification based on new Chicago consensus cover all sex chromosome DSD?

Clinical findings illustrate the wide spectrum of the phenotypic manifestations of 45,X/46,XY mosaicism in the sex chromosome disorders of sex differentiation (DSD). The objective of study is to evaluate the characteristics of 45,X/46,XY patients and questioning of their place within the DSD categorization. The clinical findings of 11 patients with 45,X/46,XY mosaicism are described including the presentation, gonadal morphology, genital anatomy, and the hormone levels among 285 patients with DSD evaluated. Sixty-seven patients were diagnosed with sex chromosome DSD (50 Turner, three Klinefelter, ten 45,X/46,XY gonadal disgenesis, one 45X/46,XY ovotesticular DSD, one 47,XYY ovotesticular DSD, and two 46,XX/46,XY ovotesticular DSD). The type and the percentage of patients with 45,X/46,XY mosaicism were as follows: Four cases of mix gonadal dysgenesis, four cases of partial gonadal dysgenesis, two cases of complete gonadal dysgenesis, one case of ovotesticular DSD. On the other hand, another patient that has 45,X/46,XX mosaicism was diagnosed with MGD with the presence of the streak gonad on the right side and the testis on the other side. Conclusion: We suggest that sex chromosome DSD categorization can include 45,X/46,XY PGD and 45,X/46,XY CGD. Mixed gonadal dysgenesis may be also placed among the disorders of testicular differentiation of 46,XY DSD subdivision.     

Germ cell tumours in a brother and sister

In familial germ cell tumour cases, a normal chromosomal karyotype pattern is rare. We report the findings of germ cell tumours in two siblings with a normal chromosomal karyotype. One of these patients had dysgerminoma in the right ovary and was treated successfully for this. At present, she is 23 years old and has two daughters. The other patient is a 15-year-old boy, who is the brother of the first patient and has mediastinal embryonal carcinoma. Although ultrasonography of the testes showed irregularity in the shape and non-homogeneity of the parenchyma, histopathological examination was found to be normal at the time of diagnosis. At present, he is doing well and his chemotherapy is continuing. Both of them have a normal chromosomal karyotype, 46, XX and 46, XY, respectively. We suggest that children who have a sibling with germ cell tumour should be carefully assessed for development of another germ cell tumour.     

Congenital lipoid adrenal hyperplasia (a rare form of adrenal insufficiency and ambiguous genitalia) caused by a novel mutation of the steroidogenic acute regulatory protein gene

Congenital lipoid adrenal hyperplasia (lipoid CAH) is a rare autosomal recessive disorder of adrenal and gonadal steroidogenesis. It is most frequently caused by mutations in the steroidogenic acute regulatory protein (StAR) gene. Patients with lipoid CAH typically present with adrenal crisis in early infancy, and those with a 46,XY karyotype have female genitalia. However, it has been recently recognized that the phenotype can be quite variable, in that adrenal insufficiency is detected later in life and patients may have partially masculinized or even normal male genitalia. We report a patient assigned and reared as a female with a 46,XY karyotype and with a homozygous intron 2 (c.178+1G>C) splice site mutation of the StAR gene, which is a novel mutation that causes lipoid CAH. Her clinical presentation was somewhat atypical for a patient with classic lipoid CAH, marked by mild masculinization of the genitalia, detectable adrenal steroids at baseline, and ability to tolerate the stress of a surgical procedure with anesthesia without receiving glucocorticoid treatment. Conclusion: There is significant phenotypic variability among patients with lipoid CAH. While splice site mutations in the StAR gene lead to premature translational termination, resulting in truncated and non-functional proteins, there is phenotypic variability among patients with such mutations. Our patient appears to have the more atypical phenotype compared to reported patients with similar mutations. The molecular mechanism underlying this heterogeneity remains unclear.     

Molecular aspects of female and male gonadal development in mammals

In mammals, the choice between male or female development is genetically determined. Sex determination takes place when the embryonic gonad becomes either a testis or an ovary. This process is directed by genes that have been discovered by genetic analysis of sex-reversed patients and confirmed by knock-out experiments in mice. The testis-determining pathway is better known than the ovary pathway. SRY, a gene located on the Y chromosome, triggers a complex genetic cascade leading to testicular differentiation. In this cascade, two genes play a crucial role in male differentiation, SOX9 and FGF9, which contribute to testicular cord formation. However, only a minority of 46,XY sex-reversed patients can be explained by mutations in known genes such as SRY, SOX9, WT1 and SF1, suggesting that other genes influencing sex determination are yet to be discovered. In females, some rare genes that induce ovarian failure or female-to-male sex-reversal, have been found through gene-targeted inactivation in mice or positional cloning of mutations in humans and goats. In both sexes, genetic analysis of sex-reversed individuals (XX males, XX and XY hermaphrodites and XY with complete or partial dysgenesis) remains an approach of choice to isolate new genes involved in sex determination.     

Disorders of sex development: Challenges in a low-resource country

AimWe aimed to identify the challenges in the management of sexual development abnormalities in a low-resource country.MethodsThe study was retrospective from January 2000 to December 2017 based on patient records from two pediatric surgery departments. Epidemiological, clinical, paraclinical, treatment, and outcome data were studied.ResultsWe collected data on 13 patients (average age = 7.95 years). The sex of rearing was as follows: three females (23%), 10 males (77%). Atypical genitalia other than hypospadias represented the reason for consultation in 92% of the cases. We could not find complete hormonal analyses; testosterone levels were studied in 69.23% of cases. We found the following disorders of sexual development (DSD): four patients with 46,XX karyotype (30.77%), eight patients with 46,XY karyotype (61.53%), and one patient with 46,XX/XY karyotype. Four patients had medical treatment only, four had surgical treatment only, and one patient had medical and surgical treatment. The medical treatment comprised topical administration of androgen. The surgical treatment consisted of feminizing genitoplasty for one patient and masculinizing genital surgeries for two patients. Six of the 13 patients were lost to follow-up.ConclusionThe socioeconomic difficulties of the population and the lack of access to basic diagnostic and paraclinical methods, coupled with the negative cultural representations of the pathology, constitute the challenges in the management of DSD in our practice.     

Familial male pseudohermaphroditism

Familial male pseudohermaphroditism (MPH) due to 17, 20-desmolase deficiency is rare. Here we present two siblings with MPH possibly due to 17, 20-desmolase deficiency. The first patient presented with unambiguous female external genitalia and hypergonadotrophic hypogonadism. Chromosomal analysis revealed 46 XY. Ultrasound evaluation of pelvis revealed gonads in the inguinal canal, and no uterus. These findings were confirmed on laparotomy. Histology revealed the gonads to be testes. The second patient had ambiguous genitalia (perineoscrotal hypospadias, bifid scrotum with palpable gonads) with a 46 XY chromosomal pattern. Both patients had high plasma 17-hydroxy progestrone (17 OHP), low normal dehydro epiandrosterone sulphate (DHEAS) and low plasma testosterone. Plasma testosterone and DHEAS showed no response to ACTH or HCG. These features are compatible with the diagnosis of 17, 20-desmolase deficiency.     

Rudimentary testes syndrome revisited

Sixteen children who were one day to 9 years of age underwent clinical, anatomic, and hormonal study because of extreme hypoplasia of the phallus and small testes associated with normal 46XY male karyotype. Two of them were first cousins. All patients had Leydig cell deficiency. Among 15 patients who received luteinizing hormone-releasing hormone stimulation during childhood, 11 had an exaggerated response of either one or both gonadotropins. Bilateral biopsy, performed in eight patients, showed a clearly testicular structure with either scant or incompletely differentiated tubules. These characteristics allow clear differentiation from chromosomal abnormalities and malformation syndromes. It is more difficult to differentiate between rudimentary testes and primary gonadotropic deficiencies and may not be possible until the child has reached adolescence. The syndrome of rudimentary testes may be a manifestation of XY primary gonadal dysplasia, along with pure XY gonadal dysgenesis, XY hermaphroditism, XY mixed gonadal dysgenesis, and congenital anorchia, probably resulting from fetal regression of the testes. The observed familial occurrence of the syndrome of rudimentary testes, as well as of XY gonadal dysgenesis, leads to speculation about the possibility of X-linked transmission.     

Gender identity and sex-of-rearing in children with disorders of sexual differentiation

AIM: To compare declared sexual identity to sex-of-rearing in individuals with disorders of sexual differentiation. METHODS: All 84 patients > or =5 years old in a pediatric psychosexual development clinic were assessed for sex-of-rearing and sexual identity. Diagnoses included 1) male-typical prenatal androgen effects but an absent or severely inadequate penis - 45 patients with cloacal exstrophy or aphallia; 2) inadequate prenatal androgens and a Y-chromosome - 28 patients with partial androgen insensitivity (pAIS), mixed gonadal dysgenesis (MGD), hermaphroditism, or craniofacial anomalies with genital ambiguity; 3) inappropriate prenatal androgen effects and a 46,XX karyotype - 11 patients with congenital adrenal hyperplasia (CAH). RESULTS: Of 73 patients with disordered sexual differentiation and a Y-chromosome, 60 were reared female; 26 of the 60 (43%) declared female identity while 32 (53%) declared male identity including 18 (55%) with cloacal exstrophy, six (55%) with MGD, four (40%) with pAIS, one (50%) with aphallia, one (100%) with hermaphroditism, and two (67%) with craniofacial anomalies; two (3%) declined to discuss identity. Nine of 11 patients with CAH and a 46,XX karyotype were reared female and two reared male; six (55%) declared female identity and five (45%) declared male identity. Of 84 total patients, 69 were reared female, but only 32 lived as female, while 29 lived as male; four patients refused to discuss sex-of-living; parents of four patients rejected their declarations of male identity. All 15 patients reared male lived as male including two genetic females. CONCLUSION: Active prenatal androgen effects appeared to dramatically increase the likelihood of recognition of male sexual identity independent of sex-of-rearing. Genetic males with male-typical prenatal androgen effects should be reared male.