Le test aux androgènes : comparaison d''un test faible et d''un test fort sur le développement du pénis dans les pseudohermaphrodismes masculins

Background.

The androgen sensitivity test used in male pseudohermaphroditism for clinical assessment of the androgen sensitivity and prediction of penile development is an important element in choice of gender. However, there is a wide range of testosterone dosage and no standardized test.

Methods and patients.

Two doses (25 mg and 100 mg) of testosterone heptylate were used in six cases of male pseudohermaphrodism with sexual ambiguity and small penis (ages 6 to 18 months). The clinical results were compared with those of the study of androgen receptors.

Results.

In two cases, both low-dose and high-dose tests resulted in only minimal changes in the penis. In two cases, the low-dose test gave a good result which was confirmed by the high-dose test; on the other hand, in two cases, the low-dose test was considered to be negative whereas the high-dose test led to the development of a normal-sized penis. In all cases except one, there was good concordance between the results of study of androgen receptors and those of the clinical test.

Conclusion.

The high-dose androgen test is thus useful in both diagnosis and treatment and facilitates the gender assignment.     

Smith-Lemli-Opitz syndrome in two 46,XY infants with female external genitalia

Two infants with features of the Smith-Lemli-Opitz (SLO) syndrome were found to have a 46,XY karyotype and female external genitalia. Autopsies showed normal testes for age with normal Wolffian duct structures and without Müllerian duct derivatives. This failure of masculinization of the external genitalia is an unusual finding and may represent the extreme of a spectrum of the genital anomalies commonly seen in males with this autosomal recessive syndrome. An endocrine evaluation on one of these infants at 3 months suggested unusually low testosterone production and meagre response to stimulation with human chorionic gonadotropin (hCG). The failure of complete masculinization of external genitalia in some cases of SLO syndrome may be due to inadequate testosterone production in utero.     

Molecular analysis of the 5α-steroid reductase type 2 gene in a family with deficiency of the enzyme

This report describes the identification of a point mutation in the 5α-reductase type 2 (5α-SR2) gene from a family in which both sibs (6 and 3 years old) have steroid 5α-reductase 2 deficiency. The five exons of the gene were individually amplified by the polymerase chain reaction (PCR) and analysed for single-strand conformation polymorphisms (SSCP) to detect mutations. Direct sequencing of the mutant PCR products demonstrated a single C→T mutation, within exon 4, changing codon 227 from CGA (Arg) to TGA (premature termination signal). Both patients were homozygous for the mutation, but their parents were heterozygous. These results suggest that the mutation at codon 227 impairs normal 5α-SR2 function, thus leading to the phenotypical expression of this rare enzymatic defect. Am. J. Med. Genet. 69:69–72, 1997. © 1997 Wiley-Liss, Inc.     

性腺疾病及其诊断思路

性腺是非常独特的人体组织器官,具有双向分化的潜能。在胚胎发育的任何时期或任何步骤出现异常,均可引起性分化或性发育异常疾病,常常表现为各性别属性的紊乱或缺陷,如核型和性染色体的异常、外生殖器辨认不清、多毛症和女性男性化等。这些表现常成为性腺疾病诊断的重要线索。故在诊断过程中应积极评估患者的染色体性别、性腺性别、生殖器性别、激素性别等一般情况,综合分析,以利于性腺疾病的快速、准确的诊断及鉴别诊断。     

A novel point mutation (R840S) in the androgen receptor in a Brazilian family with partial androgen insensitivity syndrome

Mutations of the androgen receptor gene causing androgen insensitivity syndrome in 46, XY individuals, result in phenotypes ranging from complete female to ambiguous genitalia to males with minor degrees of undervirilization. We studied two Brazilian brothers with partial androgen insensitivity syndrome. They were born with perineal hypospadias, bifid scrotum, small penis and cryptorchidism, and developed gynecomastia at puberty. Genomic DNA was extracted and denaturinggradient gel electrophoresis of exon 7 of the androgen receptor gene followed by sequence analysis revealed a new mutation, a C A transversion, altering codon 840 from arginine (CGT) to serine (AGT). R840 is located in the androgen binding domain, in a “hot spot” region, important for the formation and function of the hormone receptor‐complex and within the region that is involved in androgen receptor dimerization. Replacement of arginine (basic) by serine (neutral and polar) is a nonconservative substitution. Three mutations in this residue (R840C, R840G nonconservative and R840H, conservative) were previously reported in patients with partial androgen insensitivity syndrome and when expressed “in vitro” lead to a subnormal transactivation of a reporter gene. We conclude that the novel R840 mutation in the androgen receptor is the cause of partial androgen insensitivity syndrome in this Brazilian family. Hum Mutat 14:353, 1999. © 1999 Wiley‐Liss, Inc.     

Phenotypic classification of male pseudohermaphroditism due to steroid 5α-reductase 2 deficiency

Conversion of testosterone (T) to dihydrotestosterone (DHT) in genital tissue is catalysed by the enzyme 5α-reductase 2, which is encoded by the SRD5A2 gene. The potent androgen DHT is required for full masculinization of the external genitalia. Mutations of the SRD5A2 gene inhibit enzyme activity, diminish DHT formation, and hence cause masculinization defects of varying degree. The classical syndrome, formerly described as pseudovaginal perineoscrotal hypospadias, is characterized by a predominantly female phenotype at birth and significant virtilization without gynecomastia at puberty. We investigated nine patients with steroid 5α-reductase 2 deficiency (SRD). Phenotypes, which were classified according to the severity of the masculinization defect, varied between completely female (SRD type 5), predominantly female (SRD type 4), ambiguous (SRD type 3), predominantly male with micropenis and hypospadias (SRD type 2), and completely male without overt signs of undermasculinization (SRD type 1). T/DHT-ratios were highly increased (>50) in the classical syndrome (SRD type 5), but variable in the less severe affected patients (SRD types 1–4) (14–35). Mutations in the SRD5A2 gene had been characterized using PCR-SSCP analysis and direct DNA sequencing. A small deletion was encountered in two patients, while all other patients had single base mutations which result in amino acid substitutions. We conclude that phenotypes may vary widely in patients with SRD5A2 gene mutations spanning the whole range from completely female to normal male without distinctive clinical signs of the disease. Hence, steroid 5α-reductase deficiency should be considered not only in sex reversed patients with female or ambiguous phenotypes, but also in those with mild symptoms of undermasculinization as encountered in patients with hypospadias and/or micropenis. A classification based on the severity of the masculinization defect may be used for correlation of phenotypes with enzyme activities and genotypes, and for comparisons of phenotypes between different patients as the basis for clinical decisions to be made in patients with pseudohermaphroditism due to steroid 5α-reductase 2 deficiency. © 1996 Wiley-Liss, Inc.     

先天性尿道下裂与SRD5A2及SRY基因突变关系研究

目的　探讨中国人先天性尿道下裂的发生与５α还原酶２（ Ｓ Ｒ Ｄ５ Ａ２） 基因突变及 Ｓ Ｒ Ｙ 基因突变的关系。方法　收集先天性尿道下裂患儿静脉血２３ 例,抽提 Ｄ Ｎ Ａ。经 Ｐ Ｃ Ｒ 分别扩增 Ｓ Ｒ Ｄ５ Ａ２ 基因的第１ 至第５ 外显子及 Ｓ Ｒ Ｙ 基因的 Ｄ Ｎ Ａ 片段。对各扩增片段采用单链构象多态性诊断法（ Ｐ Ｃ Ｒ Ｓ Ｓ Ｃ Ｐ） ,筛选基因突变标本,有电泳异常的标本进行测序分析。结果　经 Ｐ Ｃ Ｒ Ｓ Ｓ Ｃ Ｐ 发现３ 例 Ｓ Ｒ Ｄ５ Ａ２ 基因的第４ 外显子 Ｄ Ｎ Ａ 扩增片段电泳带位置异常,经 Ｄ Ｎ Ａ 序列分析证实２ 例为纯合子型第２２７ 位密码子由 Ｃ Ａ Ａ 替代 Ｃ Ｇ Ａ（ Ａｒｇ２２７ Ｇｌｎ） ;１ 例为双重杂合子型突变,第２２７ 位密码子由 Ｃ Ａ Ａ 替代 Ｃ Ｇ Ａ,同时第１８６ 位密码子由 Ｔ Ｔ Ｇ 替代 Ｔ Ｔ Ｔ（ Ｐｈｅ１８６ Ｌｅｕ） 。 Ｐ Ｃ Ｒ Ｓ Ｓ Ｃ Ｐ 检测 Ｓ Ｒ Ｙ 基因片段未发现异常电泳带。结论　 Ｓ Ｒ Ｄ５ Ａ２ 基因突变,可能是先天性尿道下裂的病因之一, Ｓ Ｒ Ｄ５ Ａ２ 基因的第２２７ 位密码子可能为中国人该基因的突变热点,而尿道下裂中 Ｓ Ｒ Ｙ 基因的突变少见。     

Feasibility of perineal sagittal approaches in patients without anorectal malformations

Perineal sagittal approaches (posterior sagittal anorectoplasty and anterior and posterior sagittal transanorectal approaches) allow complete anatomic exposure of the perineum and lower pelvis. Moreover, they reduce the risk of damaging important structures because the incision is led in the midline. Therefore, many surgeons have used these approaches to treat diseases other than anorectal malformations (ARM), including intestinal dysganglionosis, trauma, pseudohermaphroditism, presacral mass, and rectal duplication. The aim of this study was to describe a small series of patients operated on via these approaches at Gaslini Childrens Hospital over a 5-year period. We retrospectively evaluated 10 patients consecutively operated on via a perineal sagittal approach, with or without sphincteric structure involvement, between January 1997 and December 2001. All of these patients were without ARM. Indications included retrorectal abscesses (two), iatrogenic anal canal stenosis (one), postinflammatory anal canal stenosis (one), internal anal sphincter neurogenic achalasia (one), female pseudohermaphroditism (one), benign sacrococcygeal teratomas (two), malignant sacrococcygeal teratoma (one), and perineal rhabdomyosarcoma (one). Protective colostomy was used in four patients. The parameters that we analysed included technical details, possible complications, perineal cosmetic appearance, and outcome. No complications were experienced. The postoperative cosmetic perineal appearance was excellent in all patients, and continence, when assessed, was always considered satisfactory. All tumours underwent complete gross resection. However, one patient with malignant sacrococcygeal teratoma died as a result of the malignant process 2 years after surgery. Although our study was carried out on a small series of patients, it confirmed that perineal sagittal approaches can be used not only for ARM but also for other conditions involving perirectal pouches, presacral space, and urogenital structures, as these approaches are safe and provide excellent cosmetic results as well as satisfactory functional outcome. Although tumours can be treated via these approaches, outcome remains related to the nature and malignancy of the disease itself.     

Female pseudohermaphroditism in a prenatally diagnosed cloacal malformation with hydronephrosis,dilated bladder,hydrometrocolpos, and oligohydramnios

ObjectiveTo present female pseudohermaphroditism in a prenatally diagnosed cloacal malformation.Case reportA 29-year-old, primigravid woman referred for counseling at 17 weeks of gestation because of oligohydramnios and an intra-abdominal cyst in the fetus. The woman was not exposed to any virilizing agent during this pregnancy. She did not undergo any assisted reproductive technology for this pregnancy. Level II ultrasound showed a singleton with fetal biometry equivalent to 16 weeks, oligohydramnios, hydrometrocolpos, dilated bladder, and bilateral hydronephrosis. A diagnosis of cloacal malformation was made. The parents elected to terminate the pregnancy at 18 weeks of gestation. A 196-g fetus was delivered with a distended abdomen, a phallus-like structure, a small perineal opening below the phallus-like structure, and an imperforate anus. At birth, the fetus was misdiagnosed as a male with an imperforate anus and a perineal fistula. Cytogenetic analysis of the cord blood revealed a karyotype of 46,XX. Array comparative genomic hybridization analysis of the fetal tissues revealed no genomic imbalance. The phallus-like structure was an enlarged clitoris and contained accessory phallic urethra.ConclusionPrenatal diagnosis of cloacal malformation with ambiguous genitalia should be paid attention to avoid misdiagnosis of a male with an imperforate anus and a perineal fistula. Cytogenetic analysis is helpful to determine the sex under such circumstances.