雄激素不敏感综合征的诊断现状及治疗

雄激素不敏感综合征（AIS）是46,XY性发育异常中最常见的疾病之一。该病表型特异性差并随年龄发生变化,且诊断标准不明确,不仅临床上诊断困难,还易与5α-还原酶缺乏症、完全性性腺发育不全等疾病相混淆,极易造成漏诊误诊。明确的诊断该病并准确的分型是提供最佳的治疗与咨询的基础,对于患者性别选择、手术方式和时机、肿瘤发生、性心理健康是至关重要的。本文从AIS的发展过程、临床特征与分型、诊断及鉴别、性别选择及性腺处理的方面进行综述,为更好的诊断及鉴别该病提供参考。     

Phenotypic diversity in siblings with partial androgen insensitivity syndrome

The androgen insensitivity syndrome is a heterogeneous disorder with a wide spectrum of phenotypic abnormalities, ranging from complete female to ambiguous forms that more closely resemble males. The primary abnormality is a defective androgen receptor protein due to a mutation of the androgen receptor gene. This prevents normal androgen action and thus leads to impaired virilisation. A point mutation of the androgen receptor gene affecting two siblings with partial androgen insensitivity syndrome is described. One had cliteromegaly and labial fusion and was raised as a girl, whereas the other sibling had micropenis and penoscrotal hypospadias and was raised as a boy. Both were shown to have the arginine 840 to cysteine mutation. The phenotypic variation in this family is thus dependent on factors other than abnormalities of the androgen receptor gene alone.     

Phenotypic variation in a family with partial androgen insensitivity syndrome

A family with partial androgen insensitivity syndrome exhibited considerable variation in phenotypic expression of their androgen resistance. One subject died at 2 1/2 years of age of a Wilms' tumor. In the two living members, one had a micropenis with otherwise normal genitalia, while the other had a small phallus, perineoscrotal hypospadias, bifid scrotum, and persistence of a vaginoutricular pouch. At puberty, plasma androgens and serum gonadotropins increased to normal or elevated values. However, despite adequate endogenous plasma testosterone levels and testosterone therapy, these patients showed poor virilization and were sterile. Studies of cultured sexual skin fibroblasts showed adequate 5 alpha-reductase activity and normal receptor affinity and capacity for dihydrotestosterone. An X-linked mode of inheritance is postulated, although autosomal dominance cannot be ruled out.     

Assessment of the gonadotrophin-gonadal axis in androgen insensitivity syndrome

AIM—To identify permanent sequelae after sports injuries in children and adolescents.
METHODS—In 1985, a prospective register was drawn up of all sports related injuries reported that year by the residents of Trieste, Italy aged 6-15 years. Moderate to severe injuries (scoring ⩾ 2 on the abbreviated injury scale (AIS)) were the object of a longitudinal clinical study. In 1988, 30.9% of the 220 subjects enrolled had sequelae. A further follow up was undertaken in 1997.
RESULTS—The follow up in 1997 involved 54 subjects (26 girls; average age 24.5 years). Subjective and objective sequelae, by now considered to be permanent, were found in 61.1%, corresponding to 15% of the AIS ⩾ 2 injuries recorded in 1985. The prevalence of sequelae was similar in the two sexes, in relation to the child''s age at time of injury, and in the different sports practised. It was higher in relation to the severity of the lesion (89% of AIS 3injuries examined, 56% of AIS 2 injuries) and to the type of lesion and its location. With regard to AIS ⩾ 2 injuries, permanent sequelae were found in 50% of ankle fractures, 43% of elbow fractures, 33% of leg/foot fractures, 25% of knee sprains, and 23% of ankle sprains.
CONCLUSIONS—The frequency of sequelae in sports injuries in children and adolescents is high. The risk appears to be connected to certain anatomical and functional age characteristics. Prevention strategies should include specific assessment of physical fitness and adequate follow up after the accident, particularly rehabilitation.

     

Complete androgen insensitivity syndrome: diagnosis and clinical characteristics

Complete androgen insensitivity syndrome (CAIS) is a genetic disease caused by mutations in the androgen receptor gene. CAIS patients are individuals with a 46, XY karyotype. The phenotype consists in female external genitalia, short vagina, absent mullerian structures, and abdominal, inguinal or intralabial testes. Our aim is to describe a group of CAIS patients in our centre and identify the difficulties in the diagnosis. The amount of patients with inguinal hernia in childhood was remarkable (83%). Interestingly, the diagnosis was suspected later when patients presented primary amenorrhea. CAIS must be suspected every time a female child shows inguinal hernia. Early diagnosis is very important for a correct genetic counseling.     

A shared decision-making tool for individuals living with complete androgen insensitivity syndrome

Reports exist regarding a gradual approach to the care of patients with differences of sexual development. Each patient and family have different values and styles of learning that have to be taken into account. The goals of care should include education about the condition, counseling of the patient and family, and a complete outlining of treatment options. Motivated by a call from the 2010 Health Reform Law for the use of shared decision-making tools and the emphasis placed on these issues by the DSD Consensus Statement, we sought to develop and implement such tools for the DSD population.^1–3 Thus, we developed an organized checklist for providers to share with a patients and families affected by CAIS, beginning with the initial visit. The development of the document enlisted input from physicians, clinical coordinator, advocacy groups and affected individuals. It allows providers to explain the process of care and develop a plan for delivery of that care over multiple visits spanning six months or more. The checklist is divided into five sections: 1) An overview addressing how much information is desired and in what manner the patient prefers to obtain information; 2) A preferred words list so that the patient can choose nomenclature that is most comfortable; 3) A list of topics to review over the course of multiple visits; 4) A list of questions to be answered by the providers or other resources over time, and; 5) A list of concerns to be addressed before surgical intervention is considered. An organized approach to long-term delivery of compassionate care and accurate information can be facilitated for patients with CAIS by the use of a shared decision-making checklist. Documentation of the care delivery process can stimulate referral to peer support and promote fully informed consent for treatment decisions. The use of the checklist should encourage trust in the provider, as well as aid in identifying and addressing stressors for the patient and family. The checklist will be updated and revised as new treatments and advanced technology emerges.     

Assessment of the gonadotrophin-gonadal axis in androgen insensitivity syndrome.

OBJECTIVE: To study the value of measuring serum luteinising hormone (LH), follicle stimulating hormone (FSH), testosterone, and dihydrotestosterone (DHT) in androgen insensitivity syndrome (AIS). DESIGN: Retrospective study of patients on a nationwide register of AIS. PATIENTS: Sixty one cases of AIS with androgen receptor (AR) dysfunction (abnormalities of the AR gene and/or abnormal AR binding) were divided into three age groups: infants, < 1 year old; children, 1-13 years old; and postpubertal, > 13 years old. MEASUREMENTS: Age, dose of human chorionic gonadotrophin (hCG) stimulation, pre-hCG and post-hCG serum testosterone values, serum DHT values, and serum LH and FSH values before and after LH releasing hormone (LHRH) stimulation. RESULTS: In 23 of 30 infants testosterone was within age related reference ranges; six were above this range. The median testosterone rise following variable dosage of hCG was 9.5 times the basal value. The increment was not related to the hCG dose, age, or basal concentration of testosterone. The median basal and stimulated testosterone:DHT ratios were 2.5 and 6.1, respectively. The median increment in DHT was 2.2-fold. Seventeen of 18 FSH and 11 of 19 LH measurements were within age related ranges in infants; in seven patients LH values were above the range. LHRH stimulation performed in 39 patients showed an exaggerated LH in all age groups. The FSH response was not exaggerated in children. CONCLUSION: Although a positive hCG test excludes biosynthetic defects of testosterone, an inadequate response does not exclude AIS. Basal LH and testosterone may not be raised during early infancy. An LHRH stimulation test might be useful for evaluating cases of suspected AIS presenting in mid-childhood.     

Incomplete androgen insensitivity syndrome. Difficulties of diagnosis and management

A familial form of incomplete androgen insensitivity syndrome (AIS) is reported. The index case was first seen at 9 months of age for ambiguous genitalia. Diagnosis of AIS, suspected but first discarded on the basis of an androgen sensitivity test, was finally made at puberty on the discordance between poor virilization and elevated levels of both testosterone and LH, a florid gynecomastia, and the exclusion of any enzymatic defect in testosterone biosynthesis of 5 alpha-reductase deficiency. Androgen receptors in public skin were within the limits of normal for total number, with normal affinity. Familial occurrence included 2 first cousins born 7 and 10 years later, a maternal grand-uncle with similar ambiguous genitalia, and a maternal uncle with the gynecomastia-preserved fertility syndrome. This case report illustrates the heterogeneity of AIS in a given family and the difficulty of and early positive diagnosis in a newborn presenting with sexual ambiguity.     

Objective use of testosterone reveals androgen insensitivity in patients with proximal hypospadias

ObjectiveWe report preoperative testosterone stimulation based on glans width measurements in patients with midshaft and proximal hypospadias, revealing androgen resistance in those with proximal hypospadias.MethodsPatients had maximum glans width measured preoperatively. Those <14 mm initially received 2 mg/kg testosterone cypionate intramuscularly for two to three doses, with the aim of increasing glans width ≥15 mm. Not all patients achieved targeted growth, and some were subsequently treated with escalating doses of testosterone.Results5/15 midshaft patients had two to three doses of 2 mg/kg testosterone, with all increasing glans width to ≥15 mm. 29/47 proximal patients had testosterone, with 13 (57%) not reaching desired glans width. Six of these and another six patients had escalating doses from 4 to 32 mg/kg testosterone, with 11 then achieving targeted glans width. Relative androgen resistance was found in 19/29 (66%) proximal cases, including all treated patients with perineal hypospadias.Conclusions39/62 (63%) patients met objective criteria for preoperative testosterone stimulation based on glans width <14 mm, which is less than the average normal newborn glans diameter. Evidence of relative androgen resistance was found in 19 (49%), all with proximal hypospadias.     

Clinical and molecular spectrum of somatic mosaicism in androgen insensitivity syndrome

We recently found that postzygotic de novo mutations occur at the expected high rate of an X-linked recessive mutation in androgen insensitivity syndrome. The resulting somatic mosaicism can be an important molecular determinant of in vivo androgen action caused by expression of the wild-type androgen receptor (AR). However, the clinical relevance of this previously underestimated genetic condition in androgen insensitivity syndrome has not been investigated in detail as yet. Here, we present the clinical and molecular spectrum of somatic mosaicism considering all five patients with mosaic androgen insensitivity syndrome, whom we have identified since 1993: Patient 1 (predominantly female, clitoromegaly), 172 TTA(Leu)/TGA(Stop); patient 2 (ambiguous), 596 GCC(Ala)/ACC(Thr); patient 3 (ambiguous), 733 CAG(Gln)/ CAT(His); patient 4 (completely female), 774 CGC(Arg)/TGC (Cys); and patient 5 (ambiguous), 866 GTG(Val)/ATG(Met). Serum sex hormone binding globulin response to stanozolol, usually correlating well with in vivo AR function, was inconclusive for assessment of the phenotypes in all tested mosaic individuals. An unexpectedly strong virilization occurred in patients 1, 3, and 5 compared with phenotypes as published with corresponding inherited mutations and compared with the markedly impaired transactivation caused by the mutant ARs in cotransfection experiments. Only the prepubertal virilization of patients 2 and 4 matched appropriately with transactivation studies (patient 4) or the literature (patients 2 and 4). However, partial pubertal virilization in patient 4 caused by increasing serum androgens and subsequent activation of the wild-type AR could not be excluded. We conclude that somatic mosaicism is of particular clinical relevance in androgen insensitivity syndrome. The possibility of functionally relevant expression of the wild-type AR needs to be considered in all mosaic individuals, and treatment should be adjusted accordingly.     

Exclusion of androgen insensitivity syndrome in girls with inguinal hernias: current surgical practice

To review the current approach of paediatric surgeons to the exclusion of androgen insensitivity syndrome (CAIS) in girls with inguinal hernias (IH), a questionnaire was sent to all specialist paediatric surgeons in the United Kingdom and Ireland asking if they exclude CAIS, how they exclude it, and what they say to parents preoperatively. In all, 32 surgeons responded (29%); 41% made no attempt to exclude CAIS because they thought the incidence was too low to justify exclusion; 19(59%) excluded CAIS at the time of surgery by assessment of the internal genitalia. Only 1 performed karyotyping primarily, and then only for bilateral IH. Although most would proceed to karyotyping if the primary assessment suggested CAIS, some would not. Of those who exclude CAIS, only 1 mentions CAIS preoperatively, 6 others mention gonadal inspection, and 12/19 (63%) make no comment. Thirty-one surgeons agreed to take part in a prospective study to define the incidence of CAIS in girls with IH. It is concluded that surgeons who exclude CAIS in girls with IH adopt different assessment methods, some of which may be unreliable. However, many do not attempt to exclude CAIS, believing the incidence to be too low. As the health and medicolegal consequences of failing to exclude CAIS may be considerable, surgeons should consider changing their practice. A prospective study should be undertaken to determine the incidence of CAIS in girls with IH.     

The approach to a neonate with a possible prenatal diagnosis of androgen insensitivity syndrome

The diagnosis of androgen insensitivity syndrome (AIS) can now be made prenatally. We present a patient for whom the diagnosis of AIS was highly suspected prenatally, but the parents preferred to deny it. The clinical findings and the diagnostic evaluation after delivery are presented. A brief discussion of the syndrome, as well as the implications of possible prenatal diagnosis and how to approach it, are provided. Full multidisciplinary diagnostic work-up immediately after delivery, as well as awareness of possible prenatal diagnosis, is the responsibility of the primary care provider for the newborn with suspected AIS.     

Complete androgen insensitivity syndrome caused by the R855H mutation in the androgen receptor gene

Complete androgen insensitivity syndrome (CAIS) is characterized by a completely female phenotype in a 46,XY individual and is caused by mutations in the androgen receptor (AR) gene. A 5 year-old girl presented with bilateral hernia and was noted to have bilateral testes. She had a 46,XY karyotype and was diagnosed with CAIS. To identify the underlying mutation, the exons 2 to 8 of the AR gene were amplified by PCR using sets of known primers and reaction conditions. The results of the mutational analysis for the AR showed the presence of the R855H mutation; her mother was found to be heterozygous and both her 46,XX sister and her aunt had a normal AR gene. This mutation, is the result of a guanine to adenine transition in codon 855 at position 2926 in exon 7 of the AR gene, which causes an alteration of the coding nucleotide triad from CGC to CAC, which subsequently causes the substitution from arginine to histidine in the amino acid sequence of the receptor protein molecule. The same mutation has been reported to cause variable phenotypic expression, which could be explained by the presence of additional co-activating factors modifying the biological activity of the AR. The identification of an AR mutation in a girl with CAIS provides important information, because of the syndrome's genetic heterogeneity. This report emphasizes the fact that genetic determinants outside the coding sequence of the AR can influence the function of the AR protein molecule. Phenotypic expression of the mutation may be used for the construction of maps of functional domains of the AR.     

Expression of two functionally different androgen receptors in a patient with androgen insensitivity

Recently, we demonstrated a previously unknown high rate of de novo mutations of the androgen receptor (AR) gene in androgen insensitivity syndrome (AIS) with some resulting in somatic mosaicism of mutant and wild type AR alleles. However, data on the genotype-phenotype relationship in the latter patients are sparse. We present here a 46,XY newborn with ambiguous genitalia carrying a mosaic of an 866 GTG (Val) → ATG (Met) mutation with the wild type AR gene. This mutation has usually been associated with complete AIS. Accordingly, we found markedly impaired transactivation due to the mutant Met⁸⁶⁶ AR. Essential information arose from Scatchard analysis of methyltrienolone binding on cultured genital skin fibroblasts. We demonstrated for the first time the expression of two functionally different ARs (K_d1: 5.58 nM = mutant, K_d2: 0.06 nM = wild type) in one AIS individual. This finding not only represents an important confirmation for the presence of the somatic mosaicism in the patient, it also indicates the most likely molecular mechanism responsible for the unexpectedly strong virilization of the patient: Androgen action through the wild type AR expressed by part of the somatic cells. Conclusions The present case clearly demonstrates the molecular mechanism by which somatic mosaicism of the androgen receptor gene can modulate in vivo androgen action. It underlines the importance of particular notice on somatic mosaicism in all androgen insensitivity syndrome patients carrying de novo mutations of the androgen receptor gene. Received: 24 August 1998 / Accepted in revised form: 5 January 1999     

A novel point mutation in the hormone binding domain of the androgen receptor associated with partial and minimal androgen insensitivity syndrome

Mutations in the coding sequence of the androgen receptor (AR) gene result in a wide range of androgen insensitivity syndromes (AIS). We report an extended family in which at least five male individuals in different generations suffer from partial AIS. The index patient presented at birth with ambiguous genitalia; the karyotype was 46,XY and subsequent sex assignment male. Elevated stimulated testosterone (T) and normal baseline gonadotropins were found. Family history revealed four additional adult males affected with various abnormalities of their external genitalia. Molecular analysis of the coding sequence of the AR gene revealed in all a novel point mutation in exon 6, changing threonine to isoleucine at codon position 800 in the hormone-binding domain. We conclude that phenotypic variations in mild AR defects are striking and can remain undetected even until late in life.     

Phenotypic variation and detection of carrier status in the partial androgen insensitivity syndrome

The partial androgen insensitivity syndrome occurs in 46,XY subjects with phenotypes ranging from perineoscrotal hypospadias with cryptorchidism and micropenis (mild undervirilisation) to clitoromegaly and partial labial fusion (marked undervirilisation). Within an affected family, wide variation in the degree of genital ambiguity between individuals can be seen. Two cousins of a previously reported subject who had severe genital ambiguity and partial androgen insensitivity were investigated. Neither of the cousins had genital abnormalities as marked as the index case, who also had qualitatively abnormal androgen binding and two mutations of the androgen receptor gene. Despite marked phenotypic differences between the index case and his cousins, similar androgen binding and the same androgen receptor mutations were shown in the cousins. Furthermore, one of the androgen receptor gene mutations has been shown in the mother and sister of one of the boys indicating that they are carriers. Thus phenotypic variation in families affected by partial androgen insensitivity is dependent on factors other than abnormalities of the androgen receptor gene alone. Although carrier status in partial androgen insensitivity can be determined, the severity of genital abnormalities in an affected offspring cannot be reliably predicted.