Androgen insensitivity syndrome.

Androgen insensitivity syndrome in its complete form is a disorder of hormone resistance characterised by a female phenotype in an individual with an XY karyotype and testes producing age-appropriate normal concentrations of androgens. Pathogenesis is the result of mutations in the X-linked androgen receptor gene, which encodes for the ligand-activated androgen receptor--a transcription factor and member of the nuclear receptor superfamily. This Seminar describes the clinical manifestations of androgen insensitivity syndrome from infancy to adulthood, reviews the mechanism of androgen action, and shows examples of how mutations of the androgen receptor gene cause the syndrome. Management of androgen insensitivity syndrome should be undertaken by a multidisciplinary team and include gonadectomy to avoid gonad tumours in later life, appropriate sex-hormone replacement at puberty and beyond, and an emphasis on openness in disclosure.

[Morris syndrome: description of a case characterized by partial androgen insensitivity]. / Sindrome di Morris: descrizione di un caso clinico caratterizzato da insensibilità parziale agli androgeni.

The Morris syndrome is a X-linked recessive condition due to a complete or partial insensitivity to androgens, resulting in a failure of normal masculinization of the external genitalia in chromosomally male individuals. This failure of virilization can be either complete or partial depending on the amount of residual androgen receptor function. The phenotype of individuals with partial androgen insensitivity syndrome may range from mildly virilized female external genitalia to mildly undervirilized male external genitalia. We describe a case of Partial Androgen Insensitivity Syndrome in a 21-year-old patient with a 46, XY karyotype, bilateral inguinal masses, clitoral enlargement and partial posterior labial fusion. Surgical care consisted of bilateral orchiectomy and plastic surgery of external genitalia. The patient underwent estrogen replacement therapy.

Androgen receptor genotyping in a large Australasian cohort with androgen insensitivity syndrome; identification of four novel mutations.

We genotyped the androgen receptor (AR) gene in 31 Australasian patients with androgen insensitivity syndrome (AIS). The entire coding region of AR was examined including analysis of polymorphic CAG and GGN repeats in all patients. AR defects were found in 66.7% (6/9) of patients with complete AIS (CAIS) and 13.6% (3/22) of patients with partial AIS (PAIS). A novel deletion (N858delG) leading to a premature stop codon was found in CAIS patient P1. CAIS patient P2 has a novel deletion (N2676delGAGT) resulting in a stop at codon 787. These mutations would result in inactivation of AR protein. A novel insertion of a cysteine residue in the first zinc finger of the AR DNA-binding domain (N2045_2047dupCTG) was found in CAIS patient P3. PAIS patient P4 has a novel amino acid substitution (Arg760Ser) in the AR ligand binding domain, which may impair ligand binding. Five patients were found to have previously reported AR mutations and no mutations were identified in the remaining patients.

Mutational analysis of Hungarian patients with androgen insensitivity syndrome.

OBJECTIVE: To support the clinical diagnosis of androgen insensitivity syndrome (AIS), we performed mutational analysis of the androgen receptor gene. DESIGN: Clinical, hormonal and molecular genetic data of ten undervirilized genetic male patients living in Hungary were recorded. METHODS: PCR-based single strand conformation polymorphism (SSCP) analysis was used to study the whole coding region of the androgen receptor gene. Direct fluorescent sequencing was applied when aberrant migration was detected by SSCP. RESULTS: Five different mutations were identified in five unrelated genetic male patients with abnormal sexual differentiation. One of these mutations was novel, while the other four mutations have been described previously in the literature. One of the mutations identified earlier in individuals with sporadic AIS showed a familial inheritance pattern in our study group. No abnormality of the androgen receptor gene was identified in three patients clinically suspected to have partial AIS. CONCLUSION: Application of molecular techniques helped to clarify the diagnosis in patients with disorders of male sexual differentiation.

[Androgen insensitivity syndrome. Clinical features and molecular genetics]. / Androgen insensitivitas syndroma. Klinikai és molekuláris genetikai spektrum.

Androgen insensitivity syndrome (AIS) is an X-linked hereditary disorder caused by the mutation of the androgen receptor gene leading to variable phenotypes according to the depth of the hormonal resistance. There is a lack of knowledge regarding the criteria used to decide the management of infants with partial AIS, particularly with respect to sex of rearing. Therefore a national survey of patients with AIS in Hungary has been decided to compose a database for analyzing current practice. Preliminary results of the analysis for the mutations in the androgen receptor gene of Hungarian patients with AIS has been presented. The authors suggest that guidelines for clinicians on appropriate diagnostic and management strategies for AIS patients, particularly in the case of suspected partial AIS, would be helpful.

The contribution of testosterone to skeletal development and maintenance: lessons from the androgen insensitivity syndrome.

Although androgen status affects bone mass in women and men, an androgen requirement for skeletal normalcy has not been established. Women with androgen insensitivity syndrome (AIS) have 46,XY genotypes with androgen receptor abnormalities rendering them partially or completely refractory to androgen. Twenty-eight women with AIS (22 complete and 6 high grade partial), aged 11-65 yr, responded to questionnaires about health history, gonadal surgery, and exogenous estrogen use and underwent bone mineral density (BMD) assessment by dual energy x-ray absortiometry. BMD values at the lumbar spine and proximal femur were compared to age-specific female normative values and listed as z-scores. Average height for adults in this cohort, 174 cm (68.5 in.), was moderately increased compared with the average height of adult American women of 162.3 cm, with skewing toward higher values: 5 women exceeded 6 ft in height, and 30% of the 18 adult women with complete AIS exceeded 5 ft, 11 in. in height. The average lumbar spine and hip BMD z-scores of the 6 women with partial AIS did not differ from population norms. In contrast, the average lumbar spine BMD z-score of women with complete AIS was significantly reduced at -1.08 (P = 0.0003), whereas the average value for hip BMD did not differ from normal. When BMD was compared between women who reported good estrogen replacement therapy compliance and those who reported poor compliance, there was a significantly greater deficit at the spine for women with poor compliance (z = -2.15 +/- 0.15 vs. -0.75 +/- 0.28; P < .0001). Furthermore, hip BMD was also significantly reduced in the noncompliant group (z = -0.95 +/- .40). Comparison of BMD values to normative male standards gave z-score reductions (z = -1.81 +/- 0.36) greater than those observed with female standards. Because of the high prevalence of tall stature in this study sample, we calculated bone mineral apparent density, a variable that adjusts for differences in bone size. Even for the estrogen-compliant group, bone mineral apparent density z-scores were subnormal at both the spine (z = -1.3 +/- 0.43; P < 0.01) and the hip (z = -1.38 +/- 0.28; P = 0.017). Six women with complete AIS had sustained cortical bone fractures, of whom 3 reported multiple (>3) fractures. We conclude that even when compliance to exogenous estrogen use is excellent, women with complete AIS show moderate deficits in spine BMD, averaging close to 1 SD from normative means, and that with correction of BMD for bone size, skeletal deficits are magnified and include the proximal femur. The results suggest that severe osteopenia in some women with AIS probably reflects a component of inadequate estrogen replacement rather than androgen lack alone.

Functional assessment and clinical classification of androgen sensitivity in patients with mutations of the androgen receptor gene. German Collaborative Intersex Study Group.

UNLABELLED: In the genetic male, mutations of the androgen receptor (AR) gene cause phenotypes ranging from female to subfertile male. Binding assays on genital skin fibroblasts and DNA analysis alone provide incomplete information about receptor function. We used the sex hormone-binding globulin (SHBG) response to stanozolol as a measure of AR function and correlated the results with phenotypes which were classified according to the degree of defective masculinization. Of the 34 patients investigated, 9 had complete, and 14 had partial androgen insensitivity syndrome (AIS) with predominantly female, ambiguous, or predominantly male phenotype. Eleven subjects served as controls. Mutations were characterized using polymerase chain reaction-single strand conformation polymorphism analysis and direct DNA sequencing. DNA analysis revealed two major deletions, two minor defects leading to premature stop codons in exon 1, and 19 point mutations in the DNA- and hormone-binding domains of the AR gene. After stanozolol, SHBG remained unchanged in patients with complete AIS (102.0 +/- 3.8 [SE]%; range 92.4%-129% of the initial value). The SHBG decrease was diminished in partial AIS with predominantly female (83.8% +/- 1.7%; range 81.3%-87.0%), ambiguous (80.4% +/- 4.4%, range 68.4%-89.1%), and predominantly male (mean 65.9% +/- 4.9%, range 48.6%-80.8%) phenotypes, and normal in controls (51.4% +/- 2.1%, range 35.6%-62.1%). Differences between controls and each AIS group were statistically significant (P < 0.05 - < 0.0001). A close correlation was found between the degree of undermasculinization (AIS phenotype) and the SHBG response. CONCLUSIONS: The SHBG test provides functional information about the severity of the receptor defect in vivo and hence adds to the structural information provided by DNA analysis. It detects receptor defects due to mutations within the entire gene, including the DNA-binding domain, and is a rapid, simple, and cost effective procedure. It may provide useful information for the diagnosis and management of affected children.

[Male pseudohermaphroditism. Testicular feminization syndrome].

Male pseudohermaphroditism--testicular feminization syndrome is a rare genetic entity with considerably familial predisposition. Of the 9 cases, 7 except 2 children were confirmed surgically. Clinical manifestations of the disorder were primary amenorrhea, infertility and a mass in groin. We suggested that orchiectomy is necessary after puberty. The genetic pattern, clinical characteristics, diagnosis and treatment of the condition were briefly discussed with a review of the literature.

Androgen insensitivity in forty-nine patients: classification based on clinical and androgen receptor phenotypes.

Androgen receptor binding was studied in genital skin fibroblasts from 49 patients with androgen insensitivity syndrome (AIS) classified as complete (CAIS) or partial (PAIS) based on the clinical phenotype. The majority (64%) of CAIS and a minority (7%) of PAIS patients were receptor negative. Only 3 receptor-positive AIS cell strains of 30 studied failed to show an increase in specific receptor binding after prolonged androgen exposure in vitro. The gene coding for the androgen receptor in such patients appears intact.

Testicular feminization syndrome: current clinical considerations.

The testicular feminization syndrome (TFS) in its complete form results in total feminization due to a nuclear inaction of androgens, and the female role should be supported with postpubertal orchiectomy to avoid the risk of malignancy. Incomplete forms of the syndrome (ITFS) include Type I n which some degree of masculinization may be observed, prompting earlier gonadectomy, and Type II or pseudovaginal perineoscrotal hypospadias (PPSH) which is always characterized by pubertal masculinization, necessitating management and support of these patients as males. Other intersex abnormalities which must be differentiated include true hermaphroditism, the Swyer syndrome, males with 17-ketosteroid reductase deficiency, and Reifenstein's syndrome.

Androgen-insensitive male pseudohermaphroditism.

Androgen insensitivity is a mendelian trait transmitted through phenotypically normal females. The affected males exhibit normal fetal testicular development and regression of the müllerian ducts. A luminized uterus is never present. External genitalia are feminine or malformed. The vagina, found in most cases, ends blindly. Female breasts are present in adults. The following three syndromes can be distinguished which differ in the character of the external genitalia: 1) Complete testicular feminization with normal female external genitalia: 2) Incomplete testicular feminization with ambiguous external genitalia showing an enlarged clitoris or phallus; 3) Testicular feminization with hypospadias (androgen-insensitive Reifenstein syndrome). External genitalia are hypospadic, exhibiting scrotal development. The presence of immature Sertoli cells in testicular tubules, in spite of hyperplastic and hypertrophic Leydig cells, is considered to be a pathognomonic histopathologic feature for androgen-insensitivity syndromes. The Leydig cells are able to produce androgens, but androgen-insensitive Sertoli cells are unable to mature.