Androgen insensitivity in man: evidence for genetic heterogeneity.
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We have studied ten phenotypically similar patients with complete androgen insensitivity. All of the patients tested had significantly elevated serum luteinizing hormone and plasma androgens within or above the normal adult male range. On the basis of specific dihydrotestosterone binding by skin fibroblasts, we identified two subgroups. Six patients from five different families had undetectable dihydrotestosterone binding, while four patients from two families had normal binding activity. Our results indicate that within the clinical syndrome of androgen insensitivity there are at least two distinct genetic variants. These variants may result from allelic mutations of the same X-linked gene specifying the dihydrotestosterone receptor or, alternatively, from mutations of separate genes both being essential for androgen action in responsive cells. (+info)
Novel mutation in the ligand-binding domain of the androgen receptor gene (l790p) associated with complete androgen insensitivity syndrome.
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Mutations in the X-linked androgen receptor (AR) gene cause androgen insensitivity syndrome (AIS), resulting in an impaired embryonic sex differentiation in 46,XY genetic men. Complete androgen insensitivity (CAIS) produces a female external phenotype, whereas cases with partial androgen insensitivity (PAIS) have various ambiguities of the genitalia. Mild androgen insensitivity (MAIS) is characterized by undermasculinization and gynecomastia. Here we describe a 2-month-old 46,XY female patient, with all of the characteristics of CAIS. Defects in testosterone (T) and dihydrotestosterone (DHT) synthesis were excluded. Sequencing of the AR gene showed the presence in exon 6 of a T to C transition in the second base of codon 790, nucleotide position 2369, causing a novel missense Leu790Pro mutation in the ligand-binding domain of the AR protein. The identification of a novel AR mutation in a girl with CAIS provides significant information due to the importance of missense mutations in the ligand-binding domain of the AR, which are able to induce functional abnormalities in the androgen binding capability, stabilization of active conformation, or interaction with coactivators. (+info)
Androgen insensitivity syndrome: do trinucleotide repeats in androgen receptor gene have any role?
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AIM: To investigate the role of CAG and GGN repeats as genetic background affecting androgen insensitivity syndrome (AIS) phenotype. METHODS: We analyzed lengths of androgen receptor (AR)-CAG and GGN repeats in 69 AIS cases, along with 136 unrelated normal male individuals. The lengths of repeats were analyzed using polymerase chain reaction (PCR) amplification followed by allelic genotyping to determine allele length. RESULTS: Our study revealed significantly shorter mean lengths of CAG repeats in patients (mean 18.25 repeats, range 14-26 repeats) in comparison to the controls (mean 22.57 repeats, range 12-39 repeats) (two-tailed P < 0.0001). GGN repeats, however, did not differ significantly between patients (mean 21.48 repeats) and controls (mean 21.21 repeats) (two-tailed P = 0.474). Among patients' groups, the mean number of CAG repeats in partial androgen insensitivity cases (mean 15.83 repeats) was significantly less than in complete androgen insensitivity cases (mean 19.46 repeats) (two-tailed P < 0.0001). CONCLUSION: The findings suggest that shorter lengths of repeats in the AR gene might act as low penetrance genetic background in varying manifestation of androgen insensitivity. (+info)
Novel missense mutation in the P-box of androgen receptor in a patient with androgen insensitivity syndrome.
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Mutations in the X-linked AR gene cause androgen insensitivity syndrome (AIS) by impairing androgen-dependent male sex differentiation to various degree. Here we describe a partial AIS patient with confliction with the assigned female sex. Although the patient was noticed to have ambiguous genitalia at birth, the patient was reared as a female with no medical intervention. At the age of 31 years, the patient visited us because the patient was dissatisfied with the assigned female sex. The patient was treated with systemic testosterone and topical dihydrotestosterone, but the external genitalia responded only minimally to the treatment. The genetic analysis revealed a novel missense K580R mutation in the P-box of the DNA-binding domain of androgen receptor, which was the first missense mutation shared by AIS and prostate cancer. Although the best predictor of the adult gender identity is documented to be the initial gender assignment in patients with partial AIS as well as those with complete AIS, deciding gender assignment for infants with partial AIS is still challenging. (+info)
Male pseudohermaphroditism presumably due to target organ unresponsiveness to androgens. Deficient 5alpha-dihydrotestosterone binding in cultured skin fibroblasts.
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Maximum specific 5alpha-dihydrotestosterone (DHT) binding activity (Bmax) had been measured in intact confluent monolayers representing fibroblast strains derived form nongenital and genital (labium majus) skin of normal individuals and of 11 patients fulfilling the clinicogenetic criteria of complete testicular feminization (TF). Nine labium majus strains from adult females had a mean Bmax value three times greater than that of seven nongenital strains from adult females (33 vs. 11 fmol/mg cell protein). The Bmax results for 13 adult nongenital strains varied from 5.6 to 23.3 fmol/mg protein; the values for males and females had very similar means and ranges. The variation could not be correlated with the chronologic age of adult skin explant donors or with the in vitro age (mean population doubling level) of the cultures assayed. The Bmax activities of three nongenital strains from normal infants (two male, one female) did not exceed 5 fmol/mg protein. Seven of eight nongenital TF strains had Bmax values below 2 fmol/mg protein; the value for the eighth coincided with the lower limit of normal adults. The lower limit of DHT binding in normal labium majus strains was 15 fmol/mg protein. Three of five labial strains from patients with TF had Bmax values close to zero; the other two fell between 10 and 15 fmol/mg protein. It is apparant that labial skin fibroblast strains from clinically homogeneous patients with TF had highly variable degrees of DHT binding deficiency, and that they permit a more reliable diagnosis of severe and intermediate degrees of DHT binding deficiency than do strains of nongenital skin fibroblasts. (+info)
Laparoscopy and intersex: report of 5 cases of male pseudohermaphroditism.
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From May, 1999 to August, 2006, we performed laparoscopic diagnosis and treatment for 103 cases of impalpable testes. Among those we found 5 cases of male pseudohermaphroditism of different etiologies. Three males presented by impalpable testes with ambiguous genitalia and 2 females presented by primary amenorrhea. All of them have 46-XY normal male chromosomal pattern. In the first 3 cases, the etiology was complete gonadal dysgenesis, and 2 cases with persistent Mullerian syndrome. Timed gonadectomy for the first case and laparoscopic orchiopexy for the other 2 cases were performed. For the other 2 female cases, the etiology was complete androgen insensitivity syndrome and laparoscopic bilateral orchiectomy was performed for both of them. All the procedures were done without complications with satisfactory results. (+info)
Comparison of bone mineral density and body proportions between women with complete androgen insensitivity syndrome and women with gonadal dysgenesis.
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