Phenotype, hormonal profile and genotype of subjects with partial androgen insensitivity syndrome: report of a family with four adult males and one child with disorder of sexual differentiation (original) (raw)
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The Journal of Clinical Endocrinology & Metabolism, 2000
Androgen insensitivity syndrome (AIS) is the most common single entity that results in male under-masculinization, but large cohort studies of AIS have rarely been performed. Over the last decade, nationwide cooperation between pediatric endocrinologists in the United Kingdom has allowed the creation of a database of cases of intersex and ambiguous genitalia where detailed clinical information on every notified case has been collected via a questionnaire. Among the 816 entries recorded by January 1999, there were 105 clinically diagnosed cases of complete AIS (CAIS) and 173 cases of partial AIS (PAIS). A masculinization score was devised by scoring the external phenotype, and a score of 12 represented normal masculinization. Androgen receptor (AR) binding was determined by studying binding capacity (B max) and receptor affinity (K d), and cases were classified as either zero, abnormal, or normal binding. Mutation screening of all eight exons of the AR gene was performed by single-strand conformational polymorphism analysis, followed by direct DNA sequencing. All cases of PAIS presented within the first month of birth. The median age at presentation of children with CAIS was 1 yr (P10,P90: 0.1,10.4). The testes were palpable in the labioscrotal folds or the inguinal region in 77% and 41% of cases of CAIS and PAIS, respectively. There was marked overlap between the masculinization score of those children with PAIS reared as girls [2.5(P10,P90:1, 6)] and those reared as boys [3(P10,P90:2, 7.5)]. Gonadectomy was performed prepubertally in 66% and postpubertally in 29% of the cases of CAIS.
Journal of pediatric …, 2009
Mutation in the androgen receptor gene (AR) is known to cause androgen insensitivity syndrome (AIS). In an X-linked recessive manner, an AR mutation gets transmitted to the offspring through carrier mothers in 70% of cases, the other 30% arising de novo. However, reports on AR mutations amongst Indian patients with AIS are scarce in the literature. This study reports mutations in AR from two Indian families, each having a proband with partial androgen insensitivity syndrome (PAIS) phenotype. Clinical, endocrine and cytogenetic evaluation of these affected children was performed. Mutational analysis was carried out by polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) analysis followed by sequencing. The two point mutations were in exon 5: p.M742I, familial in patient 1 and p.V746M de novo in patient 2. These are hitherto unrecognized mutations in our population. Similar mutational studies are suggested in patients with AIS, in order to identify their frequency and clinical severity in our population.
Phenotypic variation and detection of carrier status in the partial androgen insensitivity syndrome
Archives of Disease in Childhood, 1993
The partial androgen insensitivity syndrome occurs in 46,XY subjects with phenotypes ranging from perineoscrotal hypospadias with cryptorchidism and micropenis (mild undervirilisation) to citoromegaly 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. (Arch Dis Child 1993; 68: 453-457) androgen binding, the central domain (exons B and C) consists of two zinc finger-like elements responsible for DNA binding, and the less well characterised N terminal domain (exon A) has a role in transcriptional activation by the receptor.78
The Journal of Clinical Endocrinology & Metabolism, 1996
Mutations in the coding sequence of the androgen receptor (AR) gene result in a wild range of androgen insensitivity (AI) syndromes. Differences in the clinical expression of the same mutation in unrelated patients have been reported. However, this study reports for the first time strikingly different phenotypes among three patients within the same kindred. Two of the patients had a feminine phenotype, suggesting complete AI, but for some pubic hair. The third subject was male with partial AI, perineoscrotal hypospadias, and cryptorchidism. 5a-reductase activity measured in genital skin fibroblasts and
Androgen insensitivity syndrome: clinical features and molecular defects
HORMONES, 2008
The end-organ resistance to androgens has been designated as Androgen Insensitivity Syndrome (AIS), an X-linked disorder caused by mutations in the Androgen Receptor (AR) gene. It is generally accepted that defects in the AR gene prevent the normal development of both internal and external genital structures in 46,XY individuals, causing a variety of phenotypes ranging from male infertility to completely normal female external genitalia. Precise diagnosis requires clinical, hormonal and molecular investigation and is of great importance for appropriate gender assignment and management in general. The complexity of phenotypic presentation of AIS with genotype-phenotype variability of identical mutations complicates both the diagnostic procedure and genetic counseling of the affected families. More than 400 different AR gene mutations have thus far been reported but the receptor structure-function relationship and its phenotypic outcome is not yet fully understood. This review focuses on the clinical features and molecular pathophysiology of AIS and explores the relationship of the molecular defects in the AR gene to their clinical expression.
Eight novel mutations of the androgen receptor gene in patients with androgen insensitivity syndrome
Journal of Human Genetics, 2001
Androgen insensitivity syndrome (AIS) is an X-linked genetic disorder of male sexual differentiation caused by mutations in the androgen receptor (AR) gene. A reliable genotype-phenotype correlation in these patients does not exist as yet. Here we report the molecular studies performed on eight individuals with AIS. Exon-specific polymerase chain reaction (PCR), single-strand conformation polymorphism, and sequencing analyses, were performed in exons 2 to 8 of the AR gene. In one case, total cellular RNA was extracted from genital skin fibroblasts and reverse transcriptase-PCR was performed. Six different point mutations leading to amino acid substitutions (P682T, Q711E, G743E, F827V, H874R, D879Y), one splicejunction mutation (gAEc at ϩ5, exon 6/intron 6), and a missense mutation without amino acid substitution (S888S) were identified. All mutations, including a de novo mutation, were previously undescribed on the steroid binding domain. Of the eight mutations identified, four led to a complete female phenotype (codons 743, 827, 874 and the donor splice site ϩ5), two were detected in phenotypic females with partial virilization (codons 682 and 711), and two were present in phenotypic male subjects with undervirilized external genitalia, thus indicating that all of these sites determine AR functional activity.
Genotype Versus Phenotype in Families with Androgen Insensitivity Syndrome
The Journal of Clinical Endocrinology & Metabolism, 2001
Androgen insensitivity syndrome encompasses a wide range of phenotypes, which are caused by numerous different mutations in the AR gene. Detailed information on the genotype/ phenotype relationship in androgen insensitivity syndrome is important for sex assignment, treatment of androgen insensitivity syndrome patients, genetic counseling of their families, and insight into the functional domains of the AR. The commonly accepted concept of dependence on fetal androgens of the development of Wolffian ducts was studied in complete androgen insensitivity syndrome (CAIS) patients. In a nationwide survey in The Netherlands, all cases (n ؍ 49) with the presumptive diagnosis androgen insensitivity syndrome known to pediatric endocrinologists and clinical geneticists were studied. After studying the clinical phenotype, mutation analysis and functional analysis of mutant receptors were performed using genital skin fibroblasts and in vitro expression studies. Here we report the findings in families with multiple affected cases. Fifty-nine percent of androgen insensitivity syndrome patients had other affected relatives. A total of 17 families were studied, seven families with CAIS (18 patients), nine families with partial androgen insensitivity (24 patients), and one family with female prepubertal phenotypes (two patients). No phenotypic variation was observed in families with CAIS. However, phenotypic variation was observed in one-third of families with partial androgen insensitivity resulting in different sex of rearing and differences in requirement of reconstructive surgery. Intrafamilial phenotypic variation was observed for mutations R846H, M771I, and deletion of amino acid N682. Four newly identified mutations
Journal of Molecular Medicine, 2005
Androgen insensitivity syndrome (AIS) is characterized by deficient or absent virilization in 46,XY individuals despite normal or even elevated androgen levels. AIS is usually caused by mutations in the androgen receptor (AR) gene. We aimed at contrasting clinical, biochemical, and molecular genetic characteristics of three patients (P1-P3) with clinically evident partial (P1) and complete (P2, P3) AIS with and without AR gene mutations. AR expression was studied in cultured genital skin fibroblasts (GSF) by Western immunoblotting, ligand binding analyses, Northern blotting, semiquantitative reverse transcription-polymerase chain reaction (RT-PCR), and RT-PCR spanning exons 1-8. AR gene DNA sequence was analyzed by single-strand conformation analysis (SSCA), and DNA sequencing. GSF revealed reduced (P1) or absent (P2, P3) ligand binding. Northern blots showed either slightly reduced hybridization of the 10.5-kb AR transcript (P3) or no hybridization (P1, P2), as confirmed by semiquantitative RT-PCR. RT-PCR spanning exons 1-8 detected single AR mRNA bands in P1-P3 excluding splicing errors. Western analyses showed either low (P1) or no (P2, P3) AR protein. While SSCA initially did
Phenotypic diversity in siblings with partial androgen insensitivity syndrome
Archives of Disease in Childhood, 1997
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 aVecting 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. (Arch Dis Child 1997;76:529-531)