A young infant with complete androgen insensitivity syndrome

Complete androgen insensitivity syndrome (CAIS) is a rare X-linked recessive disorder resulting from maternally inherited or de novo mutations involving the androgen receptor (AR) gene. The AR is a vital steroid hormone receptor that has a critical role in male sexual differentiation and development and preservation of the male phenotype. The diagnosis of CAIS is based on the presence of female external genitalia in an individual with 46, XY karyotype having normally developed but undescended testes and target tissue unresponsiveness to androgen. Our case presented at the age of 2 months with asymmetric labia majora with bilateral labial mass. Ultrasonography revealed absence of female internal genital organs and presence of testes at labial folds. The child was found to have 46, XY karyotype. BIRDEM Med J 2022; 12(1): 74-77

Phát hiện đột biến mới trên Gen AR ở bệnh nhân mắc hội chứng kháng androgen

Hội chứng kháng androgen (AIS - Androgen Insensitivity Syndrome) là một trong những rối loạn di truyền phổ biến nhất ảnh hưởng đến phát triển giới tính trước khi sinh và dậy thì ở trẻ. Về di truyền, những trẻ này là nam giới, nhưng khi sinh ra có kiểu hình một phần hoặc hoàn toàn là nữ. Xét nghiệm gen AR là phương pháp xác định chính xác nguyên nhân gây hội chứng kháng androgen. Mục tiêu của nghiên cứu là xác định kiểu gen AR đột biến trên bệnh nhân nam mắc hội chứng kháng androgen có kiểu hình nữ và kiểu gen của mẹ bệnh nhân bằng phương pháp giải trình tự gen trực tiếp. Kết quả đã phát hiện một đột biến hoàn toàn mới c.2246C>T (p.Ala749Val) trên exon 5 của gene AR, đột biến chưa được báo cáo trong dữ liệu ngân hàng gen của thế giới. Đột biến ở dạng bán hợp tử được di truyền từ mẹ của bệnh nhân ở dạng dị hợp tử. Kết quả này giúp gia đình định hướng giới tính phù hợp cho bệnh nhân. Đồng thời, nghiên cứu đóng góp thêm dữ liệu đột biến mới về gen AR trong quần thể bệnh nhân AIS người Việt Nam, góp phần quản lý bệnh và tư vấn di truyền trước sinh cho gia đình người bệnh.

Rare case of two siblings with complete androgen insensitivity syndrome

Androgen insensitivity syndrome (AIS) also called testicular feminizing syndrome is a rare X linked disorder of sexual differentiation caused by mutation in the androgen receptor (AR) gene, which is located on the X chromosome (Xq11-q12). In the reported cases, individuals with complete androgen insensitivity syndrome (CAIS) presented with a female appearance and normal breast development, absence of uterus and ovaries, bilateral undescended testis, and elevated testosterone levels. The syndrome is usually detected on evaluation of a phenotypic female with primary amenorrhea who presents for treatment of infertility. Here, we report 2 cases of CAIS in siblings 21 and 19 years of age who presented to us with primary amenorrhea. The elder sibling presented to us with primary amenorrhea, thelarche +, absent adrenarche, blind pouch of vagina, b/l inguinal masses suggestive of undescended testes, raised serum testosterone and absent uterus on USG. While the younger sibling also presented with similar findings but had history of b/l orchidectomy at the age of 14 years. Both the sisters were admitted in our unit and the elder sister underwent b/l orchidectomy and McIndoe’s vaginoplasty. While the younger sister underwent McIndoe’s vaginoplasty on the same day. Post-operative recovery was uneventful and they were given hormone replacement therapy (HRT). AIS is a rare X linked disease caused by mutation in the AR gene. which when diagnosed early can be treated appropriately. Precise diagnosis requires clinical, hormonal and molecular investigation and is of great importance for appropriate gender assignment and management in general. With timely gonadectomy, vaginoplasty or vaginal pouch deepening, hormone replacement and appropriate psychological support help the person live a healthy and almost normal life.

Identification of Potential Genes in Pathogenesis and Diagnostic Value Analysis of Partial Androgen Insensitivity Syndrome Using Bioinformatics Analysis

BackgroundAndrogen insensitivity syndrome (AIS) is a rare X-linked genetic disease and one of the causes of 46,XY disorder of sexual development. The unstraightforward diagnosis of AIS and the gender assignment dilemma still make a plague for this disorder due to the overlapping clinical phenotypes.MethodsPeripheral blood mononuclear cells (PBMCs) of partial AIS (PAIS) patients and healthy controls were separated, and RNA-seq was performed to investigate transcriptome variance. Then, tissue-specific gene expression, functional enrichment, and protein–protein interaction (PPI) network analyses were performed; and the key modules were identified. Finally, the RNA expression of differentially expressed genes (DEGs) of interest was validated by quantitative real-time PCR (qRT-PCR).ResultsIn our dataset, a total of 725 DEGs were captured, with functionally enriched reproduction and immune-related pathways and Gene Ontology (GO) functions. The most highly specific systems centered on hematologic/immune and reproductive/endocrine systems. We finally filtered out CCR1, PPBP, PF4, CLU, KMT2D, GP6, and SPARC by the key gene clusters of the PPI network and manual screening of tissue-specific gene expression. These genes provide novel insight into the pathogenesis of AIS in the immune system or metabolism and bring forward possible molecular markers for clinical screening. The qRT-PCR results showed a consistent trend in the expression levels of related genes between PAIS patients and healthy controls.ConclusionThe present study sheds light on the molecular mechanisms underlying the pathogenesis and progression of AIS, providing potential targets for diagnosis and future investigation.

A deep intronic mutation in AR gene causing androgen insensitivity syndrome: difficulties of diagnostics

Partial androgen resistance syndrome (PAIS) is the most difficult form of disorders/differences of sex development 46,XY (DSD 46,XY) for choosing of patient management. To date, there are no clear biochemical criteria, especially before puberty, that allow differentiating PAIS from other PAIS-like forms of DSD 46, XY, and genetic verification of the partial form of AIS plays an important role. Meanwhile, according to the literature, mutations in the coding region of AR gene have not been identified in more than 50% of patients with suspected AIS. We performed an extensive analysis of the AR gene in a patient with clinical and laboratory signs of AIS and found a deep intron mutation in the AR gene (p. 2450–42G>A). This variant creates an alternative splice acceptor site resulted a disturbance of the AR function. These findings indicate the need for extensive genetic analysis in a cohort of patients with suspected CPA in the absence of mutations in the AR gene using standard methods of genetic diagnosis.