Абстракт

Мы представляем три клинических случая у детей в возрасте от 18 до 35 месяцев с признаками нарушения полового развития 46, XY и фенотипом, сходным с синдромом нечувствительности к андрогенам. Клинические проявления включали различные варианты хордэ, пеноскротальной транспозиции, аномалий, ассоциированных с гипоспадией, а также крипторхизмом. Первоначально на основании клинической картины у этих пациентов предполагался синдром частичной нечувствительности к андрогенам (СЧНА). Однако структурных аномалий мюллеровых структур, почек или аноректальной области выявлено не было. Эти случаи демонстрируют сложности диагностики нарушений полового развития с «отрицательным AR»-статусом, при котором фенотип, напоминающий синдром нечувствительности к андрогенам, сохраняется несмотря на отсутствие выявляемых генетических мутаций. Наличие атипичных паттернов экспрессии AR указывает на возможную дисфункцию рецептора или существование ещё не выявленных регуляторных механизмов. Для обеспечения комплексной, ориентированной на пациента медицинской помощи необходим гибкий мультидисциплинарный подход, включающий психологическую поддержку, генетическое консультирование, информированное согласие родителей и отсрочку проведения необязательных необратимых хирургических вмешательств.

Сопроводительное письмо

INTRODUCTION Disorders of Sex Development (DSD) represent a heterogeneous group of congenital conditions where chromosomal, gonadal, or anatomical sex development is atypical. Among these, 46,XY DSD caused by androgen resistance clinically termed Partial Androgen Insensitivity Syndrome  (PAIS) is a major diagnostic consideration for infants presenting with ambiguous genitalia and external virilization defects [3]. Classically, the suspicion of PAIS triggers genetic sequencing of the AR gene. However, clinical literature indicates that less than 30% of boys with phenotypes suggestive of PAIS harbor a detectable AR mutation [4]. This diagnostic gap leaves clinicians with "AR-negative" cases where the clinical and hormonal profile suggests androgen resistance, yet the molecular etiology remains elusive. Furthermore, ethical standards in paediatric surgery require strict adherence to institutional review board (IRB) oversight and explicit parental informed consent, particularly when evaluating delicate congenital variations.

MATERIALS AND METHODS Clinical Presentation and Diagnostic Findings The three patients presented between 18 and 35 months of age. Clinical features varied per individual case, encompassing localized genital anomalies without structural Müllerian, renal, or anorectal involvement. Maternal androgen exposure was ruled out in all instances. 

Baseline and Stimulated Hormonal Profile: To assess testicular function and clarify the biochemical basis of suspected androgen resistance, baseline and human chorionic gonadotropin (hCG)-stimulated hormone levels were evaluated. Basal luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone fell within age-appropriate prepubertal ranges. Post-hCG stimulation testing demonstrated appropriate testosterone increments alongside preserved serum Anti-Müllerian Hormone (AMH) and inhibin B levels, confirming functional testicular tissue without evidence of gonadal dysgenesis.

Genetic Analysis: Sequencing of the AR gene and extended panel testing for DSD-related genes were negative for pathogenic variants across all three patients.

Immunohistochemistry: Analysis of Case 1 revealed atypical AR expression, with variable, weak positivity in the prepuce and scrotal samples, and significant regions of AR-negativity. The presence of a clinical AIS-like phenotype without an identified genetic cause highlights the limitations of current targeted gene sequencing and the potential role of undiscovered molecular pathways or regulatory region abnormalities [4]. 

Management and Therapeutic Strategy A conservative management approach was adopted, with emphasis on careful longitudinal follow-up under institutional ethical guidelines and parental informed consent. The patients underwent regular endocrine monitoring, including serial hormonal evaluations to measure hypothalamic-pituitary-gonadal axis function. Growth velocity and pubertal development were monitored through periodic clinical assessments to evaluate ongoing physical maturation. Surgical strategy explicitly avoided early gonadectomy, as histological evaluation and hormonal markers confirmed functional, non-dysgenetic testes with no elevated malignancy risk. Elective reconstructive procedures (such as chordee correction, penoscrotal transposition repair, and orchidopexy) were intentionally postponed to allow for spontaneous physical development and to support shared decision-making as the child matures [5]. In addition, comprehensive psychosocial support was provided to the families to facilitate coping, address concerns related to the diagnosis, and prepare for future discussions regarding gender identity and long-term well-being.

DISCUSSION The challenge of managing AR-negative DSD lies in the unpredictability of long-term outcomes. While patients with genetically confirmed PAIS may show higher rates of complications like gynecomastia, the prognosis for those without identified mutations is less clear [4]. The use of immunohistochemistry (IHC) for AR remains a useful but supplementary tool. As seen in Case 1, patchy or weak nuclear expression does not necessarily confirm a functional defect but suggests potential receptor dysregulation. Future diagnostics may increasingly rely on Whole-Exome Sequencing (WES) to uncover novel genetic factors, as recent studies have identified causal variants in previously "idiopathic" cases through expanded research-based sequencing [6]. Recent advances in next-generation sequencing (NGS), particularly whole-exome sequencing (WES), have substantially expanded the spectrum of genes implicated in AIS-like phenotypes, facilitating the identification of pathogenic variants in genes involved in androgen biosynthesis, androgen signaling pathways, gonadal development, and other molecular mechanisms that may mimic classical AIS [7].

Some studies demonstrated that incorporating NGS into the diagnostic evaluation of patients with DSD significantly improves molecular diagnostic yield compared with conventional sequential testing [7]. Their findings emphasize that patients with an AIS-like presentation but negative AR testing frequently receive alternative molecular diagnoses through broader gene panel or exome sequencing, allowing for more accurate disease classification and personalized clinical management. Similar research highlighted the evolving role of WES as an important diagnostic tool in unresolved DSD cases, particularly when the phenotype does not clearly correspond to a single genetic disorder [6]. The authors emphasized that identifying the underlying molecular defect not only refines diagnosis but also improves genetic counseling, recurrence risk assessment, and multidisciplinary clinical decision-making.

CONCLUSION The recognition of AR-negative AIS-like phenotypes has important implications for patient management beyond establishing a molecular diagnosis. Accurate genetic and hormonal characterization contributes to individualized decisions regarding gonadal surveillance, endocrine treatment, fertility counselling, and psychosocial support. Furthermore, long-term outcome studies have reinforced the importance of integrating genetic diagnosis with careful multidisciplinary evaluation when making decisions regarding sex assignment and lifelong management. Another study emphasized that gender-related outcomes in individuals with DSD depend on multiple factors, including the underlying diagnosis, hormonal function, psychosocial environment, and ongoing clinical support [8]. Consequently, establishing a precise molecular diagnosis through comprehensive genomic testing provides a stronger foundation for patient-centered counselling and shared decision-making. Collectively, these findings support the routine integration of comprehensive genomic approaches, including WES, into the evaluation of patients with AR-negative AIS-like phenotypes to improve diagnostic accuracy, optimize long-term management, and advance understanding of the complex genetic architecture of DSD.

Фигуры

Ключевые слова

• нарушения полового развития
• синдром частичной нечувствительности к андрогенам
• ген AR
• иммуногистохимия
• полное экзомное секвенирование

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Опубликовано: 13.Oct.2026

DOI: https://doi.org/10.28942/atuj.v6i3y2026.168

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© 2022-2025. Azerbaijan Medical University. E-Journal is published by "Uptodate in Medicine" health sciences publishing. All rights reserved.

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