A Rare Case of 45,X[5]/46XX[55] 21-Hydroxylase Deficiency with Female Pseudohermaphroditism and a Giant Uterine Fibroid: Diagnosis and Treatment

A Rare Case of 45,X[5]/46XX[55] 21-Hydroxylase Deficiency with Female Pseudohermaphroditism and a Giant Uterine Fibroid: Diagnosis and Treatment | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report A Rare Case of 45,X[5]/46XX[55] 21-Hydroxylase Deficiency with Female Pseudohermaphroditism and a Giant Uterine Fibroid: Diagnosis and Treatment Wei Wang, Yang Liu, Hui Wang, Caiqun Luo This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6871714/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version Abstract Backgroud : In patients with 21-hydroxylase deficiency, the compensatory elevation of aldosterone levels can lead to increased androgen production. This excess of androgens can result in virilization, manifesting as male-like physical characteristics in genetic females and giving rise to the condition known as female pseudohermaphroditism. Case Presentation : This article reports a case of a 52-year-old patient who identifies as male, presenting with a small phallus. The patient sought medical attention due to the discovery of a giant uterine fibroid, which was also complicated by an adrenal tumor, elevated 17-hydroxyprogesterone, androstenedione, dehydroepiandrosterone sulfate. Chromosomal karyotype analysis revealed a 45,XX[5]/46,XX[55] pattern, Male genital appearance, Genetic testing for 21-hydroxylase deficiency (CYP21A2 gene) indicated compound heterozygous pathogenic variants c.293−13C/A > G and c.518T > A in the CYP21A2 gene, he simple virilizing form of 21-hydroxylase deficiency was diagnosed. The patient underwent total hysterectomy and bilateral salpingo-oophorectomy. Conclusion : This case highlights the complexity of 21-hydroxylase deficiency, a condition that can lead to significant endocrine and anatomical anomalies. The compensatory elevation of aldosterone levels in such patients often results in increased androgen production, which can cause virilization and the development of male-like physical characteristics in genetic females, leading to male female pseudohermaphroditism.This case underscores the importance of a multidisciplinary approach in managing such rare and complex conditions, involving endocrinology, genetics, and surgery. It also highlights the need for comprehensive genetic testing and hormonal evaluation to guide appropriate treatment and improve patient outcomes. 45 X[5]/46XX[55] 21-Hydroxylase Deficiency female pseudohermaphroditism giant uterine fibroid Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Introduction Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders of steroidogenesis of the adrenal cortex. 21-Hydroxylase deficiency is the most common form of congenital adrenal hyperplasia (CAH), accounting for over 90% of all CAH cases. 21-Hydroxylase deficiency is caused by mutations in the CYP21A2 gene, which leads to dysfunction of the 21-hydroxylase enzyme. This dysfunction blocks the synthetic pathways of cortisol and mineralocorticoids, resulting in the excessive accumulation of the precursor 17-hydroxyprogesterone (17-OHP) and androgens. This, in turn, triggers a series of clinical symptoms [1-3] . Based on the degree of enzyme activity deficiency caused by gene mutations and the severity of clinical symptoms, 21-OHD can be categorized into classic and non-classic types [4-6] . Patients with classic 21-hydroxylase deficiency have higher levels of androgens compared to normal individuals. Starting from intrauterine life, exposure to large amounts of androgens such as testosterone and androstenedione during the critical period of sexual differentiation can cause the external genitalia of genetic females to virilize, resulting in ambiguous genitalia at birth.The simple virilizing type has residual enzyme activity that allows for the secretion of aldosterone, which helps maintain sodium balance. However, the salt-wasting type, which accounts for about 75% of classic cases, cannot produce sufficient aldosterone. Infants with the salt-wasting form face life-threatening salt-wasting crises soon after birth, which can occur as early as within 1 to 4 weeks after birth if left untreated. Patients with 21-hydroxylase deficiency who do not receive appropriate treatment are continuously exposed to high levels of androgens. This can lead to an enlarged penis or further hypertrophy of the clitoris, premature appearance of pubic and axillary hair, and acne. Additionally, children who are chronically exposed to high levels of androgens may experience accelerated growth velocity, advanced bone age, and ultimately fail to reach their expected genetic height. In 21-hydroxylase deficiency, female fetuses exposed to excessively high levels of androgens in the body between 8 and 12 weeks of gestation may experience masculinization of the external genitalia, resulting in symptoms such as clitoral hypertrophy, labial fusion, and urogenital sinus anomalies [7] . However, the internal genitalia still differentiate into normal female internal gonads (uterus and ovaries). If left untreated in a timely manner, this condition can also lead to the premature development of pubic and axillary hair. Case Description The patient is a 52-year-old unmarried individual who has identified as male for the past 52 years. Over the past nine years, a pelvic mass has been detected, and abdominal distension has been present for two years, gradually worsening with an associated weight loss of 10 pounds. The patient’s vital signs include a blood pressure of 120/81 mmHg, a height of 158 cm, and a weight of 55 kg. The patient presents with a male appearance, including an Adam’s apple and no breast development (Fig 1) . The abdomen is distended, with a palpable abdominal mass extending upward to two transverse finger widths below the xiphoid process and downward into the pelvic cavity. The mass is firm, with clear borders, limited mobility, and no tenderness on palpation. No masses are palpable in the bilateral inguinal regions. The patient has pubic hair distributed in a male pattern. A small phallus-like structure is visible, with the urethral opening located on the posterior and inferior side of the mucosa. Additionally, a vaginal opening and bilateral labia majora-like structures are present (Fig2) . Imaging examinations: 2014 ultrasound examination revealed a solid pelvic mass measuring 106 mm ×96 mm × 67 mm and a mixed-echoic mass above the right kidney measuring 53 mm×49 mm. enhanced MRI examination showed: 1.Bilateral adrenal gland changes, suggestive of adrenal cortical hyperplasia. A mass in the right adrenal gland is considered to be a benign tumor-like lesion, most likely an adrenal adenoma.2.Pelvic and external genital changes, suggestive of female pseudo -hermaphroditism: Uterine structures with intramural leiomyoma degeneration are visible within the pelvis; underdeveloped vaginal structures and a phallus are present, with no evidence of ovaries, prostate, seminal vesicles, testes, or spermatic cord structures.3.Gallstones. 2023 the whole abdominal enhanced MRI scan show (Fig3 ): 1.Bilateral adrenal gland changes, with morphology and size essentially unchanged from the previous findings, are suggestive of adrenal cortical hyperplasia. The right adrenal gland is considered to have an associated adenoma (42 mm×33 mm).2.Pelvic and external genital changes, suggestive of female pseudohermaphroditism: Underdeveloped vaginal structures and a phallus are visible, with no evidence of ovaries, prostate, seminal vesicles, testes, or spermatic cord structures. These findings are essentially similar to the previous ones.3.Multiple masses/nodules are visible within the uterine structures in the pelvis, which have increased in number and size compared to the previous findings. These are considered to be multiple leiomyomas with degeneration (the largest measuring approximately 187mm×126 mm×178 mm).4.Multiple gallstones with chronic cholecystitis.5.A small amount of ascites in the abdominal and pelvic cavities. Physical Examination: Height 158 cm, weight 55 kg, generally in good condition, with a typical male appearance, including an Adam's apple and no breast development. Cardiopulmonary auscultation was unremarkable. The abdomen was distended, with a palpable mass extending up to 2 transverse fingers below the xiphoid process and down into the pelvic cavity. The mass was firm, well-defined, poorly mobile, and non-tender. No inguinal lymphadenopathy was detected bilaterally. Pubic hair was distributed in a male pattern. A small "phallus" was noted, with a urethral orifice on the posterior mucosa and a visible vaginal orifice. Bilateral labial-like structures were also observed. Laboratory Investigations: Table 1 Baseline laboratory test Inspection items Result Tip Unit Reference Range Cortisol 159.9 ng/ml 7-9AM：52.7-224.5 3-5PM：34.4-167.6 AFP 1.5 ng/ml 0-8.1 Total prostate-specific antigen 0.1 ng/ml 0.0-4.0 Human epididymis protein 4 203 ↓ pmol/L 34.72-114.90 Anti-Mullerian hormone <0.0098 0 ↓ ng/mL 2.150--10.100 Luteinizing hormone 3.2 mIU/L 1. 5 9. 3 Testosterone 214.8 ng/dl 187.72-694.19 Progesterone 32.47 ↑ mmol/l 0.39-3.98 Follicle-stimulating hormone 9.3 mIU/L 1.4-14.81 Prolactin 11.5 ng/ml 2.1-17.7 Estradiol 36.3 pg/ml 0.0-39.8 Aldosterone 237.88 Pg/ml Lying：10.0-160.0 Standing：40.0-310 17α-Hydroxyprogesterone 117.2 ↑ ng/ml Male 0.31-2.01 Dehydroepiandrosterone Sulfate 905.51 ↑ ug/dl 44.67-347.34 Dihydrotestosterone 691.64 ↑ pg/ml Male 143.00-842 Female 0.00-431 Na 135 mmol/l 137-147 K 4.05 mmol/l 3.5-5.3 Thyroid Stimulating Hormone(TSH) 2.602 uIU/L 0.55-4.78 Free Triiodothyronine（FT4） 4,62 pmol/L 3.5-6.5 Free Thyroxine（FT3） 16.27 pmol/L 11.5-22.7 Androstenedione 47.45 ↑ nmol/l 1.75-7.68 Chromosomal karyotype analysis of peripheral blood:45,X[5]/46,XX[55] ( Fig4 ),Suggesting Tuner syndrome mosaicism Genetic testing for 21-hydroxylase deficiency (CYP21A2 gene) indicated compound heterozygous pathogenic variants c.293-13C/A>G(12G) and c. 518T>A(p.Ile173Asn) in the CYP21A2 gene(Fig5) Clinical Management: The patient has elevated levels of 17-hydroxyprogesterone, androstenedione, and dehydroepiandrosterone sulfate (DHEAS). Imaging studies suggest adrenal hyperplasia, with the right side possibly complicated by an adenoma. Chromosomal karyotype analysis revealed a 45,XX[5]/46,XX[55] pattern, Male genital appearance, Genetic testing for 21-hydroxylase deficiency (CYP21A2) revealed compound heterozygous mutations of c.293-13C/A>G and c.518T>A. These findings are consistent with a diagnosis of the simple virilizing form of 21-hydroxylase deficiency. After the patient was hospitalized, she had no intention to change her gender and external genitalia, and requested to solve the pelvic mass problem. After consultation with the endocrinology, urology, and gynecology departments, it was recommended to treat the pelvic mass first and then the adrenal gland problem, and then further follow-up with the endocrinology department.Under general anesthesia with endotracheal intubation, the patient underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy. The uterus and fibroids removed are shown in the figure （ Fig6a). Pathological examination of the uterus, uterine fibroids, ovaries, and fallopian tubes( Fig6b.c.d ) Discussion This case report details a rare presentation of female pseudo- hermaphroditism with a 45,X[5]/46,XX[55] karyotype, resulting from 21- hydroxylase deficiency and complicated by a giant uterine fibroid. The key findings include the identification of compound heterozygous pathogenic variants in the CYP21A2 gene (c.293-13C>G and c.518T>A), elevated androgen levels, and significant anatomical anomalies such as a small phallus and a large uterine fibroid. 21-hydroxylase deficiency (21-OHD) is the most common form of congenital adrenal hyperplasia (CAH) and is caused by mutations in the CYP21A2 gene, which encodes the 21-hydroxylase enzyme (P450c21). To date, nearly 300 different mutations in the CYP21A2 gene have been reported [8, 9] . Among these, the mutations c.293-13C>G (I2G), c.518T>A (p.I173N), and c.92C>T (p.P31L) are the most prevalent in Chinese patients with 21-OHD [10] . Classic 21-hydroxylase deficiency manifests as either the salt-wasting type or the simple virilizing type. Research has demonstrated a correlation between the types of CYP21A2 gene mutations and clinical phenotypes, which depends on the residual 21-hydroxylase activity and the specific combination of mutations [11] . Approximately 65%–75% of patients with 21-hydroxylase deficiency have a compound heterozygous mutation genotype [12-14] . The clinical phenotype is related to the residual enzyme activity, which in turn is associated with the severity of the pathogenic mutations.If the mutations in the CYP21A2 gene result in a complete loss of 21-hydroxylase activity, the salt-wasting type is typically observed [15] . The c.293-13C>G (I2G) mutation carried by our patient is believed to produce a small amount of normally spliced mRNA, thereby mitigating the degree of enzyme activity deficiency. This mutation has been identified in patients with both salt-wasting and simple virilizing phenotypes. Additionally, some studies have suggested that the excessive accumulation of 17-hydroxyprogesterone (17-OHP) and progesterone can partially bind to and activate the mineralocorticoid receptor, compensating for aldosterone deficiency and resulting in a less severe salt-wasting phenotype [16] .The point mutation c.518T>A (p.I173N) is relatively common and has been shown to reduce enzyme activity to 2% in vitro, typically resulting in the simple virilizing phenotype [17, 18] . Therefore, our patient primarily presents with the simple virilizing phenotype. Females with the simple virilizing type of 21-OHD are usually diagnosed in the neonatal period or during childhood. For treatment, the current consensus is that 46,XX patients assigned male at birth should be raised as females if diagnosed at ≤2 years of age, with timely estrogen and progesterone supplementation during puberty to promote sexual maturation, maintain secondary sexual characteristics, induce menstruation, and increase bone mass [19] . For those diagnosed after 2 years of age, a cautious, multifactorial decision should be made. However, this patient was not diagnosed until the age of 52, missing the optimal treatment window. The patient’s height is 158 cm, below the average for Chinese men. The current treatment goals focus on managing the large uterine fibroids and adrenal tumors, preventing adrenal crisis, and controlling excessive adrenal androgen secretion. Glucocorticoid therapy will be considered based on subsequent clinical findings, with the aim of improving the patient’s quality of life [19] . This case highlights the potential for 21-hydroxylase deficiency to be overlooked or misdiagnosed in clinical practice. It underscores the need for further research to improve early diagnosis rates. Future studies should focus on early detection through newborn screening, hormone testing, and genetic analysis to enhance patient outcomes.Moreover, this case emphasizes the importance of multidisciplinary comprehensive treatment. Collaboration among endocrinology, genetics, and surgery is crucial. For example, the endocrinology department confirms the diagnosis through hormone testing and genetic analysis, while the surgical department alleviates symptoms by removing uterine fibroids and ovaries. The psychiatry department assesses the patient’s physiological and psychological needs and devises individualized treatment plans. Declarations Ethics Statement The study adhered to the principles of the Declaration of Helsinki, ensuring that all research procedures complied with ethical standards. Patient consent statement patient gave written informed consent for their personal or clinical details along with any identifying images to be published in this study. Data Availability Statement The data supporting the findings of this study are not publicly available due to privacy or ethical restrictions. Conflicts of Interest The authors declare no conflicts of interest. Funding This research was supported by the Sanming Project of Medicine in Shenzen Municipality (SZSM202311005) Author Contribution Statement Wei Wang: data collection, data analysis, result interpretation,article writing; Yang Liu/Hui Wang ： data collection; Caiqun Luo: data collectiondata analysis ,result interpretation,article writing and publication. Acknowledgments We thank all the participants in the study. References Merke D P, Auchus R J. Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency [J]. The New England journal of medicine, 2020, 383(13): 1248-61. Higa M, Zaha A, Takushi A, et al. Novel STAR gene variant in a patient with classic lipoid congenital adrenal hyperplasia and combined pituitary hormone deficiency [J]. Human genome variation, 2021, 8(1): 6. Bizzarri C, Pisaneschi E, Mucciolo M, et al. Lipoid congenital adrenal hyperplasia by steroidogenic acute regulatory protein (STAR) gene mutation in an Italian infant: an uncommon cause of adrenal insufficiency [J]. Italian journal of pediatrics, 2017, 43(1): 57. Bose H S, Sugawara T, Strauss J F, et al. The pathophysiology and genetics of congenital lipoid adrenal hyperplasia [J]. The New England journal of medicine, 1996, 335(25): 1870-8. Miller W L. Congenital lipoid adrenal hyperplasia: the human gene knockout for the steroidogenic acute regulatory protein [J]. Journal of molecular endocrinology, 1997, 19(3): 227-40. Mizuno Y, Ishii T, Hasegawa T. In Vivo Verification of the Pathophysiology of Lipoid Congenital Adrenal Hyperplasia in the Adrenal Cortex [J]. Endocrinology, 2019, 160(2): 331-8. White P C. Ontogeny of adrenal steroid biosynthesis: why girls will be girls [J]. The Journal of clinical investigation, 2006, 116(4): 872-4. Hatabu N, Amano N, Mori J, et al. Pubertal Development and Pregnancy Outcomes in 46,XX Patients With Nonclassic Lipoid Congenital Adrenal Hyperplasia [J]. The Journal of clinical endocrinology and metabolism, 2019, 104(5): 1866-70. Burget L, Parera L A, Fernandez-Cancio M, et al. A rare cause of primary adrenal insufficiency due to a homozygous Arg188Cys mutation in the STAR gene [J]. Endocrinology, diabetes & metabolism case reports, 2018, 2018( Wang R, Yu Y, Ye J, et al. 21-hydroxylase deficiency-induced congenital adrenal hyperplasia in 230 Chinese patients: Genotype-phenotype correlation and identification of nine novel mutations [J]. Steroids, 2016, 108(47-55. Xu C, Jia W, Cheng X, et al. Genotype-phenotype correlation study and mutational and hormonal analysis in a Chinese cohort with 21-hydroxylase deficiency [J]. Molecular genetics & genomic medicine, 2019, 7(6): e671. Wilson R C, Mercado A B, Cheng K C, et al. Steroid 21-hydroxylase deficiency: genotype may not predict phenotype [J]. The Journal of clinical endocrinology and metabolism, 1995, 80(8): 2322-9. Ezquieta B, Oliver A, Gracia R, et al. Analysis of steroid 21-hydroxylase gene mutations in the Spanish population [J]. Human genetics, 1995, 96(2): 198-204. Jääskeläinen J, Levo A, Voutilainen R, et al. Population-wide evaluation of disease manifestation in relation to molecular genotype in steroid 21-hydroxylase (CYP21) deficiency: good correlation in a well defined population [J]. The Journal of clinical endocrinology and metabolism, 1997, 82(10): 3293-7. Balsamo A, Baldazzi L, Menabò S, et al. Impact of molecular genetics on congenital adrenal hyperplasia management [J]. Sexual development : genetics, molecular biology, evolution, endocrinology, embryology, and pathology of sex determination and differentiation, 2010, 4(4-5): 233-48. Mooij C F, Parajes S, Pijnenburg-Kleizen K J, et al. Influence of 17-Hydroxyprogesterone, Progesterone and Sex Steroids on Mineralocorticoid Receptor Transactivation in Congenital Adrenal Hyperplasia [J]. Hormone research in paediatrics, 2015, New M I, Abraham M, Gonzalez B, et al. Genotype-phenotype correlation in 1,507 families with congenital adrenal hyperplasia owing to 21-hydroxylase deficiency [J]. Proc Natl Acad Sci U S A, 2013, 110(7): 2611-6. Haider S, Islam B, D'atri V, et al. Structure-phenotype correlations of human CYP21A2 mutations in congenital adrenal hyperplasia [J]. Proc Natl Acad Sci U S A, 2013, 110(7): 2605-10. Ishii T, Kashimada K, Amano N, et al. Clinical guidelines for the diagnosis and treatment of 21-hydroxylase deficiency (2021 revision) [J]. Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology, 2022, 31(3): 116-43. Additional Declarations No competing interests reported. Supplementary Files supplementaryinformationfiles.docx Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 17 May, 2026 Reviewers agreed at journal 11 May, 2026 Reviews received at journal 02 Aug, 2025 Reviewers agreed at journal 24 Jul, 2025 Reviewers invited by journal 17 Jul, 2025 Editor assigned by journal 09 Jul, 2025 Editor invited by journal 20 Jun, 2025 Submission checks completed at journal 18 Jun, 2025 First submitted to journal 18 Jun, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6871714","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":487631985,"identity":"8169a5c8-4588-4d7a-966a-814883caad4c","order_by":0,"name":"Wei Wang","email":"","orcid":"","institution":"Zhongshan City People’s Hospital","correspondingAuthor":false,"prefix":"","firstName":"Wei","middleName":"","lastName":"Wang","suffix":""},{"id":487631986,"identity":"4e1f631c-648e-41b8-8c4b-bcec9ca8ea3a","order_by":1,"name":"Yang Liu","email":"","orcid":"","institution":"Shenzhen Maternity and Child Healthcare 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\u003cstrong\u003ea\u003c/strong\u003e Underdeveloped “phallus” \u003cstrong\u003eb\u003c/strong\u003e.Urethral opening \u003cstrong\u003ec\u003c/strong\u003e.Labia majora-like structures\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6871714/v1/0ccd3a7cf9a5b3b3683a5b22.png"},{"id":87346724,"identity":"75d3c318-7439-45af-9ae9-6af5c3620e96","added_by":"auto","created_at":"2025-07-23 02:30:08","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":646784,"visible":true,"origin":"","legend":"\u003cp\u003eEnhanced magnetic resonance imaging (MRI) scan of the entire abdomen.\u003cstrong\u003eA\u003c/strong\u003e In the sagittal view of the pelvis, the uterus and part of the vagina are visible, while the prostate and male urethral structures are not seen.\u003cstrong\u003eB \u003c/strong\u003eright adrenal tumor, with a cross-sectional size of approximately 42×33 mm.\u003cstrong\u003eC.D \u003c/strong\u003eThe sagittal and axial views show that the size of the uterine fibroid is 187×126mm×178mm.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-6871714/v1/59c04b73d034f6d25a7c2386.png"},{"id":87344724,"identity":"bdb2d72d-cd50-4c0f-a699-df02e1f28c65","added_by":"auto","created_at":"2025-07-23 02:06:08","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":330404,"visible":true,"origin":"","legend":"\u003cp\u003eChromosomal karyotype analysis of peripheral blood\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-6871714/v1/81adaa3fd95c840fc53fd7e0.png"},{"id":87344727,"identity":"ff21aa5f-8f73-4de3-8b1e-c15566cef333","added_by":"auto","created_at":"2025-07-23 02:06:08","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":128197,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSanger sequencing results map.\u003c/strong\u003eA\u003cstrong\u003e CYP21A2 chr6:32006858 Intron2 NM_000500. 9:c.293-13C\u0026gt;G(p.?) reverse sequencing of heterozygous variants. \u003c/strong\u003eB \u003cstrong\u003eCYP21A2 chr6:32007203 Exon4 NM_000500.9:c. 518T\u0026gt;A(p.Ile17 3Asn) foward sequencing of heterozygous variants\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-6871714/v1/1d4d90b2e3ec345525b89125.png"},{"id":87345487,"identity":"603e26c0-2980-4e62-82e3-cea15892fa28","added_by":"auto","created_at":"2025-07-23 02:14:08","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":2348708,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ea\u003c/strong\u003e Postoperative uterus and fibroids; \u003cstrong\u003eb \u003c/strong\u003eHE staining section of endometrium(×100); \u003cstrong\u003ec \u003c/strong\u003eOvarian HE staining sections(×100); \u003cstrong\u003ed\u003c/strong\u003e Fallopian tube HE staining section(×40); \u003cstrong\u003ee \u003c/strong\u003eUterine fibroid HE staining section(×100)\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-6871714/v1/7b85ee1632e933f02d25559b.png"},{"id":87347118,"identity":"dba25bbd-469e-4f43-9ada-0c04f9c6f9a4","added_by":"auto","created_at":"2025-07-23 02:38:10","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":4905128,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6871714/v1/39831d9c-7e65-4b24-bca8-89db585f28c6.pdf"},{"id":87344725,"identity":"e80f9bd5-50d1-4599-8680-e81638155745","added_by":"auto","created_at":"2025-07-23 02:06:08","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":1646415,"visible":true,"origin":"","legend":"","description":"","filename":"supplementaryinformationfiles.docx","url":"https://assets-eu.researchsquare.com/files/rs-6871714/v1/b0c62054e8630c10829a7e54.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"A Rare Case of 45,X[5]/46XX[55] 21-Hydroxylase Deficiency with Female Pseudohermaphroditism and a Giant Uterine Fibroid: Diagnosis and Treatment","fulltext":[{"header":"Introduction","content":"\u003cp\u003eCongenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders of steroidogenesis of the adrenal cortex. 21-Hydroxylase deficiency is the most common form of congenital adrenal hyperplasia (CAH), accounting for over 90% of all CAH cases. 21-Hydroxylase deficiency is caused by mutations in the CYP21A2 gene, which leads to dysfunction of the 21-hydroxylase enzyme. This dysfunction blocks the synthetic pathways of cortisol and mineralocorticoids, resulting in the excessive accumulation of the precursor 17-hydroxyprogesterone (17-OHP) and androgens. This, in turn, triggers a series of clinical symptoms\u003csup\u003e[1-3]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eBased on the degree of enzyme activity deficiency caused by gene mutations and the severity of clinical symptoms, 21-OHD can be categorized into classic and non-classic types\u003cstrong\u003e\u003csup\u003e[4-6]\u003c/sup\u003e\u003c/strong\u003e\u003cstrong\u003e.\u0026nbsp;\u003c/strong\u003ePatients with classic 21-hydroxylase deficiency have higher levels of androgens compared to normal individuals. Starting from intrauterine life, exposure to large amounts of androgens such as testosterone and androstenedione during the critical period of sexual differentiation can cause the external genitalia of genetic females to virilize, resulting in ambiguous genitalia at birth.The simple virilizing type has residual enzyme activity that allows for the secretion of aldosterone, which helps maintain sodium balance. However, the salt-wasting type, which accounts for about 75% of classic cases, cannot produce sufficient aldosterone. Infants with the salt-wasting form face life-threatening salt-wasting crises soon after birth, which can occur as early as within 1 to 4 weeks after birth if left untreated. Patients with 21-hydroxylase deficiency who do not receive appropriate treatment are continuously exposed to high levels of androgens. This can lead to an enlarged penis or further hypertrophy of the clitoris, premature appearance of pubic and axillary hair, and acne. Additionally, children who are chronically exposed to high levels of androgens may experience accelerated growth velocity, advanced bone age, and ultimately fail to reach their expected genetic height.\u003c/p\u003e\n\u003cp\u003eIn 21-hydroxylase deficiency, female fetuses exposed to excessively high levels of androgens in the body between 8 and 12 weeks of gestation may experience masculinization of the external genitalia, resulting in symptoms such as clitoral hypertrophy, labial fusion, and urogenital sinus anomalies\u003csup\u003e[7]\u003c/sup\u003e. However, the internal genitalia still differentiate into normal female internal gonads (uterus and ovaries). If left untreated in a timely manner, this condition can also lead to the premature development of pubic and axillary hair.\u003c/p\u003e"},{"header":"Case Description","content":"\u003cp\u003eThe patient is a 52-year-old unmarried individual who has identified as male for the past 52 years. Over the past nine years, a pelvic mass has been detected, and abdominal distension has been present for two years, gradually worsening with an associated weight loss of 10 pounds. The patient\u0026rsquo;s vital signs include a blood pressure of 120/81 mmHg, a height of 158 cm, and a weight of 55 kg. The patient presents with a male appearance, including an Adam\u0026rsquo;s apple and no breast development \u003cstrong\u003e(Fig 1)\u003c/strong\u003e. The abdomen is distended, with a palpable abdominal mass extending upward to two transverse finger widths below the xiphoid process and downward into the pelvic cavity. The mass is firm, with clear borders, limited mobility, and no tenderness on palpation. No masses are palpable in the bilateral inguinal regions. The patient has pubic hair distributed in a male pattern. A small phallus-like structure is visible, with the urethral opening located on the posterior and inferior side of the mucosa. Additionally, a vaginal opening and bilateral labia majora-like structures are present\u003cstrong\u003e(Fig2)\u003c/strong\u003e. \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eImaging examinations:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e2014 ultrasound examination revealed a solid pelvic mass measuring 106 mm \u0026times;96 mm \u0026times; 67 mm and a mixed-echoic mass above the right kidney measuring 53 mm\u0026times;49 mm. enhanced MRI examination showed: 1.Bilateral adrenal gland changes, suggestive of adrenal cortical hyperplasia. A mass in the right adrenal gland is considered to be a benign tumor-like lesion, most likely an adrenal adenoma.2.Pelvic and external genital changes, suggestive of female pseudo -hermaphroditism: Uterine structures with intramural leiomyoma degeneration are visible within the pelvis; underdeveloped vaginal structures and a phallus are present, with no evidence of ovaries, prostate, seminal vesicles, testes, or spermatic cord structures.3.Gallstones.\u003c/p\u003e\n\u003cp\u003e2023 the whole abdominal enhanced MRI scan show\u003cstrong\u003e(Fig3\u003c/strong\u003e): 1.Bilateral adrenal gland changes, with morphology and size essentially unchanged from the previous findings, are suggestive of adrenal cortical hyperplasia. The right adrenal gland is considered to have an associated adenoma (42 mm\u0026times;33 mm).2.Pelvic and external genital changes, suggestive of female pseudohermaphroditism: Underdeveloped vaginal structures and a phallus are visible, with no evidence of ovaries, prostate, seminal vesicles, testes, or spermatic cord structures. These findings are essentially similar to the previous ones.3.Multiple masses/nodules are visible within the uterine structures in the pelvis, which have increased in number and size compared to the previous findings. These are considered to be multiple leiomyomas with degeneration (the largest measuring approximately 187mm\u0026times;126 mm\u0026times;178 mm).4.Multiple gallstones with chronic cholecystitis.5.A small amount of ascites in the abdominal and pelvic cavities.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePhysical Examination:\u0026nbsp;\u003c/strong\u003eHeight 158 cm, weight 55 kg, generally in good condition, with a typical male appearance, including an Adam\u0026apos;s apple and no breast development. Cardiopulmonary auscultation was unremarkable. The abdomen was distended, with a palpable mass extending up to 2 transverse fingers below the xiphoid process and down into the pelvic cavity. The mass was firm, well-defined, poorly mobile, and non-tender. No inguinal lymphadenopathy was detected bilaterally. Pubic hair was distributed in a male pattern. A small \u0026quot;phallus\u0026quot; was noted, with a urethral orifice on the posterior mucosa and a visible vaginal orifice. Bilateral labial-like structures were also observed. \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLaboratory Investigations:\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1 \u0026nbsp; Baseline laboratory test\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cdiv align=\"\"\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" align=\"\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 221px;\"\u003e\n \u003cp\u003eInspection items\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003eResult\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eTip\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 86px;\"\u003e\n \u003cp\u003eUnit Reference\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 154px;\"\u003e\n \u003cp\u003eRange\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 221px;\"\u003e\n \u003cp\u003eCortisol\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e159.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 86px;\"\u003e\n \u003cp\u003eng/ml\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 154px;\"\u003e\n \u003cp\u003e7-9AM：52.7-224.5\u003c/p\u003e\n \u003cp\u003e3-5PM：34.4-167.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 221px;\"\u003e\n \u003cp\u003eAFP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e1.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 86px;\"\u003e\n \u003cp\u003eng/ml\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 154px;\"\u003e\n \u003cp\u003e0-8.1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 221px;\"\u003e\n \u003cp\u003eTotal prostate-specific antigen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e0.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 86px;\"\u003e\n \u003cp\u003eng/ml\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 154px;\"\u003e\n \u003cp\u003e0.0-4.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 221px;\"\u003e\n \u003cp\u003eHuman epididymis protein 4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e203\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e\u0026darr;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 86px;\"\u003e\n \u003cp\u003epmol/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 154px;\"\u003e\n \u003cp\u003e34.72-114.90\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 221px;\"\u003e\n \u003cp\u003eAnti-Mullerian hormone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e\u0026lt;0.0098\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e\u0026darr;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 86px;\"\u003e\n \u003cp\u003eng/mL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 154px;\"\u003e\n \u003cp\u003e2.150--10.100\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 221px;\"\u003e\n \u003cp\u003e\u0026nbsp;Luteinizing hormone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e3.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 86px;\"\u003e\n \u003cp\u003emIU/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 154px;\"\u003e\n \u003cp\u003e1. 5 9. 3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 221px;\"\u003e\n \u003cp\u003eTestosterone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e214.8\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 86px;\"\u003e\n \u003cp\u003eng/dl\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 154px;\"\u003e\n \u003cp\u003e187.72-694.19\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 221px;\"\u003e\n \u003cp\u003eProgesterone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e32.47\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e\u0026uarr;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 86px;\"\u003e\n \u003cp\u003emmol/l\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 154px;\"\u003e\n \u003cp\u003e0.39-3.98\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 221px;\"\u003e\n \u003cp\u003eFollicle-stimulating hormone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e9.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 86px;\"\u003e\n \u003cp\u003emIU/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 154px;\"\u003e\n \u003cp\u003e1.4-14.81\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 221px;\"\u003e\n \u003cp\u003eProlactin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e11.5 \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 86px;\"\u003e\n \u003cp\u003eng/ml\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 154px;\"\u003e\n \u003cp\u003e2.1-17.7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 221px;\"\u003e\n \u003cp\u003eEstradiol\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e36.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 86px;\"\u003e\n \u003cp\u003epg/ml\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 154px;\"\u003e\n \u003cp\u003e0.0-39.8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 221px;\"\u003e\n \u003cp\u003eAldosterone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e237.88\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 86px;\"\u003e\n \u003cp\u003ePg/ml\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 154px;\"\u003e\n \u003cp\u003eLying：10.0-160.0\u003c/p\u003e\n \u003cp\u003eStanding：40.0-310\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 221px;\"\u003e\n \u003cp\u003e17\u0026alpha;-Hydroxyprogesterone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e117.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e\u0026uarr;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 86px;\"\u003e\n \u003cp\u003eng/ml\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 154px;\"\u003e\n \u003cp\u003eMale 0.31-2.01\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 221px;\"\u003e\n \u003cp\u003eDehydroepiandrosterone Sulfate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e905.51\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e\u0026uarr;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 86px;\"\u003e\n \u003cp\u003eug/dl\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 154px;\"\u003e\n \u003cp\u003e44.67-347.34\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 221px;\"\u003e\n \u003cp\u003eDihydrotestosterone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e691.64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e\u0026uarr;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 86px;\"\u003e\n \u003cp\u003epg/ml\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 154px;\"\u003e\n \u003cp\u003eMale 143.00-842\u003c/p\u003e\n \u003cp\u003eFemale 0.00-431\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 221px;\"\u003e\n \u003cp\u003eNa\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e135\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 86px;\"\u003e\n \u003cp\u003emmol/l\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 154px;\"\u003e\n \u003cp\u003e137-147\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 221px;\"\u003e\n \u003cp\u003eK\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e4.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 86px;\"\u003e\n \u003cp\u003emmol/l\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 154px;\"\u003e\n \u003cp\u003e3.5-5.3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 221px;\"\u003e\n \u003cp\u003eThyroid Stimulating Hormone(TSH)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e2.602\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 86px;\"\u003e\n \u003cp\u003euIU/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 154px;\"\u003e\n \u003cp\u003e0.55-4.78\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 221px;\"\u003e\n \u003cp\u003eFree Triiodothyronine（FT4）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e4,62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 86px;\"\u003e\n \u003cp\u003epmol/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 154px;\"\u003e\n \u003cp\u003e3.5-6.5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 221px;\"\u003e\n \u003cp\u003eFree Thyroxine（FT3）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e16.27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 86px;\"\u003e\n \u003cp\u003epmol/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 154px;\"\u003e\n \u003cp\u003e11.5-22.7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 221px;\"\u003e\n \u003cp\u003eAndrostenedione\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e47.45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e\u0026uarr;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 86px;\"\u003e\n \u003cp\u003enmol/l\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 154px;\"\u003e\n \u003cp\u003e1.75-7.68\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eChromosomal karyotype analysis of peripheral blood:45,X[5]/46,XX[55] (\u003cstrong\u003eFig4\u003c/strong\u003e),Suggesting Tuner syndrome mosaicism\u003c/p\u003e\n\u003cp\u003eGenetic testing for 21-hydroxylase deficiency (CYP21A2 gene) indicated compound heterozygous pathogenic variants c.293-13C/A\u0026gt;G(12G) and c. 518T\u0026gt;A(p.Ile173Asn) in the CYP21A2 gene(Fig5)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical Management:\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe patient has elevated levels of 17-hydroxyprogesterone, androstenedione, and dehydroepiandrosterone sulfate (DHEAS). Imaging studies suggest adrenal hyperplasia, with the right side possibly complicated by an adenoma.\u003cstrong\u003eChromosomal karyotype analysis revealed a 45,XX[5]/46,XX[55] pattern,\u003c/strong\u003e \u003cstrong\u003eMale genital appearance,\u0026nbsp;\u003c/strong\u003eGenetic testing for 21-hydroxylase deficiency (CYP21A2) revealed compound heterozygous mutations of c.293-13C/A\u0026gt;G and c.518T\u0026gt;A. These findings are consistent with a diagnosis of the simple virilizing form of 21-hydroxylase deficiency.\u0026nbsp;After the patient was hospitalized, she had no intention to change her gender and external genitalia, and requested to solve the pelvic mass problem. After consultation with the endocrinology, urology, and gynecology departments, it was recommended to treat the pelvic mass first and then the adrenal gland problem, and then further follow-up with the endocrinology department.Under general anesthesia with endotracheal intubation, the patient underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy. The uterus and fibroids removed are shown in the figure\u003cstrong\u003e（\u003c/strong\u003e\u003cstrong\u003eFig6a).\u003c/strong\u003ePathological examination of the uterus, uterine fibroids, ovaries, and fallopian tubes(\u003cstrong\u003eFig6b.c.d\u003c/strong\u003e)\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eThis case report details a rare presentation of female pseudo- hermaphroditism with a 45,X[5]/46,XX[55] karyotype, resulting from 21- hydroxylase deficiency and complicated by a giant uterine fibroid. The key findings include the identification of compound heterozygous pathogenic variants in the CYP21A2 gene (c.293-13C\u0026gt;G and c.518T\u0026gt;A), elevated androgen levels, and significant anatomical anomalies such as a small phallus and a large uterine fibroid.\u003c/p\u003e\n\u003cp\u003e21-hydroxylase deficiency (21-OHD) is the most common form of congenital adrenal hyperplasia (CAH) and is caused by mutations in the CYP21A2 gene, which encodes the 21-hydroxylase enzyme (P450c21). To date, nearly 300 different mutations in the CYP21A2 gene have been reported\u003csup\u003e[8, 9]\u003c/sup\u003e. Among these, the mutations c.293-13C\u0026gt;G (I2G), c.518T\u0026gt;A (p.I173N), and c.92C\u0026gt;T (p.P31L) are the most prevalent in Chinese patients with 21-OHD\u003csup\u003e[10]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eClassic 21-hydroxylase deficiency manifests as either the salt-wasting type or the simple virilizing type. Research has demonstrated a correlation between the types of CYP21A2 gene mutations and clinical phenotypes, which depends on the residual 21-hydroxylase activity and the specific combination of mutations\u003csup\u003e[11]\u003c/sup\u003e. Approximately 65%\u0026ndash;75% of patients with 21-hydroxylase deficiency have a compound heterozygous mutation genotype\u003csup\u003e[12-14]\u003c/sup\u003e. The clinical phenotype is related to the residual enzyme activity, which in turn is associated with the severity of the pathogenic mutations.If the mutations in the CYP21A2 gene result in a complete loss of 21-hydroxylase activity, the salt-wasting type is typically observed\u003csup\u003e[15]\u003c/sup\u003e. The c.293-13C\u0026gt;G (I2G) mutation carried by our patient is believed to produce a small amount of normally spliced mRNA, thereby mitigating the degree of enzyme activity deficiency. This mutation has been identified in patients with both salt-wasting and simple virilizing phenotypes. Additionally, some studies have suggested that the excessive accumulation of 17-hydroxyprogesterone (17-OHP) and progesterone can partially bind to and activate the mineralocorticoid receptor, compensating for aldosterone deficiency and resulting in a less severe salt-wasting phenotype\u003csup\u003e[16]\u003c/sup\u003e.The point mutation c.518T\u0026gt;A (p.I173N) is relatively common and has been shown to reduce enzyme activity to 2% in vitro, typically resulting in the simple virilizing phenotype \u003csup\u003e[17, 18]\u003c/sup\u003e. Therefore, our patient primarily presents with the simple virilizing phenotype.\u003c/p\u003e\n\u003cp\u003eFemales with the simple virilizing type of 21-OHD are usually diagnosed in the neonatal period or during childhood. For treatment, the current consensus is that 46,XX patients assigned male at birth should be raised as females if diagnosed at \u0026le;2 years of age, with timely estrogen and progesterone supplementation during puberty to promote sexual maturation, maintain secondary sexual characteristics, induce menstruation, and increase bone mass \u003csup\u003e[19]\u003c/sup\u003e. For those diagnosed after 2 years of age, a cautious, multifactorial decision should be made.\u003c/p\u003e\n\u003cp\u003eHowever, this patient was not diagnosed until the age of 52, missing the optimal treatment window. The patient\u0026rsquo;s height is 158 cm, below the average for Chinese men. The current treatment goals focus on managing the large uterine fibroids and adrenal tumors, preventing adrenal crisis, and controlling excessive adrenal androgen secretion. Glucocorticoid therapy will be considered based on subsequent clinical findings, with the aim of improving the patient\u0026rsquo;s quality of life\u003csup\u003e[19]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eThis case highlights the potential for 21-hydroxylase deficiency to be overlooked or misdiagnosed in clinical practice. It underscores the need for further research to improve early diagnosis rates. Future studies should focus on early detection through newborn screening, hormone testing, and genetic analysis to enhance patient outcomes.Moreover, this case emphasizes the importance of multidisciplinary comprehensive treatment. Collaboration among endocrinology, genetics, and surgery is crucial. For example, the endocrinology department confirms the diagnosis through hormone testing and genetic analysis, while the surgical department alleviates symptoms by removing uterine fibroids and ovaries. The psychiatry department assesses the patient\u0026rsquo;s physiological and psychological needs and devises individualized treatment plans.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study adhered to the principles of the Declaration of Helsinki, ensuring that all research procedures complied with ethical standards.\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003ePatient consent statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003epatient gave written informed consent for their personal or clinical details along with any identifying images to be published in this study. \u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eData Availability Statement \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data supporting the findings of this study are not publicly available due to privacy or ethical restrictions.\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eConflicts of Interest \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflicts of interest.\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research was supported by the Sanming Project of Medicine in Shenzen Municipality (SZSM202311005) \u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eAuthor Contribution Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eWei Wang:\u003c/strong\u003e data collection, data analysis, result interpretation,article writing; \u003cstrong\u003eYang Liu/Hui Wang\u003c/strong\u003e\u003cstrong\u003e：\u003c/strong\u003edata collection; \u003cstrong\u003eCaiqun Luo: \u003c/strong\u003edata collectiondata analysis ,result interpretation,article writing and publication.\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eAcknowledgments \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank all the participants in the study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eMerke D P, Auchus R J. Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency [J]. The New England journal of medicine, 2020, 383(13): 1248-61.\u003c/li\u003e\n\u003cli\u003eHiga M, Zaha A, Takushi A, et al. Novel STAR gene variant in a patient with classic lipoid congenital adrenal hyperplasia and combined pituitary hormone deficiency [J]. Human genome variation, 2021, 8(1): 6.\u003c/li\u003e\n\u003cli\u003eBizzarri C, Pisaneschi E, Mucciolo M, et al. Lipoid congenital adrenal hyperplasia by steroidogenic acute regulatory protein (STAR) gene mutation in an Italian infant: an uncommon cause of adrenal insufficiency [J]. Italian journal of pediatrics, 2017, 43(1): 57.\u003c/li\u003e\n\u003cli\u003eBose H S, Sugawara T, Strauss J F, et al. The pathophysiology and genetics of congenital lipoid adrenal hyperplasia [J]. The New England journal of medicine, 1996, 335(25): 1870-8.\u003c/li\u003e\n\u003cli\u003eMiller W L. Congenital lipoid adrenal hyperplasia: the human gene knockout for the steroidogenic acute regulatory protein [J]. Journal of molecular endocrinology, 1997, 19(3): 227-40.\u003c/li\u003e\n\u003cli\u003eMizuno Y, Ishii T, Hasegawa T. In Vivo Verification of the Pathophysiology of Lipoid Congenital Adrenal Hyperplasia in the Adrenal Cortex [J]. Endocrinology, 2019, 160(2): 331-8.\u003c/li\u003e\n\u003cli\u003eWhite P C. Ontogeny of adrenal steroid biosynthesis: why girls will be girls [J]. The Journal of clinical investigation, 2006, 116(4): 872-4.\u003c/li\u003e\n\u003cli\u003eHatabu N, Amano N, Mori J, et al. Pubertal Development and Pregnancy Outcomes in 46,XX Patients With Nonclassic Lipoid Congenital Adrenal Hyperplasia [J]. The Journal of clinical endocrinology and metabolism, 2019, 104(5): 1866-70.\u003c/li\u003e\n\u003cli\u003eBurget L, Parera L A, Fernandez-Cancio M, et al. A rare cause of primary adrenal insufficiency due to a homozygous Arg188Cys mutation in the STAR gene [J]. Endocrinology, diabetes \u0026amp; metabolism case reports, 2018, 2018(\u003c/li\u003e\n\u003cli\u003eWang R, Yu Y, Ye J, et al. 21-hydroxylase deficiency-induced congenital adrenal hyperplasia in 230 Chinese patients: Genotype-phenotype correlation and identification of nine novel mutations [J]. Steroids, 2016, 108(47-55.\u003c/li\u003e\n\u003cli\u003eXu C, Jia W, Cheng X, et al. Genotype-phenotype correlation study and mutational and hormonal analysis in a Chinese cohort with 21-hydroxylase deficiency [J]. Molecular genetics \u0026amp; genomic medicine, 2019, 7(6): e671.\u003c/li\u003e\n\u003cli\u003eWilson R C, Mercado A B, Cheng K C, et al. Steroid 21-hydroxylase deficiency: genotype may not predict phenotype [J]. The Journal of clinical endocrinology and metabolism, 1995, 80(8): 2322-9.\u003c/li\u003e\n\u003cli\u003eEzquieta B, Oliver A, Gracia R, et al. Analysis of steroid 21-hydroxylase gene mutations in the Spanish population [J]. Human genetics, 1995, 96(2): 198-204.\u003c/li\u003e\n\u003cli\u003eJ\u0026auml;\u0026auml;skel\u0026auml;inen J, Levo A, Voutilainen R, et al. Population-wide evaluation of disease manifestation in relation to molecular genotype in steroid 21-hydroxylase (CYP21) deficiency: good correlation in a well defined population [J]. The Journal of clinical endocrinology and metabolism, 1997, 82(10): 3293-7.\u003c/li\u003e\n\u003cli\u003eBalsamo A, Baldazzi L, Menab\u0026ograve; S, et al. Impact of molecular genetics on congenital adrenal hyperplasia management [J]. Sexual development : genetics, molecular biology, evolution, endocrinology, embryology, and pathology of sex determination and differentiation, 2010, 4(4-5): 233-48.\u003c/li\u003e\n\u003cli\u003eMooij C F, Parajes S, Pijnenburg-Kleizen K J, et al. Influence of 17-Hydroxyprogesterone, Progesterone and Sex Steroids on Mineralocorticoid Receptor Transactivation in Congenital Adrenal Hyperplasia [J]. Hormone research in paediatrics, 2015, \u003c/li\u003e\n\u003cli\u003eNew M I, Abraham M, Gonzalez B, et al. Genotype-phenotype correlation in 1,507 families with congenital adrenal hyperplasia owing to 21-hydroxylase deficiency [J]. Proc Natl Acad Sci U S A, 2013, 110(7): 2611-6.\u003c/li\u003e\n\u003cli\u003eHaider S, Islam B, D\u0026apos;atri V, et al. Structure-phenotype correlations of human CYP21A2 mutations in congenital adrenal hyperplasia [J]. Proc Natl Acad Sci U S A, 2013, 110(7): 2605-10.\u003c/li\u003e\n\u003cli\u003eIshii T, Kashimada K, Amano N, et al. Clinical guidelines for the diagnosis and treatment of 21-hydroxylase deficiency (2021 revision) [J]. Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology, 2022, 31(3): 116-43.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-endocrine-disorders","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bend","sideBox":"Learn more about [BMC Endocrine Disorders](http://bmcendocrdisord.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bend/default.aspx","title":"BMC Endocrine Disorders","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"45, X[5]/46XX[55], 21-Hydroxylase Deficiency, female pseudohermaphroditism, giant uterine fibroid","lastPublishedDoi":"10.21203/rs.3.rs-6871714/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6871714/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eBackgroud\u003c/b\u003e: In patients with 21-hydroxylase deficiency, the compensatory elevation of aldosterone levels can lead to increased androgen production. This excess of androgens can result in virilization, manifesting as male-like physical characteristics in genetic females and giving rise to the condition known as female pseudohermaphroditism.\u003c/p\u003e\u003cp\u003e\u003cb\u003eCase Presentation\u003c/b\u003e: This article reports a case of a 52-year-old patient who identifies as male, presenting with a small phallus. The patient sought medical attention due to the discovery of a giant uterine fibroid, which was also complicated by an adrenal tumor, elevated 17-hydroxyprogesterone, androstenedione, dehydroepiandrosterone sulfate. Chromosomal karyotype analysis revealed a 45,XX[5]/46,XX[55] pattern, Male genital appearance, Genetic testing for 21-hydroxylase deficiency (CYP21A2 gene) indicated compound heterozygous pathogenic variants c.293\u0026minus;13C/A\u0026thinsp;\u0026gt;\u0026thinsp;G and c.518T\u0026thinsp;\u0026gt;\u0026thinsp;A in the CYP21A2 gene, he simple virilizing form of 21-hydroxylase deficiency was diagnosed. The patient underwent total hysterectomy and bilateral salpingo-oophorectomy.\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusion\u003c/b\u003e: This case highlights the complexity of 21-hydroxylase deficiency, a condition that can lead to significant endocrine and anatomical anomalies. The compensatory elevation of aldosterone levels in such patients often results in increased androgen production, which can cause virilization and the development of male-like physical characteristics in genetic females, leading to male female pseudohermaphroditism.This case underscores the importance of a multidisciplinary approach in managing such rare and complex conditions, involving endocrinology, genetics, and surgery. It also highlights the need for comprehensive genetic testing and hormonal evaluation to guide appropriate treatment and improve patient outcomes.\u003c/p\u003e","manuscriptTitle":"A Rare Case of 45,X[5]/46XX[55] 21-Hydroxylase Deficiency with Female Pseudohermaphroditism and a Giant Uterine Fibroid: Diagnosis and Treatment","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-23 02:06:03","doi":"10.21203/rs.3.rs-6871714/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2026-05-17T13:49:24+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"89541517778076112425549030737981431251","date":"2026-05-11T08:55:30+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-03T00:36:13+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"244097311013959709016671537219224566159","date":"2025-07-24T12:47:01+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-07-17T12:36:08+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-07-09T09:20:44+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-06-20T07:14:50+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-06-18T13:07:37+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Endocrine Disorders","date":"2025-06-18T11:53:42+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-endocrine-disorders","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bend","sideBox":"Learn more about [BMC Endocrine Disorders](http://bmcendocrdisord.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bend/default.aspx","title":"BMC Endocrine Disorders","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"cc79adfb-4087-4dab-aa75-981fa0b1d7bc","owner":[],"postedDate":"July 23rd, 2025","published":true,"recentEditorialEvents":[{"type":"editorInvitedReview","content":"","date":"2026-05-17T13:49:24+00:00","index":95,"fulltext":""},{"type":"reviewerAgreed","content":"89541517778076112425549030737981431251","date":"2026-05-11T08:55:30+00:00","index":87,"fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2025-07-23T02:06:03+00:00","versionOfRecord":[],"versionCreatedAt":"2025-07-23 02:06:03","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6871714","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6871714","identity":"rs-6871714","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}