A Patient with 45 X/46, XY/47, XYY Mosaic Turner Syndrome with Virilization: A Case Report

A Patient with 45 X/46, XY/47, XYY Mosaic Turner Syndrome with Virilization: A Case Report | 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 Patient with 45 X/46, XY/47, XYY Mosaic Turner Syndrome with Virilization: A Case Report Natchanika Sinthuchai, Sinee Wanishpongpan, Phumin Wongsuwan, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3823439/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Mosaic Turner accounts for nearly half of all Turner syndrome cases and results in a broadened clinical spectrum. Case: A 26-year-old female patient presented with a pelvic mass associated with signs of virilization and Turner stigmata. Conventional karyotype testing (G-banding method) revealed 46, XY; however, a further FISH (fluorescence in situ hybridization) study showed mosaicism of 45, X/46, XY/47, XYY. The patient underwent bilateral gonadectomy with comprehensive surgical staging, and histopathology revealed a yolk sac tumor. Discussion This case highlights an uncommon presentation of mosaic Turner syndrome. Further diagnostic tests in patients with signs of Turner syndrome are encouraged to achieve an accurate diagnosis and inform appropriate treatment. Figures Figure 1 Figure 2 INTRODUCTION Sex chromosome mosaicism can lead to considerable phenotypic variability [ 1 ]. Mosaicism containing the 45, X karyotype in phenotypic females with Turner stigmata is indicative of Turner syndrome, which accounts for nearly half of all Turner syndrome cases [ 2 ]. Turner stigmata consist of characteristics unique to Turner syndrome, such as a webbed neck and short stature. Based on the consensus statement regarding differences in sex development disorder (DSD) management, genotype is the most important factor for diagnosis and classification. Hence, the provisional impression in this case was 46, XY with undervirilization (disorders of androgen synthesis or action [ 3 ]. However, the patient presented with both Turner stigmata and clitoromegaly such that the initial diagnosis was inconsistent with the clinical presentation. Therefore, further investigation was strongly suggested. Accurate diagnosis is crucial for individualized management, genetic counseling, discussion of fertility issues, and risk management of malignant gonadal transformation. CASE PRESENTATION A 26-year-old nulliparous woman was referred to our tertiary hospital after a large pelvic mass was discovered during an appendectomy at a secondary hospital. The patient had menarche at 17 years of age, with regular menstruation during the first year. She then began using the injectable contraception medroxyprogesterone acetate (150 mg) intramuscularly every 12 weeks for a year. However, even after discontinuing contraception, menstruation never resumed. Her family history could not be obtained since she was adopted. Examination revealed a short stature with a height of 145 cm and weight of 56 kg. The patient’s voice appeared to be deepened, and breast and pubic hair development were in Tanner stages 1 and 5, respectively. Genital examination revealed clitoromegaly, with clitoral length of 3 cm (Fig. 1 ), and atrophic vaginal mucosa. The examination also revealed a webbed neck, a broad chest, and wide-spaced nipples. Other systemic examination results were unremarkable. Sonographic examination revealed a small uterus with a midline solid cystic mass posterior to the uterus. Abdominal CT showed a large heterogeneous pelvic mass with rim calcification measuring 8.1 × 8.8 × 8.6 cm without visualization of both ovaries and the right kidney. Laboratory studies showed ovarian insufficiency with a follicle-stimulating hormone level of 76 IU/mL, total testosterone level of 11 ng/dL, estradiol level of 19 pg/mL, dehydroepiandrosterone sulfate level of 198 µg/dL, and 17-hydroxy progesterone level of 0.33 ng/mL. Thyroid function, HbA1C, and liver function values were within normal limits. Chromosomal analysis of peripheral blood (GTG-banding) showed a 46, XY karyotype (25 metaphases). Although the karyotype was consistent with 46, XY DSD, mosaicism was suspected due to Turner stigmata. A 50-metaphase chromosomal analysis from peripheral blood was performed, but mosaicism was not revealed. A subsequent FISH analysis probing for the SRY and X centromere was performed and showed 45, X of 27.51%, 46, XY of 41.92%, and 46, XYY of 30.57%, consistent with a diagnosis of mosaic Turner syndrome. As tumor markers showed increased alpha fetoprotein levels (76,489 ng/mL), a germ cell tumor was suspected. The patient underwent bilateral gonadectomy with comprehensive surgical staging. Intraoperative findings included a small uterus with a left gonadal tumor, normal fallopian tubes, and a right streak gonad. Postoperative chemotherapy and estrogen replacement therapy (17β- estradiol gel, 2.5 g per day) with cyclic progestins were prescribed. Echocardiography, audiography, and dual-energy X-ray absorptiometry scans were also scheduled. The histology of the left ovary was consistent with a yolk sac tumor comprised of tumor cells arranged in microcystic, solid, hepatoid, and polyvesicular vitelline patterns in the background of necrosis and peripheral calcification. Schiller–Duval bodies were also noted. The tumor cells showed diffuse positivity for alpha fetoprotein. Furthermore, right ovary histology showed nests of small, dark sex cord cells, germ cells with enlarged vesicular nuclei and clear cytoplasm, and a hyalinized basement membrane, consistent with a gonadoblastoma (Fig. 2 ). The periphery of the mass consisted of ovarian fibrothecomatous cells, hyalinized seminiferous tubules, scattered Leydig cells, and fibroadipose tissue, which were suggestive of gonadal dysgenesis. DISCUSSION Turner syndrome is diagnosed in phenotypic females with a karyotype containing one X chromosome and complete or partial absence of the second sex chromosome [ 2 ]. This case emphasizes the need for thorough evaluation of patients presenting with Turner stigmata. Our patient had signs of hyperandrogenism, such as clitoromegaly and deepened voice, consistent with an initial assessment of conventional karyotype 46, XY. However, if we had disregarded the presence of Turner stigmata, the patient may have remained misdiagnosed, resulting in missed screenings for conditions associated with Turner syndrome such as gonadal malignancy [ 4 ]. It is vital to perform a thorough clinical evaluation, as different DSDs can have overlapping phenotypes [ 5 ] At least 10% of patients with Turner syndrome, for example, manifest Y chromosome material [ 2 ], and the clinical appearance of patients with positive Y material can be very similar to those without Y chromosome material. Our patient presented with 46, X/46, XY/47, XYY, which is a rare karyotype with no previously reported incidence of Turner syndrome. Earlier cases of this karyotype have shown dissimilar presentations such as male infertility [ 6 ] and gonadoblastoma in a phenotypic female without Turner stigmata [ 7 ]. Another case of mosaicism was reported in an older adult man with short stature, exostoses, brachydactyly, and gynecomastia [ 8 ]. There are no specific lower limit percentages of 45, X for the diagnosis of Turner syndrome. Generally, 5% can be used for patients under 50 years of age [ 2 ]. According to the American College of Medical Genetics, if Turner syndrome is suspected, a minimum 30-cell karyotype should be assessed, as this can identify at least 10% mosaicism with 95% confidence in peripheral blood [ 9 ]. If standard blood karyotyping fails to reveal mosaicism, a cytogenetic study of secondary tissue, such as skin biopsy for cell culture or buccal smear for FISH, should be considered for individuals with suspected Turner syndrome [ 9 ]. Of note is that 5% and 1% mosaicism with 95% confidence can be detected if ≥ 59 and ≥ 299 metaphases respectively, are analyzed [ 10 ]; for FISH, a minimum of 200 interphase cells should be assessed using X and Y centromere probes [ 9 ]. In this case, the standard 25-cell karyotype from peripheral blood was assessed initially, revealing a 46, XY karyotype. However, due to the presence of Turner stigmata, chromosomal mosaicism was suspected. We proceeded to 50 metaphases from peripheral blood, which again failed to detect mosaicism. Therefore, FISH was performed for SRY and X centromeres from peripheral blood, with results showing 45, X of 27.51%, 46, XY of 41.92%, and 46, XYY of 30.57%. Stemming from laboratory limitations and the patient’s refusal for referral to a specialty center given financial constraints, karyotyping of non-blood specimens was not performed. There may be different proportions of mosaicism in different tissues [ 11 , 12 ] Gonadectomy is recommended in female individuals with Y chromosome material because of increased risk of gonadoblastoma, the incidence of which is around 30% in patients with gonadal dysgenesis and varies as 4–60% in patients with Turner syndrome who have Y material [ 2 ]. As the condition is predisposed to the development of malignant germ cell tumors, gonadectomy should be performed early in order to prevent malignant transformation. Our patient also received fertility counseling, opting to keep her uterus in case of future pregnancy. Comprehensive surgical staging of bilateral salpingo-oophorectomy was performed. Although the patient’s uterus was small, it was not a contraindication for pregnancy, as the size likely resulted from a low estrogenic state [ 4 , 13 ]. Patients with Turner syndrome of any karyotype are advised to undergo general surveillance management [ 2 ]. Our patient was prescribed estrogen replacement therapy after gonadectomy, to continue until the time of natural menopause, for maintenance of bone health and cardiovascular risk reduction. Furthermore, as the uterus was kept, oral progestin was prescribed to reduce the risk of endometrial hyperplasia [ 13 ]. Multidisciplinary care was chosen to optimize patient care and psychosocial support. This case highlights the importance of evaluating patients with Turner stigmata for Turner syndrome. Due to the frequency of low-level mosaicism, further tests, such as those on non-blood specimens or via different methods such as FISH, should be conducted, as specific screening and treatments are not possible without an accurate diagnosis. This case also illustrates the significance of early gonadectomy in females with Y chromosome material because of the risk of malignant transformation. When treating patients with sex chromosome atypicality, a multidisciplinary team approach is recommended to facilitate appropriate discussions concerning sex assignment, hormonal therapy, associated metabolic disorders, fertility, and psychosocial support. Declarations Conflicts of Interest The authors declare that they have no conflict of interest. Funding Statement This research did not receive any specific grants from funding agencies in the public, commercial, or not-for-profit sectors. Acknowledgements We would like to thank Dr. Suthinee Saluckpetch, Dr. Sunisa Kannawat, and Dr. Vasinee Sukchalermchai for their contributions to patient care. We would like to thank Editage (www.editage.com) for English language editing. Informed consent: The patient provided written informed consent for the disclosure of relevant history, medical information, and images. To protect her privacy, her identity is maintained as confidential. References Kamel AK, Abd El-Ghany HM, Mekkawy MK, Makhlouf MM, Mazen IM, El Dessouky N, et al. Sex chromosome mosaicism in the gonads of DSD patients: a karyotype/phenotype correlation. Sex Dev. 2015 Dec;9:279–88. Gravholt CH, Andersen NH, Conway GS, Dekkers OM, Geffner ME, Klein KO, et al. Clinical practice guidelines for the care of girls and women with Turner syndrome: proceedings from 2016 Cincinnati International Turner Syndrome Meeting. Eur J Endocrinol. 2017 Sep;177:G1–G70. Cools M, Nordenström A, Robeva R, Hall J, Westerveld P, Flück C, et al. Caring for individuals with a difference of sex development (DSD): a consensus statement. Nat Rev Endocrinol. 2018 May;14:415–29. Rasouli M, McDaniel K, Awadalla M, Chung K. Mosaic turner syndrome presenting with a 46, XY karyotype. Case Rep Obstet Gynecol. 2019 Apr;3719178:1–3. León NY, Reyes AP, Harley VR. A clinical algorithm to diagnose differences of sex development. Lancet Diabetes Endocrinol. 2019 Feb;7:560–74. Bulakbasi T, Sahin F, Maz Yil Z, Zeyneloglu H. A 45, X/47, XYY/46, XY karyotype and Y chromosome microdeletion in an infertile male. Balk J Med Genet. 2008 Nov;11:51–4. Osztovics M, Ivády G, Ruzicska P, Bühler EM, Király L. 45,X/46,XY/47,XYY mosaicism in a phenotypic female with gonadoblastoma. Acta Paediatr Acad Sci Hung. 1974;15:295–9. Monastirli A, Stephanou G, Georgiou S, Andrianopoulos C, Pasmatzi E, Tsambaos D, et al. Short stature, type E brachydactyly, exostoses, gynecomastia, and cryptorchidism in a patient with 47, XYY/45, X/46, XY mosaicism. Am J Med Sci. 2005 Apr;329:208–10. Wolff DJ, Van Dyke DL, Powell CM, Working Group of the ACMG Laboratory Quality Assurance Committee. Laboratory guideline for Turner syndrome. Genet Med. 2010 Jan;12:52–5. Hook EB. Exclusion of chromosomal mosaicism: tables of 90%, 95% and 99% confidence limits and comments on use. Am J Hum Genet. 1977 Jan;29:94–7. Bianco B, Lipay MV, Melaragno MI, Guedes AD, Verreschi IT. Detection of hidden Y mosaicism in Turner’s syndrome: importance in the prevention of gonadoblastoma. J Pediatr Endocrinol Metab. 2006 Sep;19:1113–7. Leng XF, Lei K, Li Y, Tian F, Yao Q, Zheng QM, et al. Gonadal dysgenesis in Turner syndrome with Y-chromosome mosaicism: two case reports. World J Clin Cases. 2020 Nov;8:5737–43. Klein KO, Rosenfield RL, Santen RJ, Gawlik AM, Backeljauw PF, Gravholt CH, et al. Estrogen replacement in Turner syndrome: literature review and practical considerations. J Clin Endocrinol Metab. 2018 May;103:1790–1803. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-3823439","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":265106081,"identity":"8c1e4e86-45da-4395-a38a-9035d8c1ab5b","order_by":0,"name":"Natchanika Sinthuchai","email":"data:image/png;base64,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","orcid":"","institution":"Harvard T.H. Chan School of Public Health","correspondingAuthor":true,"prefix":"","firstName":"Natchanika","middleName":"","lastName":"Sinthuchai","suffix":""},{"id":265106082,"identity":"c976cd11-4bc8-4b30-a78a-4c61c21fa251","order_by":1,"name":"Sinee Wanishpongpan","email":"","orcid":"","institution":"Nakhon Pathom Hospital","correspondingAuthor":false,"prefix":"","firstName":"Sinee","middleName":"","lastName":"Wanishpongpan","suffix":""},{"id":265106083,"identity":"b559943b-839d-4b9c-86ff-b5ed2ba60015","order_by":2,"name":"Phumin Wongsuwan","email":"","orcid":"","institution":"Nakhon Pathom Hospital","correspondingAuthor":false,"prefix":"","firstName":"Phumin","middleName":"","lastName":"Wongsuwan","suffix":""},{"id":265106084,"identity":"55224a0a-0600-4afa-a8b5-878a28c0a0cd","order_by":3,"name":"Jarika Vatrasresth","email":"","orcid":"","institution":"King Chulalongkorn Memorial Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jarika","middleName":"","lastName":"Vatrasresth","suffix":""},{"id":265106085,"identity":"a17555a6-8dab-4628-99f2-a9aa944ed28c","order_by":4,"name":"Ammarin Suwan","email":"","orcid":"","institution":"King Chulalongkorn Memorial Hospital","correspondingAuthor":false,"prefix":"","firstName":"Ammarin","middleName":"","lastName":"Suwan","suffix":""}],"badges":[],"createdAt":"2023-12-30 07:44:14","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3823439/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3823439/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":49242678,"identity":"bf7eb0b6-f082-4320-ac20-3d9b4298379a","added_by":"auto","created_at":"2024-01-05 18:31:22","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":292436,"visible":true,"origin":"","legend":"\u003cp\u003eExternal genitalia with clitoromegaly\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-3823439/v1/d8537fbb19844f61234defe7.png"},{"id":49242680,"identity":"bbda5140-64ad-4d95-b86c-1bbecc1b18e1","added_by":"auto","created_at":"2024-01-05 18:31:23","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":4352349,"visible":true,"origin":"","legend":"\u003cp\u003e(Left) Histology from the right ovary and (Right) histology from the periphery of the right ovary (both H\u0026amp;E, ×100 magnification)\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-3823439/v1/a4b4157cc60099448d20dd31.png"},{"id":60665169,"identity":"555a6f0e-4e64-4dd4-a6a9-5ea90e97ee35","added_by":"auto","created_at":"2024-07-19 09:14:34","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":4437688,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3823439/v1/d20cfebd-35dc-4b07-8a98-816beca6013a.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"A Patient with 45 X/46, XY/47, XYY Mosaic Turner Syndrome with Virilization: A Case Report","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eSex chromosome mosaicism can lead to considerable phenotypic variability [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Mosaicism containing the 45, X karyotype in phenotypic females with Turner stigmata is indicative of Turner syndrome, which accounts for nearly half of all Turner syndrome cases [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Turner stigmata consist of characteristics unique to Turner syndrome, such as a webbed neck and short stature.\u003c/p\u003e \u003cp\u003eBased on the consensus statement regarding differences in sex development disorder (DSD) management, genotype is the most important factor for diagnosis and classification. Hence, the provisional impression in this case was 46, XY with undervirilization (disorders of androgen synthesis or action [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. However, the patient presented with both Turner stigmata and clitoromegaly such that the initial diagnosis was inconsistent with the clinical presentation. Therefore, further investigation was strongly suggested. Accurate diagnosis is crucial for individualized management, genetic counseling, discussion of fertility issues, and risk management of malignant gonadal transformation.\u003c/p\u003e"},{"header":"CASE PRESENTATION","content":"\u003cp\u003eA 26-year-old nulliparous woman was referred to our tertiary hospital after a large pelvic mass was discovered during an appendectomy at a secondary hospital. The patient had menarche at 17 years of age, with regular menstruation during the first year. She then began using the injectable contraception medroxyprogesterone acetate (150 mg) intramuscularly every 12 weeks for a year. However, even after discontinuing contraception, menstruation never resumed. Her family history could not be obtained since she was adopted.\u003c/p\u003e \u003cp\u003eExamination revealed a short stature with a height of 145 cm and weight of 56 kg. The patient\u0026rsquo;s voice appeared to be deepened, and breast and pubic hair development were in Tanner stages 1 and 5, respectively. Genital examination revealed clitoromegaly, with clitoral length of 3 cm (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e), and atrophic vaginal mucosa. The examination also revealed a webbed neck, a broad chest, and wide-spaced nipples. Other systemic examination results were unremarkable.\u003c/p\u003e \u003cp\u003eSonographic examination revealed a small uterus with a midline solid cystic mass posterior to the uterus. Abdominal CT showed a large heterogeneous pelvic mass with rim calcification measuring 8.1 \u0026times; 8.8 \u0026times; 8.6 cm without visualization of both ovaries and the right kidney. Laboratory studies showed ovarian insufficiency with a follicle-stimulating hormone level of 76 IU/mL, total testosterone level of 11 ng/dL, estradiol level of 19 pg/mL, dehydroepiandrosterone sulfate level of 198 \u0026micro;g/dL, and 17-hydroxy progesterone level of 0.33 ng/mL. Thyroid function, HbA1C, and liver function values were within normal limits. Chromosomal analysis of peripheral blood (GTG-banding) showed a 46, XY karyotype (25 metaphases). Although the karyotype was consistent with 46, XY DSD, mosaicism was suspected due to Turner stigmata. A 50-metaphase chromosomal analysis from peripheral blood was performed, but mosaicism was not revealed. A subsequent FISH analysis probing for the SRY and X centromere was performed and showed 45, X of 27.51%, 46, XY of 41.92%, and 46, XYY of 30.57%, consistent with a diagnosis of mosaic Turner syndrome. As tumor markers showed increased alpha fetoprotein levels (76,489 ng/mL), a germ cell tumor was suspected. The patient underwent bilateral gonadectomy with comprehensive surgical staging.\u003c/p\u003e \u003cp\u003eIntraoperative findings included a small uterus with a left gonadal tumor, normal fallopian tubes, and a right streak gonad. Postoperative chemotherapy and estrogen replacement therapy (17β- estradiol gel, 2.5 g per day) with cyclic progestins were prescribed. Echocardiography, audiography, and dual-energy X-ray absorptiometry scans were also scheduled.\u003c/p\u003e \u003cp\u003eThe histology of the left ovary was consistent with a yolk sac tumor comprised of tumor cells arranged in microcystic, solid, hepatoid, and polyvesicular vitelline patterns in the background of necrosis and peripheral calcification. Schiller\u0026ndash;Duval bodies were also noted. The tumor cells showed diffuse positivity for alpha fetoprotein. Furthermore, right ovary histology showed nests of small, dark sex cord cells, germ cells with enlarged vesicular nuclei and clear cytoplasm, and a hyalinized basement membrane, consistent with a gonadoblastoma (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The periphery of the mass consisted of ovarian fibrothecomatous cells, hyalinized seminiferous tubules, scattered Leydig cells, and fibroadipose tissue, which were suggestive of gonadal dysgenesis.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eTurner syndrome is diagnosed in phenotypic females with a karyotype containing one X chromosome and complete or partial absence of the second sex chromosome [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. This case emphasizes the need for thorough evaluation of patients presenting with Turner stigmata. Our patient had signs of hyperandrogenism, such as clitoromegaly and deepened voice, consistent with an initial assessment of conventional karyotype 46, XY. However, if we had disregarded the presence of Turner stigmata, the patient may have remained misdiagnosed, resulting in missed screenings for conditions associated with Turner syndrome such as gonadal malignancy [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIt is vital to perform a thorough clinical evaluation, as different DSDs can have overlapping phenotypes [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] At least 10% of patients with Turner syndrome, for example, manifest Y chromosome material [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e], and the clinical appearance of patients with positive Y material can be very similar to those without Y chromosome material. Our patient presented with 46, X/46, XY/47, XYY, which is a rare karyotype with no previously reported incidence of Turner syndrome. Earlier cases of this karyotype have shown dissimilar presentations such as male infertility [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] and gonadoblastoma in a phenotypic female without Turner stigmata [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Another case of mosaicism was reported in an older adult man with short stature, exostoses, brachydactyly, and gynecomastia [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThere are no specific lower limit percentages of 45, X for the diagnosis of Turner syndrome. Generally, 5% can be used for patients under 50 years of age [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. According to the American College of Medical Genetics, if Turner syndrome is suspected, a minimum 30-cell karyotype should be assessed, as this can identify at least 10% mosaicism with 95% confidence in peripheral blood [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. If standard blood karyotyping fails to reveal mosaicism, a cytogenetic study of secondary tissue, such as skin biopsy for cell culture or buccal smear for FISH, should be considered for individuals with suspected Turner syndrome [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Of note is that 5% and 1% mosaicism with 95% confidence can be detected if\u0026thinsp;\u0026ge;\u0026thinsp;59 and \u0026ge;\u0026thinsp;299 metaphases respectively, are analyzed [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]; for FISH, a minimum of 200 interphase cells should be assessed using X and Y centromere probes [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. In this case, the standard 25-cell karyotype from peripheral blood was assessed initially, revealing a 46, XY karyotype. However, due to the presence of Turner stigmata, chromosomal mosaicism was suspected. We proceeded to 50 metaphases from peripheral blood, which again failed to detect mosaicism. Therefore, FISH was performed for SRY and X centromeres from peripheral blood, with results showing 45, X of 27.51%, 46, XY of 41.92%, and 46, XYY of 30.57%. Stemming from laboratory limitations and the patient\u0026rsquo;s refusal for referral to a specialty center given financial constraints, karyotyping of non-blood specimens was not performed. There may be different proportions of mosaicism in different tissues [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eGonadectomy is recommended in female individuals with Y chromosome material because of increased risk of gonadoblastoma, the incidence of which is around 30% in patients with gonadal dysgenesis and varies as 4\u0026ndash;60% in patients with Turner syndrome who have Y material [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. As the condition is predisposed to the development of malignant germ cell tumors, gonadectomy should be performed early in order to prevent malignant transformation. Our patient also received fertility counseling, opting to keep her uterus in case of future pregnancy. Comprehensive surgical staging of bilateral salpingo-oophorectomy was performed. Although the patient\u0026rsquo;s uterus was small, it was not a contraindication for pregnancy, as the size likely resulted from a low estrogenic state [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePatients with Turner syndrome of any karyotype are advised to undergo general surveillance management [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Our patient was prescribed estrogen replacement therapy after gonadectomy, to continue until the time of natural menopause, for maintenance of bone health and cardiovascular risk reduction. Furthermore, as the uterus was kept, oral progestin was prescribed to reduce the risk of endometrial hyperplasia [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Multidisciplinary care was chosen to optimize patient care and psychosocial support.\u003c/p\u003e \u003cp\u003eThis case highlights the importance of evaluating patients with Turner stigmata for Turner syndrome. Due to the frequency of low-level mosaicism, further tests, such as those on non-blood specimens or via different methods such as FISH, should be conducted, as specific screening and treatments are not possible without an accurate diagnosis. This case also illustrates the significance of early gonadectomy in females with Y chromosome material because of the risk of malignant transformation. When treating patients with sex chromosome atypicality, a multidisciplinary team approach is recommended to facilitate appropriate discussions concerning sex assignment, hormonal therapy, associated metabolic disorders, fertility, and psychosocial support.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eConflicts of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research did not receive any specific grants from funding agencies in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to thank Dr. Suthinee Saluckpetch, Dr. Sunisa Kannawat, and Dr. Vasinee Sukchalermchai for their contributions to patient care. We would like to thank Editage (www.editage.com) for English language editing.\u003c/p\u003e\n\u003cp\u003eInformed consent: The patient provided written informed consent for the disclosure of relevant history, medical information, and images. To protect her privacy, her identity is maintained as confidential.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eKamel AK, Abd El-Ghany HM, Mekkawy MK, Makhlouf MM, Mazen IM, El Dessouky N, et al. Sex chromosome mosaicism in the gonads of DSD patients: a karyotype/phenotype correlation. Sex Dev. 2015 Dec;9:279\u0026ndash;88. \u003c/li\u003e\n\u003cli\u003eGravholt CH, Andersen NH, Conway GS, Dekkers OM, Geffner ME, Klein KO, et al. Clinical practice guidelines for the care of girls and women with Turner syndrome: proceedings from 2016 Cincinnati International Turner Syndrome Meeting. Eur J Endocrinol. 2017 Sep;177:G1\u0026ndash;G70. \u003c/li\u003e\n\u003cli\u003eCools M, Nordenstr\u0026ouml;m A, Robeva R, Hall J, Westerveld P, Fl\u0026uuml;ck C, et al. Caring for individuals with a difference of sex development (DSD): a consensus statement. Nat Rev Endocrinol. 2018 May;14:415\u0026ndash;29. \u003c/li\u003e\n\u003cli\u003eRasouli M, McDaniel K, Awadalla M, Chung K. Mosaic turner syndrome presenting with a 46, XY karyotype. Case Rep Obstet Gynecol. 2019 Apr;3719178:1\u0026ndash;3. \u003c/li\u003e\n\u003cli\u003eLe\u0026oacute;n NY, Reyes AP, Harley VR. A clinical algorithm to diagnose differences of sex development. Lancet Diabetes Endocrinol. 2019 Feb;7:560\u0026ndash;74.\u003c/li\u003e\n\u003cli\u003eBulakbasi T, Sahin F, Maz Yil Z, Zeyneloglu H. A 45, X/47, XYY/46, XY karyotype and Y chromosome microdeletion in an infertile male. Balk J Med Genet. 2008 Nov;11:51\u0026ndash;4.\u003c/li\u003e\n\u003cli\u003eOsztovics M, Iv\u0026aacute;dy G, Ruzicska P, B\u0026uuml;hler EM, Kir\u0026aacute;ly L. 45,X/46,XY/47,XYY mosaicism in a phenotypic female with gonadoblastoma. Acta Paediatr Acad Sci Hung. 1974;15:295\u0026ndash;9.\u003c/li\u003e\n\u003cli\u003eMonastirli A, Stephanou G, Georgiou S, Andrianopoulos C, Pasmatzi E, Tsambaos D, et al. Short stature, type E brachydactyly, exostoses, gynecomastia, and cryptorchidism in a patient with 47, XYY/45, X/46, XY mosaicism. Am J Med Sci. 2005 Apr;329:208\u0026ndash;10. \u003c/li\u003e\n\u003cli\u003eWolff DJ, Van Dyke DL, Powell CM, Working Group of the ACMG Laboratory Quality Assurance Committee. Laboratory guideline for Turner syndrome. Genet Med. 2010 Jan;12:52\u0026ndash;5.\u003c/li\u003e\n\u003cli\u003eHook EB. Exclusion of chromosomal mosaicism: tables of 90%, 95% and 99% confidence limits and comments on use. Am J Hum Genet. 1977 Jan;29:94\u0026ndash;7.\u003c/li\u003e\n\u003cli\u003eBianco B, Lipay MV, Melaragno MI, Guedes AD, Verreschi IT. Detection of hidden Y mosaicism in Turner\u0026rsquo;s syndrome: importance in the prevention of gonadoblastoma. J Pediatr Endocrinol Metab. 2006 Sep;19:1113\u0026ndash;7.\u003c/li\u003e\n\u003cli\u003eLeng XF, Lei K, Li Y, Tian F, Yao Q, Zheng QM, et al. Gonadal dysgenesis in Turner syndrome with Y-chromosome mosaicism: two case reports. World J Clin Cases. 2020 Nov;8:5737\u0026ndash;43. \u003c/li\u003e\n\u003cli\u003eKlein KO, Rosenfield RL, Santen RJ, Gawlik AM, Backeljauw PF, Gravholt CH, et al. Estrogen replacement in Turner syndrome: literature review and practical considerations. J Clin Endocrinol Metab. 2018 May;103:1790\u0026ndash;1803. \u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"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":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-3823439/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3823439/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eMosaic Turner accounts for nearly half of all Turner syndrome cases and results in a broadened clinical spectrum.\u003c/p\u003e\u003ch2\u003eCase:\u003c/h2\u003e \u003cp\u003eA 26-year-old female patient presented with a pelvic mass associated with signs of virilization and Turner stigmata. Conventional karyotype testing (G-banding method) revealed 46, XY; however, a further FISH (fluorescence in situ hybridization) study showed mosaicism of 45, X/46, XY/47, XYY. The patient underwent bilateral gonadectomy with comprehensive surgical staging, and histopathology revealed a yolk sac tumor.\u003c/p\u003e\u003ch2\u003eDiscussion\u003c/h2\u003e \u003cp\u003eThis case highlights an uncommon presentation of mosaic Turner syndrome. Further diagnostic tests in patients with signs of Turner syndrome are encouraged to achieve an accurate diagnosis and inform appropriate treatment.\u003c/p\u003e","manuscriptTitle":"A Patient with 45 X/46, XY/47, XYY Mosaic Turner Syndrome with Virilization: A Case Report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-05 18:31:18","doi":"10.21203/rs.3.rs-3823439/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"863035d9-31ea-480d-bb01-25d8a55e99fe","owner":[],"postedDate":"January 5th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-07-19T09:06:26+00:00","versionOfRecord":[],"versionCreatedAt":"2024-01-05 18:31:18","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3823439","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3823439","identity":"rs-3823439","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}