A rare cause of hypergonadotropism reported for the first time; ‘DiGeorge Syndrome’

A rare cause of hypergonadotropism reported for the first time; ‘DiGeorge Syndrome’ | 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 cause of hypergonadotropism reported for the first time; ‘DiGeorge Syndrome’ Duygu Deligözoğlu, Gamze Köseoğlu, Esra Kılıç, Derya Tepe, Pınar Kocaay This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6640169/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 28 Oct, 2025 Read the published version in BMC Endocrine Disorders → Version 1 posted 13 You are reading this latest preprint version Abstract Background : DiGeorge syndrome is a common microdeletion disorder caused by deletion in the 22q11.2 region. It typically presents with immune dysfunction, parathyroid hypoplasia, and congenital heart defects. Testis-specific serine/threonine kinases (TSSKs), involved in spermatogenesis, are located in this region. Although reproductive issues like hypogonadism and infertility have been reported, hypergonadotropism has not previously been described in patients with DiGeorge syndrome. Case presentation : We report a 19-year-old male diagnosed with DiGeorge syndrome at age 13, who exhibited pubertal arrest. At age 15, his testicular volumes were 5 mL (right) and 6 mL (left). Gonadotropin levels were elevated (FSH and LH), but testosterone was adequate, so treatment was deferred. By age 19, the clinical findings remained unchanged. Despite planning for semen analysis, the patient reported limited erections and no ejaculation, preventing assessment. This represents the first reported case of hypergonadotropism in DiGeorge syndrome. Conclusions : This case expands the endocrine phenotype of DiGeorge syndrome and underscores the importance of regular pubertal assessments. When pubertal delay is suspected, timely hormonal and genetic evaluation is crucial to detect rare but significant complications such as primary gonadal failure. DiGeorge syndrome hypergonadotropism hypoparathyroidism TSSK Introduction 22q11.2 deletion syndrome, also known as DiGeorge syndrome, is one of the most common microdeletion syndromes (MIM #188400 / #192430), with an estimated incidence of 1 in 3,000 to 4,000 live births [ 1 – 4 ]. This syndrome is characterized by immune system abnormalities, parathyroid hypoplasia, and congenital heart diseases [ 5 – 7 ]. It may also be associated with growth retardation, learning difficulties, facial dysmorphism, and behavioral problems. Clinical manifestations can vary depending on the patient’s age [ 8 ]. Additionally, patients with a 22q11.2 deletion have been shown to have lower platelet counts and increased mean platelet volume compared to the healthy population. The proposed mechanism for this is haploinsufficiency of the GPIBB gene located within the deleted region [ 9 ]. Endocrine abnormalities such as hypoparathyroidism, growth hormone deficiency, thyroid dysfunction, and obesity may also be observed in DiGeorge syndrome [ 10 ]. There is insufficient data on the expected changes in the pituitary-gonadal axis with puberty. Hypogonadotropic hypogonadism has been previously reported in a case with this syndrome. In that case, hypogonadism was attributed to the loss of the TSSK gene, which plays a role in spermatogenesis and is located in the 22q11.2 deletion region, while the absence of increased gonadotropin levels was explained by the patient having additional chronic diseases that would affect the pituitary hormones [ 11 ]. In this case report, we presented for the first time, a patient with 22q11.2 deletion syndrome accompanied by hypergonadotropic hypogonadism. Written informed consent was obtained from the parents for this publication. Case presentation The patient, who was diagnosed with DiGeorge syndrome at the age of 13 and followed up in our clinic between the ages of 13 and 19, was born with a normal spontaneous vaginal delivery (NSVY) weighing 2500 g. In his family history, it was stated that his mother and father were healthy, they were from the same village and he had a healthy brother. At the age of 4, the patient was evaluated by child psychiatry due to delayed speech and cognitive function and was diagnosed with mild intellectual disability. At the age of 8, during preoperative evaluation for circumcision, a platelet count of 100 × 10⁹/L was detected. As a result, the patient was assessed by pediatric hematology and was followed up with a diagnosis of isolated thrombocytopenia. The patient was admitted to the emergency department with a complaint of seizure at the age of 13. Laboratory tests revealed glucose: 88 mg/dL, sodium: 139 mEq/L, potassium: 4.1 mEq/L, calcium: 6.3 mg/dL, ionized calcium (iCa): 0.78 mmol/L, ALP: 467 U/L, albumin: 40 g/L, phosphorus: 7.1 mg/dL, and PTH: 24 ng/L. The patient was diagnosed with hypocalcemic convulsions and was hospitalized, leading to a diagnosis of hypoparathyroidism and initiation of calcitriol therapy. On physical examination, the patient’s weight was 42 kg (21st percentile), and height was 151 cm (23rd percentile). Pubertal examination showed bilateral testicular volumes of 4 mL, stretched penile length of 7 cm, positive axillary hair, and Tanner stage 2 pubic hair development. Dysmorphic facial features included low-set ears, hypertelorism, narrow palpebral fissures, a short philtrum, and anteverted ears. Based on clinical and physical findings, DiGeorge syndrome was suspected, and chromosomal microarray analysis identified a 2.2 Mb deletion in the 22q11.21 region. This deleted region contained over 30 genes with various functions, including TBX1, DGCR2, DGCR6, TSSK2, and GP1bβ. Echocardiographic evaluation did not reveal any cardiac pathology. Assessment fder344for immune system abnormalities showed no history of frequent infections or laboratory abnormalities. The patient was discharged with calcitriol therapy but did not attend regular follow-ups. The patient was admitted to our clinic again at the age of 15 and physical examination revealed a weight of 52 kg (25th-50th percentile) and height of 165.4 cm (10th-25th percentile). In the pubertal examination, the right testicular volume was 5 mL, the left testicular volume was 6 mL, the stretched penis length was 10 cm, axillary hair was positive, and pubic hair was stage 4. Hormonal evaluation performed due to pubertal arrest revealed FSH 43.4 U/L, LH 9.0 U/L, and total testosterone 2.29 µg/L. Bone age was consistent with chronological age, and testosterone levels were deemed sufficient; therefore, no treatment was initiated. The patient was followed up for hypergonadotropic hypogonadism. Despite irregular follow-ups, his most recent examination at the age of 19 showed a body weight of 53 kg and a height of 169 cm. On genital examination, right and left testicular volumes were 6–8 mL, stretched penile length was 12 cm, axillary hair was present, and pubic hair development was stage 5. The patient continued calcitriol therapy. Current laboratory findings showed calcium at 9.8 mg/dL, ALP at 80 U/L, phosphorus at 4.1 mg/dL, and PTH at 35 ng/L. Additional hormonal evaluations revealed FSH at 34 U/L, LH at 8.8 U/L, total testosterone at 3.54 µg/L, normal thyroid function tests, prolactin at 9.4 mcg/L, anti-Müllerian hormone at 1.83 mcg/L, and inhibin B at 20.7 pg/mL. Scrotal ultrasound showed both testes located within the scrotum, with the right testis measuring 14×20×32 mm and the left testis measuring 22×18×13 mm, with normal vascularization in both testes. A semen analysis was planned; however, upon questioning the patient's erectile and ejaculatory function, it was reported that erections occurred once per week and ejaculation was absent. Consequently, semen analysis could not be performed. Discussion and Conclusion In this case report, we presented a young male patient diagnosed with DiGeorge syndrome, who has multiple endocrine disorders. In addition to the typical features seen in individuals with a 22q11 deletion, hypergonadotropism, which has not been previously reported in the literature, was detected. In the literature, a patient diagnosed with DiGeorge syndrome at the age of 35, presenting with hypocalcemia and hyperphosphatemia, was followed for hypogonadotropic hypogonadism. This patient was evaluated in his twenties for erectile dysfunction and decreased libido, with testicular volumes measured at 6–8 mL, and an insufficient testosterone response observed in a human chorionic gonadotropin (hCG) stimulation test aimed at evaluating testicular function. Further investigations revealed stage 2 chronic kidney disease and elevated prolactin levels, with the hyperprolactinemia being suggested to be due to reduced renal clearance [ 12 ]. Testis-specific serine/threonine kinases (TSSKs), members of the protein kinase family, play a crucial role in spermatogenesis due to their exclusive expression in the testis. To date, five members of the Tssk gene family, including Tssk1, Tssk2, Tssk3, Tssk4, and Tssk6, have been identified in mice [ 13 ]. In humans, the TSSK2 gene is located on the 22q11.21 region [ 14 ]. This could be associated with the hypogonadism observed in DiGeorge syndrome. It has been suggested that the hypogonadism in this reported case is related to primary testicular failure and could be explained by the TSSK2 deletion in DiGeorge syndrome. However, the failure of the patient's FSH and LH levels to rise as expected has been linked to associated hyperprolactinemia, chronic kidney disease, type 2 diabetes mellitus, and obesity, which may influence pituitary hormones [ 11 ]. In addition, cases of oligospermia and azoospermia associated with the 22q11 deletion have also been reported in the literature. Douet-Guilbert and colleagues described a case of oligozoospermia associated with a 46,XY,t(9;22) del(q21;q11.2) translocation [ 15 ]. Perrin and colleagues reported another case of oligozoospermia in a 46,XY,t(9;22)(q21;q11.2) individual [ 16 ]. In another study, azoospermia was described in patients with DiGeorge syndrome. A 35-year-old patient diagnosed with DiGeorge syndrome was evaluated for infertility, with normal levels of testosterone, LH, and FSH, but azoospermia was detected in sperm analysis. In this case, it was suggested that the co-occurrence of DiGeorge syndrome and azoospermia could be either coincidental or that azoospermia might be one of the unknown clinical features of the syndrome. Furthermore, this condition was proposed as a potential cause of reduced reproductive function in males [ 17 ]. Among the most common chromosomal abnormalities leading to azoospermia are Y chromosome microdeletions. However, independent of genetic etiologies, intelligence levels can also impact reproductive ability [ 18 ]. In our case, sperm analysis could not be performed due to insufficient erection and ejaculation. Thrombocytopenia and an increase in mean platelet volume have been reported in patients with 22q11.2 deletion syndrome in the literature. This condition is explained by the localization of the platelet receptor protein-coding GP1bβ gene in the 22q11.2 region [ 9 ]. Defects in the GP1bβ gene cause Bernard-Soulier syndrome, which is autosomal recessively inherited and characterized by macrothrombocytopenia and platelet dysfunction. Since the relevant gene is located in the 22q11.2 region, patients with DiGeorge syndrome are carriers of Bernard-Soulier syndrome. In the literature, DiGeorge syndrome patients with macrothrombocytopenia have been diagnosed with Bernard-Soulier syndrome by detecting mutations in the GP1bβ allele without a deletion through next-generation sequencing (NGS) [ 19 – 20 ]. To explain the macrothrombocytopenia detected in our patient, we planned NGS analysis of the GP1bβ gene. In this case, after pubertal arrest, insufficient testicular development and elevated gonadotropin levels were observed. However, although the testosterone level was sufficient, the patient's inadequate erection and ejaculation suggest that the current condition may lead to progressive hypogonadism. We think that this may be related to a defect in spermatogenesis due to the loss of TSSK. Reproductive system disorders such as hypogonadism, azoospermia, oligospermia, and infertility have been previously described in patients with DiGeorge syndrome. Through this case presentation, we emphasize the importance of regular and careful pubertal examinations in patients with DiGeorge syndrome and the necessity of planning appropriate investigations in suspicious cases. Additionally, we highlight that DiGeorge syndrome should always be considered in the differential diagnosis of male patients presenting with infertility and dysmorphic features in adulthood. Abbreviations TSSK Testis-specific serine/threonine kinase NSVY Normal spontaneous vaginal delivery hCG Human chorionic gonadotropin Declarations Acknowledgements Not applicable. Author contributions Patient evaluation: D.D. and P.K.; Patient treatment: D.D. and P.K.; Visualization : D.D.; Conceptualization: D.D., P.K., D.T, E.K. and G.K.; Data analysis and literature review: D.D. and G.K.; Original draft preparation: D.D.; draft revision and editing: P.K., D.T., E.K. and G.K. All authors have read and agreed to the published version of the manuscript. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Data availability No datasets were generated or analysed during the current study. Ethics approval and consent to participate All methods were carried out in accordance with relevant guidelines and regulations. The patient provided written informed consent for data collection. Consent for publication Written informed consent has been obtained from the patient for publication of this case report. Competing interests The authors declare no competing interests. References Cancrini C, Puliafito P, Digilio MC, Soresina A, Martino S, Rondelli R. Clinical features and follow-up in patients with 22q11.2 Deletion syndrome. J Pediatr. 2014;164(6):1475–80. https://doi.org/10.1016/j.jpeds.2014.01.056 . Botto LD, May K, Fernhoff PM, Correa A, Coleman K, Rasmussen SA. A population- based study of the 22q11.2 deletion: phenotype, incidence, and contribution to major birth defects in the population. Pediatrics. 2003;112(1 Pt 1):101–7. https://doi.org/10.1542/peds.112.1.101 . Bassett AS, McDonald-McGinn DM, Devriendt K, Digilio MC, Goldenberg P, Habel A. Practical guidelines for managing patients with 22q11.2 deletion syndrome. J Pediatr. 2011;159(2):332–9. https://doi.org/10.1016/j.jpeds.2011.02.039 . Ryan AK, Goodship JA, Wilson DI, Philip N, Levy A, Seidel H. Spectrum of clinical features associated with interstitial chromosome 22q11 deletions: A European collaborative study. J Med Genet. 1997;34:798–804. 10.1136/jmg.34.10.798 . Kobrynski LJ, Sullivan KE. Velocardiofacial syndrome, DiGeorge syndrome: the chromosome 22q11.2 deletion syndromes. Lancet. 2007;370(9596):1443–52. 10.1016/S0140-6736(07)61601-8 . PMID: 17950858. Goldmuntz E. 22q11.2 deletion syndrome and congenital heart disease. Am J Med Genet C Semin Med Genet. 2020;184(1):64–72. 10.1002/ajmg.c.31774 . Epub 2020 Feb 12. PMID: 32049433. Davies EG. Immunodeficiency in DiGeorge syndrome and options for treating cases with complete Athymia. Front Immunol. 2013;4:322. 10.3389/fimmu.2013.00322 . PMID: 24198816; PMCID: PMC3814041. Saitta SC, Harris SE, Gaeth AP, Driscoll DA, McDonald- McGinn DM, Maisenbacher MK. Aberrant interchromosomal exchanges are the predominant cause of the 22q11.2 deletion. Hum MolGenet. 2004;13(4):417–28. 10.1093/hmg/ddh041 . Epub 2003 Dec 17. 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PMID: 21296991. Bielke W, Blaschke RJ, Miescher GC, Zuercher G, Andres AC, Ziemiecki A. Characterization of a novel murine testis-specific serine/threonine kinase. Gen. 1994; 139 : 235–239. 10.1016/0378-1119(94)90762-5 . PMID: 8112611. Hao Z, Jha KN, Kim YH, Westbrook VS, Chertihin VA, Markgraf O, Flickinger K, Herr CJCM, Visconti JC. Expression analysis of the human testis-specific serine/threonine kinase (TSSK) homologues. A TSSK member is present in the equatorial segment of human sperm. Mol Hum Reprod. 2004;10:433–44. 10.1093/molehr/gah052 . Epub 2004 Mar 25. PMID: 15044604. Douet-Guilbert N, Bris MJ, Amice V, Marchetti C, Delobel B, Amice J. et, al. Interchromosomal effect in sperm of males with translocations: report of 6 cases and review of the literature. Int J Androl 2005;28(6):372-9. 10.1111/j.1365-2605.2005.00571.x . PMID: 16300670. Perrin A, Caer E, Oliver-Bonet M, Navarro J, Benet J, Amice V. DNA fragmentation and meiotic segregation in sperm of carriers of a chromosomal structural abnormality. Fertil Steril. 2009;92(2):583–9. 10.1016/j.fertnstert.2008.06.052 . Epub 2008 Aug 15. PMID: 18706548. Özcan A, Şahin Y. DiGeorge Syndrome Associated with Azoospermia: First case in the literature. Turk J Urol. 2017;43(3):390–2. 10.5152/tud.2017.08555 . Epub 2017 Aug 3. PMID: 28861318; PMCID: PMC5562265. Sadeghi-Nejad H, Farrokhi F. Genetics of azoospermia: current knowledge, clinical implications, and future directions. Part II: Y chromosome microdeletions. Urol J 2007 Fall;4(4):192–206. PMID: 18270942. Nagoshi R, Sakamoto A, Imai T, Uchiyama T, Kaname T, Kunishima S. Bernard-Soulier syndrome caused by a novel GP1BB variant and 22q11.2 deletion. Int J Hematol. 2024;120(1):142–5. Epub 2024 Apr 16. PMID: 38625506. Kunishima S, Imai T, Kobayashi R, Kato M, Ogawa S, Saito H. Bernard-Soulier syndrome caused by a hemizygous GPIbβ mutation and 22q11.2 deletion. Pediatr Int. 2013;55(4):434-7. 10.1111/ped.12105 . PMID: 23566026. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 28 Oct, 2025 Read the published version in BMC Endocrine Disorders → Version 1 posted Editorial decision: Revision requested 27 Jun, 2025 Reviews received at journal 25 Jun, 2025 Reviews received at journal 24 Jun, 2025 Reviews received at journal 19 Jun, 2025 Reviewers agreed at journal 15 Jun, 2025 Reviewers agreed at journal 15 Jun, 2025 Reviewers agreed at journal 15 Jun, 2025 Reviewers agreed at journal 15 Jun, 2025 Reviewers invited by journal 15 Jun, 2025 Editor assigned by journal 15 Jun, 2025 Editor invited by journal 13 Jun, 2025 Submission checks completed at journal 10 Jun, 2025 First submitted to journal 10 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-6640169","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":471662184,"identity":"666ab086-fee6-416e-9a17-be1abf34b493","order_by":0,"name":"Duygu Deligözoğlu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA3UlEQVRIiWNgGAWjYDCCA1CaXwJMScgQq8WAQXIGA2MDUAsP8VoMboC1MBDWwncj/QLDxz1/8oxvNx9/dKPGgoeB/fDRDfi0SN7IKWCc8cyg2OzOscTmnGNAh/Gkpd3Ap8XgRk4CM88Bg8RtN3IMm3PYgFokeMwIa/kD1LJ5BkjLP6K0pB9gZgBq2SAB1JLbRoQWyTNvGBh7DhgnzriRljg7t0+Ch42QX/iOpz9g+HFALrF/RvKBzznf6uT42Q8fw6uFQSDH/AeKABte5SDAf/wBQTWjYBSMglEwwgEAz5FNT3BswpUAAAAASUVORK5CYII=","orcid":"","institution":"Ankara City Hospital","correspondingAuthor":true,"prefix":"","firstName":"Duygu","middleName":"","lastName":"Deligözoğlu","suffix":""},{"id":471662185,"identity":"9e0450d8-839a-43f2-a634-64993b6b1097","order_by":1,"name":"Gamze Köseoğlu","email":"","orcid":"","institution":"Ankara City Hospital","correspondingAuthor":false,"prefix":"","firstName":"Gamze","middleName":"","lastName":"Köseoğlu","suffix":""},{"id":471662186,"identity":"a7935a52-cdb9-4896-8288-d83d63f0be26","order_by":2,"name":"Esra Kılıç","email":"","orcid":"","institution":"Ankara City Hospital","correspondingAuthor":false,"prefix":"","firstName":"Esra","middleName":"","lastName":"Kılıç","suffix":""},{"id":471662187,"identity":"76300b29-679b-4cc9-ac54-000a6d756bff","order_by":3,"name":"Derya Tepe","email":"","orcid":"","institution":"Ankara City Hospital","correspondingAuthor":false,"prefix":"","firstName":"Derya","middleName":"","lastName":"Tepe","suffix":""},{"id":471662188,"identity":"45c140c1-068d-4685-8f9d-477d15c15619","order_by":4,"name":"Pınar Kocaay","email":"","orcid":"","institution":"Ankara City Hospital","correspondingAuthor":false,"prefix":"","firstName":"Pınar","middleName":"","lastName":"Kocaay","suffix":""}],"badges":[],"createdAt":"2025-05-11 14:38:10","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6640169/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6640169/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12902-025-02060-6","type":"published","date":"2025-10-28T15:58:10+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":95040018,"identity":"b5c29228-37b9-4975-9eb1-c05482d8c569","added_by":"auto","created_at":"2025-11-03 16:07:28","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":379972,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6640169/v1/6102ae07-6768-463a-b3d8-67f59352de49.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"A rare cause of hypergonadotropism reported for the first time; ‘DiGeorge Syndrome’","fulltext":[{"header":"Introduction","content":"\u003cp\u003e22q11.2 deletion syndrome, also known as DiGeorge syndrome, is one of the most common microdeletion syndromes (MIM #188400 / #192430), with an estimated incidence of 1 in 3,000 to 4,000 live births [\u003cspan additionalcitationids=\"CR2 CR3\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. This syndrome is characterized by immune system abnormalities, parathyroid hypoplasia, and congenital heart diseases [\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. It may also be associated with growth retardation, learning difficulties, facial dysmorphism, and behavioral problems. Clinical manifestations can vary depending on the patient\u0026rsquo;s age [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Additionally, patients with a 22q11.2 deletion have been shown to have lower platelet counts and increased mean platelet volume compared to the healthy population. The proposed mechanism for this is haploinsufficiency of the GPIBB gene located within the deleted region [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Endocrine abnormalities such as hypoparathyroidism, growth hormone deficiency, thyroid dysfunction, and obesity may also be observed in DiGeorge syndrome [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. There is insufficient data on the expected changes in the pituitary-gonadal axis with puberty. Hypogonadotropic hypogonadism has been previously reported in a case with this syndrome. In that case, hypogonadism was attributed to the loss of the TSSK gene, which plays a role in spermatogenesis and is located in the 22q11.2 deletion region, while the absence of increased gonadotropin levels was explained by the patient having additional chronic diseases that would affect the pituitary hormones [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn this case report, we presented for the first time, a patient with 22q11.2 deletion syndrome accompanied by hypergonadotropic hypogonadism.\u003c/p\u003e \u003cp\u003e Written informed consent was obtained from the parents for this publication.\u003c/p\u003e"},{"header":"Case presentation","content":"\u003cp\u003eThe patient, who was diagnosed with DiGeorge syndrome at the age of 13 and followed up in our clinic between the ages of 13 and 19, was born with a normal spontaneous vaginal delivery (NSVY) weighing 2500 g. In his family history, it was stated that his mother and father were healthy, they were from the same village and he had a healthy brother. At the age of 4, the patient was evaluated by child psychiatry due to delayed speech and cognitive function and was diagnosed with mild intellectual disability. At the age of 8, during preoperative evaluation for circumcision, a platelet count of 100 \u0026times; 10⁹/L was detected. As a result, the patient was assessed by pediatric hematology and was followed up with a diagnosis of isolated thrombocytopenia.\u003c/p\u003e \u003cp\u003eThe patient was admitted to the emergency department with a complaint of seizure at the age of 13. Laboratory tests revealed glucose: 88 mg/dL, sodium: 139 mEq/L, potassium: 4.1 mEq/L, calcium: 6.3 mg/dL, ionized calcium (iCa): 0.78 mmol/L, ALP: 467 U/L, albumin: 40 g/L, phosphorus: 7.1 mg/dL, and PTH: 24 ng/L. The patient was diagnosed with hypocalcemic convulsions and was hospitalized, leading to a diagnosis of hypoparathyroidism and initiation of calcitriol therapy. On physical examination, the patient\u0026rsquo;s weight was 42 kg (21st percentile), and height was 151 cm (23rd percentile). Pubertal examination showed bilateral testicular volumes of 4 mL, stretched penile length of 7 cm, positive axillary hair,\u003c/p\u003e \u003cp\u003eand Tanner stage 2 pubic hair development. Dysmorphic facial features included low-set ears, hypertelorism, narrow palpebral fissures, a short philtrum, and anteverted ears. Based on clinical and physical findings, DiGeorge syndrome was suspected, and chromosomal microarray analysis identified a 2.2 Mb deletion in the 22q11.21 region. This deleted region contained over 30 genes with various functions, including TBX1, DGCR2, DGCR6, TSSK2, and GP1bβ. Echocardiographic evaluation did not reveal any cardiac pathology. Assessment fder344for immune system abnormalities showed no history of frequent infections or laboratory abnormalities. The patient was discharged with calcitriol therapy but did not attend regular follow-ups. The patient was admitted to our clinic again at the age of 15 and physical examination revealed a weight of 52 kg (25th-50th percentile) and height of 165.4 cm (10th-25th percentile). In the pubertal examination, the right testicular volume was 5 mL, the left testicular volume was 6 mL, the stretched penis length was 10 cm, axillary hair was positive, and pubic hair was stage 4.\u003c/p\u003e \u003cp\u003eHormonal evaluation performed due to pubertal arrest revealed FSH 43.4 U/L, LH 9.0 U/L, and total testosterone 2.29 \u0026micro;g/L. Bone age was consistent with chronological age, and testosterone levels were deemed sufficient; therefore, no treatment was initiated. The patient was followed up for hypergonadotropic hypogonadism. Despite irregular follow-ups, his most recent examination at the age of 19 showed a body weight of 53 kg and a height of 169 cm. On genital examination, right and left testicular volumes were 6\u0026ndash;8 mL, stretched penile length was 12 cm, axillary hair was present, and pubic hair development was stage 5. The patient continued calcitriol therapy. Current laboratory findings showed calcium at 9.8 mg/dL, ALP at 80 U/L, phosphorus at 4.1 mg/dL, and PTH at 35 ng/L. Additional hormonal evaluations revealed FSH at 34 U/L, LH at 8.8 U/L, total testosterone at 3.54 \u0026micro;g/L, normal thyroid function tests, prolactin at 9.4 mcg/L, anti-M\u0026uuml;llerian hormone at 1.83 mcg/L, and inhibin B at 20.7 pg/mL. Scrotal ultrasound showed both testes located within the scrotum, with the right testis measuring 14\u0026times;20\u0026times;32 mm and the left testis measuring 22\u0026times;18\u0026times;13 mm, with normal vascularization in both testes. A semen analysis was planned; however, upon questioning the patient's erectile and ejaculatory function, it was reported that erections occurred once per week and ejaculation was absent. Consequently, semen analysis could not be performed.\u003c/p\u003e"},{"header":"Discussion and Conclusion","content":" \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003cp\u003eIn this case report, we presented a young male patient diagnosed with DiGeorge syndrome, who has multiple endocrine disorders. In addition to the typical features seen in individuals with a 22q11 deletion, hypergonadotropism, which has not been previously reported in the literature, was detected. In the literature, a patient diagnosed with DiGeorge syndrome at the age of 35, presenting with hypocalcemia and hyperphosphatemia, was followed for hypogonadotropic hypogonadism. This patient was evaluated in his twenties for erectile dysfunction and decreased libido, with testicular volumes measured at 6\u0026ndash;8 mL, and an insufficient testosterone response observed in a human chorionic gonadotropin (hCG) stimulation test aimed at evaluating testicular function. Further investigations revealed stage 2 chronic kidney disease and elevated prolactin levels, with the hyperprolactinemia being suggested to be due to reduced renal clearance [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTestis-specific serine/threonine kinases (TSSKs), members of the protein kinase family, play a crucial role in spermatogenesis due to their exclusive expression in the testis. To date, five members of the Tssk gene family, including Tssk1, Tssk2, Tssk3, Tssk4, and Tssk6, have been identified in mice [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. In humans, the TSSK2 gene is located on the 22q11.21 region [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. This could be associated with the hypogonadism observed in DiGeorge syndrome. It has been suggested that the hypogonadism in this reported case is related to primary testicular failure and could be explained by the TSSK2 deletion in DiGeorge syndrome. However, the failure of the patient's FSH and LH levels to rise as expected has been linked to associated hyperprolactinemia, chronic kidney disease, type 2 diabetes mellitus, and obesity, which may influence pituitary hormones [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. In addition, cases of oligospermia and azoospermia associated with the 22q11 deletion have also been reported in the literature. Douet-Guilbert and colleagues described a case of oligozoospermia associated with a 46,XY,t(9;22) del(q21;q11.2) translocation [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Perrin and colleagues reported another case of oligozoospermia in a 46,XY,t(9;22)(q21;q11.2) individual [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. In another study, azoospermia was described in patients with DiGeorge syndrome. A 35-year-old patient diagnosed with DiGeorge syndrome was evaluated for infertility, with normal levels of testosterone, LH, and FSH, but azoospermia was detected in sperm analysis. In this case, it was suggested that the co-occurrence of DiGeorge syndrome and azoospermia could be either coincidental or that azoospermia might be one of the unknown clinical features of the syndrome. Furthermore, this condition was proposed as a potential cause of reduced reproductive function in males [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Among the most common chromosomal abnormalities leading to azoospermia are Y chromosome microdeletions. However, independent of genetic etiologies, intelligence levels can also impact reproductive ability [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. In our case, sperm analysis could not be performed due to insufficient erection and ejaculation.\u003c/p\u003e \u003cp\u003eThrombocytopenia and an increase in mean platelet volume have been reported in patients with 22q11.2 deletion syndrome in the literature. This condition is explained by the localization of the platelet receptor protein-coding GP1bβ gene in the 22q11.2 region [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Defects in the GP1bβ gene cause Bernard-Soulier syndrome, which is autosomal recessively inherited and characterized by macrothrombocytopenia and platelet dysfunction. Since the relevant gene is located in the 22q11.2 region, patients with DiGeorge syndrome are carriers of Bernard-Soulier syndrome. In the literature, DiGeorge syndrome patients with macrothrombocytopenia have been diagnosed with Bernard-Soulier syndrome by detecting mutations in the GP1bβ allele without a deletion through next-generation sequencing (NGS)\u003c/p\u003e \u003cp\u003e[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. To explain the macrothrombocytopenia detected in our patient, we planned NGS analysis of the GP1bβ gene.\u003c/p\u003e \u003cp\u003eIn this case, after pubertal arrest, insufficient testicular development and elevated gonadotropin levels were observed. However, although the testosterone level was sufficient, the patient's inadequate erection and ejaculation suggest that the current condition may lead to progressive hypogonadism. We think that this may be related to a defect in spermatogenesis due to the loss of TSSK.\u003c/p\u003e \u003cp\u003eReproductive system disorders such as hypogonadism, azoospermia, oligospermia, and infertility have been previously described in patients with DiGeorge syndrome. Through this case presentation, we emphasize the importance of regular and careful pubertal examinations in patients with DiGeorge syndrome and the necessity of planning appropriate investigations in suspicious cases. Additionally, we highlight that DiGeorge syndrome should always be considered in the differential diagnosis of male patients presenting with infertility and dysmorphic features in adulthood.\u003c/p\u003e \u003c/div\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eTSSK\u003c/p\u003e\n\u003cp\u003eTestis-specific serine/threonine kinase\u003c/p\u003e\n\u003cp\u003eNSVY\u003c/p\u003e\n\u003cp\u003eNormal spontaneous vaginal delivery\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;hCG\u003c/p\u003e\n\u003cp\u003eHuman chorionic gonadotropin\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatient evaluation: D.D. and P.K.; Patient treatment: D.D. and P.K.; Visualization : D.D.; Conceptualization: D.D., P.K., D.T, E.K. and G.K.; Data analysis and literature review: D.D. and G.K.; Original draft preparation: D.D.; draft revision and editing: P.K., D.T., E.K. and G.K. All authors have read and agreed to the published version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo datasets were generated or analysed during the current study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll methods were carried out in accordance with relevant guidelines and regulations. The patient provided written informed consent for data collection.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent has been obtained from the patient for publication of this case report.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eCancrini C, Puliafito P, Digilio MC, Soresina A, Martino S, Rondelli R. Clinical features and follow-up in patients with 22q11.2 Deletion syndrome. 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PMID: 38625506.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKunishima S, Imai T, Kobayashi R, Kato M, Ogawa S, Saito H. Bernard-Soulier syndrome caused by a hemizygous GPIbβ mutation and 22q11.2 deletion. Pediatr Int. 2013;55(4):434-7. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/ped.12105\u003c/span\u003e\u003cspan address=\"10.1111/ped.12105\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. PMID: 23566026.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"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":"DiGeorge syndrome, hypergonadotropism, hypoparathyroidism, TSSK","lastPublishedDoi":"10.21203/rs.3.rs-6640169/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6640169/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e: DiGeorge syndrome is a common microdeletion disorder caused by deletion in the 22q11.2 region. It typically presents with immune dysfunction, parathyroid hypoplasia, and congenital heart defects. Testis-specific serine/threonine kinases (TSSKs), involved in spermatogenesis, are located in this region. Although reproductive issues like hypogonadism and infertility have been reported, hypergonadotropism has not previously been described in patients with DiGeorge syndrome.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase presentation\u003c/strong\u003e: We report a 19-year-old male diagnosed with DiGeorge syndrome at age 13, who exhibited pubertal arrest. At age 15, his testicular volumes were 5 mL (right) and 6 mL (left). Gonadotropin levels were elevated (FSH and LH), but testosterone was adequate,\u003c/p\u003e\n\u003cp\u003eso treatment was deferred. By age 19, the clinical findings remained unchanged. Despite planning for semen analysis, the patient reported limited erections and no ejaculation, preventing assessment. This represents the first reported case of hypergonadotropism in DiGeorge syndrome.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e: This case expands the endocrine phenotype of DiGeorge syndrome and underscores the importance of regular pubertal assessments. When pubertal delay is suspected, timely hormonal and genetic evaluation is crucial to detect rare but significant complications such as primary gonadal failure.\u003c/p\u003e","manuscriptTitle":"A rare cause of hypergonadotropism reported for the first time; ‘DiGeorge Syndrome’","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-18 18:45:16","doi":"10.21203/rs.3.rs-6640169/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-06-27T09:06:28+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-06-25T04:28:03+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-06-24T17:52:22+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-06-19T15:05:43+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"98467557155964490377499226640830849533","date":"2025-06-16T03:32:36+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"287862727281176898025806159735094152144","date":"2025-06-16T03:20:14+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"338970276238677798548952387648916525055","date":"2025-06-16T03:17:31+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"171238124929812378132196428131836971477","date":"2025-06-16T03:13:10+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-06-16T03:09:03+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-06-16T03:00:00+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-06-13T09:16:17+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-06-10T12:53:48+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Endocrine Disorders","date":"2025-06-10T12:50:56+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":"cf59f4b5-54ac-473d-b49e-41979875fd19","owner":[],"postedDate":"June 18th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-11-03T16:02:18+00:00","versionOfRecord":{"articleIdentity":"rs-6640169","link":"https://doi.org/10.1186/s12902-025-02060-6","journal":{"identity":"bmc-endocrine-disorders","isVorOnly":false,"title":"BMC Endocrine Disorders"},"publishedOn":"2025-10-28 15:58:10","publishedOnDateReadable":"October 28th, 2025"},"versionCreatedAt":"2025-06-18 18:45:16","video":"","vorDoi":"10.1186/s12902-025-02060-6","vorDoiUrl":"https://doi.org/10.1186/s12902-025-02060-6","workflowStages":[]},"version":"v1","identity":"rs-6640169","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6640169","identity":"rs-6640169","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}