A Rare Cause of Hypercalcemia In Adults: Idiopathic Infantile Hypercalcemia

A Rare Cause of Hypercalcemia In Adults: Idiopathic Infantile Hypercalcemia | 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 Short Report A Rare Cause of Hypercalcemia In Adults: Idiopathic Infantile Hypercalcemia Fatma Tuğçe Şah Ünal, Esra Eraslan Aydemir, Can Berk Leblebici, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5775940/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 Idiopathic Infantile Hypercalcemia (IIH) is a rare disorder marked by PTH-independent hypercalcemia, usually diagnosed in infancy, with adult cases being uncommon. This report discusses a 60-year-old male with a 25-year history of type 2 diabetes, recurrent kidney stones, and stage 3a chronic kidney disease. Laboratory findings included hypercalcemia, normal phosphorus and 25-hydroxycholecalciferol levels, and suppressed PTH. Urinary ultrasonography revealed medullary nephrocalcinosis. Comprehensive evaluation ruled out malignancies, granulomatous diseases, and endocrinopathies. Genetic testing identified compound heterozygous mutations in the CYP24A1 gene, confirming IIH type 1. Initial management involved calcium- and vitamin D-restricted diets and sunlight avoidance. When hypercalcemia persisted, fluconazole treatment (50 mg/day) was trialed but proved ineffective. Cinacalcet (60 mg/day) was subsequently introduced, successfully normalizing serum calcium levels. Family genetic screening revealed biallelic mutations in two siblings and heterozygous mutations in two others, though none exhibited hypercalcemia. This case underscores the need for heightened awareness of IIH in adults, advocating for family screening to detect asymptomatic carriers early. The effectiveness of cinacalcet in managing adult IIH highlights its therapeutic potential when lifestyle modifications alone are insufficient, preventing long-term complications from untreated hypercalcemia. Idiopathic Infantile Hypercalcemia (IIH) Hypercalcemia CYP24A1 mutation Cinacalcet Parathyroid hormone Figures Figure 1 INTRODUCTION Hypercalcemia is a frequently encountered clinical condition, with its prevalence and incidence varying across different populations. While approximately 0.6% of patients presenting to the emergency department exhibit hypercalcemia, its prevalence in the general population is around 1 in 1000 individuals [ 1 ]. From an etiological standpoint, hypercalcemia is classified as either parathyroid hormone (PTH)-dependent or PTH-independent [ 2 ]. Elevated or inappropriately normal PTH levels in the presence of hypercalcemia suggest a PTH-dependent mechanism, whereas suppressed PTH levels are indicative of a PTH-independent process. The majority of hypercalcemia cases, accounting for 80–90%, are attributed to primary hyperparathyroidism or malignancies, with less common causes including vitamin D-mediated hypercalcemia [ 1 , 3 ]. Vitamin D metabolism plays a pivotal role in calcium and phosphate homeostasis. It involves a complex interplay of enzymatic steps, where the biologically active form, 1,25-dihydroxyvitamin D, is synthesized through hydroxylation processes regulated by CYP27B1 and subsequently inactivated by CYP24A1 [ 4 ]. Disruptions in this finely tuned process can lead to pathological conditions such as idiopathic infantile hypercalcemia (IIH), a rare, PTH-independent genetic disorder. IIH is most commonly diagnosed in pediatric patients and is associated with genetic variants in CYP24A1 or SLC34A1 . These defects result in excessive accumulation of active vitamin D metabolites, leading to persistent hypercalcemia, hypercalciuria, suppressed PTH levels, and an increased risk of nephrocalcinosis and nephrolithiasis. Although described as "infantile," IIH can manifest later in life, including adulthood. Here, we report a rare case of IIH in a 60-year-old male who was extensively evaluated over several years for PTH-independent hypercalcemia, initially suspected to be malignancy-related. Genetic analysis confirmed the diagnosis of IIH, and subsequent family screening revealed four asymptomatic carriers of the genetic variants. This case underscores the importance of considering rare genetic causes like IIH in the differential diagnosis of unexplained hypercalcemia, even in older patients. CASE PRESENTATION A 60-year-old male with a 25-year history of type 2 diabetes presented with renal failure and hypercalcemia detected 8 years ago. He reported a history of recurrent nephrolithiasis spanning over 20 years, passing kidney stones 1–2 times per year. Despite suboptimal glucose regulation, no micro- or macrovascular diabetic complications were observed. In 2017, laboratory evaluations revealed elevated serum calcium and creatinine levels, suppressed PTH, normal phosphorus and 25(OH)D 3 levels, and increased 24-hour urinary calcium excretion. Imaging confirmed medullary nephrocalcinosis and chronic kidney disease. Kidney stone analysis identified calcium oxalate (Whewellite, Weddellite) and calcium phosphate (Hydroxylapatite) stones. Extensive evaluations ruled out malignancy (normal PSA, stable 5-mm subsolid nodule on thoracic CT, and no hypermetabolic foci on 18F-FDG-PET CT) and granulomatous disease (normal ACE levels, no lymphadenopathy). Recurrent urinary stone disease necessitated double-J catheter placement in 2019 and 2020. DEXA scanning revealed osteopenia in the lumbar spine. Further biochemical tests in 2023 showed normal PTHrP (1.6 pmol/L) and 1,25(OH)2D3 (24.18 pg/mL) levels, though 24,25(OH)2D3 levels were unavailable. Despite ongoing investigations, no definitive etiology for the PTH-independent hypercalcemia was determined. The patient's laboratory test results are provided in the supplementary materials. The index patient had a family history of renal stones, though serum calcium levels in relatives were unknown. Genetic sequencing for IIH was performed using the next-generation sequencing (NGS) method with primers covering exon/exon-intron junctions in the CYP24A1 gene. NGS analysis revealed a heterozygous likely pathogenic variant c.428_430del, p.(Glu143del) (rs777676129) in exon 2, and a heterozygous pathogenic variant c.1186C > T, p.(Arg396Trp) (rs114368325) in exon 9 of the CYP24A1 gene in the index patient, H.Y. These findings were compatible with IIH type 1 (Table 1). Table 1: Demographic, biochemical, and genetic parameters of the index patient’s and his four siblings H.Y. (Index case) F.D. (Sister) E.K. (Sister) C.Y. (Brother) G.E. (Sister) Standart Values Age 60 62 48 55 58 Creatinine (mg/dL ) 2.41 0.71 0.73 0.68 0.81 0.7-1.2 mg/dL Estimated GFR (mL/min/1.73m 2 ) 28 91 97 98 80 >60 mL/min/1.73m 2 Urea (mg/dL) 98 24 21 18 26 12.8-42.8 mg/dL Serum Adjusted Calcium (mg/dL) 12.1 9.7 9.0 10 9.2 8.6-10.2 mg/dL Serum Phosphate (mg/dL) 4.29 3.86 3 NA 2.82 2.5-4.5 mg/dL Parathormone (pg/mL) 6 59 35 NA 25 15-65 pg/mL 25(OH)D 3 (µg/L) 32.2 6 NA 8.15 10-60 µg/L Urinary calcium (mg/24 h) 172 135 395 NA 211 100-300 mg/24 h NL*/NC** history yes yes no no yes Genetic analysis CYP24A1 c.1186C>T and c.428_430delAAG (Glu143del) CYP24A1 c.1186C>T, p.(Arg396Trp) CYP24A1 c.1186C>T, c.428_430delAAG (Glu143del) CYP24A1 c.1186C>T and c.428_430delAAG (Glu143del) CYP24A1 c.1186C>T and c.428_430delAAG (Glu143del) Abbreviations: * Nephrolithiasis, ** Nephrocalcinosis, NA: Not Available The patient initially followed a vitamin D and calcium-restricted diet, but his calcium levels remained high after three months. Fluconazole 50 mg/day was added, but calcium levels stayed elevated. He then started on cinacalcet, with a gradual dose increase from 30 mg to 60 mg/day. By the third month, his calcium levels decreased and remained normal on the 60 mg/day dose. Genetic testing for the patient’s children and siblings is planned. The patient's biochemical results during treatment are shown in Figure 1. DISCUSSION Idiopathic infantile hypercalcemia (IIH) presents with varying clinical manifestations depending on age. Infants typically exhibit weight loss, vomiting, dehydration, lethargy, and hypotonia [5, 6], while some cases may be asymptomatic and discovered through family screening [5]. In adults, renal manifestations such as nephrolithiasis (NL) and nephrocalcinosis (NC) are common, along with polyuria. In adults, renal manifestations such as nephrolithiasis (NL), nephrocalcinosis (NC), and polyuria are common, with hypercalcemia symptoms ranging from mild to severe, including neuropsychiatric symptoms, gastrointestinal issues, hypertension, and pancreatitis [7-9] . The described patient developed NL, NC, and grade 3a renal failure, and since PTH-independent hypercalcemia was found, a malignancy evaluation was performed. Though IIH is rare, it should be considered as a cause of PTH-independent hypercalcemia in adults. IIH is caused by bi-allelic (homozygous or compound heterozygous) mutations in the CYP24A1 gene. This results in a biochemical profile characterized by hypercalcemia, hypercalciuria, increased intestinal calcium absorption, suppressed PTH levels, and elevated or normal 1,25(OH) 2 D 3 levels. In symptomatic infants, calcium levels are often significantly high, whereas in adults, they are elevated but to a lesser extent. The 25(OH)D 3 level may be low, normal, or high. A defect in the 24-hydroxylase enzyme due to the CYP24A1 mutation results in low 24,25(OH) 2 D 3 levels, despite sufficient levels of the substrate 25(OH)D 3 . The 25(OH)D 3 /24,25(OH) 2 D 3 ratio can help differentiate IIH from other causes of hypercalcemia, with an elevated ratio typically seen in IIH patients. In healthy individuals, the ratio ranges from 7 to 35, but in those with CYP24A1 mutations, it exceeds 99, suggesting the need for genetic testing [8, 10-12]. Autosomal recessive inheritance characterizes IIH, driven by homozygous or compound heterozygous variants in the CYP24A1 gene. However, genetic and environmental interactions lead to significant diversity in disease expression. Individuals with bi-allelic genetic variations exhibit a more severe phenotype compared to mono-allelic carriers, who are either asymptomatic or borderline [13]. In the described case, genetic analysis revealed bi-allelic mutations in the index patient and two siblings, consistent with IIH type 1. Two other siblings had mono-allelic mutations. This genetic variability explains the differing clinical presentations within the family. Environmental factors, particularly diet and sunlight exposure, significantly impact disease expression. The index patient, a farmer with significant sunlight exposure, likely experienced exacerbated symptoms due to his occupation Treatment of IIH includes dietary restrictions on calcium and vitamin D, as well as sunlight avoidance [14, 15]. However, these lifestyle changes alone are often insufficient to control the disease or preserve kidney function [16]. Medical treatments targeting vitamin D metabolism are needed. The goal of a pharmaceutical strategy is to modify vitamin D metabolism to favor the activation of alternative catabolic pathways. Azole medications, such as fluconazole and ketoconazole, work by inhibiting the CYP27B1 enzyme and reducing 1,25(OH) 2 D 3 . The patient was initially treated with fluconazole 50 mg/day for three months, as it is less toxic than other options. Despite this, calcium levels remained high. There are also publications in which rifampin has been used in treatment as an effective inducer of CYP3A4 , a cytochrome involved in the metabolism of various xenobiotics, medications, and hormones, including vitamin D [17]. Recently, cinacalcet was reported to be helpful in these patients [18]. Cinacalcet is a calcimimetic drug that reduces serum calcium and PTH levels by activating calcium-sensing receptors (CaSR) in the parathyroid glands. Nausea, vomiting, and paresthesias were the most frequently reported side effects. These reactions were infrequent and tended to vary based on the dosage [19]. We gradually started cinacalcet and reached a dose of 60 mg/day. No side effects were observed during the 3-month follow-up, and the blood calcium level returned to normal. The patient has now completed the first year of treatment. Although no significant reduction in urinary calcium excretion was observed, there were no symptoms or findings related to renal stone disease during the past year. CONCLUSION In conclusion, although idiopathic infantile hypercalcemia (IIH) is a rare cause of PTH-independent hypercalcemia in adults, it should not be overlooked. Early diagnosis of asymptomatic individuals through family screening can prevent many long-term complications. Lifestyle changes are often insufficient to control disease. Cinacalcet has been shown to be a viable option for inducing rapid and sustained reductions in serum calcium levels, with a favorable safety profile. Long-term use of cinacalcet has not been associated with any adverse outcomes [20]. Therefore, when a low-calcium diet and sunlight avoidance fail to modify the biochemical phenotype of IIH, cinacalcet may offer an effective alternative. The patient and the family gave written informed consent for the genetic analysis and the use of their clinical data for scientific purposes, including publication. Declarations Author Contributions Fatma Tuğçe Şah Ünal, Esra Eraslan Aydemir, Can Berk Leblebici, Nüket Yürür Kutlay, and Murat Faik Erdoğan meet the authorship criteria according to the latest guidelines of the International Committee of Medical Journal Editors (ICMJE). All authors have seen and approved the manuscript being submitted and published. Fatma Tuğçe Şah Ünal contributed to the diagnosis, treatment, and follow-up of the patient and to the writing of the case report. Esra Eraslan Aydemir contributed to the diagnosis, treatment, and follow-up of the patient. Can Berk Leblebici contributed to the genetic analysis and its interpretation. Nüket Yürür Kutlay contributed to the genetic analysis and its interpretation. Murat Faik Erdoğan reviewed and finalized the manuscript and was responsible for the patient's treatment. Guarantor:Murat Faik Erdoğan is the guarantor of the work and accepts full responsibility for the integrity of the case report. Ethical Considerations and Approval The study was conducted in compliance with the Good Clinical Practices protocol and the principles of the Declaration of Helsinki. This is a case report. The Ankara University Research Ethics Committee has confirmed that no ethical approval is required. Consent for Publication All patients were informed about the study procedures and provided written consent for participation and publication. Conflict of Interest Statement Fatma Tuğçe Şah Ünal, Esra Eraslan Aydemir, Can Berk Leblebici, Nüket Yürür Kutlay, and Murat Faik Erdoğan declare that they have no conflict of interest. The ICMJE Conflict of Interest form for each author is attached herewith. Funding The authors did not receive any specific grants from funding agencies in the public, commercial, or not-for-profit sectors for this research. Data Availability Statement All data related to the presented patients are available in the hospital records where they are being followed. This data can be made available to editors, reviewers, and readers upon reasonable request. The authors have no relevant financial or non-financial interests to disclose. The authors have no competing interests to declare that are relevant to the content of this article. All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript. The authors have no financial or proprietary interests in any material discussed in this article. 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Jacobs, T.P., et al., A lifetime of hypercalcemia and hypercalciuria, finally explained. J Clin Endocrinol Metab, 2014. 99 (3): p. 708-12. Gray, T.K., W. Lowe, and G.E. Lester, Vitamin D and pregnancy: the maternal-fetal metabolism of vitamin D. Endocr Rev, 1981. 2 (3): p. 264-74. Tebben, P.J., et al., Hypercalcemia, hypercalciuria, and elevated calcitriol concentrations with autosomal dominant transmission due to CYP24A1 mutations: effects of ketoconazole therapy. J Clin Endocrinol Metab, 2012. 97 (3): p. E423-7. Shah, A.D., et al., Maternal Hypercalcemia Due to Failure of 1,25-Dihydroxyvitamin-D3 Catabolism in a Patient With CYP24A1 Mutations. J Clin Endocrinol Metab, 2015. 100 (8): p. 2832-6. Drezner, M.K., et al., 1,25-Dihydroxycholecalciferol deficiency: the probable cause of hypocalcemia and metabolic bone disease in pseudohypoparathyroidism. J Clin Endocrinol Metab, 1976. 42 (4): p. 621-8. Carpenter, T.O., CYP24A1 loss of function: Clinical phenotype of monoallelic and biallelic mutations. J Steroid Biochem Mol Biol, 2017. 173 : p. 337-340. Cappellani, D., et al., Hereditary hypercalcemia caused by a homozygous pathogenic variant in the CYP24A1 gene: a case report and review of the literature. Case reports in endocrinology, 2019. 2019 (1): p. 4982621. Brancatella, A., et al., Do the Heterozygous Carriers of a CYP24A1 Mutation Display a Different Biochemical Phenotype Than Wild Types? J Clin Endocrinol Metab, 2021. 106 (3): p. 708-717. Lenherr-Taube, N., et al., Mild Idiopathic Infantile Hypercalcemia-Part 2: A Longitudinal Observational Study. J Clin Endocrinol Metab, 2021. 106 (10): p. 2938-2948. Wang, Z., et al., An inducible cytochrome P450 3A4-dependent vitamin D catabolic pathway. Mol Pharmacol, 2012. 81 (4): p. 498-509. Khan, Z., et al., A Case of Delayed Diagnosis of Idiopathic Infantile Hypercalcemia Due to CYP24A1 Mutation: A 10-Year Journey. Cureus, 2023. 15 (8): p. e42811. Khan, A., et al., Cinacalcet normalizes serum calcium in a double-blind randomized, placebo-controlled study in patients with primary hyperparathyroidism with contraindications to surgery. Eur J Endocrinol, 2015. 172 (5): p. 527-35. Okuno, S., et al., Effects of Long-Term Cinacalcet Administration on Parathyroid Gland in Hemodialysis Patients with Secondary Hyperparathyroidism. Nephron, 2019. 142 (2): p. 106-113. Additional Declarations No competing interests reported. Supplementary Files sup.mat..docx 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. 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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-5775940","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Short Report","associatedPublications":[],"authors":[{"id":398899324,"identity":"e6594981-ba42-469c-8652-0fd64f16dc12","order_by":0,"name":"Fatma Tuğçe Şah Ünal","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA3klEQVRIiWNgGAWjYBAC9gYYS4L5AIiUIaiF5wAzTAtbAojkIUULjwFYgLAWBv5jkl9qbOz5Z/d8fnWjxoKHgf3w0Q34tTCzScscS0uccefsNuucY0CH8aSl3cCnxR6kRbLhcALDjdxtxjlsQC0SPGZ4tfBAtPy3l7+R88w45x+RWiQ/Nhxg3HAjh/lxbhsxWpiZja0ZjiUnbryRZsac2yfBw0bILzzsjQ9v/qixs5e7kfz4c863Ojl+9sPH8GphAEYLMzQu2CTAJF7lUMD4A6r7AzGqR8EoGAWjYOQBAP/JP/6eCglzAAAAAElFTkSuQmCC","orcid":"","institution":"1.\tAnkara University Faculty of Medicine, Department of Endocrinology and Metabolic Diseases","correspondingAuthor":true,"prefix":"","firstName":"Fatma","middleName":"Tuğçe Şah","lastName":"Ünal","suffix":""},{"id":398899325,"identity":"5b945a3a-91a4-4248-9283-745f9dcbc669","order_by":1,"name":"Esra Eraslan Aydemir","email":"","orcid":"","institution":"1.\tAnkara University Faculty of Medicine, Department of Endocrinology and Metabolic Diseases","correspondingAuthor":false,"prefix":"","firstName":"Esra","middleName":"Eraslan","lastName":"Aydemir","suffix":""},{"id":398899326,"identity":"db8f667a-a9a3-438f-8615-878d1b42b828","order_by":2,"name":"Can Berk Leblebici","email":"","orcid":"","institution":"2.\tAnkara University Faculty of Medicine, Department of Medical Genetics","correspondingAuthor":false,"prefix":"","firstName":"Can","middleName":"Berk","lastName":"Leblebici","suffix":""},{"id":398899327,"identity":"2c401abe-6038-4422-8735-071d1de74dc9","order_by":3,"name":"Nüket Yürür Kutlay","email":"","orcid":"","institution":"2.\tAnkara University Faculty of Medicine, Department of Medical Genetics","correspondingAuthor":false,"prefix":"","firstName":"Nüket","middleName":"Yürür","lastName":"Kutlay","suffix":""},{"id":398899328,"identity":"546c8c7f-9ea6-470d-a215-bf475665595d","order_by":4,"name":"Murat Faik Erdoğan","email":"","orcid":"","institution":"1.\tAnkara University Faculty of Medicine, Department of Endocrinology and Metabolic Diseases","correspondingAuthor":false,"prefix":"","firstName":"Murat","middleName":"Faik","lastName":"Erdoğan","suffix":""}],"badges":[],"createdAt":"2025-01-06 18:38:15","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5775940/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5775940/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":73673583,"identity":"2e75057d-2277-472c-86b9-1f4927f6d357","added_by":"auto","created_at":"2025-01-13 12:53:57","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":44127,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAdjusted (Adj.) Ca and 24-hour urinary calcium levels measured during follow-up\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-5775940/v1/b5cb0e63174d73aabdb9b495.png"},{"id":74989664,"identity":"3b492970-2174-48ca-8414-39fe02ea2ce6","added_by":"auto","created_at":"2025-01-29 07:01:49","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":509702,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5775940/v1/04e918f9-e54d-4cf6-b6cf-448cbf4689d8.pdf"},{"id":73671925,"identity":"4c4259bd-9d9d-4db7-a67c-9dd29a2491f6","added_by":"auto","created_at":"2025-01-13 12:45:57","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":18095,"visible":true,"origin":"","legend":"","description":"","filename":"sup.mat..docx","url":"https://assets-eu.researchsquare.com/files/rs-5775940/v1/9eef7f87c8fda51e2545155b.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"A Rare Cause of Hypercalcemia In Adults: Idiopathic Infantile Hypercalcemia","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eHypercalcemia is a frequently encountered clinical condition, with its prevalence and incidence varying across different populations. While approximately 0.6% of patients presenting to the emergency department exhibit hypercalcemia, its prevalence in the general population is around 1 in 1000 individuals [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. From an etiological standpoint, hypercalcemia is classified as either parathyroid hormone (PTH)-dependent or PTH-independent [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Elevated or inappropriately normal PTH levels in the presence of hypercalcemia suggest a PTH-dependent mechanism, whereas suppressed PTH levels are indicative of a PTH-independent process. The majority of hypercalcemia cases, accounting for 80\u0026ndash;90%, are attributed to primary hyperparathyroidism or malignancies, with less common causes including vitamin D-mediated hypercalcemia [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eVitamin D metabolism plays a pivotal role in calcium and phosphate homeostasis. It involves a complex interplay of enzymatic steps, where the biologically active form, 1,25-dihydroxyvitamin D, is synthesized through hydroxylation processes regulated by CYP27B1 and subsequently inactivated by \u003cem\u003eCYP24A1\u003c/em\u003e [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Disruptions in this finely tuned process can lead to pathological conditions such as idiopathic infantile hypercalcemia (IIH), a rare, PTH-independent genetic disorder. IIH is most commonly diagnosed in pediatric patients and is associated with genetic variants in \u003cem\u003eCYP24A1\u003c/em\u003e or \u003cem\u003eSLC34A1\u003c/em\u003e. These defects result in excessive accumulation of active vitamin D metabolites, leading to persistent hypercalcemia, hypercalciuria, suppressed PTH levels, and an increased risk of nephrocalcinosis and nephrolithiasis. Although described as \"infantile,\" IIH can manifest later in life, including adulthood.\u003c/p\u003e \u003cp\u003eHere, we report a rare case of IIH in a 60-year-old male who was extensively evaluated over several years for PTH-independent hypercalcemia, initially suspected to be malignancy-related. Genetic analysis confirmed the diagnosis of IIH, and subsequent family screening revealed four asymptomatic carriers of the genetic variants. This case underscores the importance of considering rare genetic causes like IIH in the differential diagnosis of unexplained hypercalcemia, even in older patients.\u003c/p\u003e"},{"header":"CASE PRESENTATION","content":"\u003cp\u003eA 60-year-old male with a 25-year history of type 2 diabetes presented with renal failure and hypercalcemia detected 8 years ago. He reported a history of recurrent nephrolithiasis spanning over 20 years, passing kidney stones 1\u0026ndash;2 times per year. Despite suboptimal glucose regulation, no micro- or macrovascular diabetic complications were observed.\u003c/p\u003e \u003cp\u003eIn 2017, laboratory evaluations revealed elevated serum calcium and creatinine levels, suppressed PTH, normal phosphorus and 25(OH)D\u003csub\u003e3\u003c/sub\u003e levels, and increased 24-hour urinary calcium excretion. Imaging confirmed medullary nephrocalcinosis and chronic kidney disease. Kidney stone analysis identified calcium oxalate (Whewellite, Weddellite) and calcium phosphate (Hydroxylapatite) stones. Extensive evaluations ruled out malignancy (normal PSA, stable 5-mm subsolid nodule on thoracic CT, and no hypermetabolic foci on 18F-FDG-PET CT) and granulomatous disease (normal ACE levels, no lymphadenopathy). Recurrent urinary stone disease necessitated double-J catheter placement in 2019 and 2020. DEXA scanning revealed osteopenia in the lumbar spine. Further biochemical tests in 2023 showed normal PTHrP (1.6 pmol/L) and 1,25(OH)2D3 (24.18 pg/mL) levels, though 24,25(OH)2D3 levels were unavailable. Despite ongoing investigations, no definitive etiology for the PTH-independent hypercalcemia was determined. The patient's laboratory test results are provided in the supplementary materials.\u003c/p\u003e \u003cp\u003eThe index patient had a family history of renal stones, though serum calcium levels in relatives were unknown. Genetic sequencing for IIH was performed using the next-generation sequencing (NGS) method with primers covering exon/exon-intron junctions in the \u003cem\u003eCYP24A1\u003c/em\u003e gene. NGS analysis revealed a heterozygous likely pathogenic variant c.428_430del, p.(Glu143del) (rs777676129) in exon 2, and a heterozygous pathogenic variant c.1186C\u0026thinsp;\u0026gt;\u0026thinsp;T, p.(Arg396Trp) (rs114368325) in exon 9 of the \u003cem\u003eCYP24A1\u003c/em\u003e gene in the index patient, H.Y. These findings were compatible with IIH type 1 (Table\u0026nbsp;1).\u003c/p\u003e \u003cp\u003eTable\u0026nbsp;1: Demographic, biochemical, and genetic parameters of the index patient\u0026rsquo;s and his four siblings\u003c/p\u003e\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"739\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003eH.Y.\u003c/p\u003e\n \u003cp\u003e(Index case)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003eF.D.\u003c/p\u003e\n \u003cp\u003e(Sister)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003eE.K.\u003c/p\u003e\n \u003cp\u003e(Sister)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003eC.Y.\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(Brother)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003eG.E.\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(Sister)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 135px;\"\u003e\n \u003cp\u003eStandart Values\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 135px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003eCreatinine (mg/dL )\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e2.41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e0.71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e0.73\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e0.68\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e0.81\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 135px;\"\u003e\n \u003cp\u003e0.7-1.2 mg/dL\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003eEstimated GFR\u003c/p\u003e\n \u003cp\u003e(mL/min/1.73m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e28\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e91\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e97\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e98\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 135px;\"\u003e\n \u003cp\u003e\u0026gt;60 mL/min/1.73m\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003eUrea\u003c/p\u003e\n \u003cp\u003e(mg/dL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e98\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 135px;\"\u003e\n \u003cp\u003e12.8-42.8 mg/dL\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003eSerum Adjusted Calcium (mg/dL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e12.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e9.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e9.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e9.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 135px;\"\u003e\n \u003cp\u003e8.6-10.2 mg/dL\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003eSerum Phosphate (mg/dL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e4.29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e3.86\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e2.82\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 135px;\"\u003e\n \u003cp\u003e2.5-4.5 mg/dL\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003eParathormone (pg/mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e6\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 135px;\"\u003e\n \u003cp\u003e15-65 pg/mL\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e25(OH)D\u003csub\u003e3\u0026nbsp;\u003c/sub\u003e(\u0026micro;g/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e32.2\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e8.15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 135px;\"\u003e\n \u003cp\u003e10-60 \u0026micro;g/L\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003eUrinary calcium (mg/24 h)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e172\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e135\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e395\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e211\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 135px;\"\u003e\n \u003cp\u003e100-300 mg/24 h\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003eNL*/NC** history\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 135px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003eGenetic analysis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e\u003cem\u003eCYP24A1\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003ec.1186C\u0026gt;T\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eand c.428_430delAAG (Glu143del)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u003cem\u003eCYP24A1\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003ec.1186C\u0026gt;T, p.(Arg396Trp)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u003cem\u003eCYP24A1\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003ec.1186C\u0026gt;T,\u003c/p\u003e\n \u003cp\u003ec.428_430delAAG (Glu143del)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e\u003cem\u003eCYP24A1\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003ec.1186C\u0026gt;T and c.428_430delAAG (Glu143del)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e\u003cem\u003eCYP24A1\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003ec.1186C\u0026gt;T and c.428_430delAAG (Glu143del)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 135px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: * Nephrolithiasis, ** Nephrocalcinosis, NA: Not Available\u003c/p\u003e\n\u003cp\u003eThe patient initially followed a vitamin D and calcium-restricted diet, but his calcium levels remained high after three months. Fluconazole 50 mg/day was added, but calcium levels stayed elevated. He then started on cinacalcet, with a gradual dose increase from 30 mg to 60 mg/day. By the third month, his calcium levels decreased and remained normal on the 60 mg/day dose. Genetic testing for the patient\u0026rsquo;s children and siblings is planned. The patient\u0026apos;s biochemical results during treatment are shown in Figure 1.\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eIdiopathic infantile hypercalcemia (IIH) presents with varying clinical manifestations depending on age. Infants typically exhibit weight loss, vomiting, dehydration, lethargy, and hypotonia [5, 6], while some cases may be asymptomatic and discovered through family screening [5]. In adults, renal manifestations such as nephrolithiasis (NL) and nephrocalcinosis (NC) are common, along with polyuria. In adults, renal manifestations such as nephrolithiasis (NL), nephrocalcinosis (NC), and polyuria are common, with hypercalcemia symptoms ranging from mild to severe, including neuropsychiatric symptoms, gastrointestinal issues, hypertension, and pancreatitis [7-9] . The described patient developed NL, NC, and grade 3a renal failure, and since PTH-independent hypercalcemia was found, a malignancy evaluation was performed. Though IIH is rare, it should be considered as a cause of PTH-independent hypercalcemia in adults.\u003c/p\u003e\n\u003cp\u003eIIH is caused by bi-allelic (homozygous or compound heterozygous) mutations in the \u003cem\u003eCYP24A1\u0026nbsp;\u003c/em\u003egene. This results in a biochemical profile characterized by hypercalcemia, hypercalciuria, increased intestinal calcium absorption, suppressed PTH levels, and elevated or normal 1,25(OH)\u003csub\u003e2\u003c/sub\u003eD\u003csub\u003e3\u003c/sub\u003e levels. In symptomatic infants, calcium levels are often significantly high, whereas in adults, they are elevated but to a lesser extent. The 25(OH)D\u003csub\u003e3\u003c/sub\u003e level may be low, normal, or high. A defect in the 24-hydroxylase enzyme due to the \u003cem\u003eCYP24A1\u003c/em\u003e mutation results in low 24,25(OH)\u003csub\u003e2\u003c/sub\u003eD\u003csub\u003e3\u003c/sub\u003e levels, despite sufficient levels of the substrate 25(OH)D\u003csub\u003e3\u003c/sub\u003e. The 25(OH)D\u003csub\u003e3\u003c/sub\u003e /24,25(OH)\u003csub\u003e2\u003c/sub\u003eD\u003csub\u003e3\u003c/sub\u003e ratio can help differentiate IIH from other causes of hypercalcemia, with an elevated ratio typically seen in IIH patients. In healthy individuals, the ratio ranges from 7 to 35, but in those with \u003cem\u003eCYP24A1\u0026nbsp;\u003c/em\u003emutations, it exceeds 99, suggesting the need for genetic testing [8, 10-12]. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAutosomal recessive inheritance characterizes IIH, driven by homozygous or compound heterozygous variants in the \u003cem\u003eCYP24A1\u003c/em\u003e gene. However, genetic and environmental interactions lead to significant diversity in disease expression. Individuals with bi-allelic genetic variations exhibit a more severe phenotype compared to mono-allelic carriers, who are either asymptomatic or borderline [13]. In the described case, genetic analysis revealed bi-allelic mutations in the index patient and two siblings, consistent with IIH type 1. Two other siblings had mono-allelic mutations. This genetic variability explains the differing clinical presentations within the family. Environmental factors, particularly diet and sunlight exposure, significantly impact disease expression. The index patient, a farmer with significant sunlight exposure, likely experienced exacerbated symptoms due to his occupation\u003c/p\u003e\n\u003cp\u003eTreatment of IIH includes dietary restrictions on calcium and vitamin D, as well as sunlight avoidance [14, 15]. However, these lifestyle changes alone are often insufficient to control the disease or preserve kidney function [16]. Medical treatments targeting vitamin D metabolism are needed. The goal of a pharmaceutical strategy is to modify vitamin D metabolism to favor the activation of alternative catabolic pathways. Azole medications, such as fluconazole and ketoconazole, work by inhibiting the \u003cem\u003eCYP27B1\u003c/em\u003e enzyme and reducing 1,25(OH)\u003csub\u003e2\u003c/sub\u003eD\u003csub\u003e3\u003c/sub\u003e. The patient was initially treated with fluconazole 50 mg/day for three months, as it is less toxic than other options. Despite this, calcium levels remained high. There are also publications in which rifampin has been used in treatment as an effective inducer of \u003cem\u003eCYP3A4\u003c/em\u003e, a cytochrome involved in the metabolism of various xenobiotics, medications, and hormones, including vitamin D [17]. Recently, cinacalcet was reported to be helpful in these patients [18]. Cinacalcet is a calcimimetic drug that reduces serum calcium and PTH levels by activating calcium-sensing receptors (CaSR) in the parathyroid glands. Nausea, vomiting, and paresthesias were the most frequently reported side effects. These reactions were infrequent and tended to vary based on the dosage [19]. We gradually started cinacalcet and reached a dose of 60 mg/day. No side effects were observed during the 3-month follow-up, and the blood calcium level returned to normal. The patient has now completed the first year of treatment. Although no significant reduction in urinary calcium excretion was observed, there were no symptoms or findings related to renal stone disease during the past year.\u003c/p\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eIn conclusion, although idiopathic infantile hypercalcemia (IIH) is a rare cause of PTH-independent hypercalcemia in adults, it should not be overlooked. Early diagnosis of asymptomatic individuals through family screening can prevent many long-term complications. Lifestyle changes are often insufficient to control disease. Cinacalcet has been shown to be a viable option for inducing rapid and sustained reductions in serum calcium levels, with a favorable safety profile. Long-term use of cinacalcet has not been associated with any adverse outcomes [20]. Therefore, when a low-calcium diet and sunlight avoidance fail to modify the biochemical phenotype of IIH, cinacalcet may offer an effective alternative.\u003c/p\u003e\n\u003cp\u003eThe patient and the family gave written informed consent for the genetic analysis and the use of their clinical data for scientific purposes, including publication.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFatma Tuğ\u0026ccedil;e Şah \u0026Uuml;nal, Esra Eraslan Aydemir, Can Berk Leblebici, N\u0026uuml;ket Y\u0026uuml;r\u0026uuml;r Kutlay, and Murat Faik Erdoğan meet the authorship criteria according to the latest guidelines of the International Committee of Medical Journal Editors (ICMJE). All authors have seen and approved the manuscript being submitted and published.\u003c/p\u003e\n\u003cp\u003eFatma Tuğ\u0026ccedil;e Şah \u0026Uuml;nal contributed to the diagnosis, treatment, and follow-up of the patient and to the writing of the case report.\u003c/p\u003e\n\u003cp\u003eEsra Eraslan Aydemir contributed to the diagnosis, treatment, and follow-up of the patient.\u003c/p\u003e\n\u003cp\u003eCan Berk Leblebici contributed to the genetic analysis and its interpretation.\u003c/p\u003e\n\u003cp\u003eN\u0026uuml;ket Y\u0026uuml;r\u0026uuml;r Kutlay contributed to the genetic analysis and its interpretation.\u003c/p\u003e\n\u003cp\u003eMurat Faik Erdoğan reviewed and finalized the manuscript and was responsible for the patient\u0026apos;s treatment.\u003c/p\u003e\n\u003cp\u003eGuarantor:Murat Faik Erdoğan is the guarantor of the work and accepts full responsibility for the integrity of the case report.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical Considerations and Approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was conducted in compliance with the Good Clinical Practices protocol and the principles of the Declaration of Helsinki. This is a case report. The Ankara University Research Ethics Committee has confirmed that no ethical approval is required.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for Publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll patients were informed about the study procedures and provided written consent for participation and publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFatma Tuğ\u0026ccedil;e Şah \u0026Uuml;nal, Esra Eraslan Aydemir, Can Berk Leblebici, N\u0026uuml;ket Y\u0026uuml;r\u0026uuml;r Kutlay, and Murat Faik Erdoğan declare that they have no conflict of interest. The ICMJE Conflict of Interest form for each author is attached herewith.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors did not receive any specific grants from funding agencies in the public, commercial, or not-for-profit sectors for this research.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data related to the presented patients are available in the hospital records where they are being followed. This data can be made available to editors, reviewers, and readers upon reasonable request.\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003e\u0026nbsp;The authors have no relevant financial or non-financial interests to disclose.\u003c/li\u003e\n \u003cli\u003e\u0026nbsp;The authors have no competing interests to declare that are relevant to the content of this article.\u003c/li\u003e\n \u003cli\u003eAll authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript.\u003c/li\u003e\n \u003cli\u003eThe authors have no financial or proprietary interests in any material discussed in this article.\u003c/li\u003e\n\u003c/ul\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eTurner, J.J.O., \u003cem\u003eHypercalcaemia - presentation and management\u0026ensp;\u003c/em\u003eClin Med (Lond), 2017. \u003cstrong\u003e17\u003c/strong\u003e(3): p. 270-273.\u003c/li\u003e\n\u003cli\u003eWalker, M.D. and E. 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Sellmeyer, \u003cem\u003eRare Causes of Hypercalcemia: 2021 Update.\u003c/em\u003e J Clin Endocrinol Metab, 2021. \u003cstrong\u003e106\u003c/strong\u003e(11): p. 3113-3128.\u003c/li\u003e\n\u003cli\u003eChristakos, S., et al., \u003cem\u003eVitamin D: metabolism.\u003c/em\u003e Endocrinol Metab Clin North Am, 2010. \u003cstrong\u003e39\u003c/strong\u003e(2): p. 243-53, table of contents.\u003c/li\u003e\n\u003cli\u003eSchlingmann, K.P., et al., \u003cem\u003eMutations in CYP24A1 and idiopathic infantile hypercalcemia.\u003c/em\u003e N Engl J Med, 2011. \u003cstrong\u003e365\u003c/strong\u003e(5): p. 410-21.\u003c/li\u003e\n\u003cli\u003eFencl, F., et al., \u003cem\u003eSevere hypercalcemic crisis in an infant with idiopathic infantile hypercalcemia caused by mutation in CYP24A1 gene.\u003c/em\u003e Eur J Pediatr, 2013. \u003cstrong\u003e172\u003c/strong\u003e(1): p. 45-9.\u003c/li\u003e\n\u003cli\u003eNesterova, G., et al., \u003cem\u003e1,25-(OH)2D-24 Hydroxylase (CYP24A1) Deficiency as a Cause of Nephrolithiasis.\u003c/em\u003e Clin J Am Soc Nephrol, 2013. \u003cstrong\u003e8\u003c/strong\u003e(4): p. 649-57.\u003c/li\u003e\n\u003cli\u003eJacobs, T.P., et al., \u003cem\u003eA lifetime of hypercalcemia and hypercalciuria, finally explained.\u003c/em\u003e J Clin Endocrinol Metab, 2014. \u003cstrong\u003e99\u003c/strong\u003e(3): p. 708-12.\u003c/li\u003e\n\u003cli\u003eGray, T.K., W. Lowe, and G.E. Lester, \u003cem\u003eVitamin D and pregnancy: the maternal-fetal metabolism of vitamin D.\u003c/em\u003e Endocr Rev, 1981. \u003cstrong\u003e2\u003c/strong\u003e(3): p. 264-74.\u003c/li\u003e\n\u003cli\u003eTebben, P.J., et al., \u003cem\u003eHypercalcemia, hypercalciuria, and elevated calcitriol concentrations with autosomal dominant transmission due to CYP24A1 mutations: effects of ketoconazole therapy.\u003c/em\u003e J Clin Endocrinol Metab, 2012. \u003cstrong\u003e97\u003c/strong\u003e(3): p. E423-7.\u003c/li\u003e\n\u003cli\u003eShah, A.D., et al., \u003cem\u003eMaternal Hypercalcemia Due to Failure of 1,25-Dihydroxyvitamin-D3 Catabolism in a Patient With CYP24A1 Mutations.\u003c/em\u003e J Clin Endocrinol Metab, 2015. \u003cstrong\u003e100\u003c/strong\u003e(8): p. 2832-6.\u003c/li\u003e\n\u003cli\u003eDrezner, M.K., et al., \u003cem\u003e1,25-Dihydroxycholecalciferol deficiency: the probable cause of hypocalcemia and metabolic bone disease in pseudohypoparathyroidism.\u003c/em\u003e J Clin Endocrinol Metab, 1976. \u003cstrong\u003e42\u003c/strong\u003e(4): p. 621-8.\u003c/li\u003e\n\u003cli\u003eCarpenter, T.O., \u003cem\u003eCYP24A1 loss of function: Clinical phenotype of monoallelic and biallelic mutations.\u003c/em\u003e J Steroid Biochem Mol Biol, 2017. \u003cstrong\u003e173\u003c/strong\u003e: p. 337-340.\u003c/li\u003e\n\u003cli\u003eCappellani, D., et al., \u003cem\u003eHereditary hypercalcemia caused by a homozygous pathogenic variant in the CYP24A1 gene: a case report and review of the literature.\u003c/em\u003e Case reports in endocrinology, 2019. \u003cstrong\u003e2019\u003c/strong\u003e(1): p. 4982621.\u003c/li\u003e\n\u003cli\u003eBrancatella, A., et al., \u003cem\u003eDo the Heterozygous Carriers of a CYP24A1 Mutation Display a Different Biochemical Phenotype Than Wild Types?\u003c/em\u003e J Clin Endocrinol Metab, 2021. \u003cstrong\u003e106\u003c/strong\u003e(3): p. 708-717.\u003c/li\u003e\n\u003cli\u003eLenherr-Taube, N., et al., \u003cem\u003eMild Idiopathic Infantile Hypercalcemia-Part 2: A Longitudinal Observational Study.\u003c/em\u003e J Clin Endocrinol Metab, 2021. \u003cstrong\u003e106\u003c/strong\u003e(10): p. 2938-2948.\u003c/li\u003e\n\u003cli\u003eWang, Z., et al., \u003cem\u003eAn inducible cytochrome P450 3A4-dependent vitamin D catabolic pathway.\u003c/em\u003e Mol Pharmacol, 2012. \u003cstrong\u003e81\u003c/strong\u003e(4): p. 498-509.\u003c/li\u003e\n\u003cli\u003eKhan, Z., et al., \u003cem\u003eA Case of Delayed Diagnosis of Idiopathic Infantile Hypercalcemia Due to CYP24A1 Mutation: A 10-Year Journey.\u003c/em\u003e Cureus, 2023. \u003cstrong\u003e15\u003c/strong\u003e(8): p. e42811.\u003c/li\u003e\n\u003cli\u003eKhan, A., et al., \u003cem\u003eCinacalcet normalizes serum calcium in a double-blind randomized, placebo-controlled study in patients with primary hyperparathyroidism with contraindications to surgery.\u003c/em\u003e Eur J Endocrinol, 2015. \u003cstrong\u003e172\u003c/strong\u003e(5): p. 527-35.\u003c/li\u003e\n\u003cli\u003eOkuno, S., et al., \u003cem\u003eEffects of Long-Term Cinacalcet Administration on Parathyroid Gland in Hemodialysis Patients with Secondary Hyperparathyroidism.\u003c/em\u003e Nephron, 2019. \u003cstrong\u003e142\u003c/strong\u003e(2): p. 106-113.\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":"Idiopathic Infantile Hypercalcemia (IIH), Hypercalcemia, CYP24A1 mutation, Cinacalcet, Parathyroid hormone","lastPublishedDoi":"10.21203/rs.3.rs-5775940/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5775940/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eIdiopathic Infantile Hypercalcemia (IIH) is a rare disorder marked by PTH-independent hypercalcemia, usually diagnosed in infancy, with adult cases being uncommon. This report discusses a 60-year-old male with a 25-year history of type 2 diabetes, recurrent kidney stones, and stage 3a chronic kidney disease. Laboratory findings included hypercalcemia, normal phosphorus and 25-hydroxycholecalciferol levels, and suppressed PTH. Urinary ultrasonography revealed medullary nephrocalcinosis.\u003c/p\u003e \u003cp\u003eComprehensive evaluation ruled out malignancies, granulomatous diseases, and endocrinopathies. Genetic testing identified compound heterozygous mutations in the \u003cem\u003eCYP24A1\u003c/em\u003e gene, confirming IIH type 1. Initial management involved calcium- and vitamin D-restricted diets and sunlight avoidance. When hypercalcemia persisted, fluconazole treatment (50 mg/day) was trialed but proved ineffective. Cinacalcet (60 mg/day) was subsequently introduced, successfully normalizing serum calcium levels.\u003c/p\u003e \u003cp\u003eFamily genetic screening revealed biallelic mutations in two siblings and heterozygous mutations in two others, though none exhibited hypercalcemia.\u003c/p\u003e \u003cp\u003eThis case underscores the need for heightened awareness of IIH in adults, advocating for family screening to detect asymptomatic carriers early. The effectiveness of cinacalcet in managing adult IIH highlights its therapeutic potential when lifestyle modifications alone are insufficient, preventing long-term complications from untreated hypercalcemia.\u003c/p\u003e","manuscriptTitle":"A Rare Cause of Hypercalcemia In Adults: Idiopathic Infantile Hypercalcemia","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-01-13 12:45:52","doi":"10.21203/rs.3.rs-5775940/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":"e3ed91c1-5add-4fa9-9cf6-a44c900f2384","owner":[],"postedDate":"January 13th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-01-29T06:53:38+00:00","versionOfRecord":[],"versionCreatedAt":"2025-01-13 12:45:52","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5775940","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5775940","identity":"rs-5775940","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}