Williams syndrome presenting as infantile hypercalcemia with acute kidney injury: A case report

Williams syndrome presenting as infantile hypercalcemia with acute kidney injury: A case report | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Williams syndrome presenting as infantile hypercalcemia with acute kidney injury: A case report Eshter Park, Soon Chul Kim This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3693127/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 Williams syndrome is an autosomal-dominant multisystem disorder. Infantile hypercalcemia has been documented in 15% of infants with Williams syndrome, and is commonly transient and mild. The need for pamidronate therapy has been reported in a few cases of Williams syndrome with severe hypercalcemia. Few cases of acute kidney injury due to severe hypercalcemia during Williams syndrome have also been recorded. We report the case of an infant with Williams syndrome who presented with acute kidney injury and severe hypercalcemia and was treated with intravenous pamidronate. In addition, we aimed to consider management strategies that maintain renal function and promote growth until adulthood. Williams syndrome Hypercalcemia Acute kidney injury Pamidronate Figures Figure 1 Figure 2 INTRODUCTION Williams syndrome (WS) (OMIM 194050) is an autosomal dominant multisystem disorder caused by the deletion of 1.5–1.8 Mb on chromosome 7q11.23. 1,2 The prevalence of WS is approximately 1/7,500 to 1/25,000 newborns. 2-4 WS is characterized by a dysmorphic facial appearance, specific neurocognitive profile, cardiovascular disease, and infantile hypercalcemia. 2 Hypercalcemia is typically mild and transient in the first few years of life; however, it can occasionally be severe and life-threatening. 4 Only two cases of acute kidney injury (AKI) due to hypercalcemia and nephrocalcinosis in patients with WS have been reported. 5,6 Herein, we report a rare case of WS in an infant who presented with AKI associated with severe hypercalcemia and was treated with intravenous pamidronate. Based on a literature review, we also suggest the treatment and management of severe hypercalcemia in WS, which has not been previously established. CASE DESCRIPTION A 12-month-old girl was brought to our hospital because of developmental delay and failure to thrive. She was born via Cesarean section at 39 weeks of gestation with a birth weight of 2800 g. She was the fourth child of non-consanguineous, healthy parents with no family history of a specific disease. She was breastfed or formula-fed until 6 months of age, and her diet consisted of mixed food. On admission, her body weight, height, and head circumference were 6700 g (−2.428 standard deviation score [SDS]), 72.1 cm (−0.743 SDS), and 42.5 cm (<3 rd percentile for age), respectively. She had a flat nose bridge and thick lips. Her blood pressure was 95/51 mmHg, and her pulse rate was 137 beats/min. The patient’s respiratory rate was 42 breaths/min, and her body temperature was 38.2 ℃. The patient was alert. Physical examination revealed generalized hypotonia with hyperextensible joints in the lower extremities. On developmental assessment, she was neither rolling over nor speaking “da” or “ba” at 12 months. The laboratory results on admission were as follows: total white blood cell count, 14,840/mm 3 ;hemoglobin, 11.3 g/dL; platelet count, 303,000/mm 3 ; sodium, 137 mEq/L; potassium, 4.7 mEq/L; chloride, 101 mEq/L; total calcium (Ca), 17.1 mg/dL (4.3 mmol/L); ionized calcium (iCa), 8.1 mg/dL (2.0 mmol/L); phosphorus, 5.5 mg/dL; blood urea nitrogen (BUN), 49 mg/dL; creatinine (Cr), 1.0 mg/dL; cystatin-C, 2.89 mg/L; uric acid, 8.0 mg/dL; alkaline phosphatase, 106 U/L; intact parathyroid hormone (PTH), 28.54 pg/mL; 25-hydroxyvitamin D (25-OHD), 118.6 ng/mL; thyroid-stimulating hormone, 3.86 uIU/mL; and free thyroxine, 13.20 pmol/L. Glomerular filtration rate (GFR) was calculated using a modified Schwartz formula. 7 Her GFR, venous pH, pCO 2 , HCO 3 , base excess, and anion gap were 30 mL/min/1.73 m 2 , 7.39 mmHg, 30.5 mmHg, 18.2 mmol/L, −5.3 mmol/L, and 15.5 mL/dL, respectively. Urinalysis revealed a pH of 6.5, specific gravity of 1.010, and negative protein on the dipstick. The spot urine test results were as follows: calcium/creatinine (Ca/Cr) ratio, 1.94 mg/mg (normal < 0.5mg/mg); osmolality, 318 mOsm/kg; and fractional excretion of sodium, 8.9%. Renal ultrasonography revealed increased parenchymal echogenicity, poor corticomedullary differentiation, and tiny cystic lesions in both the kidneys. Multiple hyperechogenic foci were observed in the right kidney cortex, some of which had posterior shadowing (Fig. 1). Echocardiography and cardiac computed tomography revealed an anomalous origin of the right coronary artery. Fluorescence in-situ hybridization analysis revealed a microdeletion in the elastin gene in the 7q11.23 region of the seventh chromosome, which was positive for WS. Abdominal computed tomography performed at 2 years of age revealed that both the kidneys contained tiny cysts. The right kidney cortex demonstrates diffuse hyperechoic foci. This finding suggests complications such as AKI, multiple tiny angiomyolipomas, or emphysematous changes (Fig. 2). Intravenous fluid, furosemide (1 mg/kg/dose, q6hr), and prednisolone (2 mg/kg/day) were administered to treat hypercalcemia. However, the patient’s calcium level did not return to the normal range after 14 days of standard treatment. The patient received 1-day intravenously administered pamidronate (1 mg/kg), and her serum calcium level normalized 5 days later. The GFR also gradually improved to 46 mL/min/1.73 m 2 . The patient was discharged from the hospital with an unrestricted calcium diet. At 7 weeks later, a second pamidronate infusion was administered because the iCa level (1.75 mmol/L) increased. After two pamidronate infusion treatments, the serum Ca levels were maintained within the normal range without any adverse effects. At the follow-up visit at 18 months of age, the serum uric acid level (8.5 mg/dL) had increased, and furosemide was discontinued. At the last follow-up visit at 22 months of age, her serum total iCa level was normal at 1.28 mmol/L with a urinary Ca/Cr ratio of 0.03 mg/mg on an unrestricted diet. However, her BUN, Cr, and cystatin-C levels remained high at 33 mg/dL, 0.65 mg/dL, and 2.27 mg/L, respectively (GFR 48 mL/min/1.73 m 2 ). Her hypercalcemia and hypercalciuria improved, and we await the complete recovery of her renal function. DISCUSSION WS, also known as Williams–Beuren syndrome, is characterized by dysmorphic facial features, intellectual disability/developmental delay, cardiovascular abnormalities, gastrointestinal difficulties, and infantile hypercalcemia. 2,4 Although infantile hypercalcemia is a well-known sign of WS, its cause is unknown and may not be PTH-dependent or excessive 25-OHD. 4 Increased calcium absorption from the gastrointestinal tract caused by haploinsufficiency of the general transcription factor II-I gene in the WS-deleted region may play a role. 4 Moreover, WS transcription factor may increase 1,25(OH)2D concentrations, thereby enhancing intestinal calcium absorption. 4 Hypercalcemia may manifest as irritability, feeding difficulties, vomiting, constipation, and hypotonia, although it is typically mild and asymptomatic. 4 The patient was irritable and developed hypotonia. Although we were unable to analyze 1.25-(OH)-vitamin D levels, they were within the normal range in our patient, suggesting a non-vitamin D-mediated cause of hypercalcemia. The PTH levels in our patient were normal. In most patients with WS, hypercalcemia improves spontaneously or can be treated with conventional therapies, such as intravenous hydration, diuretics, glucocorticoids, and dietary calcium restriction. 4 In rare cases, severe hypercalcemia in patients with WS may require additional therapies such as bisphosphonates. 5 Because pamidronate inhibits osteoclast activity in the bone, it is effectively used to treat hypercalcemia caused by various disorders. 5 In several case reports, intravenous pamidronate was used to treat severe hypercalcemia unresponsive to conventional treatments for WS-associated hypercalcemia. 5,8-13 Similar to previous reports, hypercalcemia was effectively controlled with two doses of pamidronate in our patient. Hypercalcemia decreases the GFR and causes AKI. 14 Only two case reports of AKI associated with hypercalcemia in patients with WS have been published. 5,6 Pober et al. have reported a case of transient renal failure caused by nephrocalcinosis and hypercalcemia in an 18-month-old boy with WS owing to nephrocalcinosis and hypercalcemia. 6 The patient’s serum BUN and Cr levels were 43 mg/dl and 1.4 mg/dL, respectively. 6 Baştuğ F et al. have reported effective treatment of AKI caused by hypercalcemia and nephrocalcinosis in a 23-month-old girl with WS. 5 The patient’s initial serum total Ca, BUN, and Cr levels were 16, 38, and 1.7 mg/dL, respectively. 5 Renal function was restored after treating hypercalcemia with two doses of pamidronate infusions. 5 In severe hypercalcemia, direct renal vasoconstriction contributes to a reversible decrease in the GFR. 14 Moreover, impairment of the urinary concentrating ability, which causes polyuria, leads to volume depletion, which further deteriorates kidney function. 14 This is may be caused by the downregulation of aquaporin 2 water channels in the collecting tubules and tubulointerstitial damage due to Ca deposition in the medulla. 14 Hypercalcemia-induced AKI can be typically reversed by decreasing serum calcium concentrations and increasing volume. 14 Refractory hypercalcemia may induce AKI in WS, and pamidronate can be used to treat AKI in patients with refractory hypercalcemia. Our patient presented with non-oliguric AKI, severe hypercalcemia, and hypercalciuria. After hospitalization, hypercalcemia was treated with pamidronate, and renal function improved. The patient is continuously being monitored in an outpatient clinic, and the amounts of serum calcium and urine excretion calcium have normalized. However, serum BUN, Cr, and cystatin C levels did not reach the normal range in mildly elevated states. This is a risk factor for progression to AKI or chronic kidney disease, which may recur. Therefore, patients with high anxiety should be monitored. To date, AKI in patients with WS has not progressed to chronic kidney disease; however, such cases are very rare. In fact, during the growth phase, the timing of recurrence of such changes in electrolytes and deterioration of renal function is difficult to determine despite a literature review and discussion. Therefore, the only current management policy is to evaluate and observe the patient's condition and laboratory results in an outpatient clinic while increasing the follow-up interval. To the best of our knowledge, this is the first report of AKI recovery following an improvement in hypercalcemia after pamidronate infusion in infants with WS. Occasionally, hypercalcemia in infants with WS can be severe and life-threatening. We emphasize the importance of early detection and evaluation of WS-presenting infants with AKI and hypercalcemia as well as their appropriate management to improve patient outcomes. Moreover, intravenous pamidronate is a reasonable treatment option for infants with WS and life-threatening hypercalcemia. Declarations Data Availability The datasets used in this study are available from the corresponding author upon reasonable request. Acknowledgements Not applicable. Funding This study was supported by the Biomedical Research Institute of Jeonbuk National University Hospital (2024). Ethics statement This study was approved by the Institutional Review Board (IRB) of the Jeonbuk National University Hospital (IRB no. 2022-12-020). Written informed consent for publication was obtained from the patient’s guardian. Conflict of interest The authors have no potential conflicts of interest to disclose. Author Contributions Conceptualization: Park E, Kim SC. Writing - original draft: Park E. Writing - review & editing: Kim SC. References Mervis CB, Morris CA. Williams syndrome. Neurogenetic developmental disorders: Variation of manifestation in childhood 2007:199-262. Morris CA. Introduction: Williams syndrome. Am J Med Genet C Semin Med Genet 2010;154C(2):203-8. Sugayama SMM, Koch VHK, Furusawa ÉA, Leone C, Kim CA. Renal and urinary findings in 20 patients with Williams-Beuren syndrome diagnosed by fluorescence in situ hybridization (FISH). Revista do Hospital das Clínicas 2004;59(5):266-72. Stanley TL, Leong A, Pober BR. Growth, body composition, and endocrine issues in Williams syndrome. Curr Opin Endocrinol Diabetes Obes 2021;28(1):64-74. Bastug F, Nalcacioglu H, Bas VN, Tekatli-Celik B, Cetinkaya H, Yel S. Acute renal failure due to severe hypercalcemia and nephrocalcinosis treated with two doses of pamidronate in an infant with Williams-Beuren syndrome. Turk J Pediatr 2018;60(2):210-5. Pober BR, Lacro RV, Rice C, Mandell V, Teele RL. Renal findings in 40 individuals with Williams syndrome. Am J Med Genet 1993;46(3):271-4. Schwartz GJ, Munoz A, Schneider MF, Mak RH, Kaskel F, Warady BA, et al. New Equations to Estimate GFR in Children with CKD. Journal of the American Society of Nephrology 2009;20(3):629-37. Sanjad SA, Aoun B, Yammine H, Bassyouni A, Karam PE. Pamidronate Rescue Therapy for Hypercalcemia in a Child With Williams Syndrome. Front Endocrinol (Lausanne) 2018;9:240. Gupta V, Pandita A, Panghal A, Kallem VR. Williams syndrome with severe hypercalcaemia. BMJ Case Rep 2018;2018. Sangun O, Dundar BN, Erdogan E. Severe hypercalcemia associated with Williams syndrome successfully treated with pamidronate infusion therapy. J Pediatr Endocrinol Metab 2011;24(1-2):69-70. Cagle AP, Waguespack SG, Buckingham BA, Shankar RR, Dimeglio LA. Severe infantile hypercalcemia associated with Williams syndrome successfully treated with intravenously administered pamidronate. Pediatrics 2004;114(4):1091-5. Oliveri B, Mastaglia SR, Mautalen C, Gravano JC, Pardo Argerich L. Long-term control of hypercalcaemia in an infant with williams-Beuren syndrome after a single infusion of biphosphonate (Pamidronate). Acta Paediatr 2004;93(7):1002-3. Ismail J. Pamidronate for long-term control of hypercalcemia associated with Williams syndrome. Indian Pediatr 2015;52(2):163-4. Bhat NA, Mustafa F, Sheikh RY, Wani I. Incidence, etiology, and course of hypercalcemia-induced AKI in a tertiary care center from northern India. The Egyptian Journal of Internal Medicine 2021;33(1):36. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3693127","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":277913190,"identity":"bd194b35-c2e2-4880-81f6-c4d97d2f1b25","order_by":0,"name":"Eshter Park","email":"","orcid":"","institution":"Department of Pediatrics, Jeonbuk National University Children’s Hospital","correspondingAuthor":false,"prefix":"","firstName":"Eshter","middleName":"","lastName":"Park","suffix":""},{"id":277913191,"identity":"7d89fc9e-9e18-4601-a982-366584ff689e","order_by":1,"name":"Soon Chul Kim","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA7klEQVRIie2PsYrCMBiAI4V2+VPXlhR8hZZAHSz6MIFOwbvbBAdfIA9g8T0yWzp0yQNEnERwEwSHOxDk4nUTSW90yDeEf8iX7w9CDsfbAhGMAtGN4f+UpEgyoTrFf5zbXqUoC6R5N/cqoWb18ZM3MKjO9fWLTxMf4fp4sSixLhldqwYCMmekkswsFrLUVkk1zwkWprLhKcHSMwrkkV35+L7hewNop+gNy9VDGf/0VHwPoASkweRk81exfj9WJ0oACsgEzydYtmBeoJGyKGHLDleAaDYKFN1juZwNA5FdFhblxQqe7fprxeFwOBxP/AJuQUPwM6dhygAAAABJRU5ErkJggg==","orcid":"","institution":"Department of Pediatrics, Jeonbuk National University Children’s Hospital","correspondingAuthor":true,"prefix":"","firstName":"Soon","middleName":"Chul","lastName":"Kim","suffix":""}],"badges":[],"createdAt":"2023-12-01 15:14:22","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3693127/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3693127/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":52620337,"identity":"e8caa001-f9fa-4086-a68c-a33d0b85160c","added_by":"auto","created_at":"2024-03-13 16:45:30","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":175510,"visible":true,"origin":"","legend":"\u003cp\u003eUltrasonography revealed increased parenchymal echogenicity, poor corticomedullary differentiation, and tiny cystic lesions in both the kidneys.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-3693127/v1/b194d7b9bf76591786d0348c.png"},{"id":52620336,"identity":"2c185c38-540f-4c9d-8b0b-73714e838a4b","added_by":"auto","created_at":"2024-03-13 16:45:30","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":173878,"visible":true,"origin":"","legend":"\u003cp\u003eAbdominal computed tomography scan. Both the kidneys contained tiny cysts. The cortex of the right kidney had diffuse hyperechoic foci.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-3693127/v1/0a3c4e3ef1abf13bb3de3e26.png"},{"id":56995038,"identity":"976d3cfb-6233-4148-a5f9-8a431940675c","added_by":"auto","created_at":"2024-05-23 07:15:46","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":640794,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3693127/v1/cf3bab27-b446-43f4-99e8-959df3378252.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Williams syndrome presenting as infantile hypercalcemia with acute kidney injury: A case report","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eWilliams syndrome (WS) (OMIM 194050) is an autosomal dominant multisystem disorder caused by the deletion of 1.5–1.8 Mb on chromosome 7q11.23.\u003csup\u003e1,2\u003c/sup\u003e The prevalence of WS is approximately 1/7,500 to 1/25,000 newborns.\u003csup\u003e2-4\u003c/sup\u003e WS is characterized by a dysmorphic facial appearance, specific neurocognitive profile, cardiovascular disease, and infantile hypercalcemia.\u003csup\u003e2\u003c/sup\u003e Hypercalcemia is typically mild and transient in the first few years of life; however, it can occasionally be severe and life-threatening.\u003csup\u003e4\u003c/sup\u003e Only two cases of acute kidney injury (AKI) due to hypercalcemia and nephrocalcinosis in patients with WS have been reported.\u003csup\u003e5,6\u003c/sup\u003e Herein, we report a rare case of WS in an infant who presented with AKI associated with severe hypercalcemia and was treated with intravenous pamidronate. Based on a literature review, we also suggest the treatment and management of severe hypercalcemia in WS, which has not been previously established.\u003c/p\u003e"},{"header":"CASE DESCRIPTION","content":"\u003cp\u003eA 12-month-old\u0026nbsp;girl was brought to\u0026nbsp;our hospital because of developmental delay and failure to thrive. She was born via Cesarean section at 39 weeks of gestation with a birth weight of 2800 g. She was the fourth child of non-consanguineous, healthy parents with no family history of a specific disease. She was breastfed or formula-fed until 6 months of age, and her diet consisted of mixed food.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;On admission, her body weight, height, and head circumference were 6700 g (−2.428 standard deviation score [SDS]), 72.1 cm (−0.743 SDS), and 42.5 cm (\u0026lt;3\u003csup\u003erd\u003c/sup\u003e percentile for age), respectively. She had a flat nose bridge and thick lips. Her blood pressure was 95/51 mmHg, and her pulse rate was 137 beats/min. The patient’s respiratory rate was 42 breaths/min, and her body temperature was 38.2\u0026nbsp;℃. The patient was alert. Physical examination revealed generalized hypotonia with hyperextensible joints in the lower extremities. On developmental assessment, she was neither rolling over nor speaking “da” or “ba” at 12 months.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;The laboratory results on admission were as follows: total white blood cell count, 14,840/mm\u003csup\u003e3\u003c/sup\u003e;hemoglobin, 11.3 g/dL; platelet count, 303,000/mm\u003csup\u003e3\u003c/sup\u003e; sodium, 137 mEq/L; potassium, 4.7 mEq/L; chloride, 101 mEq/L; total calcium (Ca), 17.1 mg/dL (4.3 mmol/L); ionized calcium (iCa), 8.1 mg/dL (2.0 mmol/L); phosphorus, 5.5 mg/dL; blood urea nitrogen (BUN), 49 mg/dL; creatinine (Cr), 1.0 mg/dL; cystatin-C, 2.89 mg/L; uric acid, 8.0 mg/dL; alkaline phosphatase, 106 U/L; intact parathyroid hormone (PTH), 28.54 pg/mL; 25-hydroxyvitamin D (25-OHD), 118.6 ng/mL;\u0026nbsp;thyroid-stimulating hormone, 3.86 uIU/mL; and free thyroxine, 13.20 pmol/L.\u0026nbsp;Glomerular filtration rate (GFR) was calculated using a modified Schwartz formula.\u003csup\u003e7\u003c/sup\u003e Her GFR, venous pH, pCO\u003csub\u003e2\u003c/sub\u003e, HCO\u003csub\u003e3\u003c/sub\u003e, base excess, and anion gap were 30 mL/min/1.73 m\u003csup\u003e2\u003c/sup\u003e,\u0026nbsp;7.39 mmHg, 30.5 mmHg, 18.2 mmol/L, −5.3 mmol/L, and 15.5 mL/dL, respectively. Urinalysis revealed a pH of 6.5, specific gravity of 1.010, and negative protein on the dipstick. The spot urine test results were as follows: calcium/creatinine (Ca/Cr) ratio, 1.94 mg/mg (normal \u0026lt; 0.5mg/mg); osmolality, 318 mOsm/kg; and fractional excretion of sodium, 8.9%. Renal ultrasonography revealed increased parenchymal echogenicity, poor corticomedullary differentiation, and tiny cystic lesions in both the kidneys. Multiple hyperechogenic foci were observed in the right kidney cortex, some of which had posterior shadowing\u0026nbsp;(Fig. 1). Echocardiography and cardiac computed tomography revealed an anomalous origin of the right coronary artery. Fluorescence in-situ hybridization\u0026nbsp;analysis revealed a microdeletion in the elastin gene in the 7q11.23 region of the seventh chromosome, which was positive for WS. Abdominal computed tomography performed at 2 years of age revealed that both the kidneys contained tiny cysts. The right kidney cortex demonstrates diffuse hyperechoic foci. This finding suggests complications such as AKI, multiple tiny angiomyolipomas, or emphysematous changes (Fig. 2).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Intravenous fluid, furosemide (1 mg/kg/dose, q6hr), and prednisolone (2 mg/kg/day) were administered to treat hypercalcemia. However, the patient’s calcium level did not return to the normal range after 14 days of standard treatment. The patient received 1-day intravenously administered pamidronate (1 mg/kg), and her serum calcium level normalized 5 days later. The GFR also gradually improved to 46\u0026nbsp;mL/min/1.73 m\u003csup\u003e2\u003c/sup\u003e. The patient was discharged from the hospital with an unrestricted calcium diet.\u0026nbsp;At 7 weeks later, a second pamidronate infusion was administered because the iCa level\u0026nbsp;(1.75 mmol/L) increased.\u0026nbsp;After two pamidronate infusion treatments, the serum Ca levels were maintained within the normal range without any adverse effects. At the follow-up visit at 18 months of age, the serum uric acid level (8.5 mg/dL) had increased, and furosemide was discontinued. \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;At the last follow-up visit at 22 months of age, her serum total iCa level was normal at 1.28 mmol/L with a urinary Ca/Cr ratio of 0.03 mg/mg on an unrestricted diet. However, her\u0026nbsp;BUN, Cr, and cystatin-C levels remained high at 33 mg/dL, 0.65 mg/dL, and 2.27 mg/L, respectively (GFR 48 mL/min/1.73 m\u003csup\u003e2\u003c/sup\u003e). Her hypercalcemia and hypercalciuria improved, and we await the complete recovery of her renal function.\u0026nbsp;\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eWS, also known as Williams–Beuren syndrome, is characterized by dysmorphic facial features, intellectual disability/developmental delay, cardiovascular abnormalities, gastrointestinal difficulties, and infantile hypercalcemia.\u003csup\u003e2,4\u003c/sup\u003e Although infantile hypercalcemia is a well-known sign of WS, its cause is unknown and may not be PTH-dependent or excessive 25-OHD.\u003csup\u003e4\u003c/sup\u003e Increased calcium absorption from the gastrointestinal tract caused by haploinsufficiency of the general transcription factor II-I gene in the WS-deleted region may play a role.\u003csup\u003e4\u003c/sup\u003e Moreover, WS transcription factor may increase 1,25(OH)2D concentrations, thereby enhancing intestinal calcium absorption.\u003csup\u003e4\u003c/sup\u003e Hypercalcemia may manifest as irritability, feeding difficulties, vomiting, constipation, and hypotonia, although it is typically mild and asymptomatic.\u003csup\u003e4\u003c/sup\u003e The patient was irritable and developed hypotonia. Although we were unable to analyze 1.25-(OH)-vitamin D levels, they were within the normal range in our patient, suggesting a non-vitamin D-mediated cause of hypercalcemia. The PTH levels in our patient were normal. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;In most patients with WS, hypercalcemia improves spontaneously or can be treated with conventional therapies, such as intravenous hydration, diuretics, glucocorticoids, and dietary calcium restriction.\u003csup\u003e4\u003c/sup\u003e In rare cases, severe hypercalcemia in patients with WS may require additional therapies such as bisphosphonates.\u003csup\u003e5\u003c/sup\u003e Because pamidronate inhibits osteoclast activity in the bone, it is effectively used to treat hypercalcemia caused by various disorders.\u003csup\u003e5\u003c/sup\u003e In several case reports, intravenous pamidronate was used to treat severe hypercalcemia unresponsive to conventional treatments for WS-associated hypercalcemia.\u003csup\u003e5,8-13\u003c/sup\u003e Similar to previous reports, hypercalcemia was effectively controlled with two doses of pamidronate in our patient. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Hypercalcemia decreases the GFR and causes AKI.\u003csup\u003e14\u003c/sup\u003e Only two case reports of AKI associated with hypercalcemia in patients with WS have been published.\u003csup\u003e5,6\u003c/sup\u003e Pober et al. have reported a case of transient renal failure caused by nephrocalcinosis and hypercalcemia in an 18-month-old boy with WS owing to nephrocalcinosis and hypercalcemia.\u003csup\u003e6\u003c/sup\u003e The patient’s serum BUN and Cr levels were 43 mg/dl and 1.4 mg/dL, respectively.\u003csup\u003e6\u003c/sup\u003e Baştuğ F et al. have reported effective treatment of AKI caused by hypercalcemia and nephrocalcinosis in a 23-month-old girl with WS.\u003csup\u003e5\u003c/sup\u003e The patient’s initial serum total\u0026nbsp;Ca, BUN, and Cr levels\u0026nbsp;were 16, 38, and 1.7 mg/dL, respectively.\u003csup\u003e5\u003c/sup\u003e Renal function was restored after treating hypercalcemia with two doses of pamidronate infusions.\u003csup\u003e5\u003c/sup\u003e In severe hypercalcemia, direct renal vasoconstriction contributes to a reversible decrease in the GFR.\u003csup\u003e14\u003c/sup\u003e Moreover, impairment of the urinary concentrating ability, which causes polyuria, leads to volume depletion, which further deteriorates kidney function.\u003csup\u003e14\u003c/sup\u003e This is may be caused by the downregulation of aquaporin 2 water channels in the collecting tubules and tubulointerstitial damage due to Ca deposition in the medulla.\u003csup\u003e14\u003c/sup\u003e Hypercalcemia-induced AKI can be typically reversed by decreasing serum calcium concentrations and increasing volume.\u003csup\u003e14\u003c/sup\u003e Refractory hypercalcemia may induce AKI in WS, and pamidronate can be used to treat AKI in patients with refractory hypercalcemia. Our patient presented with non-oliguric AKI, severe hypercalcemia, and hypercalciuria. After hospitalization, hypercalcemia was treated with pamidronate, and renal function improved.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;The patient is continuously being monitored in an outpatient clinic, and the amounts of serum calcium and urine excretion calcium\u0026nbsp;have normalized. However, serum\u0026nbsp;BUN, Cr, and cystatin\u0026nbsp;C levels did not reach the normal range in mildly elevated states. This\u0026nbsp;is a risk factor for progression to AKI or chronic kidney disease,\u0026nbsp;which may recur. Therefore, patients with\u0026nbsp;high anxiety should be monitored. To date, AKI in patients with WS has not progressed to chronic kidney disease; however, such cases\u0026nbsp;are very rare. In fact, during\u0026nbsp;the\u0026nbsp;growth phase, the timing of recurrence of such changes in electrolytes and deterioration of renal function is difficult to determine\u0026nbsp;despite\u0026nbsp;a literature review and discussion. Therefore, the only\u0026nbsp;current management policy\u0026nbsp;is to evaluate and observe the patient's condition and laboratory results in an outpatient clinic while increasing the follow-up interval.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; To the best of our knowledge, this is the first report of AKI recovery following an improvement in hypercalcemia after pamidronate infusion in infants with WS. Occasionally, hypercalcemia in infants with WS can be severe and life-threatening. We emphasize the importance of early detection and evaluation of WS-presenting infants with AKI and hypercalcemia as well as their appropriate management to improve patient outcomes. Moreover, intravenous pamidronate is a reasonable treatment option for infants with WS and life-threatening hypercalcemia.\u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eData Availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used in this study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by the Biomedical Research Institute of Jeonbuk National University Hospital (2024).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;This study was approved by the Institutional Review Board (IRB) of\u0026nbsp;the Jeonbuk National University Hospital\u0026nbsp;(IRB no. 2022-12-020). Written\u0026nbsp;informed consent\u0026nbsp;for publication\u0026nbsp;was obtained\u0026nbsp;from\u0026nbsp;the patient’s guardian.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no potential conflicts of interest to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConceptualization: Park E, Kim SC.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWriting - original draft: Park E.\u003c/p\u003e\n\u003cp\u003eWriting - review \u0026amp; editing: Kim SC.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eMervis CB, Morris CA. Williams syndrome.\u003cem\u003e\u0026nbsp;Neurogenetic developmental disorders: Variation of manifestation in childhood\u0026nbsp;\u003c/em\u003e2007:199-262.\u003c/li\u003e\n \u003cli\u003eMorris CA. Introduction: Williams syndrome.\u003cem\u003e\u0026nbsp;Am J Med Genet C Semin Med Genet\u0026nbsp;\u003c/em\u003e2010;154C(2):203-8.\u003c/li\u003e\n \u003cli\u003eSugayama SMM, Koch VHK, Furusawa \u0026Eacute;A, Leone C, Kim CA. Renal and urinary findings in 20 patients with Williams-Beuren syndrome diagnosed by fluorescence in situ hybridization (FISH).\u003cem\u003e\u0026nbsp;Revista do Hospital das Cl\u0026iacute;nicas\u0026nbsp;\u003c/em\u003e2004;59(5):266-72.\u003c/li\u003e\n \u003cli\u003eStanley TL, Leong A, Pober BR. Growth, body composition, and endocrine issues in Williams syndrome.\u003cem\u003e\u0026nbsp;Curr Opin Endocrinol Diabetes Obes\u0026nbsp;\u003c/em\u003e2021;28(1):64-74.\u003c/li\u003e\n \u003cli\u003eBastug F, Nalcacioglu H, Bas VN, Tekatli-Celik B, Cetinkaya H, Yel S. Acute renal failure due to severe hypercalcemia and nephrocalcinosis treated with two doses of pamidronate in an infant with Williams-Beuren syndrome.\u003cem\u003e\u0026nbsp;Turk J Pediatr\u0026nbsp;\u003c/em\u003e2018;60(2):210-5.\u003c/li\u003e\n \u003cli\u003ePober BR, Lacro RV, Rice C, Mandell V, Teele RL. Renal findings in 40 individuals with Williams syndrome.\u003cem\u003e\u0026nbsp;Am J Med Genet\u0026nbsp;\u003c/em\u003e1993;46(3):271-4.\u003c/li\u003e\n \u003cli\u003eSchwartz GJ, Munoz A, Schneider MF, Mak RH, Kaskel F, Warady BA, et al. New Equations to Estimate GFR in Children with CKD.\u003cem\u003e\u0026nbsp;Journal of the American Society of Nephrology\u0026nbsp;\u003c/em\u003e2009;20(3):629-37.\u003c/li\u003e\n \u003cli\u003eSanjad SA, Aoun B, Yammine H, Bassyouni A, Karam PE. Pamidronate Rescue Therapy for Hypercalcemia in a Child With Williams Syndrome.\u003cem\u003e\u0026nbsp;Front Endocrinol (Lausanne)\u0026nbsp;\u003c/em\u003e2018;9:240.\u003c/li\u003e\n \u003cli\u003eGupta V, Pandita A, Panghal A, Kallem VR. Williams syndrome with severe hypercalcaemia.\u003cem\u003e\u0026nbsp;BMJ Case Rep\u0026nbsp;\u003c/em\u003e2018;2018.\u003c/li\u003e\n \u003cli\u003eSangun O, Dundar BN, Erdogan E. Severe hypercalcemia associated with Williams syndrome successfully treated with pamidronate infusion therapy.\u003cem\u003e\u0026nbsp;J Pediatr Endocrinol Metab\u0026nbsp;\u003c/em\u003e2011;24(1-2):69-70.\u003c/li\u003e\n \u003cli\u003eCagle AP, Waguespack SG, Buckingham BA, Shankar RR, Dimeglio LA. Severe infantile hypercalcemia associated with Williams syndrome successfully treated with intravenously administered pamidronate.\u003cem\u003e\u0026nbsp;Pediatrics\u0026nbsp;\u003c/em\u003e2004;114(4):1091-5.\u003c/li\u003e\n \u003cli\u003eOliveri B, Mastaglia SR, Mautalen C, Gravano JC, Pardo Argerich L. Long-term control of hypercalcaemia in an infant with williams-Beuren syndrome after a single infusion of biphosphonate (Pamidronate).\u003cem\u003e\u0026nbsp;Acta Paediatr\u0026nbsp;\u003c/em\u003e2004;93(7):1002-3.\u003c/li\u003e\n \u003cli\u003eIsmail J. Pamidronate for long-term control of hypercalcemia associated with Williams syndrome.\u003cem\u003e\u0026nbsp;Indian Pediatr\u0026nbsp;\u003c/em\u003e2015;52(2):163-4.\u003c/li\u003e\n \u003cli\u003eBhat NA, Mustafa F, Sheikh RY, Wani I. Incidence, etiology, and course of hypercalcemia-induced AKI in a tertiary care center from northern India.\u003cem\u003e\u0026nbsp;The Egyptian Journal of Internal Medicine\u0026nbsp;\u003c/em\u003e2021;33(1):36.\u003cem\u003e\u003c/em\u003e\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":"Williams syndrome, Hypercalcemia, Acute kidney injury, Pamidronate","lastPublishedDoi":"10.21203/rs.3.rs-3693127/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3693127/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Williams syndrome is an autosomal-dominant multisystem disorder. Infantile hypercalcemia has been documented in 15% of infants with Williams syndrome, and is commonly transient and mild. The need for pamidronate therapy has been reported in a few cases of Williams syndrome with severe hypercalcemia. Few cases of acute kidney injury due to severe hypercalcemia during Williams syndrome have also been recorded. We report the case of an infant with Williams syndrome who presented with acute kidney injury and severe hypercalcemia and was treated with intravenous pamidronate. In addition, we aimed to consider management strategies that maintain renal function and promote growth until adulthood.","manuscriptTitle":"Williams syndrome presenting as infantile hypercalcemia with acute kidney injury: A case report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-03-13 16:45:25","doi":"10.21203/rs.3.rs-3693127/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":"87b2778b-ad93-441a-a78e-cf7d591fd5b7","owner":[],"postedDate":"March 13th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-05-23T07:07:40+00:00","versionOfRecord":[],"versionCreatedAt":"2024-03-13 16:45:25","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3693127","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3693127","identity":"rs-3693127","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}