A rare occurrence of xanthine urolithiasis in siblings with Lesch-Nyhan Syndrome treated with allopurinol- A Case Report

A rare occurrence of xanthine urolithiasis in siblings with Lesch-Nyhan Syndrome treated with allopurinol- 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 Research Article A rare occurrence of xanthine urolithiasis in siblings with Lesch-Nyhan Syndrome treated with allopurinol- A Case Report roberto jodorkovsky, Saloni Trivedi, Asama Rana, Mitchell Thomae This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4930107/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 08 Oct, 2024 Read the published version in Bulletin of the National Research Centre → Version 1 posted 5 You are reading this latest preprint version Abstract Introduction - Lesch-Nyhan Syndrome (LNS) is an X-linked disorder affecting the metabolism of the purine salvage pathway leading to excessive serum uric acid production. Treatment of hyperuricemia with Allopurinol is usually effective to lower serum uric acid concentration to acceptable levels. Allopurinol blocks the conversion of hypoxanthine and xanthine to serum uric acid in the purine degradation pathway. The effect of Allopurinol may result in excessive buildup of xanthine, potentially resulting in urolithiasis composed of xanthine. This rare occurrence poses a unique challenge maintaining a balance between lowering hyperuricemia and preventing the development of xanthine urolithiasis. This case report includes two siblings with LNS treated with Allopurinol who developed xanthine urolithiasis. Case Description - Patients are siblings, a 22-year-old male and a 21-year-old female, with LNS diagnosed in early childhood. They both share similar manifestations of the disease and were treated with allopurinol with an intended therapeutic window of serum uric acid levels since diagnosis. Both were prone to developing urolithiasis and nephrolithiasis, the male more than the female, regardless of the medical regimen. Uric acid and calcium levels were normal in the serum and urine. Chemical analysis of calculi eliminated by both siblings revealed xanthine stones. Conclusions - Patients with LNS tend to develop stones composed of urate. Rarely, they can also precipitate stones composed of xanthine resulting from its build up in serum and urine by Allopurinol. This complication should be considered in all patients undergoing treatment with allopurinol. Careful clinical monitoring and dose adjustments of Allopurinol must balance the need to control hyperuricemia with avoiding excessive blockade of hypoxanthine. Lesch-Nyhan Syndrome Hypoxanthine Urolithiasis Allopurinol Case Report BACKGROUND Lesch–Nyhan Syndrome (LNS) is an X-linked inborn error of metabolism characterized by an impaired purine salvage pathway resulting in an overproduction of uric acid ( 1 , 2 , 3 , 6 ). LNS is caused by the mutation of the enzyme hypoxanthine guanine phosphoribosyl transferase gene (HGPRT1) , which leads to its deficiency. This enzyme recycles purines by converting guanine and hypoxanthine into guanosine monophosphate and inosine monophosphate ( 1 , 4 , 6 , 7 ). Lack of the H G PRT enzyme causes an increase in guanine and hypoxanthine, resulting in increased conversion into uric acid ( 2 ). The resulting hyperuricemia may be associated with a variety of symptoms depending on the magnitude of the H G PRT deficiency. A broad and varied spectrum of clinical manifestations include: developmental, often devastating, delays; cognitive impairment; dystonic movement; gouty arthritis; urate nephropathy; aggressive behavior; self-injurious behavior; megaloblastic anemia; and progressive renal failure ( 1 , 2 ). There is no specific treatment for the underlying enzyme deficiency. Symptomatic treatment of elevated serum uric acid is managed with the xanthine oxidase inhibitor, Allopurinol by virtue of its blocking effect of the conversion of hypoxanthine and xanthine into uric acid— the pathway end product ( 3 , 8 ). Patients with LNS frequently develop urolithiasis, requiring urologic intervention when the stones obstruct their genitourinary tract, cause recurrent urinary tract infections, or become too painful. The expected composition of the stones is mainly uric acid, or sometimes calcium oxalate ( 3 ). We report two siblings with LNS managed with Allopurinol, who developed pure xanthine urolithiasis. One of the siblings is a female; most males with LNS develop symptoms, while only a few cases of symptomatic females with LNS have been reported in the literature ( 5 ). These cases revealed the intricate therapeutic challenge inherent in lowering hyperuricemia aimed at reducing the risk of uric acid lithiasis while avoiding excessive suppression of xanthine oxidase, which may result in the formation of pure xanthine stone formation. CASES DESCRIPTION CASE 1 22-year-old male with LNS diagnosed at the age of two while living in Puerto Rico. The diagnosis was suspected by a history of severe developmental delays and abnormal behaviors. He was unable to achieve proper head control, had diffuse hypotonia, and exhibited self-mutilating behaviors such as biting of his tongue and lips. He started treatment with Allopurinol, 100 mg daily, Baclofen, 20 mg twice daily and Risperidol , 2 mg twice daily. Over the next several years, the patient developed multiple bilateral kidney stones, urinary bladder stones, and 2 to 4 urinary tract infections per year . He intermittently eliminated stones spontaneously, while obstructive ones required treatment with lithotripsy and ureteral stent placements, approximately every 6 month . The family immigrated to the United States when the child was 14 years old. Clinical investigations in our hospital were significant for the following: uric acid level of 4.5 mg/dl; elevated urine albumin/creatinine ratio of 167; reduced estimated glomerular filtration (GFR) of 51 ml/min/1.73 m2 (U25 GFR formula based); normal range serum Ca, Na, Cl, CO2, K, and albumin; bilateral echo densities in both renal medulla with dilated calyces; and normal 24-hour urine calcium and uric acid, but low citrate excretion. Stone analysis showed xanthine with no calcium or uric acid. Gene sequencing testing was positive for a heterozygous c.486-3C > G (intronic) variant of pathological significance in the HPRT1 gene, thus confirming t he diagnosis of LNS. The patient was diagnosed with stage III chronic kidney disease (CKD- U25 GFR formula based) The dose of Allopurinol was lowered to 25 mg daily. He was started on Enalapril, 2.5 mg twice daily for renal protection, and Sodium Citrate, 15 mL three times daily to increase urine citrate to further reduce stone forming risks. He has been regularly followed by the pediatric nephrology office to monitor his CKD, uric acid levels, chemistries, urine calcium, uric acid and citrate excretion, imaging monitoring of his urolithiasis status, and medication dose adjustments to keep uric acid level within an intended level between 6 mg/dl and 6.5 mg/dl CASE 2 A 21-year-old female, the sister of case 1 , was diagnosed with LNS at one year of age in Puerto Rico. She also experienced severe developmental delays, self-mutilation behavior, and urolithiasis. Her treatment included Allopurinol, 100 mg twice daily, Risperidol ,, 2.5 mg twice daily, and Baclofen, 20 mg three times daily. Her urolithiasis has been less severe than her brother’s. She has always been able to pass stones spontaneously, less frequently, and without secondary complications, such as urinary infection or stone obstruction. Her evaluation in our hospital was significant for normal estimated GFR, Ca, Na, K, Cl, CO2 and Albumin levels. Uric acid has ranged between 3 mg/dl and 5 mg/dl. 24-hour urine collections showed low calcium and low uric acid. Kidney ultrasounds have shown non obstructive bilateral lithiasis. Stone analysis showed pure xanthine. Gene sequencing testing result was similar to her brother, confirming the diagnosis of LNS ,S, attributing her symptomatic status to skewed X inactivation. She is regularly followed in the nephrology office to monitor the status of her urolithiasis, kidney function, chemistries, uric acid level, and adjustments of the dose of Allopurinol as necessary to keep her uric acid level within an intended level between 6 mg/dl and 6.5 mg/dl. DISCUSSION Lesch-Nyhan Syndrome is an X-linked mutation of the HGPRT1 gene affecting the purine salvage pathway. Hypoxanthine, a byproduct of the breakdown of purines, is either recycled by HGPRT, or is further degraded by xanthine oxidase into xanthine and subsequently uric acid. The deficiency of the HGPRT enzyme alters the recycling of hypoxanthine leading to excess uric acid production, a hallmark of the disease. Allopurinol is often used to treat hyperuricemia. It inhibits xanthine oxidase, decreasing the conversion of xanthine to uric acid within the purine pathway. Lowering serum and urine uric acid may help to mitigate the development of uric acid urolithiasis. However, excessive suppression of xanthine oxidase may also rarely lead to the formation of stones composed of the uric acid precursor, xanthine. This case report the rare cases of siblings (male and female) with LNS developing pure xanthine urolithiasis caused by excessive accumulation of xanthine in serum and urine by treatment with Allopurinol . Although xanthine urolithiasis is infrequent, this potential complication needs to be considered in patients treated with Allopurinol if excessive xanthine oxidase is suspected when the serum concentration of uric acid decreases to low, or low normal levels. Symptomatic LNS is common in males and rare in females. The severe symptomatic nature of our female case is likely due to skewed X inactivation. The management of patients with LNS and recurrent urolithiasis can be very complex and challenging. Periodic monitoring of xanthine and hypoxanthine concentrations in serum and urine can help to adjust down the dose of Allopurinol as needed. Unfortunately, only a few specialized laboratory centers are able to measure xanthine and hypoxanthine. These cases remind us that when treating LNS patients with Allopurinol, it is important to maintain a delicate balance between improving hyperuricemia and preventing excessive buildup of xanthine. CONCLUSIONS Patients with Lesch-Nyhan Syndrome can rarely present with stones made of pure xanthine resulting from its accumulation in serum and urine when treatment of hyperuricemia with Allopurinol leads to excessive suppression of xanthine oxidase. This case report series of siblings with LNS treated with Allopurinol who developed pure xanthine urolithiasis exemplifies the need for careful monitoring of uric acid levels, proper adjustment of the dose of Allopurinol , and vigilance for the potential formation of xanthine urolithiasis. This report also shows that females are not always exempted from developing significant symptoms. Abbreviations - CKD: Chronic Kidney Disease - GFR: Glomerular filtration rate - HGPRT: hypoxanthine-guanine phosphoribosyl transferase - LNS: Lesch-Nyhan Syndrome Declarations -Ethics approval and consent to participate: Our institution doesn’t require ethical or IRB approval for case reports. Consent for publication: Obtained from patients’ parent Availability of data and material: Included in the body of the manuscript Competing interests: There are no competing interests Funding: There are no external funding for this paper Authors' contributions: RJ was a major contributor to the manuscript, contributed to the manuscript, and wrote the final version of the report ST did chart review and contributed to the introduction, discussion, and conclusion AR and MT did chart review and contributed to the case descriptions and introduction All authors read and approved the final manuscript Acknowledgements: There were no other people involved to acknowledge References Nanagiri A, Shabbir N. Lesch Nyhan Syndrome. Stat Pearls 2023; https://www.ncbi.nlm.nih.gov/books/NBK556079/ Jinnah, H. A. (2000). HPRT1 Disorders. In M. P. Adam (Eds.) et. al., Gene Reviews®. University of Washington, Seattle; https://www.ncbi.nlm.nih.gov/pubmed/20301328 Meagher MF, Bechis SK. Recurrent Xanthine Stones in a Young Patient with Lesch-Nyhan Syndrome. J Endourology Case Rep. 2020 Dec 29;6(4):268-270. Doi: 10.1089/cren.2020.0046. PMID: 33457651; PMCID: PMC7803241. Harris, James C. Lesch–Nyhan syndrome and its variants: examining the behavioral and neurocognitive phenotype. Current Opinion in Psychiatry 31(2): p 96-102, March 2018. | DOI: 10.1097/YCO.0000000000000388 Torres R, Puig J. HPRT deficiency in LNS. Orphan J. of Rare Diseases 2007; 2:48 Meagher MF, Bechir SK (2020). Recurrent Xanthine Stones in a Young Patient with Leisch-Nyhan Syndrome, Journal of Endocrinology Case Reports 6:4, 268-270 Cameron JS.Moro,F,Simmonds, HA, Gout, Uric Acid, and Purine Metabolism in Pediatric Nephrology. Pediatric Nephriology,1993;7:105-118 Torres RJ.Prior,C.Puig,J. Efficacy and Safety of Allopurinol in Patients with Hypoxanthine Guanine Phosphoribosyl Transferase Deficiency, Metabolism 2007;56:1179-1186 Supplementary Files CAREchecklistLNSCaseSeries11.pdf Cite Share Download PDF Status: Published Journal Publication published 08 Oct, 2024 Read the published version in Bulletin of the National Research Centre → Version 1 posted Editorial decision: Accept 01 Oct, 2024 Reviewers agreed at journal 24 Sep, 2024 Reviewers invited by journal 24 Sep, 2024 Editor assigned by journal 24 Sep, 2024 First submitted to journal 23 Sep, 2024 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-4930107","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":358543453,"identity":"56d94717-f83c-4a20-b00f-b9880258df0b","order_by":0,"name":"roberto jodorkovsky","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA6klEQVRIiWNgGAWjYFCCAwwSDAwJQAYbA8MHEMVOihbGGSCKmQh74FqYeUBcQlrMGw8fvPFxT5qcwfljadI2v7bJ8zEzMH74mINbi8yBY8mWM57lGBvcSDsmndt327CNmYFZcuY2fI46YybNc6AiceYM9jbp3J7bjEAtbMy8RGnpP94mbdlz255YLTmJ/QxAhzH8uJ1IhBaQXw6kGfNLpCVb9jbcTm5jZmzG7xcJYIh9OJAsx8Z/zPDGjz+3bee3Nx/88BGPFgaJA3AmiwRjG4hmbMCjHgj4EfLMHxj+4Fc8CkbBKBgFIxMAADxSUGqeBVHnAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0009-0007-1597-7630","institution":"Saint Joseph Regional Medical Center","correspondingAuthor":true,"prefix":"","firstName":"roberto","middleName":"","lastName":"jodorkovsky","suffix":""},{"id":358543454,"identity":"15364ae3-5bb5-4186-9998-ec01e8042dc2","order_by":1,"name":"Saloni Trivedi","email":"","orcid":"","institution":"Children’s Hospital New Orleans: Children's Hospital New Orleans","correspondingAuthor":false,"prefix":"","firstName":"Saloni","middleName":"","lastName":"Trivedi","suffix":""},{"id":358543455,"identity":"bccb0e5b-c7bc-45b2-9bc7-83d5ba4f87ab","order_by":2,"name":"Asama Rana","email":"","orcid":"","institution":"Yale New Haven Hospital","correspondingAuthor":false,"prefix":"","firstName":"Asama","middleName":"","lastName":"Rana","suffix":""},{"id":358543456,"identity":"9f38005a-99fb-4d89-8b8d-80838f144cbb","order_by":3,"name":"Mitchell Thomae","email":"","orcid":"","institution":"University of Wyoming College of Health Sciences","correspondingAuthor":false,"prefix":"","firstName":"Mitchell","middleName":"","lastName":"Thomae","suffix":""}],"badges":[],"createdAt":"2024-08-17 13:57:09","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4930107/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4930107/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s42269-024-01259-2","type":"published","date":"2024-10-08T15:57:06+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":66597071,"identity":"1a114b08-b8d1-4b2e-80c0-dfe4330e417e","added_by":"auto","created_at":"2024-10-14 16:06:50","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":228861,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4930107/v1/c96c4311-17c8-4fc0-8ead-d7f5f66b92e6.pdf"},{"id":65583343,"identity":"a584ebd4-fde8-46a3-811d-adebe3dd11d9","added_by":"auto","created_at":"2024-09-30 08:44:36","extension":"pdf","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":1343245,"visible":true,"origin":"","legend":"","description":"","filename":"CAREchecklistLNSCaseSeries11.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4930107/v1/d7e2b38b7787dbb4aa344ae2.pdf"}],"financialInterests":"","formattedTitle":"A rare occurrence of xanthine urolithiasis in siblings with Lesch-Nyhan Syndrome treated with allopurinol- A Case Report","fulltext":[{"header":"BACKGROUND","content":"\u003cp\u003eLesch–Nyhan Syndrome (LNS) is an X-linked inborn error of metabolism characterized by an impaired purine salvage pathway resulting in an overproduction of uric acid (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). LNS is caused by the mutation of the \u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003eenzyme hypoxanthine guanine phosphoribosyl transferase\u003c/span\u003e gene \u003cem\u003e(HGPRT1)\u003c/em\u003e, which leads to \u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003eits\u003c/span\u003e deficiency. This enzyme recycles purines by converting guanine and hypoxanthine into guanosine monophosphate and inosine monophosphate (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Lack of the H\u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003eG\u003c/span\u003ePRT enzyme causes an increase in guanine and hypoxanthine, resulting in increased conversion into uric acid (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). The resulting hyperuricemia may be associated with a variety of symptoms depending on the magnitude of the H\u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003eG\u003c/span\u003ePRT deficiency. A broad and varied spectrum of clinical manifestations include: developmental, often devastating, delays; cognitive impairment; dystonic movement; gouty arthritis; urate nephropathy; aggressive behavior; self-injurious behavior; megaloblastic anemia; and progressive renal failure (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). There is no specific treatment for the underlying enzyme deficiency. Symptomatic treatment of elevated serum uric acid is managed with the xanthine oxidase inhibitor, Allopurinol by virtue of its blocking effect of the conversion of hypoxanthine and xanthine into uric acid— the pathway end product (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e).\u003c/p\u003e \u003cp\u003ePatients with LNS frequently develop urolithiasis, requiring urologic intervention when the stones obstruct their \u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003egenitourinary\u003c/span\u003e tract, cause recurrent urinary tract infections, or become too painful. The expected composition of the stones is mainly uric acid, or sometimes calcium oxalate (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eWe report two siblings with LNS managed with Allopurinol, who developed pure xanthine urolithiasis. One of the siblings is a female; most males with LNS develop symptoms, while only a few cases of symptomatic females with LNS have been reported in the literature (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). These cases revealed the intricate therapeutic challenge inherent in lowering hyperuricemia aimed at reducing the risk of uric acid lithiasis while avoiding excessive suppression of xanthine oxidase, which may result in the formation of pure xanthine stone formation.\u003c/p\u003e \u003cp\u003e\u003c/p\u003e \u003cp\u003e\u003c/p\u003e"},{"header":"CASES DESCRIPTION","content":"\u003cp\u003e \u003cstrong\u003eCASE 1\u003c/strong\u003e \u003c/p\u003e\u003cp\u003e22-year-old male with LNS diagnosed at the age of two while living in Puerto Rico. The diagnosis was suspected by a history of severe developmental delays and abnormal behaviors. He was unable to achieve proper head control, had diffuse hypotonia, and exhibited self-mutilating behaviors such as biting of his tongue and lips. He started treatment with Allopurinol, 100 mg daily, Baclofen, 20 mg twice daily and \u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003eRisperidol\u003c/span\u003e, 2 mg twice daily. Over the next several years, the patient developed \u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003emultiple\u003c/span\u003e bilateral kidney stones, urinary bladder stones, and \u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003e2 to 4 urinary tract infections per year\u003c/span\u003e. He intermittently eliminated stones spontaneously, while obstructive ones required treatment with lithotripsy and ureteral stent placements, \u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003eapproximately every 6 month\u003c/span\u003e. The family immigrated to the United States when the child was 14 years old. Clinical investigations in our hospital were significant for the following: uric acid level of 4.5 mg/dl; elevated urine albumin/creatinine ratio of 167; reduced \u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003eestimated glomerular filtration\u003c/span\u003e (GFR) of 51 ml/min/1.73 m2 (U25 GFR formula based); \u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003enormal range serum Ca, Na, Cl, CO2, K, and albumin;\u003c/span\u003e bilateral echo densities in both renal medulla with dilated calyces; and normal 24-hour urine calcium and uric acid, but low citrate excretion. Stone analysis showed xanthine with no calcium or uric acid. \u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003eGene sequencing\u003c/span\u003e testing \u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003ewas positive for a heterozygous c.486-3C \u0026gt; G (intronic) variant of pathological significance in the HPRT1 gene, thus confirming t\u003c/span\u003ehe diagnosis of LNS. The \u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003epatient\u003c/span\u003e was diagnosed with stage III chronic kidney disease \u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003e(CKD- U25 GFR formula based)\u003c/span\u003e The dose of Allopurinol was lowered to 25 mg daily. He \u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003ewas\u003c/span\u003e started \u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003eon\u003c/span\u003e Enalapril, 2.5 mg twice daily for renal protection, and Sodium Citrate, 15 mL three times daily to increase urine citrate to further reduce stone forming risks. He has been regularly followed by the pediatric nephrology office to monitor his CKD, uric acid levels, chemistries, urine calcium, uric acid and citrate excretion, imaging monitoring of his urolithiasis status, and medication dose adjustments to keep uric acid level \u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003ewithin an intended level between 6 mg/dl and 6.5 mg/dl\u003c/span\u003e\u003c/p\u003e\u003cp\u003e \u003cstrong\u003eCASE 2\u003c/strong\u003e \u003c/p\u003e\u003cp\u003eA 21-year-old female, the sister of case \u003cspan refid=\"FPar2\" class=\"InternalRef\"\u003e1\u003c/span\u003e, was diagnosed with LNS at one year of age in Puerto Rico. She also experienced severe developmental delays, self-mutilation behavior, and urolithiasis. Her treatment included Allopurinol, 100 mg twice daily, \u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003eRisperidol\u003c/span\u003e,, 2.5 mg twice daily, and Baclofen, 20 mg three times daily. Her urolithiasis has been less severe than her brother’s. She has always been able to pass stones spontaneously, less frequently, and without secondary complications, such as urinary infection or stone obstruction. Her evaluation in our hospital was significant for normal estimated GFR, \u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003eCa, Na, K, Cl, CO2 and Albumin levels.\u003c/span\u003e Uric acid has ranged between 3 mg/dl and 5 mg/dl. \u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003e24-hour urine collections showed\u003c/span\u003e low calcium and low uric acid. Kidney ultrasounds have shown non obstructive bilateral lithiasis. Stone analysis showed pure xanthine. \u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003eGene sequencing testing result was similar to her brother, confirming the diagnosis of LNS\u003c/span\u003e,S, attributing her symptomatic status to skewed X inactivation. She is regularly followed in the nephrology office to monitor the status of her urolithiasis, kidney function, chemistries, uric acid level, and adjustments of the dose of Allopurinol as necessary to keep her uric acid level \u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003ewithin an intended level between 6 mg/dl and 6.5 mg/dl.\u003c/span\u003e\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eLesch-Nyhan Syndrome is an X-linked mutation of the HGPRT1 gene affecting the purine salvage pathway. Hypoxanthine, a byproduct of the breakdown of purines, is either recycled by HGPRT, or is further degraded by \u003cem\u003exanthine oxidase\u003c/em\u003e into xanthine and subsequently uric acid. The deficiency of the HGPRT enzyme alters the recycling of hypoxanthine leading to excess uric acid production, a hallmark of the disease.\u003c/p\u003e \u003cp\u003eAllopurinol is often used to treat hyperuricemia. It inhibits xanthine oxidase, decreasing the conversion of xanthine to uric acid within the purine pathway. Lowering serum and urine uric acid may help to mitigate the development of uric acid urolithiasis. However, excessive suppression of xanthine oxidase may also rarely lead to the formation of stones composed of the uric acid precursor, xanthine.\u003c/p\u003e \u003cp\u003eThis \u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003ecase\u003c/span\u003e report the rare cases of siblings (male and female) with LNS developing pure xanthine urolithiasis \u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003ecaused by excessive accumulation of xanthine in serum and urine by treatment with Allopurinol\u003c/span\u003e. Although xanthine urolithiasis is infrequent, this potential complication needs to be considered in patients treated with Allopurinol if excessive xanthine oxidase is suspected when the serum concentration of uric acid decreases to low, or low normal levels. Symptomatic LNS is common in males and rare in females. The severe symptomatic nature of our female case is likely due to skewed X inactivation.\u003c/p\u003e \u003cp\u003eThe management of patients with LNS and recurrent urolithiasis can be very complex and challenging. \u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003ePeriodic monitoring of xanthine and hypoxanthine concentrations in serum and urine can help to adjust down the dose of Allopurinol as needed. Unfortunately, only a few specialized laboratory centers are able to measure xanthine and hypoxanthine.\u003c/span\u003e\u003c/p\u003e \u003cp\u003eThese cases remind us that when treating LNS patients with Allopurinol, it is important to maintain a delicate balance between improving hyperuricemia and preventing excessive buildup of xanthine.\u003c/p\u003e"},{"header":"CONCLUSIONS","content":"\u003cp\u003ePatients with Lesch-Nyhan Syndrome can rarely present with stones made of pure xanthine resulting from its accumulation \u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003ein serum and urine\u003c/span\u003e when treatment of hyperuricemia with Allopurinol leads to excessive suppression of xanthine oxidase. This case \u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003ereport\u003c/span\u003e series of siblings with LNS treated with Allopurinol who developed pure xanthine urolithiasis exemplifies the need for careful monitoring of uric acid levels, \u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003eproper adjustment of the dose of Allopurinol\u003c/span\u003e, and vigilance for the potential formation of xanthine urolithiasis. This report also shows that females are not always exempted from developing significant symptoms.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003e- CKD: Chronic Kidney Disease \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e- GFR: Glomerular filtration rate\u003c/p\u003e\n\u003cp\u003e- HGPRT: hypoxanthine-guanine phosphoribosyl transferase\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e- LNS: Lesch-Nyhan Syndrome\u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e-Ethics approval and consent to participate: \u0026nbsp;Our institution doesn\u0026rsquo;t require ethical or IRB approval for case reports.\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eConsent for publication: Obtained from patients\u0026rsquo; parent\u003c/li\u003e\n \u003cli\u003eAvailability of data and material: Included in the body of the manuscript\u003c/li\u003e\n \u003cli\u003eCompeting interests: There are no competing interests\u003c/li\u003e\n \u003cli\u003eFunding: There are no external funding for this paper \u0026nbsp;\u003c/li\u003e\n \u003cli\u003eAuthors\u0026apos; contributions:\u0026nbsp;\u003cul\u003e\n \u003cli\u003eRJ was a major contributor to the manuscript, contributed to the manuscript, and wrote the final version of the report\u003c/li\u003e\n \u003cli\u003eST did chart review and contributed to the introduction, discussion, and conclusion\u003c/li\u003e\n \u003cli\u003eAR and MT did chart review and contributed to the case descriptions and introduction\u003c/li\u003e\n \u003cli\u003eAll authors read and approved the final manuscript\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eAcknowledgements: There were no other people involved to acknowledge\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eNanagiri A, Shabbir N. Lesch Nyhan Syndrome. \u003cem\u003eStat Pearls \u003c/em\u003e2023; https://www.ncbi.nlm.nih.gov/books/NBK556079/ \u003c/li\u003e\n \u003cli\u003eJinnah, H. A. (2000). HPRT1 Disorders. In M. P. Adam (Eds.) et. al., Gene Reviews®. University of Washington, Seattle; https://www.ncbi.nlm.nih.gov/pubmed/20301328 \u003c/li\u003e\n \u003cli\u003eMeagher MF, Bechis SK. Recurrent Xanthine Stones in a Young Patient with Lesch-Nyhan Syndrome. J Endourology Case Rep. 2020 Dec 29;6(4):268-270. Doi: 10.1089/cren.2020.0046. PMID: 33457651; PMCID: PMC7803241. \u003c/li\u003e\n \u003cli\u003eHarris, James C. Lesch–Nyhan syndrome and its variants: examining the behavioral and neurocognitive phenotype. Current Opinion in Psychiatry 31(2): p 96-102, March 2018. | DOI: 10.1097/YCO.0000000000000388\u003c/li\u003e\n \u003cli\u003eTorres R, Puig J. HPRT deficiency in LNS. Orphan J. of Rare Diseases 2007; 2:48\u003c/li\u003e\n \u003cli\u003eMeagher MF, Bechir SK (2020). Recurrent Xanthine Stones in a Young Patient with Leisch-Nyhan Syndrome, Journal of Endocrinology Case Reports 6:4, 268-270\u003c/li\u003e\n \u003cli\u003eCameron JS.Moro,F,Simmonds, HA, Gout, Uric Acid, and Purine Metabolism in Pediatric Nephrology. Pediatric Nephriology,1993;7:105-118\u003c/li\u003e\n \u003cli\u003eTorres RJ.Prior,C.Puig,J. Efficacy and Safety of Allopurinol in Patients with Hypoxanthine Guanine Phosphoribosyl Transferase Deficiency, Metabolism 2007;56:1179-1186\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bulletin-of-the-national-research-centre","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bnrc","sideBox":"Learn more about [Bulletin of the National Research Centre](https://BNRC.springeropen.com)","snPcode":"42269","submissionUrl":"https://submission.springernature.com/new-submission/42269/3","title":"Bulletin of the National Research Centre","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Open","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Lesch-Nyhan Syndrome, Hypoxanthine, Urolithiasis, Allopurinol, Case Report","lastPublishedDoi":"10.21203/rs.3.rs-4930107/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4930107/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eIntroduction\u003c/strong\u003e- Lesch-Nyhan Syndrome (LNS) is an X-linked disorder affecting the metabolism of the purine salvage pathway leading to excessive \u003cem\u003e\u003cstrong\u003eserum\u003c/strong\u003e\u003c/em\u003e uric acid production. Treatment of hyperuricemia with Allopurinol is usually effective to lower serum uric acid concentration to acceptable levels. Allopurinol blocks the conversion of hypoxanthine and xanthine to \u003cem\u003e\u003cstrong\u003eserum\u003c/strong\u003e\u003c/em\u003e uric acid in the purine degradation pathway. The effect of Allopurinol may result in excessive buildup of xanthine, potentially resulting in urolithiasis composed of xanthine. This rare occurrence poses a unique challenge maintaining a balance between lowering hyperuricemia and preventing the development of xanthine urolithiasis. This case \u003cem\u003e\u003cstrong\u003ereport\u003c/strong\u003e\u003c/em\u003e includes two siblings with LNS treated with Allopurinol who developed xanthine urolithiasis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase Description\u003c/strong\u003e- Patients are siblings, a 22-year-old male and a 21-year-old female, with LNS diagnosed in early childhood. They both share similar manifestations of the disease and were treated with allopurinol with an intended therapeutic window of serum uric acid levels since diagnosis. Both were prone to developing urolithiasis and nephrolithiasis, the male more than the female, regardless of the medical regimen. Uric acid and calcium levels were normal in the serum and urine. Chemical analysis of calculi eliminated by both siblings revealed xanthine stones.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e- Patients with LNS tend to develop stones composed of urate. Rarely, they can also precipitate stones composed of xanthine resulting from its build up in serum and urine by Allopurinol. This complication should be considered in all patients undergoing treatment with allopurinol. Careful clinical monitoring and dose adjustments of Allopurinol must balance the need to control hyperuricemia with avoiding excessive blockade of hypoxanthine.\u003c/p\u003e","manuscriptTitle":"A rare occurrence of xanthine urolithiasis in siblings with Lesch-Nyhan Syndrome treated with allopurinol- A Case Report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-09-30 08:44:32","doi":"10.21203/rs.3.rs-4930107/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Accept","date":"2024-10-01T15:10:28+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2024-09-24T15:41:10+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-09-24T15:37:44+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-09-24T13:57:55+00:00","index":"","fulltext":""},{"type":"submitted","content":"Bulletin of the National Research Centre","date":"2024-09-23T13:26:07+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bulletin-of-the-national-research-centre","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bnrc","sideBox":"Learn more about [Bulletin of the National Research Centre](https://BNRC.springeropen.com)","snPcode":"42269","submissionUrl":"https://submission.springernature.com/new-submission/42269/3","title":"Bulletin of the National Research Centre","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Open","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c7926ee9-1b8f-4255-9f42-9a72207203ef","owner":[],"postedDate":"September 30th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-10-14T15:59:34+00:00","versionOfRecord":{"articleIdentity":"rs-4930107","link":"https://doi.org/10.1186/s42269-024-01259-2","journal":{"identity":"bulletin-of-the-national-research-centre","isVorOnly":false,"title":"Bulletin of the National Research Centre"},"publishedOn":"2024-10-08 15:57:06","publishedOnDateReadable":"October 8th, 2024"},"versionCreatedAt":"2024-09-30 08:44:32","video":"","vorDoi":"10.1186/s42269-024-01259-2","vorDoiUrl":"https://doi.org/10.1186/s42269-024-01259-2","workflowStages":[]},"version":"v1","identity":"rs-4930107","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4930107","identity":"rs-4930107","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}