Hyperuricemia and gout as uncommon manifestation of Papillorenal syndrome in an 18-year-old young man with PAX 2 mutation : A Case report and review of the literature 

Hyperuricemia and gout as uncommon manifestation of Papillorenal syndrome in an 18-year-old young man with PAX 2 mutation : A Case report and review of the literature | 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 Hyperuricemia and gout as uncommon manifestation of Papillorenal syndrome in an 18-year-old young man with PAX 2 mutation : A Case report and review of the literature Boutaleb Rajae, Derwa Axel This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4836528/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 Hyperuricemia is a metabolic abnormality, either acquired or inherited, characterized by elevated levels of uric acid (UA) in the serum. We are interested in the case report regarding hereditary hyperuricemia. In this case, we are reporting on an 18-year-old man who experienced repeated gout attacks, hyperuricemia, and reduced fraction ejection of uric acid (FEUA). Additionally, he had renal anomalies such as proteinuria and renal hypoplasia and Focal and segmental glomerulosclerosis (FSGS) in the kidney biopsy and eye fundus revealed a bilateral optic disc pit .These findings prompted us to conduct a genetic study on the patient. To our surprise, the DNA sequence analysis did not detect mutations in UMOD or REN, which are commonly associated with familial juvenile hyperuricemic nephropathy (FJHN). Instead, a mutation in the paired box 2 (PAX2) gene was identified which is a very rare entity. We concluded that the patient had papillorenal syndrome (PAPRS) . Hyperuricemia is a rare and uncommon manifestation in patients with PAPRS and PAX2 mutation, and has only been documented in three studies in the literature. The diagnosis of PAPRS is often underestimated and not well-known by clinicians. It exhibits high clinical variability and phenotypic heterogeneity without well-defined diagnostic criteria. The presence of hyperuricemia should prompt consideration of this diagnosis and it should be included in the diagnostic criteria for PAPRS in the future. Hyperuricemia paired box 2 (PAX2 )mutation optic disc pit FSGS papillorenal syndrome Figures Figure 1 Figure 2 Figure 3 1. Introduction Hyperuricemia is a metabolic abnormality, either acquired or inherited, characterized by elevated levels of uric acid (UA) in the serum. UA is primarily synthesized in the liver, intestines, and vascular endothelium as the end product of purine metabolism. Purines can originate from the degradation of damaged, dying, and dead cells, either from exogenous or endogenous sources. The kidney plays a key role in excreting UA, eliminating approximately 70% of the daily produced UA through various molecules expressed in the renal proximal tubule, such as transporter 9 (GLUT9) and urate transporter 1 (URAT1). When UA production surpasses UA excretion, hyperuricemia occurs. [ 1 ] . Acquired hyperuricemia may result from a purine-rich diet, certain medications, myeloproliferative disorders, obesity, and metabolic syndrome due to insulin resistance and its impact on reducing urinary urate levels [ 2 , 3 ] . Hereditary hyperuricemia can appear as an isolated non-syndromic disease or as part of a syndromic disorder. Genome-wide association studies (GWAS) have reported associations between hyperuricemia and around 30 loci [ 4 , 5 ]. The Online Mendelian Inheritance in Man (OMIM) database lists approximately 20 syndromes associated with hyperuricemia, including Lesch–Nyhan syndrome, phosphoribosylpyrophosphate synthetase superactivity, autosomal dominant tubulointerstitial kidney disease (previously known as medullary cystic kidney disease, and familial juvenile hyperuricemic nephropathy (FJHN) ). FJHN is the most common genetic disorder associated to hyperuricemia, with a UMOD mutation caused in 25–85% of cases by a UMOD mutation, and less than 5% by a REN mutation.[ 6 , 7 ] . Studies have shown that uric acid levels increase progressively with age typically starting at around 40 years old [ 8 ]. Hyperuricemia, and especially gout attacks in a young patient, are uncommon and may indicate a genetic cause. We present a case of a young man with hyperuricemia, gout, reduced FEUA, and CKD. DNA sequence analysis did not detect mutations in UMOD or REN, but did find a mutation in the paired box 2 (PAX2) gene, which is extremely rare. 2. Case presentation We report the clinical case of an 18-year-old young man of Turkish origin, with no parental consanguinity, who presented to an internal medicine consultation for recurrent gout attacks, with three attacks in one year. On medical history, the patient complained of snoring and daytime fatigue, but no other specific complaints or symptoms, such as neurological manifestations, articular manifestations apart from at the time of the gout attacks, cutaneous or ophthalmological manifestations, the patient did not take anti-inflammatory drugs and did not consume drugs, alcohol or tobacco. The clinical examination revealed WHO grade 1 obesity, with a body mass index of 32.08 kg/m2. The rest of the clinical examination was normal, including normal blood pressure and absence of edema of the lower limbs. ENT and neurological examinations revealed no hearing loss or neurological abnormalities. In terms of family history, the patient's grandfather had chronic kidney disease, specifically immunotactoid glomerulonephritis, and there was no history of kidney disease in other family members. An initial laboratory investigations revealed hyperuricemia at 14.5 mg/dl (Normal Value ( NV) = 3.5 -7.2 mg/dl) with a reduced UAEF of 4.5% (NV = 7.5 ± 1.8%), elevated serum creatinine of 1.3 mg/dl [NV = 0.5-1.2 mg/dl], proteinuria of 1900 mg/g creatinine (NV <500 mg/g) (Table 1) . Various biological tests were conducted to exclude other causes of hyperuricemia and proteinuria, as well as other pathological conditions. The results were as follows: viral serology (HIV , Hepatitis B and C ) was negative, C3 and C4 complement levels were normal, anti-DNA , anti-PLA2r , ANCA antibodies were negative, urine sediment was negative . There was no hypergammaglobulinemia or monoclonal peak on plasma protein electrophoresis, and no diabetes. Only a slight disturbance of liver enzymes was observed. Imaging revealed hepatic steatosis and moderate hepatomegaly on abdominal ultrasound, the kidneys were small, the right kidney measuring 86x28 mm and the left kidney 84x26 mm (normal size is 95-110 x 32-38 mm). A PET-CT scan was performed to rule out malignant pathology as the cause of the hyperuricemia, but the result was negative. Regarding the eye examination, the fundus showed bilateral inferotemporal excavation of the optic disc or optic disc pits, with a sharp papilla, a normal macula, and unremarkable blood vessels and periphery as depicted in pictures 1-2. A right renal biopsy was performed, yielding 10 glomeruli, a light microscopy revealed a segmental and focal glomerulosclerosis (FSGS) with no chronic lesions and no evidence of immune-mediated glomerulonephritis, morphological classification of FSGS ( COLOMBIA ): NOS (picture 3 ).The electron microscopy showed podocyte foot process effacement typical lesion found in FSGS (picture 4 )and the immunofluorescence: IgA, IgG, IgM, C3, C1q was negative . Given all the anomalies found in our patient, such as subnephrotic proteinuria, symptomatic hyperuricemia with several gout attacks, renal hypoplasia, renal biopsy in favor of FSGS, and ophthalmic anomalies, a genetic study was conducted. The genetic sequencing confirmed the absence of UMOD and REN abnormalities. Additionally, no abnormalities were found within the SEC61A1 and HNF-1β genes, which have been reported to be associated with FJHN. Instead, a heterozygous nucleotide substitution was identified: c.310 C>T, leading to a missense mutation (p.Arg104* ) in the PAX2 gene. This mutation involves the substitution of an arginine codon by a stop codon at position 104, thus interrupting the reading frame and leading to the production of a shortened protein. This mutation has already been described in the literature and is pathogenic Table 1 : Relevant clinical and biological abnormalities in the patient : Clinical and biological investigations Results Normal Range Serum creatinine ( mg /dl ) 1,4 0,5-1,2 Estimated GFR (CKDEPI)ml/min/1,73m 70 NR >90 Proteinuria( mg/g creat) 1950 NR<500 Uric acid (mg/dl) 14,5 NR 3,5 -7,2 Gout + Fe UA % ( NR 7,5+/- 1 ,8 ) 4,5 Renal ultrasonography (mm × mm) Right :86x28 Left : 84 X27 95-110 x32-38 Eye fundus Optic disc pits bilateral Gene study heterozygous mutation in PAX2 c.310 C>T Kidney biopsy FSGS Note: + = present ; Abbreviation: GFR : glomerular filtration rate ; CKD-EPI : chronic kidney disease epidemiology collaboration (CKD-EPI) formula ; FEUA :fractional excretion of uric acid , PAX2 : Paired box 2; FSGS : Focal and segmental glomerulosclerosis The patient was treated with medication to correct the metabolic disorders caused by chronic kidney disease (CKD) and high levels of uric acid. The progress of the CKD was monitored closely, and the patient is currently stable with medical therapy. However, close follow-up is being maintained to ensure prompt intervention if there are any changes in the patient's clinical condition. The patient also underwent regular follow-up appointments for ophthalmology and hearing tests. The treatment focused on reducing protein filtration and uric acid levels by using Renin-angiotensin system inhibitors and hypouricemic medication. Additionally, the patient was advised to reduce protein, salt, and purine intake in their diet. Weight loss and regular physical exercise were strongly recommended for the patient 3. Discussion The PAX2 gene encodes a nuclear transcription factor located near bands q24 and q25 on chromosome 10. It is one of the nine PAX paired box genes that encodes a DNA binding protein. This protein is mainly expressed during early embryonic development of the kidney, eye, central nervous system, ear, urogenital tract, and pancreas. Current data shows that it plays a crucial role in embryonic kidney development by regulating differentiation and renal cell proliferation at various fetal stages [ 9 , 10 ]. Recent discoveries have found that the PAX2 gene is re-expressed in nephropathy and acts as a suppressor of WT1, an important transcription factor of podocytes. Its mutation causes congenital nephrotic syndrome and FSGS [ 11 ]. In immune kidney diseases, Letavernier et al observed changes in podocyte phenotypes in focal segmental glomerulosclerosis (FSGS) and found that PAX2 is implicated in the pathogenesis of renal interstitial fibrosis and glomerulosclerosis [ 12 ]. Zhang et al found that in primary nephrotic syndrome, PAX2 expression in renal tubules in steroid-resistant children was significantly increased compared to steroid-sensitive children [ 13 ]. In 2014, PAX2 was found to be associated with adult-onset focal segmental glomerulosclerosis (FSGS) and was listed as a causative mutation of FSGS [ 14 , 15 ]. In our case, the patient has proteinuria and FSGS in the kidney biopsy as shown in pictures 2–3. According to a recent Korean study including 27 patients with PAX2 mutations detected from 2004–2022, 4 of them had FSGS [ 16 ]. The mutations of the PAX2 gene in human and mouse models have been associated with various renal anomalies. The most commonly encountered malformation is renal hypoplasia, found in 65% of cases, including our case [ 17 ]. Other renal findings include vesicoureteral reflux (VUR), renal cysts, and multicystic dysplastic kidneys, occurring in 15%, less than 10%, and 5% of patients, respectively. Renal failure is reported in approximately 15% of cases, while chronic kidney disease (CKD) stage 5 requiring a kidney transplant is common and has a range of onset from birth to greater than 75 years of age[ 18 ]. The PAX2 gene mutations have been mostly reported in patients with Papillorenal syndrome (PAPRS). This syndrome is an autosomal dominant disease characterized by congenital renal and optic nerve abnormalities associated with mutations of the PAX2 gene [ 18 , 19 ]. PAPRS was initially described in 1977 as renal coloboma syndrome and later renamed papillorenal syndrome (PAPRS) [ 20 , 21 ]. In a series of patients with PAPRS and proven PAX2 mutations, renal, eye, and high-frequency hearing loss were found in 92%, 77%, and 7% of patients, respectively [ 18 ] . Around 77% of patients with PAX2 mutations present optic nerve involvement. Affected individuals may have unilateral or bilateral optic disc anomalies ranging from an optic disc pit to a chorio-retinal coloboma. The most common alteration is optic nerve dysplasia, characterized by an enlarged optic disc with emerging peripheral vessels and cilioretinal vessels. Other described characteristics include a vacant optic nerve with a central excavation, absence of the central retinal artery, presence of multiple cilioretinal arteries in radial formation, retinal coloboma, and retrobulbar optic nerve cysts [ 18 ]. In our case report, the patient has bilateral optic disc pits, as shown in pictures 3 and 4. According to the study by Bower et al, this anomaly was found in less than 10% of patients. Other ophthalmoscopic findings include optic nerve coloboma, optic disc dysplasia, morning glory anomaly, and hypoplastic optic discs, occurring in approximately 50%, over 10%, 5%, and less than 5% of patients, respectively [ 18 ]. Zhang et al. reviewed and summarized reported cases of PAX2 mutation from 2000 to 2016, including 46 cases. They observed the reported phenotype and genotype of PAX2 mutation, as well as the different types of PAX2 mutations, such as frame-shift, missense, splice sites, and deletions found in patients with PAPRS. There are no clear genotype/phenotype correlations, and variable types of PAX2 located across 10 of the 12 PAX2 exons can lead to similar phenotypes. Additionally, the same mutation within members of the same family can have variable penetrance and manifestations of PAPRS [ 22 ]. This was confirmed by the Korean report which performed a genotype-phenotype analysis in patients with PAX2 mutations [ 16 ]. Other less common abnormalities observed in patients with PAX2 mutations include neurosensory auditory loss (found in 7% of those affected), central nervous system malformations, cognitive delay, ligament laxity, and elevated pancreatic amylase levels [ 23 ]. Our patient presented with hyperuricemia, reduced FEUA, and recurrent gout attacks, which led to their consultation with the internal medicine department. This condition is rare and has been documented in patients with a PAX 2 mutation, with only three unrelated families reported in the literature. In 2013, Megaw et al reported a case of a family with a PAX2 frameshift mutation, involving five affected males across three generations, all of whom experienced hyperuricemia and/or gout [ 24 ]. In 2019, Deng et al. reported a study involving 10 pediatric patients with a de novo heterozygous mutation of PAX2, resulting in a missense Arg140Trp mutation. This mutation was identified in a 14.8-year-old girl who presented with hyperuricemia, gout, renal disease, and ophthalmic abnormalities consistent with PAPRS [ 25 , 26 ]. In 2020, Stevenson et al. reported a case involving a family of 9 patients, 5 of whom had the PAX2 mutation. Among them, 2 had hyperuricemia and reduced FEUA with gout [ 27 ] . The direct relationship between the PAX2 mutation and hyperuricemia is not yet clear and has not yet been studied. However, it can probably be explained by the presence of renal anomalies and agenesis encountered with a PAX2 gene mutation who plays a crucial role in embryonic renal development. Uric acid is primarily excreted by the proximal tubule, specifically by membrane transporters such as GLUT9, and URAT1 [ 28 , 29 ]. Urinary excretion of uric acid is therefore influenced by these factors. Conclusion Hyperuricemia does not seem to be a common symptom in patients with PAX2 mutations. Based on the literature, renal and ophthalmological abnormalities are the most frequently reported. However, hyperuricemia, especially in young patients, those with chronic kidney disease with no known cause, and/or family histories of kidney diseases, should alert clinicians, especially ophthalmologists, internists, and nephrologists to consider the possibility of a PAX2 mutation diagnosis. It is important to note that the diagnosis of PAPRS is underestimated and poorly known by clinicians. In conclusion, the term PAPRS should be replaced with PAX2-related disorder due to the significant clinical variability and phenotypic heterogeneity, the lack of correlation between phenotype and genotype, and the absence of well-defined diagnostic criteria of PAPRS of which hyperuricemia should definitely be included in the future. Abbreviations UA : Uric acid FEUA : Fractional extraction of uric acid GFR : Glomerular Filtration Rate UMOD: Uromodulin PAX 2 : Paired box 2 GWAS : Genome wide association studies OMIM: Online Mendelin Inheritance in Man ESRD : End stage of renal disease MCKD :Medullary cystic kidney disease FJHN: Familial juvenile hyperuricemic Nephropathy CKD : Chronic kidney Disease ENT: Ear nose throat FSGS : Focal and segmental glomerulosclerosis PAPRS : Papillorenal syndrome VUR : Vesicoureteral reflux CAKUT : Congenital kidney and urinary tractus GLUT9 : Glucose transporter URAT1 : urate transporter 1 Declarations The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the article. Funding Declaration : The authors report no funding declaration Ethic approval and Consent for publication : Written informed consent was obtained from the patient for publication of this Case Report and any accompanying images. Local Ethics Committee on Human Experimentation N°OM 072 considers that it is not necessary to submit the study to the ethics committee for an opinion in application of the national law on human experimentation. Data availability : Sequence data that support the study have been deposited in the in the National Genomics Data Center (Genome Sequence Archive repository) with the primary accession code : PRJCA027987 Author Contribution R.B and A.D both wrote the main manuscript text, prepared figures and reviewed the manuscript References Shuangshuang Zhang et al : Hyperuricemia and Cardiovascular Disease Curr Pharm Des . 2019;25(6):700-709. doi: 10.2174 Hyon K Choi et al : Purine-rich foods, dairy and protein intake, and the risk of gout in men . N Engl J Med 2004 Mar 11;350(11):1093-103. doi: 10.1056 Yael Sharon , Schlesinger N et al : Beyond Joints: a Review of Ocular Abnormalities in Gout and Hyperuricemia Curr Rheumatol Rep 2016 Jun;18(6):37. doi: 10.1007 Yang QO, Kottgen A et al : Multiple genetic loci influence serumurate levels and their relationship with gout and cardiovascular disease risk factors. Circulation-Cardiovascular Genetics. 2010;3:523–530. doi: 10.1161 Kottgen A, Albrecht E et al : M Genome-wide association analyses identify 18 new loci associated with serum urate concentrations. Nature Genetics. 2013;45:145–154. doi: 10.1038 Devuyst O, Olinger E, et al : Autosomal dominanttubulointerstitial kidney disease. Nature Reviews Disease Primers. 2019;5:60. doi: 10.1038 Bleyer AJ, Kidd K, Zivna M, Kmoch et al: Autosomal dominant tubulointerstitial kidney disease. Advances in Chronic Kidney Disease. 2017;24:86–93. doi: 10.1053 Bickel C, et al: Serum uric acid as an independent predictor of mortality in patients with angiographically proven coronary artery disease.Am J Cardiol. 2002 Jan 1;89(1):12-7. doi: 10.1016 Narlis M, Grote D et al : PAX2 and Pax8 regulate branching morphogenesis and nephron differentiation in the developing kidney. J Am Soc Nephrol. 2007;18(4):1121–1129. Rothenpieler UW, Dressler GR et al : Pax-2 is required for mesenchyme-to-epithelium conversion during kidney development. Development. 1993;119(3):711–720. Fukuzawa R, Eccles M, Ikeda M, Hata J et al : Embryonal hyperplasia of Bowman's capsular epithelium in patients with WT1 mutations. Pediatr Nephrol. 2003;18(1):9–13. [ Letavernier E, Bruneval P, Mandet C et al : High sirolimus levels may induce focal segmental glomerulosclerosis de novo. Clin J Am Soc Nephrol. 2007;2(2):326–333. Zhang HQ, Yi ZW et al : PAX2 expression in children with steroid-resistant primary nephrotic syndrome. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2005;30(5):597–600 Vivante A, Chacham OS, Shril S, et al. Dominant PAX2 mutations may cause steroid-resistant nephrotic syndrome and FSGS in children. Pediatr Nephrol. 2019;34(9): 1607–1613. Barua M, Stellacci E, Stella L, et al. Mutations in PAX2 associate with adult-onset FSGS. J Am Soc Nephrol. 2014;25(9): 1942–1953. Ji Hyun Kim et al . Genotype-phenotype analysis in patients with PAX2 mutations: beyond renal coloboma syndrome .Research square . https://doi.org/10.21203/rs.3.rs-3028260/v1 Porteous S, Torban E, Cho NP, et al : Primary renal hypoplasia in humans and mice with PAX2 mutations: evidence of increased apoptosis in fetal kidneys of PAX21Neu +/− mutant mice. Hum Mol Genet. 2000;9(1):1–11. Bower M, Salomon R, Allanson J, et al : Update of PAX2 mutations in renal coloboma syndrome and establishment of a locus-specific database. Hum Mutat. 2012;33:457–66 Bower MA, Schimmenti LA, Eccles MR et al : Renal coloboma syndrome In:, editors. GeneReviews® ; 1993-2017. 2007 Jun 08 Karcher H et al : The morning glory syndrome. Klin Monbl Augenheilkd 1979;175:835–840. Rieger G et al : On the clinical picture of Handmann’s anomaly of the optic nerve morning glory syndrome? Klin Monbl Augenheilkd 1977;170:697–706 Zangh et al : New PAX2 heterozygous mutation in a child with chronic kidney disease: a case report and review of the literature MC Nephrology (2018) 19:245 Schimmenti LA et al : Renal coloboma syndrome. Eur J Hum Genet 2011;19:1207–1212. Megaw et al : Papillorenal syndrome in a family with unusual complications. British Journal of Ophthalmology, 97, 945–946 Deng, H. et al : Diverse phenotypes in children with PAX2-related disorder.Molecular Genetics & Genomic Medicine 2019 Jun;7(6):e701.doi: 10.1002 Negrisolo S et al : PAX2 and CAKUT Phenotypes: Report on Two New Variants and a Review of Mutations from the Leiden Open Variation Database . Int J Mol Sci 2023 Feb 19;24(4):4165.doi: 10.3390 Stevenson M, Pagnamenta AT,Reichart S, et al: Whole genome sequence analysis identifies aPAX2 mutation to establish a correct diagnosis for asyndromic form of hyperuricemia. Am J Med Genet Part A. 2020;182A:2521–2528. Matsuo H , Takada M , Ichida K et al : Common defects of ABCG2, a high capacity urate exporter, cause gout: a function-based genetic analysis in a Japanese population. Sci Transl Med. 2009; 1 : 5ra11 Caulfield M.J , Munroe P.B,O'Neill D. et al : SLC2A9 is a high-capacity urate transporter in humans. PLoS Med. 2008; 5 : e197 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. 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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-4836528","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":348190816,"identity":"094d8a7b-686e-4142-87ec-7d1409b62e7b","order_by":0,"name":"Boutaleb Rajae","email":"data:image/png;base64,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","orcid":"","institution":"Saint Jean clinic","correspondingAuthor":true,"prefix":"","firstName":"Boutaleb","middleName":"","lastName":"Rajae","suffix":""},{"id":348190817,"identity":"f1c83800-98c0-43ee-87f9-f7a9303a96e8","order_by":1,"name":"Derwa Axel","email":"","orcid":"","institution":"Saint Jean clinic","correspondingAuthor":false,"prefix":"","firstName":"Derwa","middleName":"","lastName":"Axel","suffix":""}],"badges":[],"createdAt":"2024-07-31 14:55:46","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4836528/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4836528/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":64712069,"identity":"67704212-d359-47a1-88cd-b811d98d22b3","added_by":"auto","created_at":"2024-09-18 02:02:42","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":270390,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cu\u003e\u003cstrong\u003ePicture 1 -2: \u003c/strong\u003e\u003c/u\u003e\u003cstrong\u003eEye fundus showing optic disc pit inferotemporal of the both eyes\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"12.png","url":"https://assets-eu.researchsquare.com/files/rs-4836528/v1/d7f1c5a52b87ac249e03a6aa.png"},{"id":64713192,"identity":"9aefa4ed-b775-4ad8-b44a-132973a7ed79","added_by":"auto","created_at":"2024-09-18 02:10:42","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":294533,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cu\u003e\u003cstrong\u003ePicture 3\u003c/strong\u003e\u003c/u\u003e\u003cstrong\u003e: light microscopic study of kidney biopsy showing FSGS\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-4836528/v1/a13a6071bd27a9449e60431c.png"},{"id":64712070,"identity":"7136ca1b-f10d-419b-9d4b-f94030fa078c","added_by":"auto","created_at":"2024-09-18 02:02:42","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":242834,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cu\u003e\u003cstrong\u003ePicture 4:\u003c/strong\u003e\u003c/u\u003e\u003cstrong\u003e Electron microscopy study of kidney biopsy showed podocyte foot process effacement\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-4836528/v1/410e32d64d48df6fd0763b64.png"},{"id":77320976,"identity":"1a8c6147-df5f-4b28-8599-fc8f5e66ddad","added_by":"auto","created_at":"2025-02-27 11:24:09","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1497005,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4836528/v1/78beca45-ab25-46b2-95c4-7e9ab8c43fc7.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Hyperuricemia and gout as uncommon manifestation of Papillorenal syndrome in an 18-year-old young man with PAX 2 mutation : A Case report and review of the literature ","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eHyperuricemia is a metabolic abnormality, either acquired or inherited, characterized by elevated levels of uric acid (UA) in the serum. UA is primarily synthesized in the liver, intestines, and vascular endothelium as the end product of purine metabolism. Purines can originate from the degradation of damaged, dying, and dead cells, either from exogenous or endogenous sources. The kidney plays a key role in excreting UA, eliminating approximately 70% of the daily produced UA through various molecules expressed in the renal proximal tubule, such as transporter 9 (GLUT9) and urate transporter 1 (URAT1). When UA production surpasses UA excretion, hyperuricemia occurs. [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] .\u003c/p\u003e \u003cp\u003eAcquired hyperuricemia may result from a purine-rich diet, certain medications, myeloproliferative disorders, obesity, and metabolic syndrome due to insulin resistance and its impact on reducing urinary urate levels [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] .\u003c/p\u003e \u003cp\u003eHereditary hyperuricemia can appear as an isolated non-syndromic disease or as part of a syndromic disorder. Genome-wide association studies (GWAS) have reported associations between hyperuricemia and around 30 loci [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. The Online Mendelian Inheritance in Man (OMIM) database lists approximately 20 syndromes associated with hyperuricemia, including Lesch\u0026ndash;Nyhan syndrome, phosphoribosylpyrophosphate synthetase superactivity, autosomal dominant tubulointerstitial kidney disease (previously known as medullary cystic kidney disease, and familial juvenile hyperuricemic nephropathy (FJHN) ). FJHN is the most common genetic disorder associated to hyperuricemia, with a UMOD mutation caused in 25\u0026ndash;85% of cases by a UMOD mutation, and less than 5% by a REN mutation.[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] .\u003c/p\u003e \u003cp\u003eStudies have shown that uric acid levels increase progressively with age typically starting at around 40 years old [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Hyperuricemia, and especially gout attacks in a young patient, are uncommon and may indicate a genetic cause.\u003c/p\u003e \u003cp\u003eWe present a case of a young man with hyperuricemia, gout, reduced FEUA, and CKD. DNA sequence analysis did not detect mutations in UMOD or REN, but did find a mutation in the paired box 2 (PAX2) gene, which is extremely rare.\u003c/p\u003e"},{"header":"2. Case presentation","content":"\u003cp\u003eWe report the clinical case of an 18-year-old young man of Turkish origin, with no parental consanguinity, who presented to an internal medicine consultation for recurrent gout attacks, with three attacks in one year. On medical history, the patient complained of snoring and daytime fatigue, but no other specific complaints or symptoms, such as neurological manifestations, articular manifestations apart from at the time of the gout attacks, cutaneous or ophthalmological manifestations, the patient did not take anti-inflammatory drugs and did not consume drugs, alcohol or tobacco. The clinical examination revealed WHO grade 1 obesity, with a body mass index of 32.08 kg/m2. The rest of the clinical examination was normal, including normal blood pressure and absence of edema of the lower limbs. ENT and neurological examinations revealed no hearing loss or neurological abnormalities. In terms of family history, the patient\u0026apos;s grandfather had chronic kidney disease, specifically immunotactoid glomerulonephritis, and there was no history of kidney disease in other family members.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAn initial laboratory investigations \u0026nbsp;revealed hyperuricemia at 14.5 mg/dl (Normal Value ( NV) = 3.5 -7.2 mg/dl) with a reduced UAEF of 4.5% (NV = 7.5 \u0026plusmn; 1.8%), elevated serum creatinine of 1.3 mg/dl [NV = 0.5-1.2 mg/dl], proteinuria of 1900 mg/g creatinine (NV \u0026lt;500 mg/g) (Table 1) .\u0026nbsp;Various biological tests were conducted to\u0026nbsp;exclude other causes of hyperuricemia and proteinuria, as well as other pathological conditions. The results were as follows: viral serology (HIV , Hepatitis B and C ) was negative, C3 and C4 complement levels were normal, anti-DNA , anti-PLA2r , ANCA antibodies were negative, urine sediment was negative . There was no hypergammaglobulinemia or monoclonal peak on plasma protein electrophoresis, and no diabetes. Only a slight disturbance of liver enzymes was observed.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Imaging revealed hepatic steatosis and moderate hepatomegaly on abdominal ultrasound, the kidneys were small, the right kidney measuring 86x28 mm and the left kidney 84x26 mm (normal size is 95-110 x 32-38 mm). A PET-CT scan was performed to rule out malignant pathology as the cause of the hyperuricemia, but the result was negative.\u003c/p\u003e\n\u003cp\u003eRegarding the eye examination, the fundus showed bilateral inferotemporal excavation of the optic disc or optic disc pits, with a sharp papilla, a normal macula, and unremarkable blood vessels and periphery as depicted in pictures 1-2.\u003c/p\u003e\n\u003cp\u003eA right renal biopsy was performed, yielding 10 glomeruli, a light microscopy revealed a segmental and focal glomerulosclerosis (FSGS) \u0026nbsp;with no chronic lesions and no evidence of immune-mediated glomerulonephritis, morphological classification of FSGS ( COLOMBIA ): NOS (picture 3 ).The electron microscopy showed podocyte foot process \u0026nbsp;effacement typical lesion found in \u0026nbsp;FSGS \u0026nbsp;(picture 4 )and the immunofluorescence: IgA, IgG, IgM, C3, C1q was negative .\u003c/p\u003e\n\u003cp\u003eGiven all the anomalies found in our patient, such as subnephrotic proteinuria, symptomatic hyperuricemia with several gout attacks, renal hypoplasia, renal biopsy in favor of FSGS, and ophthalmic anomalies, a genetic study was conducted. The genetic sequencing confirmed the absence of UMOD and REN abnormalities. Additionally, no abnormalities were found within the SEC61A1 and HNF-1\u0026beta; genes, which have been reported to be associated with FJHN. Instead, a heterozygous nucleotide substitution was identified: c.310 C\u0026gt;T, leading to a missense mutation (p.Arg104* ) in the PAX2 gene. This mutation involves the substitution of an arginine codon by a stop codon at position 104, thus interrupting the reading frame and leading to the production of a shortened protein. This mutation has already been described in the literature and is pathogenic\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eTable 1 :\u003c/u\u003eRelevant clinical and biological abnormalities in the patient :\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"449\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.73942093541203%\" valign=\"top\"\u003e\n \u003cp\u003eClinical and biological investigations\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.271714922048996%\" valign=\"top\"\u003e\n \u003cp\u003eResults\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"44.98886414253897%\" valign=\"top\"\u003e\n \u003cp\u003eNormal Range\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.73942093541203%\" valign=\"top\"\u003e\n \u003cp\u003eSerum creatinine ( mg \u0026nbsp;/dl )\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.271714922048996%\" valign=\"top\"\u003e\n \u003cp\u003e1,4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"44.98886414253897%\" valign=\"top\"\u003e\n \u003cp\u003e0,5-1,2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.73942093541203%\" valign=\"top\"\u003e\n \u003cp\u003eEstimated \u0026nbsp;GFR (CKDEPI)ml/min/1,73m\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.271714922048996%\" valign=\"top\"\u003e\n \u003cp\u003e70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"44.98886414253897%\" valign=\"top\"\u003e\n \u003cp\u003eNR \u0026gt;90\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.73942093541203%\" valign=\"top\"\u003e\n \u003cp\u003eProteinuria( mg/g creat)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.271714922048996%\" valign=\"top\"\u003e\n \u003cp\u003e1950\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"44.98886414253897%\" valign=\"top\"\u003e\n \u003cp\u003eNR\u0026lt;500\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.73942093541203%\" valign=\"top\"\u003e\n \u003cp\u003eUric acid \u0026nbsp;(mg/dl)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.271714922048996%\" valign=\"top\"\u003e\n \u003cp\u003e14,5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"44.98886414253897%\" valign=\"top\"\u003e\n \u003cp\u003eNR 3,5 -7,2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.73942093541203%\" valign=\"top\"\u003e\n \u003cp\u003eGout\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.271714922048996%\" valign=\"top\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"44.98886414253897%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.73942093541203%\" valign=\"top\"\u003e\n \u003cp\u003eFe UA % ( NR 7,5+/- 1\u0026nbsp;,8 )\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.271714922048996%\" valign=\"top\"\u003e\n \u003cp\u003e4,5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"44.98886414253897%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.73942093541203%\" valign=\"top\"\u003e\n \u003cp\u003eRenal ultrasonography (mm \u0026times; mm)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.271714922048996%\" valign=\"top\"\u003e\n \u003cp\u003eRight :86x28\u003c/p\u003e\n \u003cp\u003eLeft : 84 X27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"44.98886414253897%\" valign=\"top\"\u003e\n \u003cp\u003e95-110 x32-38\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.73942093541203%\" valign=\"top\"\u003e\n \u003cp\u003eEye fundus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.271714922048996%\" valign=\"top\"\u003e\n \u003cp\u003eOptic disc pits bilateral\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"44.98886414253897%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.73942093541203%\" valign=\"top\"\u003e\n \u003cp\u003eGene study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.271714922048996%\" valign=\"top\"\u003e\n \u003cp\u003eheterozygous mutation in PAX2 \u0026nbsp;c.310 C\u0026gt;T\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"44.98886414253897%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.73942093541203%\" valign=\"top\"\u003e\n \u003cp\u003eKidney biopsy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.271714922048996%\" valign=\"top\"\u003e\n \u003cp\u003eFSGS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"44.98886414253897%\" valign=\"top\"\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\u003eNote: + = present ; Abbreviation: GFR : glomerular filtration rate ; CKD-EPI : chronic kidney disease epidemiology collaboration (CKD-EPI) formula ; FEUA :fractional excretion of uric acid , PAX2 : Paired box 2; FSGS : Focal and segmental glomerulosclerosis\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe patient was treated with medication to correct the metabolic disorders caused by chronic kidney disease (CKD) and high levels of uric acid. The progress of the CKD was monitored closely, and the patient is currently stable with medical therapy. However, close follow-up is being maintained to ensure prompt intervention if there are any changes in the patient\u0026apos;s clinical condition. The patient also underwent regular follow-up appointments for ophthalmology and hearing tests.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe treatment focused on reducing protein filtration and uric acid levels by using Renin-angiotensin system inhibitors and hypouricemic medication. Additionally, the patient was advised to reduce protein, salt, and purine intake in their diet. Weight loss and regular physical exercise were strongly recommended for the patient\u003c/p\u003e"},{"header":"3. Discussion","content":"\u003cp\u003eThe PAX2 gene encodes a nuclear transcription factor located near bands q24 and q25 on chromosome 10. It is one of the nine PAX paired box genes that encodes a DNA binding protein. This protein is mainly expressed during early embryonic development of the kidney, eye, central nervous system, ear, urogenital tract, and pancreas. Current data shows that it plays a crucial role in embryonic kidney development by regulating differentiation and renal cell proliferation at various fetal stages [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eRecent discoveries have found that the PAX2 gene is re-expressed in nephropathy and acts as a suppressor of WT1, an important transcription factor of podocytes. Its mutation causes congenital nephrotic syndrome and FSGS [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. In immune kidney diseases, Letavernier et al observed changes in podocyte phenotypes in focal segmental glomerulosclerosis (FSGS) and found that PAX2 is implicated in the pathogenesis of renal interstitial fibrosis and glomerulosclerosis [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Zhang et al found that in primary nephrotic syndrome, PAX2 expression in renal tubules in steroid-resistant children was significantly increased compared to steroid-sensitive children [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. In 2014, PAX2 was found to be associated with adult-onset focal segmental glomerulosclerosis (FSGS) and was listed as a causative mutation of FSGS [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. In our case, the patient has proteinuria and FSGS in the kidney biopsy as shown in pictures 2\u0026ndash;3. According to a recent Korean study including 27 patients with PAX2 mutations detected from 2004\u0026ndash;2022, 4 of them had FSGS [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe mutations of the PAX2 gene in human and mouse models have been associated with various renal anomalies. The most commonly encountered malformation is renal hypoplasia, found in 65% of cases, including our case [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Other renal findings include vesicoureteral reflux (VUR), renal cysts, and multicystic dysplastic kidneys, occurring in 15%, less than 10%, and 5% of patients, respectively. Renal failure is reported in approximately 15% of cases, while chronic kidney disease (CKD) stage 5 requiring a kidney transplant is common and has a range of onset from birth to greater than 75 years of age[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe PAX2 gene mutations have been mostly reported in patients with Papillorenal syndrome (PAPRS). This syndrome is an autosomal dominant disease characterized by congenital renal and optic nerve abnormalities associated with mutations of the PAX2 gene [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. PAPRS was initially described in 1977 as renal coloboma syndrome and later renamed papillorenal syndrome (PAPRS) [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. In a series of patients with PAPRS and proven PAX2 mutations, renal, eye, and high-frequency hearing loss were found in 92%, 77%, and 7% of patients, respectively [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] .\u003c/p\u003e \u003cp\u003eAround 77% of patients with PAX2 mutations present optic nerve involvement. Affected individuals may have unilateral or bilateral optic disc anomalies ranging from an optic disc pit to a chorio-retinal coloboma. The most common alteration is optic nerve dysplasia, characterized by an enlarged optic disc with emerging peripheral vessels and cilioretinal vessels. Other described characteristics include a vacant optic nerve with a central excavation, absence of the central retinal artery, presence of multiple cilioretinal arteries in radial formation, retinal coloboma, and retrobulbar optic nerve cysts [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. In our case report, the patient has bilateral optic disc pits, as shown in pictures 3 and 4. According to the study by Bower et al, this anomaly was found in less than 10% of patients. Other ophthalmoscopic findings include optic nerve coloboma, optic disc dysplasia, morning glory anomaly, and hypoplastic optic discs, occurring in approximately 50%, over 10%, 5%, and less than 5% of patients, respectively [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eZhang et al. reviewed and summarized reported cases of PAX2 mutation from 2000 to 2016, including 46 cases. They observed the reported phenotype and genotype of PAX2 mutation, as well as the different types of PAX2 mutations, such as frame-shift, missense, splice sites, and deletions found in patients with PAPRS. There are no clear genotype/phenotype correlations, and variable types of PAX2 located across 10 of the 12 PAX2 exons can lead to similar phenotypes. Additionally, the same mutation within members of the same family can have variable penetrance and manifestations of PAPRS [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. This was confirmed by the Korean report which performed a genotype-phenotype analysis in patients with PAX2 mutations [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOther less common abnormalities observed in patients with PAX2 mutations include neurosensory auditory loss (found in 7% of those affected), central nervous system malformations, cognitive delay, ligament laxity, and elevated pancreatic amylase levels [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOur patient presented with hyperuricemia, reduced FEUA, and recurrent gout attacks, which led to their consultation with the internal medicine department. This condition is rare and has been documented in patients with a PAX 2 mutation, with only three unrelated families reported in the literature. In 2013, Megaw et al reported a case of a family with a PAX2 frameshift mutation, involving five affected males across three generations, all of whom experienced hyperuricemia and/or gout [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn 2019, Deng et al. reported a study involving 10 pediatric patients with a de novo heterozygous mutation of PAX2, resulting in a missense Arg140Trp mutation. This mutation was identified in a 14.8-year-old girl who presented with hyperuricemia, gout, renal disease, and ophthalmic abnormalities consistent with PAPRS [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. In 2020, Stevenson et al. reported a case involving a family of 9 patients, 5 of whom had the PAX2 mutation. Among them, 2 had hyperuricemia and reduced FEUA with gout [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e] .\u003c/p\u003e \u003cp\u003eThe direct relationship between the PAX2 mutation and hyperuricemia is not yet clear and has not yet been studied. However, it can probably be explained by the presence of renal anomalies and agenesis encountered with a PAX2 gene mutation who plays a crucial role in embryonic renal development. Uric acid is primarily excreted by the proximal tubule, specifically by membrane transporters such as GLUT9, and URAT1 [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Urinary excretion of uric acid is therefore influenced by these factors.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eHyperuricemia does not seem to be a common symptom in patients with PAX2 mutations. Based on the literature, renal and ophthalmological abnormalities are the most frequently reported. However, hyperuricemia, especially in young patients, those with chronic kidney disease with no known cause, and/or family histories of kidney diseases, should alert clinicians, especially ophthalmologists, internists, and nephrologists to consider the possibility of a PAX2 mutation diagnosis. It is important to note that the diagnosis of PAPRS is underestimated and poorly known by clinicians. In conclusion, the term PAPRS should be replaced with PAX2-related disorder due to the significant clinical variability and phenotypic heterogeneity, the lack of correlation between phenotype and genotype, and the absence of well-defined diagnostic criteria of PAPRS of which hyperuricemia should definitely be included in the future.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eUA : Uric acid\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFEUA : Fractional extraction of uric acid\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eGFR : Glomerular Filtration Rate\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eUMOD:\u0026nbsp;Uromodulin\u003c/p\u003e\n\u003cp\u003ePAX 2 : Paired box 2\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eGWAS : Genome wide association studies\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOMIM: Online Mendelin Inheritance in Man\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eESRD : End stage of renal disease\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMCKD :Medullary cystic kidney disease\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFJHN: Familial juvenile hyperuricemic Nephropathy\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCKD : Chronic kidney Disease\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eENT: Ear nose throat\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFSGS : Focal and segmental glomerulosclerosis\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePAPRS : Papillorenal syndrome\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eVUR : Vesicoureteral reflux\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCAKUT : Congenital kidney and urinary tractus\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eGLUT9 : Glucose transporter\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eURAT1 : urate transporter 1\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eThe authors report no conflicts of interest. The authors alone are responsible for the content and writing of the article.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding Declaration :\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors report no \u0026nbsp;funding declaration\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthic approval \u0026nbsp;and Consent for publication :\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from the patient for publication of this Case Report and any accompanying images.\u003c/p\u003e\n\u003cp\u003eLocal Ethics Committee on Human Experimentation N°OM 072 considers that it is not necessary to submit the study to the ethics committee for an opinion in application of the national law on human experimentation.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData \u0026nbsp;availability :\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSequence data that support the study have been deposited in the in the National Genomics Data Center (Genome Sequence Archive repository) \u0026nbsp; \u0026nbsp;with the primary accession code : PRJCA027987\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eR.B and A.D both wrote the main manuscript text, prepared figures and reviewed the manuscript\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eShuangshuang Zhang et al : Hyperuricemia and Cardiovascular Disease Curr Pharm Des . 2019;25(6):700-709. doi: 10.2174\u003c/li\u003e\n\u003cli\u003eHyon K Choi et al : Purine-rich foods, dairy and protein intake, and the risk of gout in men . 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Nature Reviews Disease Primers. 2019;5:60. doi: 10.1038\u003c/li\u003e\n\u003cli\u003eBleyer AJ, Kidd K, Zivna M, Kmoch et al: Autosomal dominant tubulointerstitial kidney disease. Advances in Chronic Kidney Disease. 2017;24:86\u0026ndash;93. doi: 10.1053\u003c/li\u003e\n\u003cli\u003eBickel C, et al: Serum uric acid as an independent predictor of mortality in patients with angiographically proven coronary artery disease.Am J Cardiol. 2002 Jan 1;89(1):12-7. doi: 10.1016\u003c/li\u003e\n\u003cli\u003eNarlis M, Grote D et al : PAX2 and Pax8 regulate branching morphogenesis and nephron differentiation in the developing kidney. J Am Soc Nephrol. 2007;18(4):1121\u0026ndash;1129.\u003c/li\u003e\n\u003cli\u003eRothenpieler UW, Dressler GR et al : Pax-2 is required for mesenchyme-to-epithelium conversion during kidney development. Development. 1993;119(3):711\u0026ndash;720.\u003c/li\u003e\n\u003cli\u003eFukuzawa R, Eccles M, Ikeda M, Hata J et al : Embryonal hyperplasia of Bowman\u0026apos;s capsular epithelium in patients with WT1 mutations. Pediatr Nephrol. 2003;18(1):9\u0026ndash;13. [\u003c/li\u003e\n\u003cli\u003eLetavernier E, Bruneval P, Mandet C et al : High sirolimus levels may induce focal segmental glomerulosclerosis de novo. Clin J Am Soc Nephrol. 2007;2(2):326\u0026ndash;333.\u003c/li\u003e\n\u003cli\u003eZhang HQ, Yi ZW et al : PAX2 expression in children with steroid-resistant primary nephrotic syndrome. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2005;30(5):597\u0026ndash;600\u003c/li\u003e\n\u003cli\u003eVivante A, Chacham OS, Shril S, et al. Dominant PAX2 mutations may cause steroid-resistant nephrotic syndrome and FSGS in children. Pediatr Nephrol. 2019;34(9): 1607\u0026ndash;1613.\u003c/li\u003e\n\u003cli\u003eBarua M, Stellacci E, Stella L, et al. Mutations in PAX2 associate with adult-onset FSGS. J Am Soc Nephrol. 2014;25(9): 1942\u0026ndash;1953.\u003c/li\u003e\n\u003cli\u003eJi Hyun Kim et al . Genotype-phenotype analysis in patients with PAX2 mutations: beyond renal coloboma syndrome .Research square . https://doi.org/10.21203/rs.3.rs-3028260/v1\u003c/li\u003e\n\u003cli\u003ePorteous S, Torban E, Cho NP, et al : Primary renal hypoplasia in humans and mice with PAX2 mutations: evidence of increased apoptosis in fetal kidneys of PAX21Neu +/\u0026minus; mutant mice. Hum Mol Genet. 2000;9(1):1\u0026ndash;11.\u003c/li\u003e\n\u003cli\u003eBower M, Salomon R, Allanson J, et al : Update of PAX2 mutations in renal coloboma syndrome and establishment of a locus-specific database. Hum Mutat. 2012;33:457\u0026ndash;66\u003c/li\u003e\n\u003cli\u003eBower MA, Schimmenti LA, Eccles MR et al : Renal coloboma syndrome In:, editors. 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British Journal of Ophthalmology, 97, 945\u0026ndash;946\u003c/li\u003e\n\u003cli\u003eDeng, H. et al : Diverse phenotypes in children with PAX2-related disorder.Molecular Genetics \u0026amp; Genomic Medicine 2019 Jun;7(6):e701.doi: 10.1002\u003c/li\u003e\n\u003cli\u003eNegrisolo S et al : PAX2 and CAKUT Phenotypes: Report on Two New Variants and a Review of Mutations from the Leiden Open Variation Database . Int J Mol Sci 2023 Feb 19;24(4):4165.doi: 10.3390\u003c/li\u003e\n\u003cli\u003eStevenson M, Pagnamenta AT,Reichart S, et al: Whole genome sequence analysis identifies aPAX2 mutation to establish a correct diagnosis for asyndromic form of hyperuricemia. Am J Med Genet Part A. 2020;182A:2521\u0026ndash;2528.\u003c/li\u003e\n\u003cli\u003eMatsuo H , Takada M , Ichida K et al : \u003cstrong\u003eCommon defects of ABCG2, a high capacity urate exporter, cause gout: a function-based genetic analysis in a Japanese population.\u003c/strong\u003e\u003cem\u003eSci Transl Med.\u003c/em\u003e 2009; \u003cstrong\u003e1\u003c/strong\u003e: 5ra11\u003c/li\u003e\n\u003cli\u003eCaulfield M.J , Munroe P.B,O\u0026apos;Neill D. et al : \u003cstrong\u003eSLC2A9 is a high-capacity urate transporter in humans.\u003c/strong\u003e\u003cem\u003ePLoS Med.\u003c/em\u003e 2008; \u003cstrong\u003e5\u003c/strong\u003e: e197\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":"Hyperuricemia, paired box 2 (PAX2 )mutation, optic disc pit, FSGS, papillorenal syndrome","lastPublishedDoi":"10.21203/rs.3.rs-4836528/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4836528/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eHyperuricemia is a metabolic abnormality, either acquired or inherited, characterized by elevated levels of uric acid (UA) in the serum. We are interested in the case report regarding hereditary hyperuricemia.\u003c/p\u003e \u003cp\u003eIn this case, we are reporting on an 18-year-old man who experienced repeated gout attacks, hyperuricemia, and reduced fraction ejection of uric acid (FEUA). Additionally, he had renal anomalies such as proteinuria and renal hypoplasia and Focal and segmental glomerulosclerosis (FSGS) in the kidney biopsy and eye fundus revealed a bilateral optic disc pit .These findings prompted us to conduct a genetic study on the patient. To our surprise, the DNA sequence analysis did not detect mutations in UMOD or REN, which are commonly associated with familial juvenile hyperuricemic nephropathy (FJHN). Instead, a mutation in the paired box 2 (PAX2) gene was identified which is a very rare entity. We concluded that the patient had papillorenal syndrome (PAPRS) .\u003c/p\u003e \u003cp\u003eHyperuricemia is a rare and uncommon manifestation in patients with PAPRS and PAX2 mutation, and has only been documented in three studies in the literature. The diagnosis of PAPRS is often underestimated and not well-known by clinicians. It exhibits high clinical variability and phenotypic heterogeneity without well-defined diagnostic criteria. The presence of hyperuricemia should prompt consideration of this diagnosis and it should be included in the diagnostic criteria for PAPRS in the future.\u003c/p\u003e","manuscriptTitle":"Hyperuricemia and gout as uncommon manifestation of Papillorenal syndrome in an 18-year-old young man with PAX 2 mutation : A Case report and review of the literature ","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-09-18 02:02:37","doi":"10.21203/rs.3.rs-4836528/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":"91dc8dd9-590a-4918-8f08-bab482a80881","owner":[],"postedDate":"September 18th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-02-27T11:23:48+00:00","versionOfRecord":[],"versionCreatedAt":"2024-09-18 02:02:37","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4836528","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4836528","identity":"rs-4836528","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}