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Novel Variant in CLDN16: a Further Step in the Diagnosis of Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis—A Case Report

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Novel Variant in CLDN16: a Further Step in the Diagnosis of Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis—A Case Report Case Report Novel Variant in CLDN16: A Further Step in the Diagnosis of Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis—A Case Report Gopal Narang 1,*, Tim Shimon 2, Jonathan Moore 1, Megan Hager 3, Filippo Pinto e Vairo 4,5 , Karen Stern 1, Mira Keddis 6 and Mitchell Humphreys 1 1 Department of Urology, Mayo Clinic, Phoenix, AZ 85054, USA; [email protected] (J.M.); [email protected] (K.S.); [email protected] (M.H.) 2 Creighton Medical School, Omaha, NE 68178, USA; [email protected] 3 Department of Clinical Genomics, Mayo Clinic, Rochester, MN 55902, USA; [email protected] 4 Center for Individualized Medicine, Mayo Clinic, Rochester, MN 55902, USA; vairo.fi[email protected] 5 Department of Clinical Genomics, Mayo Clinic, Phoenix, AZ 85054, USA 6 Department of Nephrology, Mayo Clinic, Phoenix, AZ 85054, USA; [email protected] * Correspondence: [email protected] Abstract: Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare tubulopathy characterized by renal loss of calcium and magnesium leading to progressive renal failure. The disorder is caused by variants to the tight junction proteins claudin-16 and -19. While rare, this disorder causes a significant burden to patients based on its clinical manifestations of various electrolyte abnormalities, nephrocalcinosis, and early progression to renal failure. In this Citation: Narang, G.; Shimon, T.; Moore, J.; Hager, M.; Pinto e Vairo, F.; report we describe the diagnosis of a novel variant of CLDN16 which clinically presented with severe Stern, K.; Keddis, M.; Humphreys, M. hypomagnesemia, hypocalcemia, nephrocalcinosis, and renal failure. Novel Variant in CLDN16: A Further Step in the Diagnosis of Familial Keywords: FHHNC; CLDN16; nephrocalcinosis; nephrolithiasis Hypomagnesemia with Hypercalciuria and Nephrocalcinosis—A Case Report. Uro 2021, 1, 76–81. https://doi.org/ 1. Introduction 10.3390/uro1030011 Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare autosomal recessive disorder caused by pathogenic variants in CLDN16 and CLDN19, Academic Editor: Tommaso Cai which encode the tight junction proteins claudin-16 and -19 [1–3]. Defects in these proteins lead to defective paracellular reabsorption of magnesium and calcium in the thick ascend- Received: 1 June 2021 ing limb of the loop of Henle and subsequent hypomagnesemia and hypercalciuria [4]. Accepted: 25 June 2021 Published: 30 June 2021 Sequela of these electrolyte abnormalities are responsible for FHHNC’s clinical presen- tation, characterized by polyuria, urinary tract infections, nephrocalcinosis, and chronic kidney disease (CKD) with early progression to renal failure [5]. Biochemical findings and Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in clinical features are suggestive of FHHNC, but genetic testing has been increasingly used published maps and institutional affil- in a confirmatory role. iations. The understanding of the pathophysiology of FHHNC continues to evolve with approximately 130 cases reported since its initial description in the 1970s. Here we add to that fund of knowledge with a case report of an individual with symptomology typical of FHHNC, with a novel variant of uncertain significance (VUS), and a pathogenic variant in CLDN16. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. 2. Case Report This article is an open access article distributed under the terms and A 43-year-old male with a longstanding history of nephrolithiasis was transferred to conditions of the Creative Commons our hospital in late 2017. His first stone episode was at the age of 10 years and since then Attribution (CC BY) license (https:// he has passed ‘hundreds to thousands of stones’. His past medical history is notable for creativecommons.org/licenses/by/ gout, recurrent urinary tract infections (UTI) and CKD stage III, and creatinine (Cr) 1.7 2 4.0/). (eGFR 53 mL/min/1.73 m ), stable over the past 13 years. He had no other hormonal or Uro 2021, 1, 76–81. https://doi.org/10.3390/uro1030011 https://www.mdpi.com/journal/uro Uro 2021, 1, FOR PEER REVIEW 2 Uro 2021, 1 77 gout, recurrent urinary tract infections (UTI) and CKD stage III, and creatinine (Cr) 1.7 (eGFR 53 mL/min/1.73 m2), stable over the past 13 years. He had no other hormonal or metabolicmetabolic disorders. disorders. His His past past surgical surgical history history included included multiple multiple failed failed treatments treatments with with extracorporealextracorporeal shockwave shockwave lithotripsy.lithotripsy. HeHe reportedreported no family family history history of of nephrolithiasis nephrolithiasis or orrenal renal disease. disease. Prior Prior to topresentation, presentation, he hewas was managed managed on onhydrochlorot hydrochlorothiazidehiazide (HCTZ) (HCTZ) 12.5 12.5mg mgdaily, daily, potassium potassium chloride chloride 15 15 mEq mEq twice twice a aday, day, colchicine 0.6 mgmg twicetwice aa day,day, and and prophylacticprophylactic trimethoprim/sulfamethoxazole trimethoprim/sulfamethoxazole (dose (dose unknown). unknown). HeHe was was transferredtransferred toto the Mayo Clinic Clinic due due to to severe severe electrolyte electrolyte abnormalities abnormalities in inOc- 2 Octobertober 2017. 2017. His His labs labs were were notable notable for for a Cr a Crof 1.95 of 1.95 (eGFR (eGFR 49 mL/min/1.73 49 mL/min/1.73 m2), potassium m ), potas- of sium2.6 mmol/L, of 2.6 mmol/L, bicarbonate bicarbonate 26.5 mmol/L, 26.5 mmol/L, magnesiu magnesiumm of 0.5 mg/dL, of 0.5 and mg/dL, calcium and of calcium 5.2 mg/dL. of 5.2His mg/dL. parathyroid His parathyroid hormone (PTH hormone) was (PTH) 96.3 pg/mL, was 96.3 vitamin pg/mL, D vitamin 27 ng/mL, D 27 and ng/mL, 1,25-dihy- and 1,25-dihydroxydroxy vitamin vitamin D 47 pg/mL. D 47 pg/mL.Of note, Of the note, pati theent patienthad had had a computational had a computational tomography tomog- of raphythis neck of this in the neck past in theto evaluate past toevaluate his elevat hised elevatedPTH. This PTH. showed This no showed parathyroid no parathyroid adenomas adenomasor masses. or CT masses. of the abdomen CT of the and abdomen pelvis du andring pelvis admission during was admission notable wasfor extensive notable for cal- extensivecifications calcifications of the medullary of the re medullarygions of both regions kidneys of both consiste kidneysnt with consistent nephrocalcinosis with nephro- and calcinosisan obstructing and an 1 obstructingcm right renal 1 cm pelvis right stone renal (Figure pelvis stone 1). The (Figure patient1). Thehad patienta ureteral had stent a ureteralplaced stentfor the placed obstructing for the stone obstructing and his stone electrolytes and his were electrolytes normalized were with normalized supplementa- with supplementation.tion. He was discharged He was on discharged magnesium on oxide magnesium 800 mg oxide four times 800 mg a day, four calcium times a carbonate day, cal- cium1000 carbonate mg three times 1000 mg a day, three amiloride times a day,5 mg amiloride daily, colchicine 5 mg daily, 0.6 mg colchicine twice a 0.6day, mg and twice allo- apurinol day, and 100 allopurinol mg daily, 100and mgadvised daily, to and contin advisedue HCTZ to continue 12.5 mg HCTZ daily and 12.5 potassium mg daily andchlo- potassium chloride 15 mEq twice a day. ride 15 mEq twice a day. FigureFigure 1. 1.CT CT scan scan on on presentation presentation demonstrating demonstrating bilateral bilateral large large volume volume stone stone burden burden and an and obstruct- an ob- ingstructing 1 cm right 1 cm ureteropelvic right ureteropelvic junction stone.junction Burden stone. of Burden stone disease of stone consistent disease consistent with nephrocalcinosis. with nephro- calcinosis. He underwent a standard (30 fr) right percutaneous nephrolithotomy in December 2017. This demonstrated a large right renal pelvis stone as well as numerous stones in the collecting system and emanating from the parenchyma. Given the extensive stone Uro 2021, 1 78 burden, he was unable to be rendered visually stone-free. Stone analysis revealed a mixed composition stone, 70% calcium phosphate (apatite), 20% calcium oxalate monohydrate, and 10% calcium oxalate dehydrate. The patient underwent a metabolic urine evaluation in January 2018. This demon- strated hypercalciuria, severe hypocitraturia, elevated urinary pH, and adequate urinary volume (Table1). The patient was started on chlorthalidone 12.5 mg daily in lieu of HCTZ for management of hypercalciuria, his allopurinol dose was increased to 200 mg daily and he was advised to continue electrolyte supplementation. Table 1. 24 h urine samples. 24 h Urinary January 2018 #1 January 2018 #2 May 2018 November 2020 Reference Range Units/24 h Parameters Volume 4.11 4.15 4.07 3.7 0.5–4 L Calcium 327 366 320 269 <250 mg Oxalate 25 24 22 19 20–40 mg Citrate <62 <62 <61 <55 >450 mg Uric Acid 0.362 0.374 0.381 0.198 <0.800 g Sodium 153 184 201 164 50–150 mEq/L pH 6.732 6.671 6.599 6.973 5.8–6.2 SS calcium 2.88 2.75 2.16 2.03 6–10 RS oxalate SS calcium 0.83 0.81 0.7 0.91 0.5–2 RS phosphate SS uric acid 0.04 0.05 0.06 0.01 0–1 RS Over the next 26 months, the patient had a total of eight ureteroscopic stone procedures to treat his extensive bilateral nephrocalcinosis. At each procedure complete stone clearance was attempted. Given the patients large stone burden, staged procedures were required. Ureteral stents were placed after each procedure and removed after 5 days unless a staged procedure was planned in the future. Of note, the patients most recent ureteroscopies were performed with the thulium fiber laser and, anecdotally, superior stone clearance was noted. Subsequent stone analysis revealed predominantly calcium phosphate (apatite) stones. Throughout this period, the patient continued to have hypercalciuria (269–320 mg/day) and hypomagnesaemia (1.2 mg/dL) on laboratory evaluations.
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