{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,3]],"date-time":"2026-05-03T07:50:42Z","timestamp":1777794642985,"version":"3.51.4"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,3,28]],"date-time":"2025-03-28T00:00:00Z","timestamp":1743120000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:p>We report on a 3-year and 5-month-old boy who was referred for suspected rickets, due to knee valgus deformity developed over the previous year. The child had a history of epilepsy well-controlled with phenobarbital. His psychomotor development and growth metrics were appropriate for his age. On admission, laboratory work-up revealed elevated alkaline phosphatase (1289 U\/L) and parathyroid hormone (PTH) (417 pg\/ml), normal corrected calcium (9,3 mg\/dl) and creatinine (0,21 mg\/dl), low phosphate (3,2 mg\/dl), 25-hydroxy vitamin D (6 ng\/ml) and 1-25 hydroxy vitamin D (13.4 pg\/mL, nv 20-80) concentrations. Urinalysis indicated low tubular reabsorption of phosphate (TRP % 10,7), along with bicarbonate, uric acid and amino acid loss, consistent with renal Fanconi syndrome. Based on these results, a genetic form of renal tubular dysfunction was suspected, and thus a clinical exome sequencing was requested. In the meanwhile, the child was commenced on Joulie solution (70 mg\/kg\/day of phosphate), calcitriol (0.03 mcg\/kg\/die), and ergocalciferol (1000 IU daily). FGF-23 concentrations were found to be within the normal range, thus ruling out FGF23-dependent forms of rickets. Surprisingly, we observed a dramatic improvement in laboratory parameters within two weeks from the treatment initiation, including normalisation of phosphate and PTH concentrations and resolution of Fanconi syndrome, prompting discontinuation of phosphate supplements. Molecular analysis identified a <jats:italic>de novo<\/jats:italic> monoallelic mutation (C.1006 + 1 G&amp;gt;A) in the solute carrier family 34 member 1(SLC34A1) gene encoding a protein involved in actively transporting phosphate into cells via Na+ cotransport in the renal brush border membrane. However, even without phosphate substitution no further drops in serum phosphate concentrations and persistently normal proximal renal tubular function were observed. Moreover the rickets changes had almost healed six months after starting vitamin D supplementation. This case provides further evidence that vitamin D deficiency may rarely cause renal Fanconi syndrome, reversible upon vitamin D replacement. This is particularly relevant in children with risk factors for vitamin D deficiency, including use of anticonvulsants.<\/jats:p>","DOI":"10.3389\/fendo.2025.1553032","type":"journal-article","created":{"date-parts":[[2025,3,28]],"date-time":"2025-03-28T05:58:31Z","timestamp":1743141511000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Case report: Reversible Fanconi syndrome due to vitamin D deficiency in a patient with epilepsy harbouring a pathogenic variant in the SLC34A1 gene"],"prefix":"10.3389","volume":"16","author":[{"given":"Nicola","family":"Improda","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesco Maria","family":"Rosanio","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luigi","family":"Annicchiarico Petruzzelli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gyusy","family":"Ambrosio","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabriele","family":"Malgieri","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claudia","family":"Mandato","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Rosaria","family":"Licenziati","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,3,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1007\/s00774-023-01490-3","article-title":"Inherited Fanconi renotubular syndromes: unveiling the intricacies of hypophosphatemic rickets\/osteomalacia","volume":"42","author":"Ragate","year":"2024","journal-title":"J Bone Miner Metab"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1159\/000446396","article-title":"Hepatocyte nuclear factor-4 alfa mutation associated with hyperinsulinaemic hypoglycaemia and atypical renal Fanconi syndrome: expanding the clinical phenotype","volume":"86","author":"Improda","year":"2016","journal-title":"Horm Res Paediatr"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-3476(75)80214-9","article-title":"Fanconi syndrome following bowel surgery and hepatitis reversed by 25 hydroxycholecalciferol","volume":"86","author":"Chesney","year":"1975","journal-title":"J Pediatr"},{"key":"B4","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1007\/s00467-015-3050-5","article-title":"Interactions of vitamin D and the proximal tubule","volume":"31","author":"Chesney","year":"2016","journal-title":"Pediatr Nephrol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1111\/j.1440-1797.2006.00704.x","article-title":"Proximal tubule endocytic apparatus as the specific renal uptake mechanism for vitamin D-binding protein\/25-(OH)D3 complex","volume":"11","author":"Negri","year":"2006","journal-title":"Nephrol (Carlton)"},{"key":"B6","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1016\/j.pcl.2018.09.004","article-title":"Hypophosphatemic rickets","volume":"66","author":"Bitzan","year":"2018","journal-title":"Pediatr Clin North Am"},{"key":"B7","doi-asserted-by":"publisher","first-page":"17101","DOI":"10.1038\/nrdp.2017.101","article-title":"Rickets","volume":"3","author":"Carpenter","year":"2017","journal-title":"Nat Rev Dis Prim"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1111\/jpc.14941","article-title":"Global consensus on nutritional rickets: Implications for Australia","volume":"56","author":"Siafarikas","year":"2020","journal-title":"J Paediatr Child Health"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0502249102","article-title":"Hypophosphatemia leads to rickets by impairing caspase-mediated apoptosis of hypertrophic chondrocytes","volume":"102","author":"Sabbagh","year":"2005","journal-title":"Proc Natl Acad Sci USA"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1111\/j.1651-2227.1973.tb08154.x","article-title":"Proximal renal tubular acidosis in vitamin D deficiency rickets","volume":"62","author":"Guignard","year":"1973","journal-title":"Acta Paediatr Scand"},{"key":"B11","article-title":"Clearance of free amino acids in vitamin D deficiency rickets before and following therapy with vitamin D","volume":"119","author":"Brodehl","year":"1971","journal-title":"Monatsschr Kinderheilkd"},{"key":"B12","article-title":"Jakel A Influence of phosphate load on renal amino-acid transport","volume":"121","author":"Weber","year":"1973","journal-title":"Monatsschr Kinderheilkd"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.3109\/10408368009108730","article-title":"Aminoaciduria\u2013its relationship to vitamin D and parathyroid hormone","volume":"12","author":"Phillips","year":"1980","journal-title":"Crit Rev Clin Lab Sci"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.4158\/EP.12.5.559","article-title":"Renal tubular acidosis type 2 with Fanconi\u2019s syndrome, osteomalacia, osteoporosis, and secondary hyperaldosteronism in an adult consequent to vitamin D and calcium deficiency: effect of vitamin D and calcium citrate therapy","volume":"12","author":"Taylor","year":"2006","journal-title":"Endocr Pract"},{"key":"B15","first-page":"35","article-title":"Proximal renal tubular acidosis in vitamin D deficiency rickets","volume":"22","author":"Vainsel","year":"1974","journal-title":"Biomedicine"},{"key":"B16","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1016\/S0140-6736(01)42380-4","article-title":"Acidosis in relation to acute rickets","volume":"1","author":"Burgess","year":"1924","journal-title":"Lancet"},{"key":"B17","article-title":"Observations on the metabolic effects of vitamin D in Fanconi\u2019s syndrome","volume":"29","author":"Salassa","year":"1954","journal-title":"Mayo Clin Proc"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1136\/adc.49.12.955","article-title":"Infantile rickets with severe proximal renal tubular acidosis, responsive to vitamin D","volume":"49","author":"Huguenin","year":"1974","journal-title":"Arch Dis Child"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/s0022-3476(80)80748-7","article-title":"Vitamin D-resistant rickets: end-organ unresponsiveness to 1,25(OH)2D3","volume":"96","author":"Sockalosky","year":"1980","journal-title":"J Pediatr"},{"key":"B20","article-title":"Renal tubular acidosis and amino aciduria of dietary or intestinal origin","volume":"37","author":"Muldowney","year":"1968","journal-title":"Q J Med"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/0002-9343(77)90290-x","article-title":"Rickets in adult cystic fibrosis with myopathy, pancreatic insufficiency and proximal tubular dysfunction","volume":"63","author":"Scott","year":"1997","journal-title":"Am J Med"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2362.1992.tb01455.x","article-title":"Berlin T The human renal 25-hydroxyvitamin D3-1 alpha-hydroxylase: properties studied by isotope-dilution mass spectrometry","volume":"22","author":"Hagenfeldt","year":"1992","journal-title":"Eur J Clin Invest"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1097\/01.asn.0000013885.23734.ca","article-title":"Identification of a renal proximal tubular cell-specific enhancer in the mouse 25- hydroxyvitamin D 1alpha-hydroxylase gene","volume":"13","author":"Yoshida","year":"2002","journal-title":"J Am Soc Nephrol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1203\/00006450-196711000-00001","article-title":"Hyperparathyroidism as the cause of hyperaminoaciduria and phosphaturia in human vitamin D deficiency","volume":"1","author":"Fraser","year":"1967","journal-title":"Pediatr Res"},{"key":"B25","article-title":"Physiology of vitamin D","volume":"14","author":"Harrison","year":"1959","journal-title":"Helv Paediatr Acta"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/0002-9343(74)90766-9","article-title":"Rickets and the pathogenesis of impaired tubular transport of phosphate and other solutes","volume":"57","author":"Scriver","year":"1974","journal-title":"Am J Med"},{"key":"B27","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1016\/0885-4505(90)90046-4","article-title":"Perturbation of renal amino acid transport by brush border membrane vesicles in the vitamin D-deficient rat","volume":"44","author":"Dabbagh","year":"1990","journal-title":"Biochem Med MetabBiol"},{"key":"B28","article-title":"Aminoaciduria of vitamin D deficiency is independent of PTH levels and urinary cyclic AMP","volume":"15","author":"Dabbagh","year":"1989","journal-title":"Miner Electrolyte Metab"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/gfs493","article-title":"Proximal renal tubular acidosis: a not so rare disorder of multiple etiologies","volume":"27","author":"Haque","year":"2012","journal-title":"Nephrol Dial Transplant"},{"key":"B30","article-title":"Familial renal tubular acidosis","volume":"23","author":"Alper","year":"2010","journal-title":"J Nephrol"},{"key":"B31","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1542\/peds.56.1.45","article-title":"Osteomalacia associated with anticonvulsant drug therapy in mentally retarded children","volume":"56","author":"Tolman","year":"1975","journal-title":"Pediatrics"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.2147\/RMHP.S316897","article-title":"A literature review of the potential impact of medication on vitamin D status","volume":"14","author":"Wakeman","year":"2021","journal-title":"Risk Manag Healthc Policy"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2007.03.177","article-title":"Phenobarbital suppresses vitamin D3 25-hydroxylase expression: a potential new mechanism for drug-induced osteomalacia","volume":"357","author":"Hosseinpour","year":"2007","journal-title":"Biochem Biophys Res Commun"},{"key":"B34","article-title":"Drug-induced osteomalacia","volume":"89","author":"D\u2019 Erasmo","year":"1998","journal-title":"Recenti Prog Med"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.nu.02.070182.001221","article-title":"Iatrogenic nutritional deficiencies","volume":"2","author":"Young","year":"1982","journal-title":"Annu Rev Nutr"},{"key":"B36","doi-asserted-by":"publisher","first-page":"394","DOI":"10.1210\/jc.2015-2175","article-title":"Global consensus recommendations on prevention and management of nutritional rickets","volume":"101","author":"Munns","year":"2016","journal-title":"J\u00a0Clin Endocrinol Metab"},{"key":"B37","doi-asserted-by":"publisher","first-page":"e60856","DOI":"10.1371\/journal.pone.0060856","article-title":"Vitamin D deficiency in children with a chronic illness\u2013seasonal and age-related variations in serum 25-hydroxy vitamin D concentrations","volume":"8","author":"Holmlund-Suila","year":"2013","journal-title":"PloS One"},{"key":"B38","doi-asserted-by":"publisher","first-page":"7975","DOI":"10.1038\/ncomms8975","article-title":"Common and rare variants associated with kidney stones and biochemical traits","volume":"6","author":"Oddsson","year":"2015","journal-title":"Nat Commun"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.9.5372","article-title":"Targeted inactivation of Npt2 in mice leads to severe renal phosphate wasting, hypercalciuria, and skeletal abnormalities","volume":"95","author":"Beck","year":"1998","journal-title":"Proc Natl Acad Sci U S A"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0905647","article-title":"A loss-of-function mutation in NaPi-IIa and renal Fanconi\u2019s syndrome","volume":"362","author":"Magen","year":"2010","journal-title":"N Engl J Med"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM198809293191307","article-title":"Elevated serum 1,25-dihydroxyvitamin D concentrations in siblings with primary Fanconi\u2019s syndrome","volume":"319","author":"Tieder","year":"1988","journal-title":"N Engl J Med"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00211","article-title":"Genetic, pathophysiological, and\u00a0clinical aspects of nephrocalcinosis","volume":"311","author":"Oliveira","year":"2016","journal-title":"Am J Physiol Renal Physiol"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00362.2003","article-title":"1alpha-Hydroxylase gene ablation and pi supplementation inhibit renal calcification in mice homozygous for the disrupted Npt2a gene","volume":"286","author":"Tenenhouse","year":"2004","journal-title":"Am J Physiol Renal Physiol"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa020028","article-title":"Nephrolithiasis and osteoporosis associated with hypophosphatemia caused by mutations in the type 2a sodium-phosphate cotransporter","volume":"347","author":"Pri\u00e9","year":"2002","journal-title":"N Engl J Med"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1359\/jbmr.2003.18.12.2135","article-title":"Functional Characterization of two naturally occurring mutations in the human sodium-phosphate cotransporter type IIa","volume":"18","author":"Virkki","year":"2003","journal-title":"J Bone Miner Res"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1038\/sj.ki.5000437","article-title":"NPT2a gene variation in calcium nephrolithiasis with renal phosphate leak","volume":"69","author":"Lapointe","year":"2006","journal-title":"Kidney Int"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-018-2246-5","article-title":"Clinical aspects of the phosphate transporters NaPi-IIa and NaPi-IIb: mutations and disease associations","volume":"471","author":"Lederer","year":"2019","journal-title":"Pflugers Arch"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1177\/0300060519896146","article-title":"Heterozygous mutation of SLC34A1 in patients with hypophosphatemic kidney stones and osteoporosis: a case report","volume":"48","author":"Ma","year":"2020","journal-title":"J Int Med Res"},{"key":"B49","doi-asserted-by":"publisher","first-page":"587","DOI":"10.1016\/j.arcped.2021.08.008","article-title":"X-linked hypophosphatemia, a genetic and treatable cause of rickets","volume":"28","author":"Linglart","year":"2021","journal-title":"Arch Pediatr"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(03)14636-3","article-title":"Rickets","volume":"362","author":"Wharton","year":"2003","journal-title":"Lancet"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2025.1553032\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,28]],"date-time":"2025-03-28T05:58:41Z","timestamp":1743141521000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2025.1553032\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,28]]},"references-count":50,"alternative-id":["10.3389\/fendo.2025.1553032"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2025.1553032","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,28]]},"article-number":"1553032"}}