nefrНефрологияNephrology (Saint-Petersburg)1561-62742541-9439Pavlov First Saint-Petersburg State Medical University10.24884/1561-6274-2018-22-2-88-96nefr-356Research ArticleСЛУЧАЙ ИЗ ПРАКТИКИPRACTICAL NOTESНАСЛЕДСТВЕННЫЙ ГИПОФОСФАТЕМИЧЕСКИЙ РАХИТ С ГИПЕРКАЛЬЦИУРИЕЙ (КЛИНИЧЕСКОЕ НАБЛЮДЕНИЕ)HEREDITARY HYPOPHOSPHATEMIC RICKETS WITH HYPERCALCIURIA (CASE REPORT)ПапижС. В.PapizhS. V.

Папиж Светлана Валентиновна, кандидат медицинских наук, Научно-исследовательский клинический институт педиатрии им. акад. Ю.Е. Вельтищева РНИМУ им. Н.И. Пирогова, отдел наследственных и приобретенных болезней почек 

 

 125412, Россия,  Москва, ул. Талдомская, д. 2

Svetlana V. Papizh, MD, PhD. Research Clinical Institute for Pediatrics n.a. acad. Y.E. Veltishev, Division of Inherited & Acquired Kidney Diseases125412 Moscow, Taldomskaya St., 2

papijsveta@mail.ruБашироваЗ. Р.BashirovaZ. R.

Баширова Зиля Рамилевна, Научно-исследовательский клинический институт педиатрии им. акад. Ю.Е. Вельтищева РНИМУ им. Н.И. Пирогова, отдел наследственных и приобретенных болезней почек 

125412, Россия,  Москва, ул. Талдомская, д. 2

Zilya

Zilya Bashirova,MD, Research Clinical Institute for Pediatrics n.a. acad. Y.E. Veltishev, Division of Inherited & Acquired Kidney Diseases 

125412 Moscow, Taldomskaya St., 2

,MD, Research Clinical Institute for Pediatrics n.a. acad. Y.E. Veltishev, Division of Inherited & Acquired Kidney Diseases 

125412 Moscow, Taldomskaya St., 2

bashirova@pedklin.ruРоссийский национальный исследовательский медицинский университет им. Н.И. ПироговаРоссияPirogov Russian National Research Medical UniversityRussian Federation2018120220202228896Copyright © Папиж С.В., Баширова З.Р., 20202020Папиж С.В., Баширова З.Р.Papizh S.V., Bashirova Z.R.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://journal.nephrolog.ru/jour/article/view/356

Наследственный гипофосфатемический рахит с гиперкальциурией – аутосомно-рецессивное заболевание, патогенетической основой которого является нарушение реабсорбции фосфора в проксимальном отделе нефрона с последующим развитием гипофосфатемии, гиперкальциурии, повышением уровня кальцитриола, снижением уровня паратиреоидного гормона, остеопорозом и костными деформациями. Заболевание относится к группе гипофосфатемических рахитов, обусловлено мутацией в гене SLC34A3, кодирующим натрий-фосфорный ко-транспортер NaPiIIc, ответственный за реабсорбцию фосфора в проксимальном отделе нефрона. В данной статье мы приводим клиническое наблюдение за ребенком с неклассическими проявлениями наследственного гипофосфатемического рахита с гиперкальциурией. Непостоянный характер гипофосфатемии, нормальные значения максимального тубулярного транспорта фосфора, отсутствие повышения сывороточной концентрации кальцитриола, рахитических изменений и нарушения минеральной плотности костной ткани в течение длительного периода наблюдения не позволяли клинически идентифицировать у ребенка один из вариантов гипофосфатемического рахита. Диагноз был подтвержден благодаря результатам полного секвенирования экзома – выявлена ранее неописанная компаунд-гетерозиготная мутация c.1382G>A (p.Trp461Ter) в 13-м экзоне и с.1094-3C>T в 10-м интроне гена SLC34A3. Верификация диагноза позволила пересмотреть подходы к терапии: при наследственном гипофосфатемическом рахите рекомендуется использование только препаратов фосфора, а назначение препаратов витамина D противопоказано в связи с его повышенной эндогенной продукцией.

Hereditary hypophosphatemic rickets with hypercalciuria  is a very rare autosomal recessive disease, pathogenic base of which is phosphorus reabsorption disorder in proximal nephron with following development of hypophsphatemia, hypercalciuria calcitriol level increase, decrease of parathyroid hormone, osteopenia and bony deformity. This disease refers to hypophosphatemic rickets, due to mutations in the SLC34A3 gene that encodes the sodium-phosphate cotransporter NaPi-IIc, which is responsible for phosphorus reabsorption in the proximal nephron. In this article, we present a clinical observation for a child with atypical manifestations of hereditary hypophosphatemic rickets with hypercalciuria. The clinical examination showed non constant hypophosphatemia, normal values of  maximum tubular phosphate transport, absence of calcitriol serum concentrations increase, rachitic changes and bone mineral disorders during a long period of observation. It didn’t allow clinically to identify one of the variants of hypophosphatemic rickets in a child. The diagnosis was confirmed by the results of complete exome sequencing which revealed previously undescribed compound heterozygous mutation c.1382G> A (p.Trp461Ter) in exon 13 and p.1094-3C> T in  intron 10 of the SLC34A3 gene. A correct diagnosis allowed us to reconsider the approaches of the treatment: in hereditary rickets recommended only phosphorus supplementation and prescription of vitamin D due to its increased endogenous production. 

гипофосфатемический рахитгиперкальциуриянефрокальцинозhypophosphatemic ricketshypercalciurianephrocalcinosisReferencesTieder M, Modai D, Samuel R et al. Hereditary hypophosphatemic rickets with hypercalciuria. N Engl J Med 1985; 312: 611–617 doi:10.1056/NEJM198503073121003Tieder M, Modai D, Samuel R et al. Hereditary hypophosphatemic rickets with hypercalciuria. N Engl J Med 1985; 312: 611–617 doi:10.1056/NEJM198503073121003Tieder M, Modai D, Shaked U. et al. «Idiopathic» hypercalciuria and hereditary hypophosphatemic rickets. Two phenotypical expressions of a common genetic defect. N Engl J Med 1987; 316: 125–129 doi:10.1056/NEJM198701153160302Tieder M, Modai D, Shaked U. et al. «Idiopathic» hypercalciuria and hereditary hypophosphatemic rickets. Two phenotypical expressions of a common genetic defect. N Engl J Med 1987; 316: 125–129 doi:10.1056/NEJM198701153160302Dasgupta D, Wee MJ, Reyes M et al. Mutations in SLC34A3/NPT2c are associated with kidney stones and nephrocalcinosis. Am Soc Nephrol 2014; 25(10): 2366–2375 doi: 10.1681/ASN.2013101085Dasgupta D, Wee MJ, Reyes M et al. Mutations in SLC34A3/NPT2c are associated with kidney stones and nephrocalcinosis. Am Soc Nephrol 2014; 25(10): 2366–2375 doi: 10.1681/ASN.2013101085Papizh S, Prikhodina L, Vladimirova T et al. Clinical and genetic heterogeneity of early-onset nephrocalcinosis in children. Ped Nephrol 2017; 32: 1758 doi: 10.1007/s00467-017-3753-xPapizh S, Prikhodina L, Vladimirova T et al. Clinical and genetic heterogeneity of early-onset nephrocalcinosis in children. Ped Nephrol 2017; 32: 1758 doi: 10.1007/s00467-017-3753-xBergwitz С, Roslin NM, Tieder M et al. SLC34A3 Mutations in patients with hereditary hypophosphatemic rickets with hypercalciuria predict a key role for the sodium-phosphate cotransporter NaP-IIc in maintaining phosphate homeostasis. Am J Hum Genet 2006; 78(2): 179–192 doi: 10.1086/499409Bergwitz С, Roslin NM, Tieder M et al. SLC34A3 Mutations in patients with hereditary hypophosphatemic rickets with hypercalciuria predict a key role for the sodium-phosphate cotransporter NaP-IIc in maintaining phosphate homeostasis. Am J Hum Genet 2006; 78(2): 179–192 doi: 10.1086/499409Negri AL. Hereditary hypophosphatemias: New genes in the bone-kidney axis. Nephrology 2007; 12: 317–320 doi: 10.1111/j.1440-1797.2007.00824.xNegri AL. Hereditary hypophosphatemias: New genes in the bone-kidney axis. Nephrology 2007; 12: 317–320 doi: 10.1111/j.1440-1797.2007.00824.xPhulwani P, Bergwitz C, Jaureguiberry G. et al. Hereditary hypophosphatemic rickets with hypercalciuria and nephrolithiasisidentification of a novel SLC34A3/NaPi-IIc mutation. Am J Med Genet 2011; 155A: 626–633 doi: 10.1002/ajmg.a.33832Phulwani P, Bergwitz C, Jaureguiberry G. et al. Hereditary hypophosphatemic rickets with hypercalciuria and nephrolithiasisidentification of a novel SLC34A3/NaPi-IIc mutation. Am J Med Genet 2011; 155A: 626–633 doi: 10.1002/ajmg.a.33832Tencza AL, Ichikawa S, Dang A et al. Hypophosphatemic rickets with hypercalciuria due to mutation in SLC34A3/Type IIc sodium-phosphate cotransporter: Presentatión as hypercalciuria and nephrolithiasis. J Clin Endocrinol Metab 2009; 94: 4433–4438 doi: 10.1210/jc.2009-1535Tencza AL, Ichikawa S, Dang A et al. Hypophosphatemic rickets with hypercalciuria due to mutation in SLC34A3/Type IIc sodium-phosphate cotransporter: Presentatión as hypercalciuria and nephrolithiasis. J Clin Endocrinol Metab 2009; 94: 4433–4438 doi: 10.1210/jc.2009-1535Yu Y, Sanderson SR, Reyes M et al. Novel NaPi-IIc mutations causing HHRH and idiopathic hypercalciuria in several unrelated families: long-term follow-up in one kindred. Bone 2012; 50(5): 1100–1106 doi:10.1016/j.bone.2012.02.015Yu Y, Sanderson SR, Reyes M et al. Novel NaPi-IIc mutations causing HHRH and idiopathic hypercalciuria in several unrelated families: long-term follow-up in one kindred. Bone 2012; 50(5): 1100–1106 doi:10.1016/j.bone.2012.02.015Habbig S, Beck BB, Hoppe B. Nephrocalcinosis and urolithiasis in children. Kidney Int 2011; 80(12): 1278–1291 doi: 10.1038/ki.2011.336Habbig S, Beck BB, Hoppe B. Nephrocalcinosis and urolithiasis in children. Kidney Int 2011; 80(12): 1278–1291 doi: 10.1038/ki.2011.336Miyamoto K, Segawa H, Ito M, Kuwahata M. Physiological regulation of renal sodium-dependent phosphate cotransporters. Jpn J Physiol 2004; 54: 93–102 doi: 10.2170/jjphysiol.54.93Miyamoto K, Segawa H, Ito M, Kuwahata M. Physiological regulation of renal sodium-dependent phosphate cotransporters. Jpn J Physiol 2004; 54: 93–102 doi: 10.2170/jjphysiol.54.93Payne RB. Renal tubular reabsorption of phosphate (TmP/GFR): indications and interpretation. Ann Clin Biochem 1998; 35: 201–206 doi: 10.1177/000456329803500203 13. Pettifor JM, Thandrayen K. Hypophosphatemic Rickets: Unraveling the Role of FGF23. Calcif Tissue Int 2012; 91: 297–306 doi: 10.1007/s00223-012-9651-0Payne RB. Renal tubular reabsorption of phosphate (TmP/GFR): indications and interpretation. Ann Clin Biochem 1998; 35: 201–206 doi: 10.1177/000456329803500203 13. Pettifor JM, Thandrayen K. Hypophosphatemic Rickets: Unraveling the Role of FGF23. Calcif Tissue Int 2012; 91: 297–306 doi: 10.1007/s00223-012-9651-0Areses-Trapote R, López-García JA, Ubetagoyena-Arrieta M. et al. Hereditary hypophosphatemic rickets with hypercalciuria: a case report. Nefrologia 2012; 32(4): 529–534 doi: 10.3265/Nefrologia.pre2012.Apr.11321.Areses-Trapote R, López-García JA, Ubetagoyena-Arrieta M. et al. Hereditary hypophosphatemic rickets with hypercalciuria: a case report. Nefrologia 2012; 32(4): 529–534 doi: 10.3265/Nefrologia.pre2012.Apr.11321.Segawa H, Kaneko I, Takahashi A et al. Growth-related renal type II Na/Pi cotransporter. J Biol Chem 2002; 277: 19665– 9672 doi: 10.1074/jbc.M200943200Segawa H, Kaneko I, Takahashi A et al. Growth-related renal type II Na/Pi cotransporter. J Biol Chem 2002; 277: 19665– 9672 doi: 10.1074/jbc.M200943200Mejia-Gaviria N, Gil-Peña H, Coto E et al. Genetic and clinical peculiarities in a new family with hereditary hypophosphatemic rickets with hypercalciuria: a case report. Orphanet J Rare Dis 2010; 5: 1 doi: 10.1186/1750-1172Mejia-Gaviria N, Gil-Peña H, Coto E et al. Genetic and clinical peculiarities in a new family with hereditary hypophosphatemic rickets with hypercalciuria: a case report. Orphanet J Rare Dis 2010; 5: 1 doi: 10.1186/1750-1172Kremke B, Bergwitz C, Ahrens W et al. Hypophosphatemic rickets with hypercalciuria due to mutation in SLC34A3/NaPi-IIc can be masked by vitamin D deficiency and can be associated with renal calcifications. Exp Clin Endocrinol Diabetes 2009; 117: 49–56 doi: 10.1055/s-2008-1076716Kremke B, Bergwitz C, Ahrens W et al. Hypophosphatemic rickets with hypercalciuria due to mutation in SLC34A3/NaPi-IIc can be masked by vitamin D deficiency and can be associated with renal calcifications. Exp Clin Endocrinol Diabetes 2009; 117: 49–56 doi: 10.1055/s-2008-1076716Carpenter TO, Imel EA, Holm IA et al. A clinician’s guide to X-linked hypophosphatemia. J Bone Miner Res 2011; 26:1381–1388. doi: 10.1002/jbmr.340Carpenter TO, Imel EA, Holm IA et al. A clinician’s guide to X-linked hypophosphatemia. J Bone Miner Res 2011; 26:1381–1388. doi: 10.1002/jbmr.340Li Y, Caballero D, Ponsetto J et al. Response of Npt2a knockout mice to dietary calcium and phosphorus. PLoS One 2017; 12(4): e0176232 doi: 10.1371/journal.pone.0176232Li Y, Caballero D, Ponsetto J et al. Response of Npt2a knockout mice to dietary calcium and phosphorus. PLoS One 2017; 12(4): e0176232 doi: 10.1371/journal.pone.0176232

The authors declare that there are no conflicts of interest present.