Osteologie 2018; 27(04): 208-214
DOI: 10.1055/s-0038-1676924
Seltene Knochenerkrankungen – Rare bone diseases
Georg Thieme Verlag KG Stuttgart · New York

Die X-Chromosomale Hypophosphatämie – XLH

X-Chromosomal Hypophosphatemia – XLH
L. Seefried
1   Klinische Studieneinheit, Orthopädische Klinik – König-Ludwig-Haus, Universität Würzburg
,
F. Genest
1   Klinische Studieneinheit, Orthopädische Klinik – König-Ludwig-Haus, Universität Würzburg
,
D. Rak
1   Klinische Studieneinheit, Orthopädische Klinik – König-Ludwig-Haus, Universität Würzburg
,
F. Böhle
1   Klinische Studieneinheit, Orthopädische Klinik – König-Ludwig-Haus, Universität Würzburg
› Author Affiliations
Further Information

Publication History

eingereicht: 01 October 2018

angenommen: 15 October 2018

Publication Date:
18 December 2018 (online)

Zusammenfassung

Bei der X-chromosomalen Hypophosphatämischen Rachitis (XLH) handelt es sich um eine seltene, aber mit einer Prävalenz von 1 : 20 000 gleichzeitig die häufigste genetisch bedingte Phosphatverlusterkrankung. Ursächlich sind Veränderungen im PHEX-Gen (Phosphate Regulating Endopeptidase Homolog, X-linked) auf dem X-Chromosom. Die Mutationen führen zu einer Störung der Metabolisierung des vorwiegend von Osteozyten sezernierten FGF-23 und bedingen über eine Verminderung von Natrium-Phosphat Co- Transportern in der apikalen Membran des proximalen Tubulus eine verminderte renale Phosphat-Reabsorption und eine Hemmung der 1-α-Hydroxylierung und Aktivierung von Vitamin D. In der Summe führt dies u. a. zu Phosphaturie, Hypophosphatämie und einer Mineralisierungsstörung des Knochens. Das klinische Bild im Kindesalter ist gekennzeichnet durch Zeichen der Rachitis mit Kleinwuchs und Knochendeformierungen. Im Erwachsenenalter stehen Arthralgien, (Pseudo-) Frakturen, Kontrakturen und die frühzeitige Entwicklung einer Arthrose im Vordergrund. Wesentliche Säulen der Therapie sind derzeit die Substitution von Phosphat und von unzureichend gebildetem aktivem Vitamin D. Aktuell für Kinder und zukünftig auch für Erwachsene könnte ein Antikörper gegen FGF-23 (Bursosumab) die Therapie verbessern.

Summary

X-linked hypophosphataemia (XLH) is a rare, and still the most frequent genetically determined phosphate wasting disorder with a prevalence of 1 in 20,000. It is caused by alterations in the Phosphate Regulating Endopeptidase Homolog, X-linked (PHEX). The mutations affect the metabolism of fibroblast growth factor 23 (FGF-23), a phosphatonin secreted preferentially by osteocytes. Elevated FGF-23 reduces the number and activation of sodium phosphate cotransporters (NaPi IIa and NaPi IIc) within the apical membrane of the proximal renal tubule, entailing decreased renal phosphate reabsorption. In addition FGF-23 reduces vitamin D activation by inhibiting 1-α-hydroxalyse activity, resulting in low or inappropriately normal 1,25-(OH)2-Vitamin D3 levels. Altogether, this results in phosphaturia, hypophosphatemia and deficient bone mineralization with rickets and osteomalacia in children and adults, respectively. The clinical phenotype seen in children is characterized by signs of rickets with short stature and bowing of the lower extremities. In adulthood, leading symptoms are arthralgia, fractures, contractures and early development of osteoarthritis. Established treatment in XLH comprises supplementation of phosphorus and active Vitamin D. Currently available for children and perspectively also for adults, an FGF-23 targeted antibody (Burosumab) could improve treatment options.

 
  • Literatur

  • 1 Pavone V, Testa G, Gioitta SIachino, Evola FR, Avondo S, Sessa G. Hypophosphatemic rickets: etiology, clinical features and treatment. Eur J Orthop Surg Traumatol 2015; 25 (02) 221-226.
  • 2 Bergwitz C, Juppner H. FGF23 and syndromes of abnormal renal phosphate handling. Adv Exp Med Biol 2012; 728: 41-64.
  • 3 Huang X, Jiang Y, Xia W. FGF23 and Phosphate Wasting Disorders. Bone research 2013; 01 (02) 120-1 32.
  • 4 Ruppe MD. X-Linked Hypophosphatemia. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K. et al. editors. GeneReviews((R)). Seattle (WA): 1993
  • 5 Wolf M, White KE. Coupling fibroblast growth factor 23 production and cleavage: iron deficiency, rickets, and kidney disease. Curr Opin Nephrol Hypertens 2014; 23 (04) 411-419.
  • 6 Cavalli L, Mazzotta C, Brandi ML. Phosphatonins: physiological role and pathological changes. Clin Cases Miner Bone Metab 2012; 09 (01) 9-12.
  • 7 Fearn A, Allison B, Rice SJ, Edwards N, Halbritter J, Bourgeois S. et al. Clinical, biochemical, and pathophysiological analysis of SLC34A1 mutations. Physiol Rep 2018; 06 (12) e13715.
  • 8 Bergwitz C, Roslin NM, Tieder M, Loredo-Osti JC, Bastepe M, Abu-Zahra H. et al. SLC34A3 mutations in patients with hereditary hypophosphatemic rickets with hypercalciuria predict a key role for the sodium-phosphate cotransporter NaPi-IIc in maintaining phosphate homeostasis. Am J Hum Genet 2006; 78 (02) 179-192.
  • 9 Chesher D, Oddy M, Darbar U, Sayal P, Casey A, Ryan A. et al. Outcome of adult patients with X-linked hypophosphatemia caused by PHEX gene mutations. J Inherit Metab Dis. 2018
  • 10 Imel EA, Econs MJ. Fibroblast growth factor 23: roles in health and disease. J Am Soc Nephrol 2005; 16 (09) 2565-2575.
  • 11 Andrukhova O, Smorodchenko A, Egerbacher M, Streicher C, Zeitz U, Goetz R. et al. FGF23 promotes renal calcium reabsorption through the TRPV5 channel. EMBO J 2014; 33 (03) 229-246.
  • 12 Econs MJ. Conventional Therapy in Adults With XLH Improves Dental Manifestations, But Not Enthesopathy. J Clin Endocrinol Metab 2015; 100 (10) 3622-3624.
  • 13 Bielesz B. Emerging role of a phosphatonin in mineral homeostasis and its derangements. European journal of clinical investigation 2006; 36 (Suppl. 02) 34-42.
  • 14 Feng JQ, Clinkenbeard EL, Yuan B, White KE, Drezner MK. Osteocyte regulation of phosphate homeostasis and bone mineralization underlies the pathophysiology of the heritable disorders of rickets and osteomalacia. Bone 2013; 54 (02) 213-221.
  • 15 Guven A, Al-Rijjal RA, BinEssa HA, Dogan D, Kor Y, Zou M. et al. Mutational analysis of PHEX, FGF23 and CLCN5 in patients with hypophosphataemic rickets. Clin Endocrinol (Oxf) 2017; 87 (01) 103-112.
  • 16 Shimada T, Muto T, Urakawa I, Yoneya T, Yamazaki Y, Okawa K. et al. Mutant FGF-23 responsible for autosomal dominant hypophosphatemic rickets is resistant to proteolytic cleavage and causes hypophosphatemia in vivo. Endocrinology 2002; 143 (08) 3179-3182.
  • 17 Acar S, BinEssa HA, Demir K, Al-Rijjal RA, Zou M, Catli G. et al. Clinical and genetic characteristics of 15 families with hereditary hypophosphatemia: Novel Mutations in PHEX and SLC34A3. PLoS One 2018; 13 (03) e0193388.
  • 18 Lichter-Konecki U, Broman KW, Blau EB, Konecki DS. Genetic and physical mapping of the locus for autosomal dominant renal Fanconi syndrome, on chromosome 15q15.3. Am J Hum Genet 2001; 68 (01) 264-268.
  • 19 Ballinger AE, Palmer SC, Nistor I, Craig JC, Strippoli GF. Calcimimetics for secondary hyperparathyroidism in chronic kidney disease patients. The Cochrane database of systematic reviews 2014; (12) CD006254.
  • 20 Seikaly MG, Quigley R, Baum M. Effect of dipyridamole on serum and urinary phosphate in X-linked hypophosphatemia. Pediatr Nephrol 2000; 15 1–2): 57-59.
  • 21 Sullivan R, Abraham A, Simpson C, Olear E, Carpenter T, Deng Y. et al. Three-Month Randomized Clinical Trial of Nasal Calcitonin in Adults with X-linked Hypophosphatemia. Calcif Tissue Int 2018; 102 (06) 666-670.
  • 22 Aono Y, Yamazaki Y, Yasutake J, Kawata T, Hasegawa H, Urakawa I. et al. Therapeutic effects of anti-FGF23 antibodies in hypophosphatemic rickets/ osteomalacia. J Bone Miner Res 2009; 24 (11) 1879-1888.
  • 23 Imel EA, Zhang X, Ruppe MD, Weber TJ, Klausner MA, Ito T. et al. Prolonged Correction of Serum Phosphorus in Adults With X-Linked Hypophosphatemia Using Monthly Doses of KRN23. J Clin Endocrinol Metab 2015; 100 (07) 2565-2573.
  • 24 Insogna KL, Briot K, Imel EA, Kamenicky P, Ruppe MD, Portale AA. et al. A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial Evaluating the Efficacy of Burosumab, an Anti-FGF23 Antibody, in Adults With X-Linked Hypophosphatemia: Week 24 Primary Analysis. J Bone Miner Res. 2018
  • 25 Gizard A, Rothenbuhler A, Pejin Z, Finidori G, Glorion C, de Billy B. et al. Outcomes of orthopedic surgery in a cohort of 49 patients with X-linked hypophosphatemic rickets (XLHR). Endocrine connections 2017; 06 (08) 566-573.
  • 26 Goldsweig BK, Carpenter TO. Hypophosphatemic rickets: lessons from disrupted FGF23 control of phosphorus homeostasis. Curr Osteoporos Rep 2015; 13 (02) 88-97.