Die X-Chromosomale Hypophosphatämie – XLH

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 (NaP_i IIa and NaP_i 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.

Schlüsselwörter

Hypophosphatämie - XLH - Phosphatdiabetes - Osteomalazie

Keywords

Hypophosphatemia - XLH - Phosphate diabetes - Osteomalacia

• Literatur

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