Novel PHEX nonsense mutation in a patient with X-linked hypophosphatemic rickets and review of current therapeutic regimens

• Published in: Experimental and clinical endocrinology & diabetes Vol. 119; no. 7; p. 431
• Main Authors: Kienitz, T, Ventz, M, Kaminsky, E, Quinkler, M
• Format: Journal Article
• Language: English
• Published: Germany 01.07.2011
• Subjects: Adolescent; Adult; Arthroplasty, Replacement, Hip; Bone Density Conservation Agents - administration & dosage; Calcinosis - drug therapy; Calcinosis - enzymology; Calcinosis - etiology; Calcinosis - genetics; Calcinosis - pathology; Calcitriol - administration & dosage; Codon, Nonsense; Exons; Familial Hypophosphatemic Rickets - complications; Familial Hypophosphatemic Rickets - drug therapy; Familial Hypophosphatemic Rickets - enzymology; Familial Hypophosphatemic Rickets - genetics; Familial Hypophosphatemic Rickets - pathology; Female; Genetic Diseases, X-Linked; Hearing Loss; Humans; Male; PHEX Phosphate Regulating Neutral Endopeptidase - genetics; PHEX Phosphate Regulating Neutral Endopeptidase - metabolism
• ISSN: 1439-3646
• DOI: 10.1055/s-0031-1277162

The most common form of familial hypophosphatemic rickets is X-linked. PHEX has been identified as the gene defective in this phosphate wasting disorder leading to decreased renal phosphate reabsorption, hypophosphatemia and inappropriate concentrations of 1,25-dihydroxyvitamin D in regard to hypophosphatemia. Clinical manifestation are skeletal deformities, short stature, osteomalacia, dental abscesses, bone pain, and loss of hearing. We report 3 cases of hypophosphatemic rickets with genetic mutational analysis of the PHEX gene. In 1 male patient an unknown nonsense mutation was found in exon 7, codon 245 (c.735T>G, Tyr245Term, Y245X). In both female patients known mutations were found: c.682delTC (exon 6, codon 228) and c.1952G>C (exon 19, codon 651, R651P). Age at diagnosis ranged from early childhood to the age of 35 years. Clinical complications were hip replacement in 1 patient, mild nephrocalcinosis in 2 patients and loss of hearing in 1 patient. All 3 patients have been treated with phosphate supplements and receive 1,25-dihydroxyvitamin D. Under this regimen all patients show stable biochemical markers with slight hyperparathyreoidism. In all patients at least one family member is affected by rickets, as well. We report a novel nonsense mutation of PHEX that has not been identified so far. The recent discovery of FGF23 and MEPE has changed our understanding of the kidney-bone metabolism, but also raises concerns about the efficacy of current therapeutic regimens that are reviewed in this context.