Abstract
ObjectiveX-linked dominant hypophosphatemia (XLH) is the most prevalent form of inherited rickets/osteomalacia in humans. The aim of this study was to identify PHEX gene mutations and describe the clinical features observed in 6 unrelated Chinese families and 3 sporadic patients with hypophosphatemic rickets/osteomalacia.MethodsFor this study, 45 individuals from 9 unrelated families of Chinese Han ethnicity (including 16 patients and 29 normal phenotype subjects), and 250 healthy donors were recruited. All 22 exons and exon-intron boundaries of the PHEX gene were amplified by polymerase chain reaction (PCR) and directly sequenced.ResultsThe PHEX mutations were detected in 6 familial and 3 sporadic hypophosphatemic rickets/osteomalacia. Altogether, 2 novel mutations were detected: 1 missense mutation c.1183G>C in exon 11, resulting in p.Gly395Arg and 1 missense mutation c.1751A>C in exon 17, resulting in p.His584Pro. No mutations were found in the 250 healthy controls.ConclusionsOur study increases knowledge of the PHEX gene mutation types and clinical phenotypes found in Chinese patients with XLH, which is important for understanding the genetic basis of XLH. The molecular diagnosis of a PHEX genetic mutation is of great importance for confirming the clinical diagnosis of XLH, conducting genetic counseling, and facilitating prenatal intervention, especially in the case of sporadic patients.
Highlights
Hypophosphatemic rickets/osteomalacia is characterized by defective renal phosphate re-absorption and abnormal bone mineralization [1,2,3,4]
The most common disease-causing genetic mutations in these cases occur in the PHEX gene and cause 87% of familial X-linked dominant hypophosphatemia (XLH) and 72% of the sporadic cases [9]
XLH is characterized by renal phosphate wasting, which causes hypophosphatemia and normal to low 1,25-dihydroxy-vitamin D3 serum levels [10]; together, these indicate defects in phosphate and vitamin D metabolism
Summary
Hypophosphatemic rickets/osteomalacia is characterized by defective renal phosphate re-absorption and abnormal bone mineralization [1,2,3,4]. X-linked dominant hypophosphatemia (XLH), autosomal dominant hypophosphatemic rickets (ADHR), and autosomal recessive hypophosphatemic rickets (ARHR) are the three main types of hypophosphatemic rickets and are associated with mutations in the phosphate-regulating endopeptidase gene (PHEX), the fibroblast growth factor 23 gene (FGF23), and the dentin matrix acidic phosphoprotein gene (DMP1), respectively. XLH (MIM 307800), which was first reported in 1939 [5], is the most common genetic form of hypophosphatemic rickets/osteomalacia and has an incidence rate of 3.9–5.0 per 100,000 [6,7,8]. The most common disease-causing genetic mutations in these cases occur in the PHEX gene and cause 87% of familial XLH and 72% of the sporadic cases [9]. XLH is characterized by renal phosphate wasting, which causes hypophosphatemia and normal to low 1,25-dihydroxy-vitamin D3 serum levels [10]; together, these indicate defects in phosphate and vitamin D metabolism
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