Clinical and molecular heterogeneity in a large series of patients with hypophosphatemic rickets

Bone. 2015 Oct;79:143-9. doi: 10.1016/j.bone.2015.05.040. Epub 2015 Jun 5.


Context: Hypophosphatemic rickets (HR) is a rare disease that includes a group of hereditary and sporadic conditions characterized by renal phosphate loss associated with normal to low vitamin D serum concentration. The most common form is the X-linked hypophosphatemic rickets, with an incidence of 1:20,000. Several mutations have recently been identified in the PHEX, FGF23, DMP1 and ENPP1 genes in patients with HR. Moreover, in vitro and in vivo studies suggested an involvement of MEPE for defective mineralization in HR.

Objective: The present case series describes the clinical features and the analysis of genes implicated in HR in a cohort of 26 Italian HR patients.

Setting and design: All patients were analyzed for the PHEX and FGF23 genes by direct sequencing. When no mutations were detected, Multiplex Ligation-dependent Probe Amplification (MLPA) analysis was performed. The negative patients were screened for the DMP1, MEPE and ENPP1 genes by direct sequencing.

Results: Twenty-two patients (84%) harbored mutations in the PHEX gene. In particular, we detected 19 different mutations, 15 of which were novel. One patient presented a novel splice variation in the ENPP1 gene while no alterations were identified in the FGF23, DMP1 and MEPE genes. The genetic study of the families showed that 11 patients (55%) had de novo mutations. Clinical presentation and disease severity did not show an evident correlation between the mutation types.

Conclusions: This report represents the first large familial study performed on Italian patients. It confirms that mutations in PHEX are the most frequent cause of HR. Furthermore, the variety of clinical manifestations identified in our HR patients underlines the extreme clinical and genetic heterogeneity of this disease.

Keywords: Hypophosphatemic rickets; Mutational analysis; Phosphate metabolism; X-linked hypophosphatemic rickets.

MeSH terms

  • Adult
  • Child
  • Child, Preschool
  • DNA Mutational Analysis
  • Extracellular Matrix Proteins / genetics
  • Familial Hypophosphatemic Rickets / genetics*
  • Female
  • Fibroblast Growth Factors / genetics
  • Glycoproteins / genetics
  • Humans
  • Infant
  • Male
  • Multiplex Polymerase Chain Reaction
  • PHEX Phosphate Regulating Neutral Endopeptidase / genetics*
  • Phosphoproteins / genetics
  • Phosphoric Diester Hydrolases / genetics
  • Pyrophosphatases / genetics


  • DMP1 protein, human
  • Extracellular Matrix Proteins
  • Glycoproteins
  • MEPE protein, human
  • Phosphoproteins
  • Fibroblast Growth Factors
  • fibroblast growth factor 23
  • Phosphoric Diester Hydrolases
  • ectonucleotide pyrophosphatase phosphodiesterase 1
  • PHEX Phosphate Regulating Neutral Endopeptidase
  • PHEX protein, human
  • Pyrophosphatases