X-linked, dominant, hypophosphatemic rickets (XLHR)

(OMIM phenotype number #307800)

See FACT SHEET X-Linked Hypophosphatemia (XLH)

X-linked, dominant, hypophosphatemic rickets (XLHR) is a genetic disorder caused by inactivating mutations in the PHEX gene (phosphate-regulating gene with homologies to endopeptidase on the X chromosome). XLHR, first described by Albright in 1937, is the most frequent form of hypophosphatemic rickets, with a prevalence of 1/20.000. The disease affects both sexes. Mutations of PHEX inhibit FGF23 inactivation, and the latter has been reported to be 5 times higher in XLH patients compared to healthy controls. High free FGF23 levels in plasma cause hyperphosphaturia, decreasing phosphate reabsorption by down-regulating NaPi-IIa and NaPi-IIc at the apical membrane of proximal renal tubular cells and inhibit 1a-hydroxylase, resulting in decreased intestinal absorption of calcium and phosphate (see also ADHR). Chronic low serum phosphorus levels lead to defective bone mineralization and, consequently, to rickets in children and osteomalacia in adults. During the first 1–2 years of life, children with XLHR may present bowing of the weight-bearing extremities, frontal bossing, and growth retardation. Others clinical manifestations, such as joint pain, arthritis, enthesopathy (calcification of ligaments and their attachment to bone), dentin malformation, and recurrent spontaneous abscesses of the teeth may occur with increasing age. Radiographic features include: genu varum, widened metaphyses, bilateral femoral distal metaphysis epiphyseal line blurred, and a general decrease in bone density. Molecular genetic testing confirms the diagnosis.

Treatment: For most children consists of oral phosphate and high-dose calcitriol, the active form of vitamin D. In adults, treatment with calcitriol and phosphate is generally reserved in the case of symptoms, such as bone pain, upcoming orthopedic surgery, biochemical evidence of osteomalacia with an elevated alkaline phosphatase, or recurrent pseudofractures or stress fractures. Currently, a novel therapeutic agent  for XLH, humanized monoclonal antibody FGF23 (burosumab), has been approved by the FDA and EMA. 

Gene

PHEX gene, Xp22.11 (OMIM gene/locus number #300550).

Phenotype

Rickets, osteomalacia, late dentition, tooth abscesses secondary to poor mineralization, bowing of lower extremities, enlarged costochondral junctions of the ribs, pectum carinatum, metaphyseal flaring of the wrists or ankles, genus varus, frontal bossing enlarges sutures and fotanels or craniotabes.

Main biochemical alterations

High Ur P, low Pi, low renal TmP/GFR, normal Ca, low-normal Ur Ca, normal 25 OH D, low-normal 1,25(OH)2D, high bone ALP, high intact FGF23, normal PTH, and rarely low GH.

Images

X-linked, dominant, hypophosphatemic rickets (XLHR) X-linked, dominant, hypophosphatemic rickets (XLHR)
X-linked, dominant, hypophosphatemic rickets (XLHR) X-linked, dominant, hypophosphatemic rickets (XLHR)

Fig. Patients affected by XLHR. (a,b) Radiographs and (c) image showing genu varus deformities in the lower extremities. (d) Patient with dental crowding and dental absences. 

Reproduced from Gene, Vol 565, Huang Y, Mei L, Pan Q, et al. Novel de novo nonsense mutation of the PHEX gene (p.Lys50Ter) in a Chinese patient with hypophosphatemic rickets, Pages 150-4, Copyright 2015, with permission from Elsevier.

 

Other resources

XLH Network
Yale Center for X-linked Hypophosphatemia
 

References
  1. Yang L, Yang J, Huang X. PHEX gene mutation in a Chinese family with six cases of X-linked hypophosphatemic rickets. J Pediatr Endocrinol Metab. 2013;26(11-12):1179-83.
  2. Kienitz T, Ventz M, Kaminsky E, Quinkler M. Novel PHEX nonsense mutation in a patient with X-linked hypophosphatemic rickets and review of current therapeutic regimens. Exp Clin Endocrinol Diabetes. 2011 Jul;119(7):431-5.
  3. Imel EA, Gray AK, Padgett LR et al. Iron and fibroblast growth factor 23 in X-linked hypophosphatemia. Bone. 2014 Mar;60:87-92. Epub 2013 Dec 8.
  4. Ruppe MD. X-Linked Hypophosphatemia. Editors In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, Bird TD, Fong CT, Mefford HC, Smith RJH, Stephens K, editors. SourceGeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2015.
  5. Pavone V, Testa G, Gioitta Iachino S, et al.  Hypophosphatemic rickets: etiology, clinical features and treatment. Eur J Orthop Surg Traumatol. 2015 Feb;25(2):221-6.
  6. Huang Y, Mei L, Pan Q, et al. Novel de novo nonsense mutation of the PHEX gene (p.Lys50Ter) in a Chinese patient with hypophosphatemic rickets. Gene. 2015 Jul 1;565(1):150-4.
  7. Brame LA, White KE, Econs MJ. Renal phosphate wasting disorders: clinical features and pathogenesis. Semin Nephrol. 2004 Jan;24(1):39-47.
  8. Rowe PS. The wrickkened pathways of FGF23, MEPE and PHEX. Crit Rev Oral Biol Med. 2004 Sep 1;15(5):264-81.
  9. Masi L, Agnusdei D, Bilezikian J et al. Taxonomy of rare genetic metabolic bone disorders. Osteoporos Int. 2015 Jun 13.
  10. http://www.omim.org