Accessible Unlicensed Requires Authentication Published by De Gruyter March 4, 2015

Early onset hearing loss in autosomal recessive hypophosphatemic rickets caused by loss of function mutation in ENPP1

Elisabeth Steichen-Gersdorf, Bettina Lorenz-Depiereux, Tim Matthias Strom and Nicholas J. Shaw


Autosomal recessive hypophosphatemic rickets 2 (ARHR2) is a rare form of renal tubular phosphate wasting disorder. Loss of function mutations of the ecto-nucleotide pyrophosphatase/pyrophosphodiesterase 1 gene (ENPP1) causes a wide spectrum of phenotypes, ranging from lethal generalized arterial calcification of infancy to hypophosphatemic rickets with hypertension. Hearing loss was not previously thought to be one of the features of the disease entities and was merely regarded as a complication rather than a part of the disease. We report two children who presented in mid to late childhood with progressive varus deformity of their legs due to hypophosphatemic rickets caused by mutations in the ENPP1 gene. Both children had evidence of progressive hearing loss requiring the use of hearing aids. This report of two unrelated infants with compound heterozygous mutations in ENPP1 and previously published cases confirms that mild to moderate hearing loss is frequently associated with ARHR2. Early onset conductive hearing loss may further distinguish the autosomal recessive ENPP1 related type from other types of hypophosphatemia.

Corresponding author: Elisabeth Steichen-Gersdorf, Pediatrics I, Medical University of Innsbruck, Anichstraße 35, A-6020 Innsbruck, Austria, Phone: +43 51250423600, Fax: +43 51250424904, E-mail:


1. Francis F, Hennig S, Korn B, Reinhardt R, de Jong P, et al. A gene (PEX) with homologies to endopeptidases is mutated in patients with X-linked hypophosphatemic rickets. The HYP Consortium. Nat Genet 1995;11:130–6. Search in Google Scholar

2. Consortium A. Autosomal dominant hypophosphatemic rickets is associated with mutations in FGF23. Nat Genet 2000;26:345–8. Search in Google Scholar

3. Lorenz-Depiereux B, Bastepe M, Benet-Pagès A, Amyere M, Wagenstaller J, et al. DMP1 mutations in autosomal recessive hypophosphatemia implicate a bone matrix protein in the regulation of phosphate homeostasis. Nat Genet 2006;38:1248–50. Search in Google Scholar

4. Levy-Litan V, Hershkovitz E, Avizov L, Leventhal N, Bercovich D, et al. Autosomal-recessive hypophosphatemic rickets is associated with an inactivation mutation in the ENPP1 gene. Am J Hum Genet 2010;86:273–8. Search in Google Scholar

5. Rutsch F, Ruf N, Vaingankar S, Toliat MR, Suk A, et al. Mutations in ENPP1 are associated with ‘idiopathic’ infantile arterial calcification. Nat Genet 2003;34:379–81. Search in Google Scholar

6. Ruf N, Uhlenberg B, Terkeltaub R, Nürnberg P, Rutsch F. The mutational spectrum of ENPP1 as arising after the analysis of 23 unrelated patients with generalized arterial calcification of infancy (GACI). Hum Mutat 2005;25:98. Search in Google Scholar

7. Edouard T, Chabot G, Miro J, Buhas DC, Nitschke Y, et al. Efficacy and safety of 2-year etidronate treatment in a child with generalized arterial calcification of infancy. Eur J Pediatr 2011;170:1585–90. Search in Google Scholar

8. Stamp TC, Baker LR. Recessive hypophosphatemic rickets, and possible aethiology of the ‘vitamin D-resistant’ syndrome. Arch Dis Child 1976;51:360–5. Search in Google Scholar

9. Weir N. Sensorineural deafness associated with recessive hypophosphatemic rickets. J Laryngol Otol 1977;91:717–22. Search in Google Scholar

10. Brachet C, Mansbach AL, Clerckx A, Deltenre P, Heinrichs C. Hearing loss is part of clinical picture of ENPP1 loss of function mutation. Horm Res Paediatr 2014;81:63–6. Search in Google Scholar

11. Nitschke Y, Baujat G, Botschen U, Wittkampf T, du Moulin M, et al. Generalized arterial calcification of infancy and pseudoxanthoma elasticum can be caused by mutations in either ENPP1 or ABCC6. Am J Hum Genet 2012;90:25–39. Search in Google Scholar

12. Nitschke Y, Rutsch F. Genetics in arterial calcification: lessons learned from rare diseases. Trends Cardiovasc Med 2012;22:145–9. Search in Google Scholar

13. Davies M, Kane R, Valentine J. Impaired hearing in X-linked hypophospatemic (vitamin-D-resistent) osteomalacia. Ann Intern Med 1984;100:230–2. Search in Google Scholar

14. Meister M, Johnson A, Popelka GR, Kim GS, Whyte MP. Audiologic findings in young patients with hypophosphatemic bone disease. Ann Otol Rhinol Laryngol 1986;95: 415–20. Search in Google Scholar

15. Fishman G, Miller-Hansem D, Jacobsen C, Singhal V, Alon U. Hearing impairment in familial X-linked hypophosphatemic rickets. Eur J Pediatr 2004;163:622–3. Search in Google Scholar

16. 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;119:431–5. Search in Google Scholar

17. Linglart A, Biosse-Duplan M, Briot K, Chausain C, Esterle L, et al. Therapeutic management of hypophosphatemic rickets from infancy to adulthood. Endocr Connect 2014;3:R13–30. Search in Google Scholar

Received: 2014-12-25
Accepted: 2015-2-4
Published Online: 2015-3-4
Published in Print: 2015-7-1

©2015 by De Gruyter