Correspondence

Case 29-2001: Oncogenic Hypophosphatemic Osteomalacia

N Engl J Med 2002; 346:381-382January 31, 2002

Article

To the Editor:

Several important issues were overlooked in the Case Record of the 14-year-old boy with oncogenic hypophosphatemic osteomalacia (Sept. 20 issue).1 Terek was correct in stating that oncogenic hypophosphatemic osteomalacia has many similarities to X-linked hypophosphatemia. However, the onset of hypophosphatemia is not delayed in X-linked hypophosphatemia. Terek did not consider a diagnosis of autosomal dominant hypophosphatemic rickets, which has incomplete penetrance and a variable age of onset.2 Therefore, an affected child's parent may carry a mutation for autosomal dominant hypophosphatemic rickets that is nonpenetrant, and the child may have delayed phosphate wasting. It is important to note that weakness, fatigue, and fracture are prominent features in patients with autosomal dominant hypophosphatemic rickets who present with delayed onset of disease and that these patients are clinically indistinguishable from patients with oncogenic hypophosphatemic osteomalacia.

Recent work regarding fibroblast growth factor 23 should also have been addressed. Missense mutations in the gene encoding fibroblast growth factor 23 cause autosomal dominant hypophosphatemic rickets.3 In addition, fibroblast growth factor 23 is highly expressed by tumors causing oncogenic hypophosphatemic osteomalacia.4 Fibroblast growth factor 23 is therefore a strong candidate for “phosphatonin,” the factor implicated as a cause of the phosphate wasting in patients with oncogenic hypophosphatemic osteomalacia. The mutations that cause autosomal dominant hypophosphatemic rickets stabilize fibroblast growth factor 23, potentially elevating its concentration in serum and leading to renal phosphate wasting.5 Because fibroblast growth factor 23 is produced in tumors causing oncogenic hypophosphatemic osteomalacia at high levels, the same net result as in autosomal dominant hypophosphatemic rickets — elevated serum concentrations of the factor — would be present in oncogenic hypophosphatemic osteomalacia, albeit by a different mechanism. In conclusion, a diagnosis of autosomal dominant hypophosphatemic rickets should be considered in patients with late-onset hypophosphatemia, especially in the light of the implications for genetic testing and counseling.

Kenneth E. White, Ph.D.
Steven G. Waguespack, M.D.
Michael J. Econs, M.D.
Indiana University School of Medicine, Indianapolis, IN 46202
mecons@iupui.edu

5 References

1. 1

   Case Records of the Massachusetts General Hospital (Case 29-2001). N Engl J Med 2001;345:903-908
   Full Text | Web of Science | Medline

2. 2

   Econs MJ, McEnery PT. Autosomal dominant hypophosphatemic rickets/osteomalacia: clinical characterization of a novel renal phosphate-wasting disorder. J Clin Endocrinol Metab 1997;82:674-681
   CrossRef | Web of Science | Medline

3. 3

   The ADHR Consortium. Autosomal dominant hypophosphatemic rickets is associated with mutations in FGF23. Nat Genet 2000;26:345:8-8
   CrossRef | Web of Science | Medline

4. 4

   Shimada T, Mizutani S, Muto T, et al. Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia. Proc Natl Acad Sci U S A 2001;98:6500-6505
   CrossRef | Web of Science | Medline

5. 5

   White KE, Carn G, Lorenz-Depiereux B, Benet-Pages A, Strom TM, Econs MJ. Autosomal-dominant hypophosphatemic rickets (ADHR) mutations stabilize FGF-23. Kidney Int 2001;60:2079-2086
   CrossRef | Web of Science | Medline

Author/Editor Response

Dr. Terek replies:

To the Editor: White and colleagues are correct to point out that one cause of delayed-onset vitamin D–resistant rickets is autosomal dominant hypophosphatemic rickets. However, the importance of ruling out the presence of a tumor cannot be overstated. In this case, the tumor was malignant and required multidisciplinary treatment, which not only cured the tumor but also reversed the metabolic derangements associated with vitamin D–resistant rickets.

Identification of fibroblast growth factor 23 as phosphatonin is an exciting advance in our understanding of the pathophysiology of vitamin D–resistant rickets. The publication of these findings postdated the clinicopathological conference at which I discussed the case.

Richard M. Terek, M.D.
Brown Medical School, Providence, RI 02912

Citing Articles (3)

Citing Articles

1. 1

   Despina Sitara, Mohammed S. Razzaque, Martina Hesse, Subbiah Yoganathan, Takashi Taguchi, Reinhold G. Erben, Harald J+APw-ppner, Beate Lanske. (2004) Homozygous ablation of fibroblast growth factor-23 results in hyperphosphatemia and impaired skeletogenesis, and reverses hypophosphatemia in Phex-deficient mice. Matrix Biology 23:7, 421-432
   CrossRef

2. 2

   Andrew L. Folpe, Julie C. Fanburg-Smith, Steven D. Billings, Michele Bisceglia, Franco Bertoni, Justin Y. Cho, Michael J. Econs, Carrie Y. Inwards, Suzanne M. Jan de Beur, Thomas Mentzel, Elizabeth Montgomery, Michal Michal, Markku Miettinen, Stacey E. Mills, John D. Reith, John X. O'Connell, Andrew E. Rosenberg, Brian P. Rubin, Donald E. Sweet, Tuyethoa N. Vinh, Lester E. Wold, Brett M. Wehrli, Kenneth E. White, Richard J. Zaino, Sharon W. Weiss. (2004) Most Osteomalacia-associated Mesenchymal Tumors Are a Single Histopathologic Entity. The American Journal of Surgical Pathology 28:1, 1-30
   CrossRef

3. 3

   (2002) Current Awareness. Pharmacoepidemiology and Drug Safety 11:5, 421-436
   CrossRef