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Tumor-Induced Osteomalacia and Rickets


Modern understanding of rachitic syndromes, originally referred to as vitamin D-resistant rickets, is based on the identification of a novel phosphate-regulating homeostatic system and its underlying diverse genetic background. Essential to this understanding were discoveries of two mutated genes involved in the development of somewhat overlapping yet distinct phosphaturic disorders. The first one involved the identification of phosphate regulating endopeptidase homolog on chromosome X ( PHEX ) as the mutated gene in X-linked phosphatemia. The second was the discovery that a mutant fibroblast growth factor 23 ( FGF23 ) plays a role in the development of tumor induced osteomalacia and rickets as well as an autosomal dominant X-linked variant of hypophosphatemic rickets. A more complete list of phosphatemic disorders with their genetic background and biochemistry is provided in Table 22-1 . Their detailed description is beyond the scope of this book, and this chapter focuses primarily on tumor-induced osteomalacia and rickets.

TABLE 22-1
Biochemistry and Genetics of Hypophosphatemic Disorders
Reprinted with permission from Carpenter TO, et al: J Bone Miner Metab 30:1–9, 2012.
Calcium Metabolism Phosphate Metabolism Vitamin D Metabolism Mutation
serum calcium urine calcium serum pth gi calcium absorption serum phosphate tmp / gfr serum 1,25( oh ) 2 d gene
FGF23 -mediated
XLH N ↓ N, ↑ ↓ ↓ ↓ (↓) PHEX
ADHR N ↓ N ↓ ↓ ↓ (↓) FGF23
ARHR1 N N, ↓ N, ↑ ? ↓ ↓ (↓) DMP1
TIO N N, ↓ N, ↓, ↑ ↓ ↓ ↓ ↓ FGF23
ARHR2 N N, ↓ N ? ↓ ↓ (↓) ENPP1
McCune-Albright N, ↑ N N, ↑ ? N, ↓ N, ↓ N, ↓ GNAS1
ENS N, ↑ N, ↓ N, ↑ ? N, ↓ N, ↓ (↓) ? FGFR3 *
NF N, ↓ N, ↓ N ? N, ↓ N, ↓ N, (↓) NF1
OGD N N N ? ↓ ↓ (↓) FGFR1
HRHPT N, ↑ N, ↑ ↑ ? ↓ ↓ (↓) KL (klotho)
Non- FGF2 3-mediated
XLRH N ↑ N, ↓, ↑ N, ↑ ↓ ↓ ↑ CLCN5
HHRH N, ↑ ↑ N, ↓ ↑ ↓ ↓ ↑ SLC34A3
Fanconi N, ↓, ↑ N, ↑ N ? N, ↓ N, ↓ N, ↓ Various ( SLC34A1 )
NHERF1 N ? (stones) N ? ↓ ↓ N, ↑ NHERF1
ADHR, autosomal dominant hypophosphatemic rickets; ARHR, autosomal recessive hypophosphatemic rickets; ENS, epidermal nevus syndrome; HHRH, hereditary hypophosphatemic rickets with hypercalciuria; HRHPT, hypophosphatemic rickets with hyperparathyroidism; NF neurofibromatosis; N, normal; NHERF, Na + /H + exchanger regulatory factor; OGD, osteoglophonic dysplasia;, TIO, tumor-induced osteomalacia; XLH, X-linked hypophosphatemia; XLRH, X-linked recessive hypophosphatemia (Dent's disease); ↓, decreased; (↓), decreased relative to the serum phosphorus concentration; ↑, increased; ?, not well documented.

* Mosaic FGF23 mutations account for some cases of ENS; however, in reported cases due to this mutation hypophosphatemia is not reported.

The cause-and-effect relationship between certain mesenchymal tumors and severe osteomalacia or rickets was first recognized in 1959 by Prader et al. The original description of this peculiar paraneoplastic syndrome was provided in 1947 by McCance, who reported a case of resolution of vitamin D-resistant rickets after removal of “degenerated osteoid tissue.”

Tumor-Induced Osteomalacia

Tumor-induced osteomalacia (oncogenic osteomalacia) is a clinicopathologic entity in which vitamin D-resistant osteomalacia or rickets occurs in association with a bone or soft tissue tumor. These tumors have exhibited a wide spectrum of histologic features that have only recently been gathered under a unifying concept of phosphaturic mesenchymal tumors . Overlapping clinical presentation and biochemical abnormalities can be present in X-linked hypophosphatemia and autosomal dominant hyphosphatemia. A similar syndrome has also been reported in association with the linear sebaceous nevus syndrome and fibrous dysplasia.

Clinical Data

The majority of patients with tumor-induced osteo­malacia are adults; two thirds are age 30 years or older. The ages of reported patients range from 7 to 73 years, and the male-to-female ratio is 1.2 : 1. The typical presentation is a gradual onset of bone pain in weight bearing areas such as the legs, ankles, hips, and back. Some patients have pathologic fractures. The pain is frequently accompanied by generalized muscular weakness, leading to a severely debilitated state in which the patient is bedridden. Hence, in some patients an initial misdiagnosis of a primary muscular disorder is made. Symptoms are usually present anywhere from 3 months to 17 years before diagnosis. In some cases, a mass was noted up to 20 years before the onset of generalized symptoms. Occasionally an asymptomatic bone tumor is identified in radiographs in a patient with a diagnosis of vitamin-D resistant rickets. Children may initially have malaise, gait disturbance, swollen joints, and genu valgum or varum.

Characteristic metabolic abnormalities include a low serum phosphorus level (2.2 to 0.33 mg/dL), normal or slightly low serum calcium level, and variably elevated alkaline phosphatase activity (occasionally up to 1700 to 2300 IU). The urinary phosphate level is usually elevated, and most cases exhibit decreased tubular reabsorption of phosphate (23% to 70%). Urinary calcium levels tend to be low. Serum levels of 1,25-dihydroxyvitamin D 3 are low or detectable, whereas serum levels of 25-hydroxyvitamin D 3 are generally normal. In addition, aminoaciduria and glycosuria with normal serum glucose levels may be present.

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