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.7,10 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.56 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 22-1.7 Their detailed description is beyond the scope of this book, and this chapter focuses primarily on tumor-induced osteomalacia and rickets.
Biochemistry and Genetics of Hypophosphatemic Disorders
|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)2D||GENE|
|ARHR1||N||N, ↓||N, ↑||?||↓||↓||(↓)||DMP1|
|TIO||N||N, ↓||N, ↓, ↑||↓||↓||↓||↓||FGF23|
|McCune-Albright||N, ↑||N||N, ↑||?||N, ↓||N, ↓||N, ↓||GNAS1|
|ENS||N, ↑||N, ↓||N, ↑||?||N, ↓||N, ↓||(↓)||? FGFR3*|
|NF||N, ↓||N, ↓||N||?||N, ↓||N, ↓||N, (↓)||NF1|
|HRHPT||N, ↑||N, ↑||↑||?||↓||↓||(↓)||KL (klotho)|
|XLRH||N||↑||N, ↓, ↑||N, ↑||↓||↓||↑||CLCN5|
|HHRH||N, ↑||↑||N, ↓||↑||↓||↓||↑||SLC34A3|
|Fanconi||N, ↓, ↑||N, ↑||N||?||N, ↓||N, ↓||N, ↓||Various (SLC34A1)|
|NHERF1||N||? (stones)||N||?||↓||↓||N, ↑||NHERF1|
The cause-and-effect relationship between certain mesenchymal tumors and severe osteomalacia or rickets was first recognized in 1959 by Prader et al.54 The original description of this peculiar paraneoplastic syndrome was provided in 1947 by McCance,41 who reported a case of resolution of vitamin D-resistant rickets after removal of “degenerated osteoid tissue.”
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.1,64,72 These tumors have exhibited a wide spectrum of histologic features that have only recently been gathered under a unifying concept of phosphaturic mesenchymal tumors.20,82,83 Overlapping clinical presentation and biochemical abnormalities can be present in X-linked hypophosphatemia and autosomal dominant hyphosphatemia.7,37 A similar syndrome has also been reported in association with the linear sebaceous nevus syndrome and fibrous dysplasia.2,15,25,29
The majority of patients with tumor-induced osteomalacia are adults; two thirds are age 30 years or older.36,45,55,58,63,74,89 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.40 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 D3 are low or detectable, whereas serum levels of 25-hydroxyvitamin D3 are generally normal. In addition, aminoaciduria and glycosuria with normal serum glucose levels may be present.
In skeletally immature patients, radiographs show widening of growth plates and radiolucent zones in the metaphyses consistent with rachitic changes (Fig. 22-1). Lower-extremity long bones may show bowing deformities. In skeletally mature patients, radiographic features consist of generalized osteopenia with Milkman’s pseudofractures or Looser’s lines, characteristic of osteomalacia. In addition, skeletal radiographs may reveal the presence of an asymptomatic or symptomatic tumor.11 Pathologic fractures in adults, particularly of the femoral neck, are relatively common.
Histomorphometry on undecalcified bone sections shows hyperosteoidosis with increased osteoid volume and increased width of osteoid seams. In approximately 50% of cases, the tumor is primary in bone.49 Half of the cases involving bone occurred in the long bones of the lower extremities, particularly in the femur and tibia. The second most common location of osseous tumors is in the craniofacial bones.31,47 Soft tissue tumors comprise the other half of all cases and follow the same pattern of anatomic distribution as skeletal tumors—they occur in the soft tissues of the lower extremities and craniofacial region.
Histologically, 40% of reported cases are vascular tumors (Table 22-2). Of these, hemangiopericytoma is the most common, representing about half of the vascular tumors and approximately 20% of the total (Fig. 22-2).6,24,26,42,60,65,77,83,84,89 Primary hemangiopericytoma of bone is extremely rare and comprises 0.08% of all primary tumors of bone.79 Other vascular tumors include hemangioma, angiofibroma, low-grade hemangioendothelioma, and very rarely, high-grade angiosarcoma.1,13,39,43,63,81,89
Types of Tumors Producing Osteomalacia and Rickets
|Histologic Type||No. of Cases|
|Giant cell lesions||9|
|GCT of bone||2|
|Soft tissue GCT||2|
|Giant cell variant of soft-part chondroma|
|Giant cell MFH|
|“Mesenchymal” tumors (malignant)||9|
|“Degenerate osteoid tissue”|
|“Vascular” fibrous histiocytoma|
The second group of tumors associated with rickets or osteomalacia can be histologically classified as having features of fibrohistiocytic and giant cell lesions exhibiting prominent vasculature (Fig. 22-3). The specific lesions of this group are nonossifying fibromas and giant cell reparative granuloma, giant cell tumor, and pigmented villonodular synovitis.3 A small proportion of reported tumors represent malignant lesions, which include osteosarcoma and mesenchymal chondrosarcoma.28,46,48,75,76,87