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Review
. 2020 May 8:11:293.
doi: 10.3389/fendo.2020.00293. eCollection 2020.

Hyperphosphatemic Tumoral Calcinosis: Pathogenesis, Clinical Presentation, and Challenges in Management

Alison M Boyce  1 , Alisa E Lee  1 , Kelly L Roszko  1 , Rachel I Gafni  1
Affiliations
Review

Hyperphosphatemic Tumoral Calcinosis: Pathogenesis, Clinical Presentation, and Challenges in Management

Alison M Boyce et al. Front Endocrinol (Lausanne). .

Abstract

Hyperphosphatemic familial tumoral calcinosis (HFTC) is a rare and disabling disorder of fibroblast growth factor 23 (FGF23) deficiency or resistance. The disorder is manifest by hyperphosphatemia, inappropriately increased tubular reabsorption of phosphate and 1,25-dihydroxy-Vitamin D, and ectopic calcifications. HFTC has been associated with autosomal recessive pathogenic variants in: (1) the gene encoding FGF23; (2) GALNT3, which encodes a protein responsible for FGF23 glycosylation; and (3) KL, the gene encoding KLOTHO, a critical co-receptor for FGF23 signaling. An acquired autoimmune form of hyperphosphatemic tumoral calcinosis has also been reported. Periarticular tumoral calcinosis is the primary cause of disability in HFTC, leading to pain, reduced range-of-motion, and impaired physical function. Inflammatory disease is also prominent, including diaphysitis with cortical hyperostosis. Multiple treatment strategies have attempted to manage blood phosphate, reduce pain and inflammation, and address calcifications and their complications. Unfortunately, efficacy data are limited to case reports and small cohorts, and no clearly effective therapies have been identified. The purpose of this review is to provide a background on pathogenesis and clinical presentation in HFTC, discuss current approaches to clinical management, and outline critical areas of need for future research.

Keywords: ectopic calcification; fibroblast growth factor 23; heterotopic ossification; metabolic bone disease; phosphate.

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Figures

Figure 1
Figure 1
Images of tumoral calcinosis lesions. (A) Photograph (left panel) of a patient with swelling and decreased range-of-motion of the left lower extremity (arrow). The corresponding radiograph (right panel) shows a large area of tumoral calcinosis involving the left proximal femur. (B) Photograph (upper panel) of a patient with painful swelling and reduced range-of-motion of the left shoulder (white arrow). Note the overlying skin pigmentation and increased vascularity (black arrowhead). A corresponding three-dimensional computed tomography scan shows a large calcified mass involving the left shoulder (arrow). (C) Hematoxylin and eosin stained sections from resected tumoral calcinosis lesions. The upper panel shows a subcutaneous calcification (arrows). The lower panel shows heterotopic ossification (white asterisk) with active osteoblasts laying down new bone (black arrowheads). Note the presence of chronic inflammation with visible foamy macrophages (black arrows). These figures are original, and have not been previously published or obtained from a private database. There is no unpublished data in any of the figures.
Figure 2
Figure 2
Representative images of hyperostosis. Images are from a 4-year-old girl who presented with pain and tenderness over her tibia. (A) Technetium-99 bone scintigraphy shows increased uptake in the bilateral tibias, greater on the left (red arrow). (B) Radiograph of the left tibia shows thickened cortices with patchy radio-opacities in the medullary canal (yellow arrowhead). (C) Hematoxylin and Eosin stained section of periosteal bone from a tibial biopsy shows sheets of mineralized lamellar bone (arrows) replacing central areas of woven bone (asterisks). (D) Goldner trichrome staining in an undecalcified section reveals mature lamellar bone in blue and woven bone in red. These figures are original, and have not been previously published or obtained from a private database. There is no unpublished data in any of the figures.
Figure 3
Figure 3
Clinical images of extraskeletal features in hyperphosphatemic tumoral calcinosis. (A) Computed tomography scan from a 36-year-old man demonstrates calcification in the abdominal aorta (white arrow). Small submucosal bowel calcifications are also visible (yellow arrowhead). (B) Computed tomography scan of the heart in a 29-year-old man demonstrates a calcified lesion in the papillary muscle (arrow). (C) Testicular ultrasound from a 32-year-old man showing diffuse microlithiasis. (D) Panoramic dental radiograph from an 18-year-old woman shows teeth with short, bulbous roots (white arrow) and obliteration of dental pulp (yellow arrowhead). (E) Periapical dental radiograph from a 12-year-old girl shows thistle-shaped root (white arrows) and obliteration of dental pulp (yellow arrowheads). These figures are original, and have not been previously published or obtained from a private database. There is no unpublished data in any of the figures.
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