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Hyperphosphatemic familial tumoral calcinosis (FGF23, GALNT3 and αKlotho)

https://doi.org/10.1016/j.berh.2011.10.020Get rights and content

Familial tumoral calcinosis (TC) is a rare disorder distinguished by the development of ectopic and vascular calcified masses that occur in settings of hyperphosphatemia (hFTC) and normophosphatemia (nFTC). Serum phosphorus concentrations are relatively tightly controlled by interconnected endocrine activity at the level of the intestine, kidney, and skeleton. Discovering the molecular causes for heritable forms of hFTC has shed new light on the regulation of serum phosphate balance. This review will focus upon the genetic basis and clinical approaches for hFTC, due to genes that are related to the phosphaturic hormone fibroblast growth factor-23 (FGF23). These include FGF23 itself, an FGF23-glycosylating enzyme (GALNT3), and the FGF23 co-receptor α-Klotho (αKL). Our understanding of the molecular basis of hFTC will, in the short term, aid in understanding normal phosphate balance, and in the future, provide potential insight into the design of novel therapeutic strategies for both rare and common disorders of phosphate metabolism.

Introduction

Familial tumoral calcinosis (TC) is a rare autosomal recessive metabolic disorder characterised by the progressive deposition of calcium phosphate crystals in periarticular spaces and soft tissues. TC may manifest under situations of hyperphosphatemia (hyperphosphatemic familial TC; hFTC; MIM ID #211900) or normophosphatemia (normophophatemic familial TC; nFTC; MIM ID #610455). Maintenance of serum phosphate concentrations is required for proper skeletal development and for preservation of bone integrity. In addition, phosphate is required for cellular processes involving energy transfer in the form of adenosine triphosphate (ATP), is an integral molecule in DNA and RNA and is a critical component of multiple intracellular signalling pathways. Recent advances in our understanding of hFTC have shed light on the underlying mechanisms that control phosphate homeostasis in normal and in disordered states. The biochemical hallmark of TC is hyperphosphatemia caused by increased renal reabsorption of phosphate. This review summarises the heterogeneous genetic defects, and molecular mechanisms that lead to hFTC involving the phosphaturic hormone, fibroblast growth factor-23 (FGF23; nFTC will be reviewed elsewhere in this issue).

Section snippets

Phosphate homeostasis

Maintenance of serum phosphate concentrations involves hormonal regulation at the level of the intestine, skeleton and kidneys. The skeleton represents the largest stores of phosphate complexed with calcium in hydroxyapatite crystals, which constitute the main inorganic component of the mineralised bone matrix. Normal serum concentrations of phosphate in adults range from 2.5–4.5 mg dl−1 and are fairly tightly regulated. Serum phosphate concentrations are higher in infancy, decreasing as the

Disorders of elevated FGF23

The biochemical abnormalities in hFTC include hyperphosphatemia, increased %TRP and inappropriately normal or elevated 1,25D concentrations. HFTC can be considered as the clinical converse of several diseases characterised by elevation of the phosphaturic hormone FGF23. The FGF23 gene, composed of three exons encoding a 251 residue polypeptide, is located on the human chromosome 12p13 [9]. Although FGF23 messenger RNA (mRNA) can be detected at low levels in many tissues including heart, liver,

Bioactivity of FGF23

FGF23 is central to renal phosphate and vitamin D metabolism, and has emerging roles in the regulation of PTH. FGF23-dependent control of renal phosphate reabsorption was demonstrated by the finding that mice transgenic for human FGF23 had markedly increased phosphate excretion secondary to decreased PT Npt2a and Npt2c expression [18], [19]. In normal individuals, hypophosphatemia is typically a strong stimulator for increased serum 1,25D [20]. However, in patients with syndromes caused by

TC due to loss of function in FGF23-related genes

hFTC is a genetically heterogeneous syndrome, caused by loss-of-function mutations in genes relevant to the production of the intact, bioactive form of FGF23 (FGF23 and GalNAc transferase 3 (GALNT3)), and to the end-organ effects of FGF23 bioactivity (αKlotho). Human genetic studies, taken together with analyses of corresponding animal models, have provided key insight into the molecular etiology of hFTC.

Therapeutic avenues

TC lesions can become very large and frequently require surgical resection due to pain, deformity and limitation of joint movements (Fig. 2). Surgery may be curative but, unfortunately, these lesions typically recur [64], [65], [66] due to persistence of the underlying metabolic defect.

Medical treatment for TC is based on limited clinical evidence. Due to the rarity of hFTC, controlled trials are lacking and all available treatment information is based on case reports or case series. Assessment

Summary

Familial hyperphosphatemic TC is a genetically heterogeneous disorder due to mutations in genes that affect FGF23 bioactivity and result in either reduced intact FGF23 (FGF23 and GALNT3 loss-of-function mutations) or end-organ resistance to serum FGF23 (αKlotho loss-of-function mutation). Although the field is still challenged with developing reliable therapeutics targeting hFTC, investigating the molecular nature of this syndrome has been invaluable in providing insight into normal and

Conflict of interest statement

KEW receives royalties for licensing the FGF23 gene to Kyowa Hakko Kirin Co. Ltd., and EAI is involved in a clinical trial with Kyowa Hakko Kirin Co. Ltd. EGF has no conflicts to declare.

Acknowledgements

The authors would like to acknowledge the funding support of NIH through grants R01-DK063934 and R21-AR059278 (KEW), and K23AR057096 (EAI), Genzyme GRIP award (KEW), as well as the Indiana Genomic Initiative (INGEN) of Indiana University, supported in part by Lilly Endowment, Inc. EGF is supported by a fellowship from the National Kidney Foundation (NKF). The sponsors had no role in the collection, analysis and interpretation of data and in the writing of the manuscript.

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