Familial Tumoral Calcinosis: From Characterization of a Rare Phenotype to the Pathogenesis of Ectopic Calcification
2009; Elsevier BV; Volume: 130; Issue: 3 Linguagem: Inglês
10.1038/jid.2009.337
ISSN1523-1747
Autores Tópico(s)Medical Imaging and Pathology Studies
ResumoFamilial tumoral calcinosis (FTC) refers to a heterogeneous group of inherited disorders characterized by the occurrence of cutaneous and subcutaneous calcified masses. Two major forms of the disease are now recognized. Hyperphosphatemic FTC has been shown to result from mutations in three genes: fibroblast growth factor-23 (FGF23), coding for a potent phosphaturic protein, KL encoding Klotho, which serves as a co-receptor for FGF23, and GALNT3, which encodes a glycosyltransferase responsible for FGF23 O-glycosylation; defective function of any one of these three proteins results in hyperphosphatemia and ectopic calcification. The second form of the disease is characterized by absence of metabolic abnormalities, and is, therefore, termed normophosphatemic FTC. This variant was found to be associated with absence of functional SAMD9, a putative tumor suppressor and anti-inflammatory protein. The data gathered through the study of these rare disorders have recently led to the discovery of novel aspects of the pathogenesis of common disorders in humans, underscoring the potential concealed within the study of rare diseases. Familial tumoral calcinosis (FTC) refers to a heterogeneous group of inherited disorders characterized by the occurrence of cutaneous and subcutaneous calcified masses. Two major forms of the disease are now recognized. Hyperphosphatemic FTC has been shown to result from mutations in three genes: fibroblast growth factor-23 (FGF23), coding for a potent phosphaturic protein, KL encoding Klotho, which serves as a co-receptor for FGF23, and GALNT3, which encodes a glycosyltransferase responsible for FGF23 O-glycosylation; defective function of any one of these three proteins results in hyperphosphatemia and ectopic calcification. The second form of the disease is characterized by absence of metabolic abnormalities, and is, therefore, termed normophosphatemic FTC. This variant was found to be associated with absence of functional SAMD9, a putative tumor suppressor and anti-inflammatory protein. The data gathered through the study of these rare disorders have recently led to the discovery of novel aspects of the pathogenesis of common disorders in humans, underscoring the potential concealed within the study of rare diseases. fibroblast growth factor-23 familial tumoral calcinosis hyerphosphatemic FTC matrix metalloproteinase normophosphatemic FTC polypeptide N-acetylgalactosaminyltransferase-3 Familial tumoral calcinosis (FTC) represents a clinically and genetically heterogeneous group of inherited diseases manifesting with dermal and subcutaneous deposition of calcified materials. In recent years, the pathogenesis of these disorders has been elucidated, not only leading to delineation of the major pathways responsible for regulating extraosseous calcification, but also shedding new light on the pathogenesis of pathologies as common as renal failure and autoimmune diseases. The first clinical description of familial tumoral calcinosis (FTC) dates back to 1898 when two French dermatologists, Giard and Duret, reported for the first time the cardinal features of the disorder under the name endotheliome calcifié (Giard, 1898Giard A. Sur la calcification tibernale.CR Soc Biol. 1898; 10: 1015-1021Google Scholar; Duret, 1899Duret M.H. Tumeurs multiples and singuliers de bourses sereuses.Bull Mem Soc Ant. 1899; 74: 725-731Google Scholar). The disease was later described in the German literature as lipocalcinogranulomatosis or Teutschlaender's disease after the German dermatologist who studied a large number of such cases (Tseutschlaender, 1935Tseutschlaender O. Uber progressive lipogranulomatose der muskulatur.Klin Wochenschr. 1935; 13 (Zugleich ein beitrag zur pathogenese der myopathia osteoplystica progressive): 451-453Crossref Scopus (22) Google Scholar). The term tumoral calcinosis was coined in the American literature by Inclan et al., 1943Inclan A. Leon P. Camejo M.G. Tumoral calcinosis.JAMA. 1943; 121: 490-495Crossref Google Scholar. Inclan et al. were also the first to accurately differentiate this inherited disease from other related but acquired conditions, which later became known as metastatic calcinosis and dystrophic calcinosis. Subsequently, numerous reports, initially emanating from travelers who had returned from Africa, indicated that the disease is apparently prevalent in this region of the world (McClatchie and Bremner, 1969McClatchie S. Bremner A.D. Tumoral calcinosis—an unrecognized disease.Br Med J. 1969; 1: 153-155Crossref PubMed Google Scholar; Owor, 1972Owor R. Tumoral calcinosis in Uganda.Trop Geogr Med. 1972; 24: 39-43PubMed Google Scholar). Despite these advances, it was not until 1996 that Smack et al. formally established the distinction between normophosphatemic (NFTC) and hyperphosphatemic FTC (HFTC) (Smack et al., 1996Smack D. Norton S.A. Fitzpatrick J.E. Proposal for a pathogenesis-based classification of tumoral calcinosis.Int J Dermatol. 1996; 35: 265-271Crossref PubMed Google Scholar), a classification that proved to be instrumental in guiding the molecular studies that eventually led to the identification of the genetic basis of FTC. As mentioned above, FTC has been mainly (but not exclusively) reported in Africa, the Middle-East, and in populations originating from these regions of the world. Its exact prevalence is unknown, but it is considered to be exceedingly rare. Although the disease was initially reported to be inherited in an autosomal dominant fashion (Lyles et al., 1985Lyles K.W. Burkes E.J. Ellis G.J. Lucas K.J. Dolan E.A. Drezner M.K. Genetic transmission of tumoral calcinosis: autosomal dominant with variable clinical expressivity.J Clin Endocrinol Metab. 1985; 60: 1093-1096Crossref PubMed Google Scholar), the recent identification of the genetic defects underlying all forms of FTC definitely established an autosomal recessive mode of inheritance (Topaz et al., 2004Topaz O. Shurman D.L. Bergman R. Indelman M. Ratajczak P. Mizrachi M. et al.Mutations in GALNT3, encoding a protein involved in O-linked glycosylation, cause familial tumoral calcinosis.Nat Genet. 2004; 36: 579-581Crossref PubMed Scopus (277) Google Scholar; Benet-Pages et al., 2005Benet-Pages A. Orlik P. Strom T.M. Lorenz-Depiereux B. An FGF23 missense mutation causes familial tumoral calcinosis with hyperphosphatemia.Hum Mol Genet. 2005; 14: 385-390Crossref PubMed Scopus (285) Google Scholar; Ichikawa et al., 2005Ichikawa S. Lyles K.W. Econs M.J. A novel GALNT3 mutation in a pseudoautosomal dominant form of tumoral calcinosis: evidence that the disorder is autosomal recessive.J Clin Endocrinol Metab. 2005; 90: 2420-2423Crossref PubMed Scopus (95) Google Scholar). Serum phosphate levels demarcate the two major subtypes of FTC: HFTC (MIM211900) and NFTC (MIM610455; Sprecher, 2007Sprecher E. Tumoral calcinosis: new insights for the rheumatologist into a familial crystal deposition disease.Curr Rheumatol Rep. 2007; 9: 237-242Crossref PubMed Scopus (9) Google Scholar). Although these two disorders were initially considered part of a clinical continuum (Metzker et al., 1988Metzker A. Eisenstein B. Oren J. Samuel R. Tumoral calcinosis revisited—common and uncommon features. Report of ten cases and review.Eur J Pediatr. 1988; 147: 128-132Crossref PubMed Google Scholar), it is today clear that they represent distinct entities, not only at the metabolic level, but also at the clinical, epidemiological, and genetic (see below) levels. HFTC is generally characterized by a relatively late onset from the first to the third decade of life (Prince et al., 1982Prince M.J. Schaeffer P.C. Goldsmith R.S. Chausmer A.B. Hyperphosphatemic tumoral calcinosis: association with elevation of serum 1,25-dihydroxycholecalciferol concentrations.Ann Intern Med. 1982; 96: 586-591Crossref PubMed Google Scholar; Metzker et al., 1988Metzker A. Eisenstein B. Oren J. Samuel R. Tumoral calcinosis revisited—common and uncommon features. Report of ten cases and review.Eur J Pediatr. 1988; 147: 128-132Crossref PubMed Google Scholar; Slavin et al., 1993Slavin R.E. Wen J. Kumar D. Evans E.B. Familial tumoral calcinosis. A clinical, histopathologic, and ultrastructural study with an analysis of its calcifying process and pathogenesis.Am J Surg Pathol. 1993; 17: 788-802Crossref PubMed Google Scholar), although appearance of calcified nodules has been reported as early as at 6 weeks of age (Polykandriotis et al., 2004Polykandriotis E.P. Beutel F.K. Horch R.E. Grunert J. A case of familial tumoral calcinosis in a neonate and review of the literature.Arch Orthop Trauma Surg. 2004; 124: 563-567Crossref PubMed Scopus (0) Google Scholar). It has been mainly reported in individuals of Middle Eastern and African origins (Metzker et al., 1988Metzker A. Eisenstein B. Oren J. Samuel R. Tumoral calcinosis revisited—common and uncommon features. Report of ten cases and review.Eur J Pediatr. 1988; 147: 128-132Crossref PubMed Google Scholar; Slavin et al., 1993Slavin R.E. Wen J. Kumar D. Evans E.B. Familial tumoral calcinosis. A clinical, histopathologic, and ultrastructural study with an analysis of its calcifying process and pathogenesis.Am J Surg Pathol. 1993; 17: 788-802Crossref PubMed Google Scholar). Many patients are often incidentally diagnosed while undergoing radiographic investigation for unrelated reasons. Slowly growing calcified masses develop mainly at periarticular locations, with a predilection for skin areas overlying large joints. The hips are most often involved. These calcified masses are initially asymptomatic, but progressively reach large sizes (up to 1.5kg), thereby interfering with movements around the joints (Figure 1a). Ulceration is usually accompanied by intolerable pain and is occasionally associated with secondary infections, rarely reported as a cause of death (Sprecher, 2007Sprecher E. Tumoral calcinosis: new insights for the rheumatologist into a familial crystal deposition disease.Curr Rheumatol Rep. 2007; 9: 237-242Crossref PubMed Scopus (9) Google Scholar). In some affected individuals, extracutaneous signs may predominate. Dental manifestations, including pulp calcifications and obliteration of the pulp cavity, may be prominent (Burkes et al., 1991Burkes Jr., E.J. Lyles K.W. Dolan E.A. Giammara B. Hanker J. Dental lesions in tumoral calcinosis.J Oral Pathol Med. 1991; 20: 222-227Crossref PubMed Google Scholar; Campagnoli et al., 2006Campagnoli M.F. Pucci A. Garelli E. Carando A. Defilippi C. Lala R. et al.Familial tumoral calcinosis and testicular microlithiasis associated with a new mutation of GALNT3 in a White family.J Clin Pathol. 2006; 59: 440-442Crossref PubMed Scopus (43) Google Scholar; Specktor et al., 2006Specktor P. Cooper J.G. Indelman M. Sprecher E. Hyperphosphatemic familial tumoral calcinosis caused by a mutation in GALNT3 in a European kindred.J Hum Genet. 2006; 51: 487-490Crossref PubMed Scopus (47) Google Scholar); testicular microlithiasis has been reported as part of the disease (Campagnoli et al., 2006Campagnoli M.F. Pucci A. Garelli E. Carando A. Defilippi C. Lala R. et al.Familial tumoral calcinosis and testicular microlithiasis associated with a new mutation of GALNT3 in a White family.J Clin Pathol. 2006; 59: 440-442Crossref PubMed Scopus (43) Google Scholar); angioid streaks and corneal calcifications have been observed as well (Ghanchi et al., 1996Ghanchi F. Ramsay A. Coupland S. Barr D. Lee W.R. Ocular tumoral calcinosis. A clinicopathologic study.Arch Ophthalmol. 1996; 114: 341-345Crossref PubMed Google Scholar); and bone manifestations (diaphysitis and hyperostosis) may be more common than initially thought (Clarke et al., 1984Clarke E. Swischuk L.E. Hayden Jr., C.K. Tumoral calcinosis, diaphysitis, and hyperphosphatemia.Radiology. 1984; 151: 643-646Crossref PubMed Google Scholar; Mallette and Mechanick, 1987Mallette L.E. Mechanick J.I. Heritable syndrome of pseudoxanthoma elasticum with abnormal phosphorus and vitamin D metabolism.Am J Med. 1987; 83: 1157-1162Abstract Full Text PDF PubMed Google Scholar; Ballina-Garcia et al., 1996Ballina-Garcia F.J. Queiro-Silva R. Fernandez-Vega F. Fernandez-Sanchez J.A. Weruaga-Rey A. Perez-Del Rio M.J. et al.Diaphysitis in tumoral calcinosis syndrome.J Rheumatol. 1996; 23: 2148-2151PubMed Google Scholar). HFTC has been reported in association with pseudoxanthoma elasticum (Mallette and Mechanick, 1987Mallette L.E. Mechanick J.I. Heritable syndrome of pseudoxanthoma elasticum with abnormal phosphorus and vitamin D metabolism.Am J Med. 1987; 83: 1157-1162Abstract Full Text PDF PubMed Google Scholar). Recently, a long-term follow-up study of one of the largest HFTC kindreds described revealed salient features of the disease, including overall good prognosis, lack of efficient treatments for the disorder apart from surgical removal of calcified tumors (most patients undergo over 20 major operations during their life time), and possible association with hypertension and pulmonary restrictive disease (Carmichael et al., 2009Carmichael K.D. Bynum J.A. Evans E.B. Familial tumoral calcinosis: a forty-year follow-up on one family.J Bone Joint Surg Am. 2009; 91: 664-671Crossref PubMed Scopus (21) Google Scholar). Medical treatment is notoriously frustrating. Isolated reports have suggested benefit from combined treatment of HFTC with acetazolamide and sevelamer hydrochloride, a non-calcium phosphate binder (Garringer et al., 2006Garringer H.J. Fisher C. Larsson T.E. Davis S.I. Koller D.L. Cullen M.J. et al.The role of mutant UDP-N-acetyl-alpha-D-galactosamine-polypeptide N-acetylgalactosaminyltransferase 3 in regulating serum intact fibroblast growth factor 23 and matrix extracellular phosphoglycoprotein in heritable tumoral calcinosis.J Clin Endocrinol Metab. 2006; 91: 4037-4042Crossref PubMed Scopus (61) Google Scholar; Lammoglia and Mericq, 2009Lammoglia J.J. Mericq V. Familial tumoral calcinosis caused by a novel FGF23 mutation: response to induction of tubular renal acidosis with acetazolamide and the non-calcium phosphate binder sevelamer.Horm Res. 2009; 71: 178-184Crossref PubMed Scopus (16) Google Scholar). NFTC seems to be even less prevalent than HFTC, with only six families reported to date (Topaz et al., 2006Topaz O. Indelman M. Chefetz I. Geiger D. Metzker A. Altschuler Y. et al.A deleterious mutation in SAMD9 causes normophosphatemic familial tumoral calcinosis.Am J Hum Genet. 2006; 79: 759-764Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar; Chefetz et al., 2008Chefetz I. Ben Amitai D. Browning S. Skorecki K. Adir N. Thomas M.G. et al.Normophosphatemic familial tumoral calcinosis is caused by deleterious mutations in SAMD9, encoding a TNF-alpha responsive protein.J Invest Dermatol. 2008; 128: 1423-1429Crossref PubMed Scopus (28) Google Scholar). The disease often initially manifests with a nonspecific erythematous rash and mucosal inflammation during the first year of life (Metzker et al., 1988Metzker A. Eisenstein B. Oren J. Samuel R. Tumoral calcinosis revisited—common and uncommon features. Report of ten cases and review.Eur J Pediatr. 1988; 147: 128-132Crossref PubMed Google Scholar; Katz et al., 1989Katz J. Ben-Yehuda A. Machtei E.E. Danon Y.L. Metzker A. Tumoral calcinosis associated with early onset periodontitis.J Clin Periodontol. 1989; 16: 643-646Crossref PubMed Google Scholar). Inflammatory manifestations in the oral cavity can be particularly debilitating (Gal et al., 1994Gal G. Metzker A. Garlick J. Gold Y. Calderon S. Head and neck manifestations of tumoral calcinosis.Oral Surg Oral Med Oral Pathol. 1994; 77: 158-166Abstract Full Text PDF PubMed Scopus (0) Google Scholar). This eruption heralds the progressive, but often rapid, development of small, acrally located calcified nodules, which almost invariably lead to ulceration of the overlying skin and discharge of chalky material (Figure 1b). Here too, unremitting pain and infection are major causes of morbidity. Histopathologically (Figure 1c), two major stages in calcified tumor formation have been recognized: an active phase characterized by the presence of multinucleated giant cells and macrophages surrounding calcified deposits in the dermis, and a chronic or inactive phase associated with dense fibrous tissue (Veress et al., 1976Veress B. Malik M.O. El Hassan A.M. Tumoral lipocalcinosis: a clinicopathological study of 20 cases.J Pathol. 1976; 119: 113-118Crossref PubMed Google Scholar). Biochemical analysis of extruded calcified masses indicated that they are mainly composed of calcium hydroxyapatite with amorphous calcium carbonate and calcium phosphate (Boskey et al., 1983Boskey A.L. Vigorita V.J. Sencer O. Stuchin S.A. Lane J.M. Chemical, microscopic, and ultrastructural characterization of the mineral deposits in tumoral calcinosis.Clin Orthop Relat Res. 1983; 178: 258-269PubMed Google Scholar). As mentioned above, metabolic abnormalities are the major features distinguishing HFTC from NFTC. HFTC patients invariably show elevated levels of circulating phosphate (in the range of 5 to 7mgdl−1, normal levels=2.5–4.5mgdl−1 or 0.80–1.44mmol), which are due to decreased fractional phosphate excretion through the kidney proximal tubules (White et al., 2006White K.E. Larsson T.E. Econs M.J. The roles of specific genes implicated as circulating factors involved in normal and disordered phosphate homeostasis: frizzled related protein-4, matrix extracellular phosphoglycoprotein, and fibroblast growth factor 23.Endocr Rev. 2006; 27: 221-241Crossref PubMed Scopus (104) Google Scholar). Calcium levels are typically normal in HFTC, and 1,25-dihydroxyvitamin-D levels are normal or inappropriately elevated (Steinherz et al., 1985Steinherz R. Chesney R.W. Eisenstein B. Metzker A. DeLuca H.F. Phelps M. Elevated serum calcitriol concentrations do not fall in response to hyperphosphatemia in familial tumoral calcinosis.Am J Dis Child. 1985; 139: 816-819Crossref PubMed Scopus (1) Google Scholar). In contrast, NFTC patients do not show any metabolic abnormality (Metzker et al., 1988Metzker A. Eisenstein B. Oren J. Samuel R. Tumoral calcinosis revisited—common and uncommon features. Report of ten cases and review.Eur J Pediatr. 1988; 147: 128-132Crossref PubMed Google Scholar; Topaz et al., 2006Topaz O. Indelman M. Chefetz I. Geiger D. Metzker A. Altschuler Y. et al.A deleterious mutation in SAMD9 causes normophosphatemic familial tumoral calcinosis.Am J Hum Genet. 2006; 79: 759-764Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar). In fact, these differences are very much reminiscent of the dichotomous nature of acquired calcinosis (Touart and Sau, 1998Touart D.M. Sau P. Cutaneous deposition diseases. Part II.J Am Acad Dermatol. 1998; 39 (quiz 545–526): 527-544Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar). Here, calcinosis can either manifest as a result of an underlying metabolic disorder as in chronic renal failure, or develop as a reaction to tissue damage, as in autoimmune diseases (Figure 1d) or as in atherosclerosis (Touart and Sau, 1998Touart D.M. Sau P. Cutaneous deposition diseases. Part II.J Am Acad Dermatol. 1998; 39 (quiz 545–526): 527-544Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar). When cutaneous calcinosis is due to deranged phosphate or calcium metabolism (e.g., chronic renal failure), it is termed metastatic calcinosis; by contrast, when it is secondary to tissue damage (e.g., autoimmune disease), it is known as dystrophic calcinosis (Touart and Sau, 1998Touart D.M. Sau P. Cutaneous deposition diseases. Part II.J Am Acad Dermatol. 1998; 39 (quiz 545–526): 527-544Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar). At this regard, clinical and metabolic features of HFTC very much resemble metastatic calcinosis, while NFTC models dystrophic calcinosis, thus suggesting that elucidation of the molecular basis of FTC may shed light on the pathogenesis of these two major forms of acquired calcinosis. This assumption was the impetus that drove a large international effort aimed at deciphering the molecular cause and biochemical mechanisms underlying the various forms of FTC. We owe to the study of rare diseases the discovery of many key physiological pathways (Antonarakis and Beckmann, 2006Antonarakis S.E. Beckmann J.S. Mendelian disorders deserve more attention.Nat Rev Genet. 2006; 7: 277-282Crossref PubMed Scopus (96) Google Scholar). In less than 5 years, the study of FTC has revealed a surprisingly intricate regulatory network of proteins responsible for regulation of phosphate homeostasis and extraosseous calcification (Sprecher, 2007Sprecher E. Tumoral calcinosis: new insights for the rheumatologist into a familial crystal deposition disease.Curr Rheumatol Rep. 2007; 9: 237-242Crossref PubMed Scopus (9) Google Scholar; Chefetz and Sprecher, 2009Chefetz I. Sprecher E. Familial tumoral calcinosis and the role of O-glycosylation in the maintenance of phosphate homeostasis.Biochim Biophys Acta. 2009; 1792: 847-852Crossref PubMed Scopus (26) Google Scholar). Using homozygosity mapping, HFTC was initially mapped to 2q24–q31 and found to be associated with mutations in GALNT3, gene encoding a glycosyltransferase termed UDP-N-acetyl-α-D-galactosamine-polypeptide N-acetylgalactosaminyltransferase-3 (ppGalNacT3; Topaz et al., 2004Topaz O. Shurman D.L. Bergman R. Indelman M. Ratajczak P. Mizrachi M. et al.Mutations in GALNT3, encoding a protein involved in O-linked glycosylation, cause familial tumoral calcinosis.Nat Genet. 2004; 36: 579-581Crossref PubMed Scopus (277) Google Scholar). ppGalNacT3 catalyses the initial step of O-glycosylation of serine and threonine residues, and is ubiquitously expressed (Ten Hagen et al., 2003Ten Hagen K.G. Fritz T.A. Tabak L.A. All in the family: the UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferases.Glycobiology. 2003; 13: 1R-16RCrossref PubMed Scopus (284) Google Scholar; Wopereis et al., 2006Wopereis S. Lefeber D.J. Morava E. Wevers R.A. Mechanisms in protein O-glycan biosynthesis and clinical and molecular aspects of protein O-glycan biosynthesis defects: a review.Clin Chem. 2006; 52: 574-600Crossref PubMed Scopus (82) Google Scholar). ppGalNacT3 is one of a family of 24 acetylgalactosaminyltransferases, which are expressed in a tissue-specific manner and play an important role in the development and maintenance of a variety of tissues (Ten Hagen et al., 2003Ten Hagen K.G. Fritz T.A. Tabak L.A. All in the family: the UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferases.Glycobiology. 2003; 13: 1R-16RCrossref PubMed Scopus (284) Google Scholar). Most congenital disorders of glycosylation result from impaired N-glycosylation and are characterized by pleiotropic clinical manifestations (Freeze, 2006Freeze H.H. Genetic defects in the human glycome.Nat Rev Genet. 2006; 7: 537-551Crossref PubMed Scopus (231) Google Scholar); in this regard, HFTC is unique in that it results from abnormal O-glycosylation and seems to be associated exclusively with ectopic calcification. More than 10 mutations have so far been reported in GALNT3 (Topaz et al., 2004Topaz O. Shurman D.L. Bergman R. Indelman M. Ratajczak P. Mizrachi M. et al.Mutations in GALNT3, encoding a protein involved in O-linked glycosylation, cause familial tumoral calcinosis.Nat Genet. 2004; 36: 579-581Crossref PubMed Scopus (277) Google Scholar; Ichikawa et al., 2005Ichikawa S. Lyles K.W. Econs M.J. A novel GALNT3 mutation in a pseudoautosomal dominant form of tumoral calcinosis: evidence that the disorder is autosomal recessive.J Clin Endocrinol Metab. 2005; 90: 2420-2423Crossref PubMed Scopus (95) Google Scholar, Ichikawa et al., 2006Ichikawa S. Imel E.A. Sorenson A.H. Severe R. Knudson P. Harris G.J. et al.Tumoral calcinosis presenting with eyelid calcifications due to novel missense mutations in the glycosyltransferase domain of the GALNT3 gene.J Clin Endocrinol Metab. 2006; 91: 4472-4475Crossref PubMed Scopus (43) Google Scholar; Campagnoli et al., 2006Campagnoli M.F. Pucci A. Garelli E. Carando A. Defilippi C. Lala R. et al.Familial tumoral calcinosis and testicular microlithiasis associated with a new mutation of GALNT3 in a White family.J Clin Pathol. 2006; 59: 440-442Crossref PubMed Scopus (43) Google Scholar; Garringer et al., 2006Garringer H.J. Fisher C. Larsson T.E. Davis S.I. Koller D.L. Cullen M.J. et al.The role of mutant UDP-N-acetyl-alpha-D-galactosamine-polypeptide N-acetylgalactosaminyltransferase 3 in regulating serum intact fibroblast growth factor 23 and matrix extracellular phosphoglycoprotein in heritable tumoral calcinosis.J Clin Endocrinol Metab. 2006; 91: 4037-4042Crossref PubMed Scopus (61) Google Scholar, Garringer et al., 2007Garringer H.J. Mortazavi S.M. Esteghamat F. Malekpour M. Boztepe H. Tanakol R. et al.Two novel GALNT3 mutations in familial tumoral calcinosis.Am J Med Genet. 2007; 143A: 2390-2396Crossref PubMed Scopus (27) Google Scholar; Specktor et al., 2006Specktor P. Cooper J.G. Indelman M. Sprecher E. Hyperphosphatemic familial tumoral calcinosis caused by a mutation in GALNT3 in a European kindred.J Hum Genet. 2006; 51: 487-490Crossref PubMed Scopus (47) Google Scholar; Barbieri et al., 2007Barbieri A.M. Filopanti M. Bua G. Beck-Peccoz P. Two novel nonsense mutations in GALNT3 gene are responsible for familial tumoral calcinosis.J Hum Genet. 2007; 52: 464-468Crossref PubMed Scopus (20) Google Scholar; Dumitrescu et al., 2009Dumitrescu C.E. Kelly M.H. Khosravi A. Hart T.C. Brahim J. White K.E. et al.A case of familial tumoral calcinosis/hyperostosis–hyperphosphatemia syndrome due to a compound heterozygous mutation in GALNT3 demonstrating new phenotypic features.Osteoporos Int. 2009; 20: 1273-1278Crossref PubMed Scopus (21) Google Scholar; Laleye et al., 2008Laleye A. Alao M.J. Gbessi G. Adjagba M. Marche M. Coupry I. et al.Tumoral calcinosis due to GALNT3 C.516-2A>T mutation in a black African family.Genet Couns. 2008; 19: 183-192PubMed Google Scholar); all of these are predicted or have been found (Topaz et al., 2005Topaz O. Bergman R. Mandel U. Maor G. Goldberg R. Richard G. et al.Absence of intraepidermal glycosyltransferase ppGalNac-T3 expression in familial tumoral calcinosis.Am J Dermatopathol. 2005; 27: 211-215Crossref PubMed Scopus (16) Google Scholar) to result in loss of function of ppGalNacT3. Deleterious alterations in GALNT3 were also found to underlie at least one additional autosomal recessive syndrome, hyperostosis–hyperphosphatemia syndrome (MIM610233), which, as HFTC, is also associated with elevated levels of serum phosphate (Melhem et al., 1970Melhem R.E. Najjar S.S. Khachadurian A.K. Cortical hyperostosis with hyperphosphatemia: a new syndrome?.J Pediatr. 1970; 77: 986-990Abstract Full Text PDF PubMed Google Scholar; Altman and Pomerance, 1971Altman H.S. Pomerance H.H. Cortical hyperostosis with hyperphosphatemia.J Pediatr. 1971; 79: 874-875Abstract Full Text PDF PubMed Google Scholar; Mikati et al., 1981Mikati M.A. Melhem R.E. Najjar S.S. The syndrome of hyperostosis and hyperphosphatemia.J Pediatr. 1981; 99: 900-904Abstract Full Text PDF PubMed Google Scholar). This syndrome manifests with episodes of excruciating pain associated with swelling, along the long bones. Despite the fact that HFTC and hyperostosis–hyperphosphatemia syndrome manifest phenotypically in two different tissues, skin and bone, mutations in the same gene, GALNT3, and in one instance, the very same mutation (Frishberg et al., 2005Frishberg Y. Topaz O. Bergman R. Behar D. Fisher D. Gordon D. et al.Identification of a recurrent mutation in GALNT3 demonstrates that hyperostosis–hyperphosphatemia syndrome and familial tumoral calcinosis are allelic disorders.J Mol Med. 2005; 83: 33-38Crossref PubMed Scopus (67) Google Scholar), were found to underlie both syndromes (Ichikawa et al., 2007aIchikawa S. Guigonis V. Imel E.A. Courouble M. Heissat S. Henley J.D. et al.Novel GALNT3 mutations causing hyperostosis–hyperphosphatemia syndrome result in low intact fibroblast growth factor 23 concentrations.J Clin Endocrinol Metab. 2007; 92: 1943-1947Crossref PubMed Scopus (47) Google Scholar; Dumitrescu et al., 2009Dumitrescu C.E. Kelly M.H. Khosravi A. Hart T.C. Brahim J. White K.E. et al.A case of familial tumoral calcinosis/hyperostosis–hyperphosphatemia syndrome due to a compound heterozygous mutation in GALNT3 demonstrating new phenotypic features.Osteoporos Int. 2009; 20: 1273-1278Crossref PubMed Scopus (21) Google Scholar; Olauson et al., 2008Olauson H. Krajisnik T. Larsson C. Lindberg B. Larsson T.E. A novel missense mutation in GALNT3 causing hyperostosis-hyperphosphataemia syndrome.Eur J Endocrinol. 2008; 158: 929-934Crossref PubMed Scopus (15) Google Scholar; Gok et al., 2009Gok F. Chefetz I. Indelman M. Kocaoglu M. Sprecher E. Newly discovered mutations in the GALNT3 gene causing autosomal recessive hyperostosis–hyperphosphatemia syndrome.Acta Orthop. 2009; 80: 131-134Crossref PubMed Scopus (10) Google Scholar). Interestingly, coexistence of the two diseases in one family has been reported (Narchi, 1997Narchi H. Hyperostosis with hyperphosphatemia: evidence of familial occurrence and association with tumoral calcinosis.Pediatrics. 1997; 99: 745-748Crossref PubMed Google Scholar; Nithyananth et al., 2008Nithyananth M. Cherian V.M. Paul T.V. Seshadri M.S. Hyperostosis and hyperphosphataemia syndrome: a diagnostic dilemma.Singapore Med J. 2008; 49: e350-e352PubMed Google Scholar). In fact, phenotypic heterogeneity seems to be quite characteristic of the HFTC group of diseases, with a widely variable spectrum of disease severity and tissue involvement (Sprecher, 2007Sprecher E. Tumoral calcinosis: new insights for the rheumatologist into a familial crystal deposition disease.Curr Rheumatol Rep. 2007; 9: 237-242Crossref PubMed Scopus (9) Google Scholar). Large-scale screening of HFTC families revealed that GALNT3 mutations cannot be found in all HFTC families. In parallel
Referência(s)