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Title: Alterations in SAMD9, AHSG, FRG2C, and FGFR4 genes in a case of late-onset massive tumoral calcinosis
Authors: Leow, Melvin Khee Shing
Ang, Joshur
Bi, Xinyan
Koh, Ee Tzun
McFarlane, Craig
Keywords: Science::Medicine
Issue Date: 2023
Source: Leow, M. K. S., Ang, J., Bi, X., Koh, E. T. & McFarlane, C. (2023). Alterations in SAMD9, AHSG, FRG2C, and FGFR4 genes in a case of late-onset massive tumoral calcinosis. AACE Clinical Case Reports, 9(5), 153-157.
Journal: AACE Clinical Case Reports 
Abstract: Background/Objective: Tumoral calcinosis (TC) is a rare, arcane, and debilitating disorder of phosphate metabolism manifesting as hard masses in soft tissues. Primary hyperphosphatemic TC has been shown to be caused by pathogenic variants in the genes encoding FGF23, GALNT3, and KLOTHO. We report a case of massive TC mechanistically associated with phosphatonin resistance associated with heterozygous alterations in the sterile alfa motif domain–containing protein-9 gene (SAMD9), alfa 2-Heremans-Schmid glycoprotein gene (AHSG), FSHD region gene 2-family member-C gene (FRG2C), and fibroblast growth factor receptor-4 gene (FGFR4). Case Report: A middle-aged Malay woman with systemic sclerosis presented with painful hard lumps of her axillae, lower limbs, and external genitalia. She was eucalcemic with mild hyperphosphatemia associated with reduced urinary phosphate excretion. Magnetic resonance imaging revealed calcified soft tissue masses. Paradoxically, the serum intact FGF23 level increased to 89.6 pg/mL, corroborated by Western blots, which also showed overexpression of sFRP4 and MEPE, consistent with phosphatonin resistance. Discussion: Whole genome sequencing identified 2 heterozygous alterations (p.A454T and p.T479M) in SAMD9, 2 heterozygous alterations (p.M248T and p.S256T) in AHSG, a frameshift alteration (p.Arg156fs) in FRG2C, and a heterozygous alteration (p.G388R) in FGFR4, all of which are associated with calcinosis. Nonsynonymous alterations of FRP4 and MEPE were also detected. Conclusion: This highlights that the simultaneous occurrence of alterations in several genes critical in phosphate homeostasis may trigger massive TC despite their heterozygosity. These findings should prompt functional studies in cell and animal models to reveal mechanistic insights in the pathogenesis of such crippling mineralization disorders.
ISSN: 2376-0605
DOI: 10.1016/j.aace.2023.05.004
Schools: Lee Kong Chian School of Medicine (LKCMedicine) 
Organisations: Singapore Institute for Clinical Sciences, A*STAR 
Yong Loo Lin School of Medicine, NUS 
Duke-NUS Medical School 
Tan Tock Seng Hospital 
Rights: © 2023 AACE. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (
Fulltext Permission: open
Fulltext Availability: With Fulltext
Appears in Collections:LKCMedicine Journal Articles

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