Alterations in SAMD9, AHSG, FRG2C, and FGFR4 Genes in a Case of Late-Onset Massive Tumoral Calcinosis

Melvin Khee Shing Leow; Joshur Ang; Xinyan Bi; Ee Tzun Koh; Craig McFarlane

doi:10.1016/j.aace.2023.05.004

Alterations in SAMD9, AHSG, FRG2C, and FGFR4 Genes in a Case of Late-Onset Massive Tumoral Calcinosis

AACE Clin Case Rep. 2023 May 11;9(5):153-157. doi: 10.1016/j.aace.2023.05.004. eCollection 2023 Sep-Oct.

Authors

Melvin Khee Shing Leow^{1

2

3

4

5}, Joshur Ang¹, Xinyan Bi⁶, Ee Tzun Koh^{2

3

7}, Craig McFarlane⁸

Affiliations

¹ Singapore Institute for Clinical Sciences (A∗STAR), Brenner Centre for Molecular Medicine, Singapore.
² Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
³ Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.
⁴ Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, Singapore.
⁵ Department of Endocrinology, Division of Medicine, Tan Tock Seng Hospital, Singapore.
⁶ Singapore Institute of Food and Biotechnology Innovation (A∗STAR), Singapore.
⁷ Department of Rheumatology, Allergy and Immunology, Tan Tock Seng Hospital, Singapore.
⁸ Department of Molecular & Cell Biology, College of Public Health, Medical and Veterinary Sciences, James Cook University, Townsville, QLD, Australia.

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.

Keywords: ectopic calcification; heterozygous calcinosis gene alterations; massive tumoral calcinosis; phosphatonin resistance; whole genome sequencing.

Publication types

Case Reports