Human Preosteoblastic Cell Culture from a Patient with Severe Tumoral Calcinosis-Hyperphosphatemia Due to a New GALNT3 Gene Mutation: Study of In Vitro Mineralization

Abstract

Human disorders of phosphate (Pi) handling and skeletal mineralization represent a group of rare bone diseases. One of these disease is tumoral calcinosis (TC). In this study, we present the case of a patient with TC with a new GALNT3 gene mutation. We also performed functional studies using an in vitro cellular model. Genomic DNA was extracted from peripheral blood collected from a teenage Caucasian girl affected by TC, and from her parents. A higher capability to form mineralization nodules in vitro was found in human preosteoblastic cells of mutant when compared to wild-type controls. We found a novel homozygous inactivating splice site mutation in intron I (c.516-2a>g). A higher capability to form mineralization nodules in vitro was found in the mutant cells in human preosteoblastic cells when compared to wild-type controls. Understanding the functional significance and molecular physiology of this novel mutation will help to define the role of FGF23 in the control of Pi homeostasis in normal and in pathological conditions.

Phenotypic and Genotypic Characterization and Treatment of a Cohort With Familial Tumoral Calcinosis/Hyperostosis-Hyperphosphatemia Syndrome

“…Two previously reported subjects had evidence of increased inflammation. (31,34) In our cohort, three of the eight subjects had overwhelming systemic inflammation. Inflammation correlated with severity of clinical disease, but there was no correlation with TRP.…”

Hyperphosphatemic Familial Tumoral Calcinosis With Galnt3 Mutation: Transient Response to Anti‐Interleukin‐1 Treatments

“…We report on a case of HFTC, complicated by severe inflammatory flares, which is a previously described complication of the disease . The hypothesis of an auto‐inflammatory‐like syndrome is suggested by the clinical and biological presentation, its tendency to evolve through inflammatory flares, and enhanced by the reported presence of macrophages on biopsies of patients with HFTC .…”

“…We report on a case of HFTC, complicated by severe inflammatory flares, which is a previously described complication of the disease. (12)(13)(14) The hypothesis of an auto-inflammatory-like syndrome is suggested by the clinical and biological presentation, its tendency to evolve through inflammatory flares, and enhanced by the reported presence of macrophages on biopsies of patients with HFTC. (7) With this rationale, the effect of anti-IL-1 treatment has been reported so far only in two cases, (12) one treated with anakinra, 100 mg subcutaneously daily, then twice daily, and the other one with canakinumab 100 mg every 8 weeks, ie, a sixfold lower dose than the one we used.…”

Hyperphosphatemic Familial Tumoral Calcinosis in Two Siblings with a Novel Mutation in <i>GALNT3</i> Gene: Experience from Southern Turkey

“…Differential diagnosis includes chronic renal failure, hypervitaminosis D, primary hyperparathyroidism or connective tissue diseases with particular emphasis on dermatomyositis and scleroderma. HFTC is very rare, approximately 75 cases have been genetically described worldwide to the best of our knowledge and almost all of the information is based on case reports (5,6,7,8,9,10). Homozygote mutations in the GALNT3 , FGF23 and KL genes were found in patients with the HHS phenotype.…”