Hyperphosphatemic Familial Tumoral Calcinosis in Two Siblings with a Novel Mutation in GALNT3 gene: Experience from Southern Turkey

Abstract

Inactivating autosomal recessive mutations in both FGF23, KL and GALNT3 genes lead to a rare disorder, hyperphosphatemic familial tumoral calcinosis (HFTC). Patients with HFTC constantly present hyperphosphatemia and tumor like soft tissue calcifications. Although 78% of patients develop their first symptoms between 2-13 years of age, diagnosis is usually delayed until adulthood. Some individuals with the same genetic defect overlap a condition named Hyperphosphatemic hyperostosis syndrome (HHS). Herein we report two siblings suffering from periarticular warm, hard and tender subcutaneous masses. Subcutaneous calcifications were present on X-ray and biopsy results were consistent with calcinosis in both patients. Laboratory results showed marked hyperphosphatemia and elevated renal tubular phosphate reabsorption, normal renal function tests and serum 25 hydroxyvitamin D levels. Thus, we suspected HFTC and performed next generation sequencing for GALNT3 gene, mostly causative in the literature. A novel homozygote P85Rfs*6 (c.254_255delCT) mutation in GALNT3 gene was identified in both siblings. Our report introduces two new patients to the knowledge about a rare genetic disease and suggests that small deletions in GALNT3 gene may be related with HFTC phenotype. Increased knowledge of physicians about this disease and studying phenotypegenotype correlation with more patients are needed to confirm our suggestion.

Three Siblings With a Rare Familial Hyperphosphatemia Syndrome: A Case Series

“…HHS/HFTC are rare autosomal recessive diseases (Genetic and Rare Diseases Information Center, GARD 0010879); approximately 75 cases have been genetically described worldwide [8,10,11]. They are caused by mutations in the GALNT3, FGF23, and KL genes.…”

“…Therefore, this disorder can be either secondary to an inactivating mutation in GALNT3 preventing proper a-linked glycosylation of FGF23 or due to a mutation in the FGF23 gene. As a result, the mutations will lead to increased renal tubular phosphate reabsorption and usually elevated 1,25-dihydroxy vitamin D3, which promotes gastrointestinal absorption of calcium and phosphate [8]. As for the role of the KL gene, studies have shown that klotho is an additional cofactor that is required by FGF23 to exert its activity, as it converts canonical FGF receptors into specific receptors for FGF23, thus allowing their binding and signaling through the receptors [9].…”

Novel genetic mutation associated with hyperphosphatemic familial tumoral calcinosis/hyperostosis-hyperphosphatemia syndrome treated with denosumab: a case report

“…The latter occurs due to local inflammatory reactions around calcifications or inside hyperostotic regions (1). To date, 48 cases of HFTC/HHS attributed to N-acetylgalactosaminyltransferase 3 (GALNT3) mutations (type 1 disease) have been documented, along with 21 cases of HFTC/HHS resulting from fibroblast growth factor 23 (FGF23) mutations (type 2 disease) and a single case involving a Klotho (type 3 disease) mutation (2)(3)(4)(5). Moreover, an acquired autoimmune form of HFTC/HHS has been reported, character-ized by pathogenic autoantibodies targeting FGF23.…”