We believe this is the first report of a pathologic fracture secondary to HFTC in the literature. While periarticular bony involvement is a common feature of HFTC, direct involvement of the bone is rare. Bone involvement is, however, common in hyperostosis-hyperphosphatemia syndrome (HHS). Hyperostosis-hyperphosphatemia syndrome is characterized by hyperostosis and recurrent bone lesions, which occur as a result of hyperphosphatemia. The characteristic radiographic features of affected bones include periosteal reaction, cortical hyperostosis, and diaphysitis.6,9 Clinical presentation of HHS was discovered to originate from a mutation in GALNT3, the same gene as HFTC, and, as such, the two diseases were considered allelic disorders.6 Occurrences of HFTC and HHS have even been reported in the same family.3,10 Therefore, HHS is now thought to be a mild variant of HFTC.9,11 While HFTC and HHS exert their effects primarily in two different tissues, namely soft tissue and bone, respectively, they were also found to co-manifest in the same patient.2,11 A recent literature review demonstrated more subjects with a combined HFTC-HHS phenotype than initially thought.3 Furthermore, a recent study reported a patient that presented with signs of HHS but later progressed to a predominantly HFTC phenotypic presentation, thereby concluding that the two conditions represent a spectrum of the same disease.9 Although our patient was initially diagnosed with HFTC due to clinical manifestations, hyperphosphatemia, and a mutation in GALNT3, it is conceivable that the described bone involvement in the setting of pathologic fracture places him on the HFTC-HHS spectrum, thereby contributing another patient with this rare combined phenotype to the small patient pool.
The GALNT3 (c.1524+1G>A) variant was discovered in families of Druze ethnic descent8 and was later identified in Arab Muslim families with HHS.6 This sequence is highly conserved in all species, thus highlighting the importance of the mutation. A haplotype analysis of this population estimated an allele frequency of 0.70%, and a likely founder effect with the mutation arising approximately 88 to 200 years ago.6 This also suggests a genetic founder linkage between Muslim and Druze communities in the Middle East and a tight genetic correlation between HFTC and HHS. These new findings amplify the need to screen patients’ families for the genetic mutation as well as possible bony involvement in order to avoid future fracture complications.
Our patient underwent numerous debulking procedures due to symptomatic tumoral calcinosis. He was not treated medically, as no definitive treatment currently exists, and only case reports and case series have been published on this rare condition. Certain reported treatments have attempted to lower serum phosphate levels, though with inconsistent results. These include a low-phosphate diet, phosphate chelation, as well as medications promoting the renal excretion of phosphate.7 Recently, a prospective study has demonstrated a promising role for sodium thiosulfate, a drug primarily used to treat cyanide poisoning, as a treatment for ectopic calcification resulting from HFTC and HHS.12 Due to the recurrence potential of the disease, this treatment option should be considered for symptomatic relief.
The importance of identifying a fracture occurring secondary to HFTC-HHS demonstrates the need to monitor patients with bone involvement and severe periarticular calcinosis for impending fracture. Repair of the fracture was especially difficult in our case with regard to preoperative planning and intraoperative navigation due to limited X-ray penetration through periarticular calcifications. Thus, the operation was performed as an open reduction and internal fixation. The fracture site was opened in order to visualize and reduce the fracture appropriately. Due to the complexity of the operation that occurred later in the course of disease, we suggest actively monitoring patients with periarticular bone involvement to rule out impending fracture. Should additional similar cases be reported, prophylactic surgical correction with intramedullary fixation and bone stabilization may help to prevent such late, complicated fracture repair.