Multifocal calcific periarthritis with distinctive clinical and radiological features in patients with CD73 deficiency

Abstract

Objective Arterial calcification due to deficiency of CD73 (ACDC) is a hereditary autosomal recessive ectopic mineralization syndrome caused by loss-of-function mutations in the 5'-nucleotidase Ecto (NT5E) gene. Periarticular calcification has been reported but the clinical characterization of arthritis as well as the microstructure and chemical composition of periarticular calcifications and synovial fluid crystals has not been systematically investigated. Methods Eight ACDC patients underwent extensive rheumatological and radiological evaluation over a period of 11 years. Periarticular and synovial biopsies were obtained from four patients. Characterization of crystal composition was evaluated by compensated polarized light microscopy, Alizarin red staining for synovial fluid along with x-ray diffraction and x-ray micro tomosynthesis for periarticular calcification. Results Arthritis in ACDC patients has a clinical presentation of mixed erosive-degenerative joint changes with a median onset of articular symptoms at 17 years of age and progresses over time to the development of fixed deformities and functional limitations of small peripheral joints with eventually, larger joint and distinct axial involvement later in life. We have identified calcium pyrophosphate (CPP) and calcium hydroxyapatite (CHA) crystals in synovial fluid specimens and determined that CHA crystals are the principal component of periarticular calcifications. Conclusion This is the largest study in ACDC patients to describe erosive peripheral arthropathy and axial enthesopathic calcifications over a period of 11 years and the first to identify the composition of periarticular calcifications and synovial fluid crystals. ACDC should be considered among the genetic causes of early-onset osteoarthritis, as musculoskeletal disease signs may often precede vascular symptoms.

Evidence for a genetic contribution to the ossification of spinal ligaments in Ossification of Posterior Longitudinal Ligament and Diffuse idiopathic skeletal hyperostosis: A narrative review

“…A recently described hereditary autosomal recessive ectopic mineralization syndrome in patients with arterial Calcification due to deficiency of CD73 (ACDC), was the result of a loss of function mutations in the 5′-nucleoside Ecto (NT5E) gene. These patients had erosive peripheral arthropathy and axial enthesopathic calcifications, resembling DISH although with decreased disc space height and the presence of large intervertebral disk calcifications (Cudrici et al, 2021). The similarities to both DISH and AS of the outcome of spine imaging of ACDC patients are noteworthy.…”

“…Other bone morphogenetic protein genes have been associated with OPLL; two SNPs in BMP-9 were found to be associated with OPLL: rs75024165 and rs34379100 (Ikuma et al, 2022). BMP-4 SNPs rs17563 (Mader et al, 2013;Cudrici et al, 2021), rs76335800 and a specific haplotype, TGGGCTT (Mader et al, 2013), were identified as risk factors for developing OPLL in the Chinese population. Furushima et al (Ramos et al, 2015) also confirmed the association of BMP-4 with OPLL, in a large scale screening study, in which only BMP-4 reached criteria of suggestive evidence of linkage.…”

A new perspective on intervertebral disc calcification—from bench to bedside

“… 76 , 77 Likewise, inactivating mutations in CD73 result in late-onset ectopic mineralization of periarticular ligaments and the arteries of the lower extremities. 78 , 79 Finally, the absence of functional TNAP results in hypophosphatasia due to increased local levels of PPi and, consequently, hypomineralization of bones. 80 …”

Insights in Genetics of Common and Rare Diseases: 2022

“…Other bone morphogenetic protein genes have been associated with OPLL; two SNPs in BMP-9 were found to be associated with OPLL: rs75024165 and rs34379100 (Ikuma et al, 2022). BMP-4 SNPs rs17563 (Mader et al, 2013;Cudrici et al, 2021), rs76335800 and a specific haplotype, TGGGCTT (Mader et al, 2013), were identified as risk factors for developing OPLL in the Chinese population. Furushima et al (Ramos et al, 2015) also confirmed the association of BMP-4 with OPLL, in a large scale screening study, in which only BMP-4 reached criteria of suggestive evidence of linkage.…”