From variome to phenome: Pathogenesis, diagnosis and management of ectopic mineralization disorders

Abstract

Ectopic mineralization - inappropriate biomineralization in soft tissues - is a frequent finding in physiological aging processes and several common disorders, which can be associated with significant morbidity and mortality. Further, pathologic mineralization is seen in several rare genetic disorders, which often present life-threatening phenotypes. These disorders are classified based on the mechanisms through which the mineralization occurs: metastatic or dystrophic calcification or ectopic ossification. Underlying mechanisms have been extensively studied, which resulted in several hypotheses regarding the etiology of mineralization in the extracellular matrix of soft tissue. These hypotheses include intracellular and extracellular mechanisms, such as the formation of matrix vesicles, aberrant osteogenic and chondrogenic signaling, apoptosis and oxidative stress. Though coherence between the different findings is not always clear, current insights have led to improvement of the diagnosis and management of ectopic mineralization patients, thus translating pathogenetic knowledge (variome) to the phenotype (phenome). In this review, we will focus on the clinical presentation, pathogenesis and management of primary genetic soft tissue mineralization disorders. As examples of dystrophic calcification disorders Pseudoxanthoma elasticum, Generalized arterial calcification of infancy, Keutel syndrome, Idiopathic basal ganglia calcification and Arterial calcification due to CD73 (NT5E) deficiency will be discussed. Hyperphosphatemic familial tumoral calcinosis will be reviewed as an example of mineralization disorders caused by metastatic calcification.

Keywords: Ectopic mineralization; Pseudoxanthoma elasticum; Pseudoxanthoma elasticum-like syndrome; Generalized arterial calcification of infancy; Keutel syndrome; Idiopathic basal ganglia calcification; Arterial calcification due to CD73 deficiency; Hyperphosphatemic familial tumoral calcinosis; Etiology; Phenotype

Core tip: Ectopic mineralization disorders represent a broad range of phenotypically heterogenous diseases, often leading to significant morbidity and mortality. Involving a complex interplay between different pro-osteogenic mediators and inhibitors of calcification, the mechanisms of ectopic mineralization are progressively being unveiled. Though current knowledge is beyond any doubt the tip of the proverbial iceberg, insights already have significant implications in the diagnosis and daily management of these patients. As such, ectopic mineralization diseases are a fine example of translating variome data to the clinic. Here, we will discuss prototype hereditary ectopic calcification diseases with respect to their presentation, diagnosis and management.