Prospective phenotyping of long-term survivors of generalized arterial calcification of infancy (GACI)

Abstract

Purpose Generalized Arterial Calcification of Infancy (GACI), characterized by vascular calcifications that are often fatal shortly after birth, is usually caused by deficiency of ENPP1. A small fraction of GACI cases result from deficiency of ABCC6, a membrane transporter. The natural history of GACI survivors has not been established in a prospective fashion. Methods We performed deep phenotyping of 20 GACI survivors. Results Sixteen of twenty subjects presented with arterial calcifications, but only 5 had residual involvement at the time of evaluation. Individuals with ENPP1 deficiency either had hypophosphatemic rickets or were predicted to develop it by 14 years of age; 14/16 had elevated intact FGF23 levels (iFGF23). Blood phosphate levels correlated inversely with iFGF23. For ENPP1-deficient individuals, the lifetime risk of cervical spine fusion was 25%, that of hearing loss was 75%, and the main morbidity in adults was related to enthesis calcification. Four ENPP1-deficient individuals manifested classic skin or retinal findings of PXE. We estimated the minimal incidence of ENPP1 deficiency at ~1 in 200,000 pregnancies. Conclusions GACI appears to be more common than previously thought, with an expanding spectrum of overlapping phenotypes. The relationships among decreased ENPP1, increased iFGF23, and rickets could inform future therapies.

Musculoskeletal Comorbidities and Quality of Life in ENPP1-Deficient Adults and the Response of Enthesopathy to Enzyme Replacement Therapy in Murine Models

“…(1) Patients who survive, as well as ENPP1-deficient individuals who do not exhibit neonatal calcifications, can develop fibroblast growth factor 23 (FGF23)-mediated hypophosphatemic rickets in later life. (2) Other skeletal complications briefly mentioned in prior series include cervical spine fusion and enthesis calcification. (2) The enthesis is the site of attachment of tendons or ligaments to bone, and is structured in four zones: the dense fibrous connective tissue zone, populated by fibroblast-type cells (tenocytes) and composed of collagen types I and III and decorin; the unmineralized fibrocartilage, populated by fibrochondrocytes and composed of collagen types I and II and aggrecan; the mineralized fibrocartilage, populated by hypertrophic chondrocytes and composed of collagen types II and X and aggrecan; and the bone, populated by osteoblasts, osteocytes, and osteoclasts, and composed of collagen type I.…”

“…(2) Other skeletal complications briefly mentioned in prior series include cervical spine fusion and enthesis calcification. (2) The enthesis is the site of attachment of tendons or ligaments to bone, and is structured in four zones: the dense fibrous connective tissue zone, populated by fibroblast-type cells (tenocytes) and composed of collagen types I and III and decorin; the unmineralized fibrocartilage, populated by fibrochondrocytes and composed of collagen types I and II and aggrecan; the mineralized fibrocartilage, populated by hypertrophic chondrocytes and composed of collagen types II and X and aggrecan; and the bone, populated by osteoblasts, osteocytes, and osteoclasts, and composed of collagen type I. (3) The entheses thus represent a musculoskeletal structure that allows a smooth transition between two widely different tissues, the tendons or ligaments (compliant soft tissues) and bone (a stiff hard tissue).…”

“…(14) Excessive enthesis mineralization does not represent the only musculoskeletal comorbidity seen in patients with FGF23-mediated hypophosphatemic rickets; osteoarthritis and interosseous membrane ossification have been described in patients with XLH. (15) Patients with ENPP1 deficiency, on the other hand, can additionally develop fusion of the posterior elements of the cervical spine, (2) a complication not seen in other etiologies of FGF23-mediated rickets.…”

Consensus Recommendations for the Diagnosis and Management of X-Linked Hypophosphatemia in Belgium

“…Many children with ENPP1 mutations who survive GACI will go on to develop ARHR2 (56,57). The mechanism underlying raised FGF23 (58) and hypophosphatemia in GACI/ARHR2 remains incompletely understood. Extraskeletal features of GACI including hearing loss (59), thrombocytopenia, neurologic, cardiovascular, hepatic manifestations and hypoglycemia have recently been described (60).…”

Case Report: A Novel Genetic Mutation Causes Idiopathic Infantile Arterial Calcification in Preterm Infants

“…Individuals may die suddenly due to myocardial infarction. A small number of survivors may have intractable hypertension, recurrent cardiopulmonary failure ( Nael et al, 2014 ) renal impairment, cervical spine fusion, and hearing loss ( Ferreira et al, 2021b ). Survivors require long-term oral antihypertensive drugs and medications to improve cardiac function.…”