Phenotypic characterization of ENPP1 deficiency: generalized arterial calcification of infancy and autosomal recessive hypophosphatemic rickets type 2

Abstract

Generalized arterial calcification of infancy (GACI) and autosomal recessive hypophosphatemic rickets type 2 (ARHR2) are age-related phenotypes of the rare genetic mineralization disorder, ENPP1 Deficiency, which evolve on a phenotypic continuum. To date, our understanding of the clinical spectrum of ENPP1 Deficiency is based on small studies or case reports, across which there is significant variability in clinical presentation, and limited duration of follow-up. From a previously published large retrospective natural history study, we performed a subgroup analysis to elucidate the most prevalent signs and symptoms of ENPP1 Deficiency diagnosed as GACI or ARHR2, to illustrate the onset and incidence of these complications over the lifetime, and to characterize the associated medical burden of disease. Of the 84 individuals with ENPP1 Deficiency analyzed, 51 had a recorded diagnosis of GACI, 11 were diagnosed with ARHR2, and 22 were diagnosed with both. We confirmed that those diagnosed with GACI presented predominantly with early-onset arterial calcification, respiratory distress, heart failure, and hypertension, necessitating acute inpatient care and leading to high (44%) infant mortality. Notably, we found that the majority (60.3%) of those with a history of GACI had prenatal ultrasound anomalies, including effusions, polyhydramnios, and hydrops fetalis. We estimated that 70% of individuals with ENPP1 Deficiency who survive to age 10 will have developed musculoskeletal complications, primarily rickets and/or osteomalacia. The clinical picture of ARHR2 in this study extended beyond skeletal deformities to include hearing impairment, joint involvement, and ongoing risk of cardiovascular problems. This study sheds light on the signs and symptoms of ENPP1 Deficiency in the real world, with implications for life-long patient monitoring.

Keywords: diseases and disorders of/related to bone; disorders of calcium/phosphate metabolism; epidemiology; genetics; osteomalacia and rickets.

Graphical Abstract

Figure 1

(A) Cumulative incidence of ectopic calcification over the first 20 yr of life; (B) cumulative incidence of cardiovascular, musculoskeletal, and other organ manifestations over the first 20 yr of life.

Figure 2

(A) Pharmacological treatments received by diagnosis; (B) proportion of the total population treated for hypertension who received 1, 2, or 3 or more antihypertensive medications, n = 41. Antihypertensive medications included angiotensin-converting enzyme (ACE) inhibitors, beta blockers, calcium channel blockers, thiazide diuretics, vasodilators, adrenergic receptor blockers, angiotensin receptor blockers, renin inhibitors, and mineralocorticoid receptor antagonist. Heart failure medications included diuretics, ACE inhibitors, beta blockers, aspirin, calcium channel blockers, digoxin, hydralazine, mineralocorticoid receptor antagonist, and nitrate.

Figure 3

Timing of manifestations (presentation, age at last follow-up or death) in individuals with an ARHR2-only diagnosis. Where no date of event was provided, the age at last follow-up was used to mark the presence of the manifestation. Abbreviation: ARHR2, autosomal recessive hypophosphatemic rickets type 2.