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 20 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.

Conclusion: 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.

Keywords: ABCC6 deficiency; ENPP1 deficiency; autosomal recessive hypophosphatemic rickets type 2; generalized arterial calcification of infancy; pseudoxanthoma elasticum.

Figure 1.. Clinical presentation of ENPP1 deficiency.

(A) Histopathology of the aorta of the first brother of Patient 6 (deceased at 49 days), showing pronounced thickening of the tunica intima (indicated by white line, both in affected aorta and in the insert depicting a normal aorta) with consequent luminal narrowing, as well as internal elastic lamina distorted by dystrophic calcification (black arrows). (B) Histopathology of the heart of the second brother of Patient 6 (deceased at 38 days), revealing deposition of calcium along the internal elastic lamina (disparate elastic fibers with severe degenerative changes separating the media from the intima), accompanied by fibrous thickening of the intima that results in luminal narrowing of the right coronary artery (hematoxylin and eosin). (C) Coronal computed tomography (CT) of Patient 6 at 4 weeks of life, showing calcification of the distal abdominal aorta and proximal bilateral iliac arteries (yellow arrows). (D) Axial CT scan of Patient 6 at 4 weeks of life showing calcification (yellow arrows) of the left main (LM), left anterior descending (LAD) and left circumflex (LCX) coronary arteries. (E) Three-dimensional CT reconstruction of Patient 10 at 5 years old revealing bilateral external iliac artery occlusion (yellow arrows) with prominent collaterals.

Figure 2.. Calcification of arteries, joints and organs in patients with GACI.

The total length of each bar represents the frequency of calcification in affected patients, while the hatched bars represent the percentage of patients that showed resolution of calcification at last examination.

Figure 3.. Rickets in ENPP1 deficiency.

(A) Three-dimensional CT reconstruction showing periarticular calcification of the shoulder of Patient 9 at 4 days of life. (B) Fusion of the C2-C3 and C4-C5 posterior vertebral bodies, articular processes, and laminae (Patient 11, 25.5 years). (C) Calcification of the posterior longitudinal ligament enthesis (Patient 16, 56.2 years). (D) Metaphyseal irregularities of the lateral distal femora as a result of untreated rickets (Patient 13, 6.6 years). (E) Serum phosphate decreased with age; dashed line represents lower limit of normal (Z-score −1.96). (F) Correlation of serum phosphate and intact FGF23 levels. (G) Kaplan-Meier curve showing the probability of remaining free of hypophosphatemic rickets in the sub-population of patients with GACI due to ENPP1 variants. (H) Neck skin in Patient 3 at 8.9 years showing classical findings of PXE. (I) Fundus photography in Patient 16 at 56 years of age, demonstrating known retinal complications of PXE, i.e., macular hemorrhage (arrows), angioid streaks (carets) and peau d’orange (oval). (J) Kaplan-Meier curve showing the probability of remaining free of hearing loss in the sub-population of patients with GACI due to ENPP1 variants.