Genetic and Clinical Diversity in Generalized Arterial Calcification of Infancy: Insights from Two Families

Introduction

Generalized arterial calcification of infancy (GACI) is a rare genetic disorder characterized by arterial calcifications, stenoses, and hypertension, often leading to intrauterine or early infancy death.

Method

We report two recently diagnosed families in Normandy, each presenting with distinct clinical features linked to different genetic mutations.

Results

Family 1: The index patient presented at 10 days of life with heart failure, severe hypertension, myocardial infarction, and vascular calcifications, leading to a diagnosis of GACI type 1 (ENPP1, two pathogenic mutations). Treatment with bisphosphonate infusions over 16 months, combined with antihypertensive therapy, resulted in clinical improvement and complete regression of tissue calcifications (Figure 1). This diagnosis also led to the identification of an older sibling with a milder phenotype, characterized by periarticular and aortic valve calcifications. Family 2: The index patient was diagnosed at 2 months of age, before the onset of clinical manifestations, during a routine echocardiographic evaluation for the follow-up of in utero left ventricular hypertrophy (LVH) in the context of maternal diabetes. Echocardiography revealed LV dysfunction, LV dilation and hypertrophy, a mildly reduced ejection fraction (50%), and repolarization abnormalities on ECG. The patient later developed vascular calcifications, leading to a diagnosis of GACI type 2 (ABCC6, pathogenic mutation). His condition improved with cardiovascular treatment, and compassionate use of specific enzyme replacement therapy was considered. These cases illustrate the phenotypic variability of GACI and highlight key considerations: 1- the critical importance of early neonatal recognition for timely diagnosis; 2- Contrasting clinical presentations of ENPP1- and ABCC6-related GACI, with ENPP1 mutations generally associated with more severe disease; 3- Current therapeutic strategies, including non-specific cardiac treatments, bisphosphonate infusion, and emerging enzyme replacement therapy (ERT), which remains under evaluation.

Conclusion

These cases emphasize the importance of early diagnosis, genetic characterization, and evolving treatment strategies in GACI. Further research is needed to refine genotype-phenotype correlations and assess the long-term benefits of ERT.