ESPE Yearbook of Paediatric Endocrinology

Annual Review of Pathology, (2024). 19, 507-540. https://doi.org/10.1146/annurev-pathmechdis-051222-121126

Brief Summary: This retrospective natural history study analysed data from 84 individuals with ENPP1 deficiency in order to characterise the clinical presentation and progression of generalised arterial calcification of infancy (GACI) and autosomal recessive hypophosphataemic rickets type 2 (ARHR2). The study confirmed the high infant mortality rate associated with GACI, identified prenatal anomalies as common and demonstrated that survivors often develop musculoskeletal complications. This highlights the continuous phenotypic spectrum of the disease.

Commentary: ENPP1 deficiency is a rare genetic mineralization disorder characterized by a spectrum of age-related phenotypes, primarily GACI and ARHR2. Previous understanding of this condition was limited due to small studies and varied clinical presentations with short follow-up durations. This study provides the largest retrospective analysis to date, encompassing 84 individuals, thereby offering a more comprehensive understanding of the disease’s natural history and clinical evolution.

First, this study reported the onset and cumulative incidence of ENPP1 deficiency’s clinical complications, categorized into calcification, cardiovascular, musculoskeletal, and other organ involvement. The study confirmed that GACI and ARHR2 represent a phenotypic continuum rather than distinct diseases, with many GACI survivors later developing ARHR2. A significant majority (76%) of affected individuals presented in infancy with severe cardiovascular issues and respiratory distress, often requiring acute inpatient care, and noted a high infant mortality rate of 44% in GACI cases. Another finding is the high prevalence of prenatal ultrasound anomalies, such as polyhydramnios and hydrops fetalis, in GACI patients, suggesting the possibility of early diagnosis. For survivors, musculoskeletal complications, particularly rickets, were common, affecting an estimated 70% of individuals by age 10. This study also sheds light on the variable clinical presentation, even among siblings, and the challenges in diagnosis due to the overlap of symptoms with other conditions, such as FGF23-related hypophosphatemic rickets.