Case reports

Vol. 117: Issue 6 - December 2025

Marked hepatic fibrosis with progression towards cirrhosis in generalized arterial calcification of infancy: an unreported association observed in a case carryng a novel ENPP1 variant

Authors

Anna Maria Buccoliero , Giorgia Mancano , Maria Luce Cioni , Caterina Panzuto , Rosangela Artuso , Viviana Palazzo , Giovanni Battista Calabri , Guglielmo Capponi , Abramo Ponticelli , Chiara Caporalini , Federico Bertini , Ludovico D'Incerti , Elisa Severi , Angela Peron , Marco Moroni

DOI: 10.32074/1591-951X-1624
Publication Date: 2026-02-06

Abstract

Generalized arterial calcification of infancy (GACI) is a rare autosomal recessive disorder characterized by dysregulated calcium-phosphate metabolism, leading to mineral deposition within the internal elastic lamina of medium- and large-sized arteries. This results in arterial wall thickening and luminal narrowing due to intimal hyperplasia, causing significant vascular disruption. Approximately 70% of cases (GACI type 1) are caused by biallelic loss-of-function mutations in the ENPP1 gene, with nearly 40 pathogenic variants reported. We report a case of an infant diagnosed with GACI type 1 who died at 7 weeks of age. The patient was delivered via cesarean section at 36 weeks of gestation after a pregnancy complicated by polyhydramnios. The parents were second-degree cousins, with a history of two neonatal deaths of unknown etiology and one miscarriage. Autopsy revealed diffuse arterial calcification with prominent involvement of the coronary arteries. Notably, the liver showed fibrosis progressing to cirrhosis. Genetic analysis through trio exome sequencing identified a novel homozygous nonsense variant in ENPP1 (c.553C > T; p.Gln185Ter), inherited from both parents. This stop-gain variant is predicted to produce a severely truncated, non-functional or absent protein. This case is notable for two key aspects: a previously unreported association between GACI and progressive hepatic fibrosis evolving into cirrhosis, and the identification of a novel pathogenic ENPP1 variant not previously described in the literature.

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Authors

Anna Maria Buccoliero - Pathology Unit, Meyer Children’s Hospital IRCCS, Florence, Italy

Giorgia Mancano - Division of Medical Genetics, Meyer Children's Hospital IRCCS, Florence, Italy.

Maria Luce Cioni - Neonatal Intensive Care Unit, Interdisciplinary Specialistic Department, Intensive Activity and Emergency Area, Meyer Children's Hospital IRCCS, Florence, Italy.

Caterina Panzuto - Neonatal Intensive Care Unit, Interdisciplinary Specialistic Department, Intensive Activity and Emergency Area, Meyer Children's Hospital IRCCS, Florence, Italy.

Rosangela Artuso - Division of Medical Genetics, Meyer Children's Hospital IRCCS, Florence, Italy.

Viviana Palazzo - Division of Medical Genetics, Meyer Children's Hospital IRCCS, Florence, Italy

Giovanni Battista Calabri - Cardiology Unit, Meyer Children's Hospital IRCCS, Firenze, Italy

Guglielmo Capponi - Department of Pediatric Cardiology and Congenital Heart Disease, National Research Council-Tuscany Region G. Monasterio Foundation (FTGM), Massa, Pisa, Italy

Abramo Ponticelli - Pathology Unit, Meyer Children's Hospital IRCCS, Florence Italy

Chiara Caporalini - Pathology Unit, Meyer Children’s Hospital IRCCS, Florence, Italy

Federico Bertini - Radiology, Meyer Children’s Hospital IRCCS, Florence, Italy.

Ludovico D'Incerti - Department of Neuroradiology, Meyer Children’s Hospital IRCCS, Florence, Italy

Elisa Severi - Department of Pediatric abdomninal, thoracic and genitourinary surgery, Meyer IRCCS, Florence, Italy

Angela Peron - Division of Medical Genetics, Meyer Children's Hospital IRCCS, Florence, Italy

Marco Moroni - Neonatal Intensive Care Unit, Interdisciplinary Specialistic Department, Intensive Activity and Emergency Area, Meyer Children's Hospital IRCCS, Florence, Italy.

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Copyright

Copyright (c) 2026 Società Italiana di Anatomia Patologica e Citopatologia Diagnostica, Divisione Italiana della International Academy of Pathology

How to Cite
Buccoliero, A. M., Mancano, G., Cioni, M. L., Panzuto, C., Artuso, R., Palazzo, V., Calabri, G. B., Capponi, G., Ponticelli, A., Caporalini, C., Bertini, F., D’Incerti, L., Severi, E., Peron, A., & Moroni, M. (2026). Marked hepatic fibrosis with progression towards cirrhosis in generalized arterial calcification of infancy: an unreported association observed in a case carryng a novel ENPP1 variant. Pathologica - Journal of the Italian Society of Anatomic Pathology and Diagnostic Cytopathology, 117(6). https://doi.org/10.32074/1591-951X-1624
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