CARMIL2 Deficiency Presenting as Very Early Onset Inflammatory Bowel Disease

Magg T1, Shcherbina A2, Arslan D3, Desai MM4, Wall S5, Mitsialis V6,7, Conca R1, Unal E8,9, Karacabey N3, Mukhina A2, Rodina Y2, Taur PD4, Illig D1, Marquardt B1, Hollizeck S1, Jeske T1, Gothe F1, Schober T1, Rohlfs M1, Koletzko S1,10, Lurz E1, Muise AM11,12,13,10, Snapper SB5,6,7,10, Hauck F1, Klein C1,10, Kotlarz D1,10. Inflamm Bowel Dis. 2019 May 22. pii: izz103. doi: 10.1093/ibd/izz103. [Epub ahead of print]


Author information

1 Dr. von Hauner Children's Hospital, Department of Pediatrics, University Hospital, LMU Munich, Munich, Germany.

2 Institute of Hematology, Immunology and Cell Technologies, National Medical Research Center of Pediatric Hematology, Oncology and Immunology named after Dmitry Rogachev, Moscow, Russian Federation.

3 Division of Pediatric Gastroenterology, Department of Pediatrics, Faculty of Medicine, Erciyes University, Melikgazi, Kayseri, Turkey.

4 Bai Jerbai Wadia Children Hospital, Mumbai, Parel, India.

5 Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, USA.

6 Division of Gastroenterology, Brigham and Women's Hospital, Boston, MA, USA.

7 Department of Medicine, Harvard Medical School, Boston, MA, USA.

8 Department of Pediatrics, Division of Pediatric Hematology & Oncology & HSCT Unit, Erciyes University, Melikgazi, Kayseri, Turkey.

9 Molecular Biology and Genetic Department, Gevher Nesibe Genom and Stem Cell Institution, Genome and Stem Cell Center (GENKOK), Erciyes University, Melikgazi, Kayseri, Turkey.

10 VEO-IBD Consortium, University Hospital, LMU Munich, Germany.

11 SickKids Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.

12 Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics University of Toronto, Hospital for Sick Children, Toronto, Ontario, Canada.

13 Department of Biochemistry University of Toronto, Toronto, Ontario, Canada.


BACKGROUND: Children with very early onset inflammatory bowel diseases (VEO-IBD) often have a refractory and severe disease course. A significant number of described VEO-IBD-causing monogenic disorders can be attributed to defects in immune-related genes. The diagnosis of the underlying primary immunodeficiency (PID) often has critical implications for the treatment of patients with IBD-like phenotypes.

METHODS: To identify the molecular etiology in 5 patients from 3 unrelated kindred with IBD-like symptoms, we conducted whole exome sequencing. Immune workup confirmed an underlying PID.

RESULTS: Whole exome sequencing revealed 3 novel CARMIL2 loss-of-function mutations in our patients. Immunophenotyping of peripheral blood mononuclear cells showed reduction of regulatory and effector memory T cells and impaired B cell class switching. The T cell proliferation and activation assays confirmed defective responses to CD28 costimulation, consistent with CARMIL2 deficiency.

CONCLUSION: Our study highlights that human CARMIL2 deficiency can manifest with IBD-like symptoms. This example illustrates that early diagnosis of underlying PID is crucial for the treatment and prognosis of children with VEO-IBD.

© Copyright 2013-2024 GI Health Foundation. All rights reserved.
This site is maintained as an educational resource for US healthcare providers only. Use of this website is governed by the GIHF terms of use and privacy statement.