Magg T¹, Shcherbina A², Arslan D³, Desai MM⁴, Wall S⁵, Mitsialis V^6,7, Conca R¹, Unal E^8,9, Karacabey N³, Mukhina A², Rodina Y², Taur PD⁴, Illig D¹, Marquardt B¹, Hollizeck S¹, Jeske T¹, Gothe F¹, Schober T¹, Rohlfs M¹, Koletzko S^1,10, Lurz E¹, Muise AM^11,12,13,10, Snapper SB^5,6,7,10, Hauck F¹, Klein C^1,10, Kotlarz D^1,10. 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.

Abstract

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.