Inborn errors of immunity (IEI) are a heterogeneous group of disorders characterized by increased risk of infections, autoimmunity, autoinflammatory diseases, malignancy and allergy. Next-generation sequencing has revolutionized the identification of genetic background of these patients and assists in diagnosis and treatment. In this study, we identified a probable unique monogenic cause of IEI, and evaluated the immunological methods and pathogenic detections.
A family with a member with a clinical diagnosis of IEI was screened by whole genomic sequencing (WGS). Demographic data, clinical manifestations, medical history, physical examination, laboratory findings and imaging features of the patient were extracted from medical records. Comprehensive immune monitoring methods include a complete blood count with differential, serum levels of cytokines and autoantibodies, T-cell and B-cell subsets analysis and measurement of serum immunoglobulins. In addition, metagenomic sequencing (mNGS) of blood, cerebrospinal fluid and biopsy from small intestine were used to detect potential pathogens.
The patient manifested with recurrent infections and autoimmune disorders, who was eventually diagnosed with IEI. Repetitive mNGS tests of blood, cerebrospinal fluid and biopsy from small intestine didn\'t detect pathogenic microorganism. Immunological tests showed a slightly decreased level of IgG than normal, elevated levels of tumor necrosis factor and interleukin-6. Lymphocyte flow cytometry showed elevated total B cells and natural killer cells, decreased total T cells and B-cell plasmablasts. WGS of the patient identified a novel heterozygous mutation in IRF2BP2 (c.439_450dup p. Thr147_Pro150dup), which was also confirmed in his father. The mutation was classified as variant of uncertain significance (VUS) according to the American College of Medical Genetics and Genomics guidelines.
We identified a novel IRF2BP2 mutation in a family with a member diagnosed with IEI. Immune monitoring and WGS as auxiliary tests are helpful in identifying genetic defects and assisting diagnosis in patients with clinically highly suspected immune abnormalities and deficiencies in inflammation regulation. In addition, mNGS techniques allow a more comprehensive assessment of the pathogenic characteristics of these patients. This report further validates the association of IRF2BP2 deficiency and IEI, and expands IEI phenotypes.

BACKGROUND: Mutations or polymorphisms of genes that are associated with inflammasome functions are known to predispose individuals to Crohn\'s disease and likely affect clinical presentations and responses to therapeutic agents in patients with Crohn\'s disease. The presence of additional gene mutations/polymorphisms that can modify immune responses may further affect clinical features, making diagnosis and management of Crohn\'s disease even more challenging. Whole-exome sequencing is expected to be instrumental in understanding atypical presentations of Crohn\'s disease and the selection of therapeutic measures, especially when multiple gene mutations/polymorphisms affect patients with Crohn\'s disease. We report the case of a non-Hispanic Caucasian female patient with Crohn\'s disease who was initially diagnosed with pediatric acute-onset neuropsychiatric syndrome with fluctuating anxiety symptoms at 9 years of age. This patient was initially managed with pulse oral corticosteroid treatment and then intravenous immunoglobulin due to her immunoglobulin G1 deficiency. At 15 years of age, she was diagnosed with Crohn\'s disease, following onset of acute abdomen. Treatment with oral corticosteroid and then tumor necrosis factor-α blockers (adalimumab and infliximab) led to remission of Crohn\'s disease. However, she continued to suffer from chronic abdominal pain, persistent headache, general fatigue, and joint ache involving multiple joints. Extensive gastrointestinal workup was unrevealing, but whole-exome sequencing identified two autosomal dominant gene variants: NLRP12 (loss of function) and IRF2BP2 (gain of function). Based on whole-exome sequencing findings, infliximab was discontinued and anakinra, an interleukin-1β blocker, was started, rendering marked improvement of her clinical symptoms. However, Crohn\'s disease lesions recurred following Yersinia enterocolitis. The patient was successfully treated with a blocker of interleukin-12p40 (ustekinumab), and anakinra was discontinued following remission of her Crohn\'s disease lesions.
CONCLUSIONS: Loss-of-function mutation of NRLRP12 gene augments production of interleukin-1β and tumor necrosis factor-α, while gain-of-function mutation of IRF2BP2 impairs cytokine production and B cell differentiation. We propose that the presence of these two autosomal dominant variants caused an atypical clinical presentation of Crohn\'s disease.