Whole-exome sequencing in a subject with fluctuating neuropsychiatric symptoms, immunoglobulin G1 deficiency, and subsequent development of Crohn’s disease: a case report

Abstract

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. Case summary 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. Conclusion 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.

Identification of a Novel NLRP12 Frameshift Mutation (Val730Glyfs∗41) by Whole-Exome Sequencing in Patients with Crohn’s Disease

“…Although the exact mechanistic links between these two genes and his clinical phenotypes could not be determined, the heterozygous frameshift mutation (c.1113_ 1116delGGAA) in the NLRP12 gene may partially account for his CD-like clinical manifestations. More recently, Jyonouchi and Geng [37] also presented the case of a female patient with an NLRP12 mutation (C.1054C>T) in addition to a variant of interferon regulatory factor 2 binding protein 2 (IRF2BP2). She was initially diagnosed with pediatric acute-onset neuropsychiatric syndrome…”

Pediatric Acute-Onset Neuropsychiatric Syndrome: Current Perspectives

“…For example, a child diagnosed with PANS-like symptoms and Crohn’s disease, who was found to have a rare variant in the inflammasome related NLRP12 gene, was treated successfully (based on this finding) with Anakinra, an IL-1B receptor blocker, which targets one of the cytokines activated as a result of inflammasome activation. 27 …”

“…For example, a child diagnosed with PANS-like symptoms and Crohn's disease, who was found to have a rare variant in the inflammasome related NLRP12 gene, was treated successfully (based on this finding) with Anakinra, an IL-1B receptor blocker, which targets one of the cytokines activated as a result of inflammasome activation. 27 Our review is meant not only to help clinicians consider the possibility of an autoimmune cause for possible organic forms of PANS, but also to propose new criteria supporting a decision on offering further investigation or appropriate immunotherapies. Finding new criteria for probable or definite diagnosis of autoimmune OCD or PANS necessarily relies on serious paraclinical investigations consistent with inflammation of the CNS, which are yet to be fully clarified.…”

“…Five further readings have been added to implement discussion section (Figure 1). [27][28][29][30][31]…”