Autoinflammation With Infantile Enterocolitis

A number sign (#) is used with this entry because autoinflammation with infantile enterocolitis (AIFEC) is caused by heterozygous mutation in the NLRC4 gene (606831) on chromosome 2p22.

Description

Autoinflammation with infantile enterocolitis is an autosomal dominant disorder characterized by onset of recurrent flares of autoinflammation in early infancy. Affected individuals tend to have poor overall growth and gastrointestinal symptoms in infancy associated with laboratory evidence of activated inflammation. This initial presentation is followed by recurrent febrile episodes with splenomegaly and sometimes hematologic disturbances, arthralgias, or myalgias. The disorder results from overactivation of an arm of the immune response system (Romberg et al., 2014; Canna et al., 2014).

Clinical Features

Romberg et al. (2014) reported a father and his 2 sons with an autoinflammatory syndrome characterized by neonatal-onset enterocolitis, periodic fever, and fatal or near-fatal episodes of autoinflammation. The proband presented at 1 week of age with secretory diarrhea, fever, and laboratory evidence of systemic inflammation, including increased ferritin and increased C-reactive protein. He developed a coagulopathy with pancytopenia and died at age 23 days from diffuse alveolar hemorrhage. Postmortem examination showed splenomegaly, bowel autolysis, villous blunting with inflammatory cells, and activated macrophages in the central nervous system. The patient's father had colitis as an infant that resolved by 1 year of age, as well as recurrent periodic fevers, erythematous plaques, and seronegative psoriatic arthritis. At age 43 years, he had an acute inflammatory episode complicated by disseminated intravascular coagulation with increased IL18 (600953), ferritin, and C-reactive protein. Bone marrow biopsy showed erythro- and myelophagocytosis. Both patients also had NK cell lymphopenia. The proband's 5-year-old paternal half brother had similar symptoms.

Canna et al. (2014) reported a 7-year-old girl of European descent with a recurrent autoinflammatory syndrome. She presented at age 2 months with failure to thrive associated with anemia and increased serum ferritin. Around age 6 months, she developed vomiting and loose stools; upper endoscopy showed a nonspecific inflammatory infiltrate in the lamina propria and mild villous blunting. At 2 years of age, she developed recurrent episodic flares manifest as fever, malaise, and splenomegaly, and precipitated by viral infections, stress, or fatigue.

Clinical Management

Canna et al. (2014) found that treatment of an AIFEC patient with an IL1R (147810) antagonist reduced flare frequency, C-reactive protein levels, splenomegaly, and prednisone dose.

Inheritance

The transmission pattern of AIFEC in the family reported by Romberg et al. (2014) was consistent with autosomal dominant inheritance.

Molecular Genetics

In a father and his 2 sons with autoinflammation with infantile enterocolitis, Romberg et al. (2014) identified a heterozygous missense mutation in the NLRC4 gene (V341A; 606831.0001). The mutation, which was identified by exome sequencing, occurred de novo in the father. Simultaneously and independently, Canna et al. (2014) identified a de novo heterozygous missense mutation in the NLRC4 gene (T337S; 606831.0002) in a girl with AIFEC. Both Romberg et al. (2014) and Canna et al. (2014) demonstrated that patient-derived monocytes and macrophages had increased and constitutive inflammasome activation and increased secretion of IL1B (147720) and IL18 (600953), as well as increased cell death (pyroptosis), compared to controls. Cellular transfection of the mutations also resulted in increased secretion of IL1B and IL18, indicating that both mutations caused a gain of function with constitutive activation of CASP1 (147678).