Recurrent Attacks of Abdominal Pain and Fever With Familial Segmentation Arrest of Granulocytes

Abstract

In a family four sisters have suffered, the oldest two for nearly 20 yr, from recurring attacks of abdominal pain and fever of unknown etiology. Clinical similarity to familial Mediterranean fever is striking. However, they all have a segmentation arrest of granulocytes, which resembles the Pelger-Huet anomaly. It seems that the association is more than a mere coincidence.

Gain-of-function CEBPE mutation causes noncanonical autoinflammatory inflammasomopathy

“…Patients' neutrophils presented both primary and secondary granules, and no difference was observed in comparison with healthy control subjects (see Fig E8, A, in this article's Online Repository at www.jacionline.org). However, as seen earlier, 16 20% of patients' neutrophils were hyposegmented (see Fig E8, B). Eosinophils and basophils also showed normal granules compared with those of healthy control subjects.…”

“…In the 1970s, affected members of the index family were thought to have atypical Pelger-Hu€ et anomaly because they presented with neutrophil hyposegmentation, aberrant neutrophil responsiveness, and impaired chemotaxis. [16][17][18] Patients experienced recurrent attacks of abdominal pain, aseptic fever, and systemic inflammation lasting 4 to 5 days. These were accompanied by an acute-phase response and occasionally by nailbed, tongue, submandibular and gluteal abscesses; intra-abdominal granulomas; pyoderma gangrenosum; and buccal ulcerations.…”

“…The novel homozygous CEBPE 14:23586886 C>T mutation cosegregated perfectly with the disease phenotype (Fig 1, A, and see Fig E1 in this article's Online Repository at www.jacionline.org). [16][17][18] Arg219His was predicted to be detrimental and not listed in major public or in-house databases. It resided in the highly conserved basic zipper region's carboxyl terminal DNA-binding domain shared by all 4 C/EBPε isoforms (Fig 1, B and C).…”

“…14 Early studies in Cebpe knockout mice showed Cebpe to be integral for maintenance of constitutive levels of several cytokines, including IFN-g. 15 We report an autosomal recessive GOF PID, C/EBPε-associated autoinflammation and immune impairment of neutrophils (CAIN), in a family with a genetically uncharacterized autoinflammatory syndrome. [16][17][18] According to our results, C/EBPε acts as a regulator of both the inflammasome and interferome. Homozygous missense mutations in CEBPE (14:23586886 C->T;p.Arg219His) resulted in markedly decreased C/EBPε association with transcriptional repressors and increased occupancy on chromatin, leading to dysregulated C/EBPε-mediated transcription of interleukin and interferon response genes in neutrophils.…”

Impaired heme synthesis in a family with Pelger‐Huët anomaly, recurrent abdominal pain attacks and impaired neutrophil motility in vitro

“…Patients. The patients, their family history and the clinical and laboratory findings have been described earlier (4). In short, the proposita was a young female suffering from recurrent attacts of abdominal pain and fever since early childhood.…”