Novel NLRC4 Mutation Causes a Syndrome of Perinatal Autoinflammation With Hemophagocytic Lymphohistiocytosis, Hepatosplenomegaly, Fetal Thrombotic Vasculopathy, and Congenital Anemia and Ascites

Jiancong Liang, Danielle N. Alfano, James E. Squires, Melissa M. Riley, W. Tony Parks, Julia Kofler, Areeg El-Gharbawy, Suneeta Madan-Kheterpal, Roxanne Acquaro, Jennifer Picarsic*

*Corresponding author for this work

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

Autoinflammatory diseases are caused by pathologic activation of the innate immune system. Primary hemophagocytic lymphohistiocytosis (HLH) is an aggressive syndrome of excessive immune activation caused by monogenic mutations resulting in cytotoxic cell defects and subsequent failure to eliminate activated macrophages. Secondary HLH is often diagnosed in cases without a known Mendelian inheritance. However, some cases of “secondary” HLH have been shown to harbor mutations with partial dysfunction of the cytotoxic system. Recently, macrophage intrinsic abnormalities caused by NLRC4 inflammasome mutations have been linked to autoinflammation and recurrent macrophage activation syndromes resembling a primary HLH. We report a case of a former 28-week preterm infant with congenital anemia, ascites, and a heavy edematous placenta with fetal thrombotic vasculopathy, who developed hepatosplenomegaly and unexplained systemic inflammation with laboratory features of HLH in the early postnatal course and died at 2 months of age. Postmortem examination confirmed the hepatosplenomegaly with marked sinusoidal hemophagocytosis, along with striking hemophagocytosis in the bone marrow and lymph nodes. There was extensive acute and chronic ischemic bowel disease with matted bowel loops, fibrous adhesions, and patchy necrotizing enterocolitis features. Whole exome sequencing analysis demonstrated a novel mosaic heterozygous NLRC4 512 C> T (p.Ser171Phe) de novo mutation predicated to cause a dominant, gain-of-function mutation resulting in a constitutively active protein. The assembly of NLRC4-containing inflammasomes via an induced self-propagation mechanism likely enables a perpetuating process of systemic macrophage activation, presumed to be initiated in utero in this patient.

Original languageEnglish (US)
Pages (from-to)498-505
Number of pages8
JournalPediatric and Developmental Pathology
Volume20
Issue number6
DOIs
StatePublished - Dec 1 2017

Keywords

  • NLRC4
  • autoinflammation
  • congenital anemia
  • congenital ascites
  • fetal thrombotic vasculopathy
  • hemophagocytic lymphohistiocytosis
  • hepatosplenomegaly
  • inflammasome
  • macrophage activation
  • prematurity

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Pathology and Forensic Medicine

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