title: Novel NLRC4 Mutation Causes a Syndrome of Perinatal Autoinflammation With Hemophagocytic Lymphohistiocytosis, Hepatosplenomegaly, Fetal Thrombotic Vasculopathy, and Congenital Anemia and Ascites.
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.
authors.affiliation: 1 Department of Pathology, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pennsylvania.|2 Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Tennessee.
authors.forename: Jiancong
authors.initials: J
authors.lastname: Liang
authors.affiliation: 3 Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, Pennsylvania.
authors.forename: Danielle N
authors.initials: DN
authors.lastname: Alfano
authors.affiliation: 3 Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, Pennsylvania.
authors.forename: James E
authors.initials: JE
authors.lastname: Squires
authors.affiliation: 3 Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, Pennsylvania.
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Riley
authors.affiliation: 4 Department of Pathology, Dartmouth-Hitchcock Medical Center, New Hampshire.
authors.forename: W Tony
authors.initials: WT
authors.lastname: Parks
authors.affiliation: 5 University of Pittsburgh School of Medicine, Pennsylvania.
authors.forename: Julia
authors.initials: J
authors.lastname: Kofler
authors.affiliation: 6 Department of Pediatrics-Medical Genetics, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pennsylvania.
authors.forename: Areeg
authors.initials: A
authors.lastname: El-Gharbawy
authors.affiliation: 6 Department of Pediatrics-Medical Genetics, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pennsylvania.
authors.forename: Suneeta
authors.initials: S
authors.lastname: Madan-Kheterpal
authors.affiliation: 6 Department of Pediatrics-Medical Genetics, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pennsylvania.
authors.forename: Roxanne
authors.initials: R
authors.lastname: Acquaro
authors.affiliation: 1 Department of Pathology, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pennsylvania.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Picarsic
mesh_terms: D000740:Anemia / Q000151:congenital / Q000175:diagnosis / Q000235:genetics; D001201:Ascites / Q000151:congenital / Q000175:diagnosis / Q000235:genetics; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics*; D002135:Calcium-Binding Proteins / Q000235:genetics*; D017809:Fatal Outcome; D005260:Female; D000073659:Gain of Function Mutation; D005819:Genetic Markers; D006529:Hepatomegaly / Q000151:congenital / Q000175:diagnosis / Q000235:genetics*; D056660:Hereditary Autoinflammatory Diseases / Q000175:diagnosis / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D007223:Infant; D051359:Lymphohistiocytosis, Hemophagocytic / Q000151:congenital / Q000175:diagnosis / Q000235:genetics*; D013163:Splenomegaly / Q000151:congenital / Q000175:diagnosis / Q000235:genetics*; D013577:Syndrome; D013927:Thrombosis / Q000151:congenital / Q000175:diagnosis / Q000235:genetics
chemical_list: D053468:CARD Signaling Adaptor Proteins; D002135:Calcium-Binding Proteins; D005819:Genetic Markers; C435692:NLRC4 protein, human
keywords: NLRC4; autoinflammation; congenital anemia; congenital ascites; fetal thrombotic vasculopathy; hemophagocytic lymphohistiocytosis; hepatosplenomegaly; inflammasome; macrophage activation; prematurity