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

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.

A Newborn With Familial Hemophagocytic Lymphohistiocytosis Complicated With Transfusion Associated Graft Versus Host Disease.

Hemophagocytic lymphohistiocytosis (HLH) is characterized by activation of cytotoxic T and natural killer (NK) cells, and macrophages related to a spectrum of hyperinflammatory disorders. The clinical findings mainly include high fever, cytopenia, splenomegaly, phagocytosis, and proliferation of histiocytes in lymphoreticular tissue. To the best of our knowledge, transfusion-associated graft versus host disease (TA-GVHD) in a 13-day old male newborn with HLH is being reported first time in the literature. The aim of this report was to emphasize the importance of blood products irradiation in the prevention of the development of graft versus host disease especially among high-risk subjects such as newborns with HLH.

Congenital hemophagocytic lymphohistiocytosis presenting as thrombocytopenia in a newborn.

Hemophagocytic lymphohistiocytosis (HLH) is a disease caused by dysregulation and hyperactivation of the immune system, and can be familial or acquired. HLH presenting in infancy can be rapidly fatal if not promptly recognized and treated. Congenital HLH can be caused by various genetic mutations or part of immunodeficiency syndromes. We present an infant with Griscelli syndrome and familial HLH with atypical genetic mutations, presenting as thrombocytopenia on the first day of life, cured with chemotherapy and unrelated cord blood transplant.

Congenital hemophagocytic lymphohistiocytosis in a preterm infant: cytokine profile and a review of the disease.

A preterm infant with very low birth weight was born with fetal onset familial hemophagocytic lymphohistiocytosis. Known gene abnormalities responsible for the disease were not identified in the patient. The infant died at 13 months of age owing to complications from cord blood stem cell transplantation. We found selectively elevated expression of interleukin-6 and chemokines in the cord blood of the patient. We also reviewed 7 other preterm cases of congenital hemophagocytic lymphohistiocytosis to highlight the significance of this condition, as it can cause ascites and hepatosplenomegaly in utero and be mistaken for congenital infection in the fetus.

Fulminant neonatal liver failure in siblings: probable congenital hemophagocytic lymphohistiocytosis.

Familial hemophagocytic lymphohistiocytosis (HLH) is an autosomal recessive disorder of immune regulation characterized by fever, splenomegaly, cytopenia, hypertriglyceridemia, hypofibrinogenemia, and hyperferritinemia. Although presentation usually occurs during the first 2 years of life, congenital presentation is rare. We report siblings with a presumptive diagnosis of familial HLH who presented with hydrops fetalis and severe hepatic involvement ultimately resulting in their deaths. This report emphasizes the difficulty of confirming the diagnosis of HLH. However, establishing the diagnosis has important implications for genetic counseling and family planning. HLH should be considered in the setting of perinatal liver failure. The immunologic basis of the disease is incompletely understood but testing for natural killer cell function, and perforin defects may be helpful in establishing a diagnosis. HLH can be treated with chemotherapy, immunotherapy, and stem cell transplantation.