Two Brothers with Atypical UNC13D-Related Hemophagocytic Lymphohistiocytosis Characterized by Massive Lung and Brain Involvement.

Giuliana Giardino,Emilia Cirillo,Laura Papetti,Claudio Pignata,Massimiliano Valeriani,Roberta Romano,Carol Saunders,Maia De Luca,Caterina Cancrini,Paolo Palma

doi:10.3389/fimmu.2017.01892

Abstract

Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal hyperinflammatory condition. Variants in different genes have been associated with the familial forms of the syndrome (FHL), usually presenting within the first 2 years of life. Due to increasing awareness of the signs and symptoms of HLH and a better understanding of the genetic basis of the disease, FHL has been increasingly diagnosed in patients presenting beyond infancy. Here, we report on two brothers with atypical, late-onset HLH in which whole exome sequencing revealed a homozygous pathogenic UNC13D variant. In the first brother, the clinical phenotype was dominated by a massive lung involvement. In the second brother a progressive neurological deterioration was observed. In both cases, the clinical manifestations at symptom onset were misleading, making the diagnosis difficult to achieve. This report expands the spectrum of clinical presentations of FLH3. Moreover, it highlights the importance to warn clinicians to keep a high level of suspicion in patients presenting with fever, cytopenia, splenomegaly of unknown origin, and unresponsiveness to conventional treatment even beyond early childhood. Moreover, this report emphasizes that insidious neurologic symptoms may represent the initial or sole presenting sign of FHL, even in the absence of peripheral signs of activation.

Highlights

Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal hyperinflammatory condition characterized by prolonged and unexplained fever, unresponsiveness to conventional treatment, hepatosplenomegaly, cytopenia, hypertriglyceridemia, and hypofibrinogenemia [1, 2]
Encoding MUNC13-4, STX11 encoding SYNTAXIN11, and STXBP2 encoding MUNC18-2 are implicated in the trafficking and exocytosis of lytic granules, and mediate the release at the cell surface of perforin1 and other effector molecules implicated in cytotoxicity [4,5,6,7]
Gray et al reported on a case of late-onset FHL3 in which the clinical presentation was characterized by growth arrest, inflammatory arachnoiditis, and dysgammaglobulinemia, without any signs of HLH [10]

Summary

INTRODUCTION

Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal hyperinflammatory condition characterized by prolonged and unexplained fever, unresponsiveness to conventional treatment, hepatosplenomegaly, cytopenia, hypertriglyceridemia, and hypofibrinogenemia [1, 2]. We report on two brothers with atypical, late-onset HLH in which whole exome sequencing (WES) revealed a homozygous pathogenic UNC13D variant. In both cases, the clinical manifestations at symptom onset were misleading, making the diagnosis difficult to achieve. Immunological studies revealed normal IgG, IgA, and IgM levels and slightly increased CD3+ cells, mainly showing a memory phenotype, absent degranulation of the NK cells after the stimulus with K562 cells, normal perforin expression, suggesting a diagnosis of HLH (Table 1). WES revealed a homozygous pathogenic UNC13D variant, 1847A>G (p.Glu616Gly) This variant has been previously reported in affected individuals, and functionally demonstrated to result in deranged splicing of the gene [12, 13].

DISCUSSION

Findings

CONCLUDING REMARKS

ETHICS STATEMENT