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

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.

Lentiviral Gene Therapy for Familial Hemophagocytic Lymphohistiocytosis Type 3, Caused by UNC13D Genetic Defects

“…Munc13-4 has been implicated in the exocytosis of lytic granules from cytotoxic cells, 8,33 tertiary, and mucincontaining granules from neutrophils, 34,35 dense granules from platelets, 36 and secretory granules from mast cells during regulated exocytosis. 37 Although much of HLH research has focused on pathology arising from impairment of CD8 T cell and natural killer cell cytotoxic function, 8 it is worth noting that FHL3 patients also suffer from susceptibility to fungal infection, 38 neurological symptoms, 39 exacerbated response to lung infection, 26,39 and macrophage activation syndrome, 26 which could be related to impaired degranulation from other cell types. Although Munc13-4 is expressed in other tissues, [40][41][42] the fact that HSCT results in cure suggests that its most critical role is in cells derived from the hematopoietic lineage, and therefore its role in nonhematopoietic tissues might be limited or complemented by other proteins in degranulation pathways.…”

FHLdb: A Comprehensive Database on the Molecular Basis of Familial Hemophagocytic Lymphohistiocytosis

“…Although a distinctive constellation of clinical and laboratory features has been described for HLH, diagnosis remains challenging as patients may have very different clinical manifestations associated with a variety of triggers (9). Atypical presentations involving mainly CNS or chronic pathologic inflammation manifestations are examples of such complexity (10)(11)(12).…”

“…To date, 4 genes (PRF1, UNC13D, STXBP2, and STX11) and 1 genomic region (9q21. [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22] have been identified as candidate causes of FHL2 (13), FHL3 (14), FHL4 (15), FHL5 (16), and FHL1 (17), respectively (18). Other monogenic diseases that produce HLH are Chédiak-Higashi syndrome (LYST), Griscelli syndrome type 2 (RAB27A), Hermansky-Pudlak syndrome (AP3B1), Xlinked lymphoproliferative syndrome (XLP)-1 (SH2D1A), and XLP-2 (XIAP) (19).…”

Case report: EBV-related eye orbits and sinuses lymphohistiocytic infiltration responsive to rituximab in a patient with X lymphoproliferative syndrome type 1

“…HLH may be triggered by viral infections, especially due to EBV or CMV ( 1 , 6 ). Infiltration of activated lymphocyte and histocytes in HLH is usually detected within liver, spleen, lymph nodes, bone marrow, and central nervous system, but it can virtually affect any organ ( 7 , 8 ). Lymphohistiocytic infiltration may be clinically indistinguishable from lymphomas, thus creating problems in the diagnosis and definition of the therapeutic approach especially considering that lymphoma, particularly abdominal B-cell non-Hodgkin, develops in a third of patients with XLP1.…”