Genotype-phenotype study of familial haemophagocytic lymphohistiocytosis type 3

Abstract

Background-Mutations of UNC13D are causative for familial haemophagocytic lymphohistiocytosis type 3 (FHL3; OMIM 608898).

Distinct mutations in STXBP2 are associated with variable clinical presentations in patients with familial hemophagocytic lymphohistiocytosis type 5 (FHL5)

“…Interestingly, patients with FHL2 and patients with FHL3 with missense mutations have a significantly later onset of disease than patients with nonsense mutations. [34][35][36] As has been described for patients with FHL5 before, our patients also displayed a large spectrum of features that are not part of the typical HLH clinical picture. 26,27 Previous studies have reported an ubiquitous Munc18-2 RNA expression not restricted to hematopoietic cells, suggesting a role of the protein in vesicle transport in many mammalian tissues.…”

Familial hemophagocytic lymphohistiocytosis type 3 (FHL3) caused by deep intronic mutation and inversion in UNC13D

“…By comparison, the age at diagnosis is similar to patients with 2 disruptive mutations in UNC13D (3 months). 39 Thus, although a slight improvement in degranulation and cytotoxicity was seen in the patients carrying the inversion, no difference was seen in terms of age at onset in this group of patients compared with other FHL3 patients.…”

A prospective evaluation of degranulation assays in the rapid diagnosis of familial hemophagocytic syndromes

“…45 In both cohorts, we observed previously that the nature of the mutation, disruptive or missense, could explain a certain heterogeneity of residual degranulation, as described for FHL3 patients. 46 In contrast, resting NK-cell degranulation was above 5% in 29 of 30 patients (97%) with FHL2 or with 1 of the 2 XLP variants and in 58 of 59 patients (98%) with secondary HLH. Therefore, as suggested previously in smaller studies, 29,30,37,42 the assay clearly discriminated between patients with genetic disorders predisposing to HLH that are associated with impaired degranulation and those that are not.…”