Genetic subtypes of familial hemophagocytic lymphohistiocytosis: correlations with clinical features and cytotoxic T lymphocyte/natural killer cell functions

Abstract

Mutations of the perforin (PRF1) and MUNC13-4 genes distinguish 2 forms of familial hemophagocytic lymphohistiocytosis (FHL2 and FHL3, respectively)

Atypical familial hemophagocytic lymphohistiocytosis due to mutations in UNC13D and STXBP2 overlaps with primary immunodeficiency diseases

“…Late onset of HLH has been described in patients with perforin, [17][18][19][20][22][23][24][25]36 SYNTAXIN11, [14][15][16] MUNC13-4 27-29 and MUNC18-2 deficiency. 7,8 While lateonset FHL-2 patients mostly carry missense mutations, late onset of FHL-3 is predominantly associated with splice-site mutations and in late-onset FHL-4 patients also nonsense mutations and deletions have been described.…”

“…These atypical presentations have been reported in adolescents and even in adults as late as 62 years of age. 7,8,[14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29] They may be associated with milder and often recurrent HLH episodes and prolonged survival in the absence of hematopoietic stem cell transplantation (HSCT), which is unusual in patients with the typical disease. "Atypical FHL" is usually associated with missense or splice-site mutations in the affected genes.…”

UNC13D is the predominant causative gene with recurrent splicing mutations in Korean patients with familial hemophagocytic lymphohistiocytosis

“…Three patients with FHL3 in our series (38%) had CNS involvement at initial diagnosis, which is lower than previously reported rates (range, 60% -90%). 16,27,30 CNS involvement is the most discouraging clinical manifestation in FHL, and the association of CNS involvement with FHL3 might be related to the role of UNC13D in CNS function. 34 Two of these three patients succumbed to the disease, and also the single patient with FHL2 developed CNS involvement and died during the course of HLH-2004 treatment.…”

“…15,24 Among Asian countries, data on the molecular genetics of FHL are available only from Japan; 18,19,26,27 FHL2 and FHL3 accounted for approximately 19% and between 20% and 25% of cases of FHL in Japan, respectively. This contrasts with our result that FHL3 accounted for 89% of cases of FHL in Korea.…”

Perforin gene mutations in adult-onset hemophagocytic lymphohistiocytosis

“…The gene product associated with the PRF1 nonsense mutation 1090-1091delCT present in this patient has been reported to produce a band of 55 kDa under reducing conditions and no band under non-reducing condition. 8,9 Under reducing conditions, the patient's CTL showed a slightly smaller amount of normal-size perforin than controls, plus a weak band at 55 kDa. Under non-reducing conditions to detect an active form of perforin, this active mature form was markedly reduced in the patient ( Figure 1C).…”