This is a heterogeneous group of disorders characterized by abnormal proliferation of histiocytes, and nonmalignant histiocytic disorders are subdivided into two major types: (1) Langerhans’ cell histiocytosis (including histiocytosis X, eosinophilic granuloma, Letterer–Siwe disease, and Hand– Schuller–Christian disease and are characterized by the presence of the Birbeck granule) and (2) hemophagocytic syndromes (which include familial erythrophagocytic lymphocytosis, also known as familial lymphohistiocytosis or familial reticuloendotheliosis).
Langerhans cell histiocytosis (LCH) is considered a nonhereditary disorder but rarely may be familial (Arico et al. 1999). Most such cases are in monozygotic twins and the concordance rate is 85 % (this does not necessarily indicate genetic factors as in utero spread via intraplacental anastomosis cannot be excluded).
A hereditary predisposition to B cell proliferative diseases has been established, and IgG/A and IgM disorders may occur together in families, where enhanced B cell responsiveness may be found in healthy subjects clustered around cases (Steingrimsdottir et al. 2011).
Familial hemophagocytic lymphohistiocytosis is a rare autosomal recessive disorder (1.2 cases/million children each year), which usually presents in early childhood (80 % by the age of 2 years) with failure to thrive, fever, anemia and hepatosplenomegaly and, histologically, multisystem (liver, spleen, lymph nodes, bone marrow, central nervous system) lymphohistiocytic infiltrates. Without treatment the prognosis is very poor. Familial hemophagocytic lymphohistiocytosis is a heterogeneous disorder. Mutations in the perforin gene account for >30 % of cases, and about 10 % are linked to the chromosome 9 FHL1 locus (Goransdotter Ericson et al. 2001). Recently mutations in hMunc13-4, a member of the Munc13 family of proteins involved in vesicle priming function, were identified in a further subset of familial hemophagocytic lymphohistiocytosis (FHL3). Inactivation of hMunc13-4 causes defective exocytosis of perforin containing lytic granules (Feldmann et al. 2003). Other genes that may be involved in different families include RAG1 and RAG2, the syntaxin-11 gene, and syntaxin-binding protein 2.
An autosomal recessive form of histiocytosis associated with sensorineural deafness and joint contractures, Faisalabad histiocytosis, has been mapped to 11q25. Further genetic heterogeneity in familial hemophagocytic lymphohistiocytosis was suggested by a study in which FHL in 2 unrelated Canadian families with affected first cousins was not linked to 9q21.3-q22 or 10q21-q22 (Graham et al. 2000).