Familial hemophagocytic lymphohistiocytosis

Recommended panel testing for this condition at Breda Genetics (EXOME PANEL):

Familial hemophagocytic lymphohistiocytosis and its differential diagnosis (PRF1, UNC13D, STX11, STXBP2, RAB27A, XIAP, SH2D1A, CHS1)

Summary

Familial hemophagocytic lymphohistiocytosis (FHL, also known as familial hemofagocytic syndrome) is a rare immunologic disorder which can be caused by mutation in one of different genes (genetic heterogeneity). The disorder is consistent with a hyperinflammatory syndrome causing fever, hepatosplenomegaly, cytopenia, hypertriglyceridemia, hyperferritinemia, and hemophagocytosis in bone marrow, liver, spleen or lymph nodes. Onset of the disease is typically within the first months or years of life and, rarely, in utero (fetal onset FHL is considered to be the most severe form of FHL, as it manifests itself in the form of hydrops fetalis).

There are also non-genetic causes (secondary hemofagocytic lymphohistiocytosis) like malignancies, infections (often caused by the Epstein-Barr virus, cytomegalovirus or untreated HIV), systemic lupus erythematosus or adult-onset Still disease.

Molecular genetics

The genes of which mutations are known to cause familial hemophagocytic syndrome are PRF1 (familial hemophagocytic lymphohistiocytosis 2 – FHL2), UNC13D (FHL3), STX11 (FHL4), and STXBP2 (FHL5). One additional genetic subtype (FHL1) has been mapped on chromosome 9 in four consanguineous Pakistani families, although the gene has not been identified yet. Moreover, further genetic heterogeneity (i.e. mutations in additional unknown genes) is plausible, as almost 30% of patients do not show mutations in any of the above genes (which also means that negative genetic testing does not exclude the diagnosis of FHL).

FHL is inherited in an autosomal recessive manner, although in some patients only one single mutation is identified (being possible that the second one is located in deep intronic regions – such mutations have been already described in the UNC13D gene -, in the gene promoter or in another yet unknown gene in the context of digenic inheritance).

Mostly punctiform mutations detectable by sequencing have been described in the above genes, whereas large deletions/duplications usually detectable by MLPA are thought to be rare (such mutations have been reported in the STX11 gene).

Differential diagnosis

A small minority of patients with FHL have pathogenic mutations in the RAB27A gene (which is primarily associated to Griscelli syndrome type 2). These individuals may not show evidence of partial albinism or other pigmentary abnormalities typically reported with Griscelli syndrome type 2 and RAB27A sequencing may therefore be considered in every FHL patient who tests negative to PRF1, UNC13D, STX11, and STXBP2 sequencing.

If RAB27A is also negative, XIAP and SH2D1A sequencing can be considered, since X-linked lymphoproliferative disease 1 and 2 may show clinical overlap with FHL.

Chediak-Higashi syndrome, caused by CHS1 mutations, can also have clinical similarity with FHL, although skin biopsy may help differentiating the diagnosis at the beginning.

Recommended panel testing for this condition at Breda Genetics (EXOME PANEL):

Familial hemophagocytic lymphohistiocytosis and its differential diagnosis (PRF1, UNC13D, STX11, STXBP2, RAB27A, XIAP, SH2D1A, CHS1)

References: 

Hemophagocytic Lymphohistiocytosis, Familial. Zhang K, Filipovich AH, Johnson J, Marsh RA, Villanueva J. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. 2006 Mar 22 [updated 2013 Jan 17]. PMID: 20301617

Familial Hemophagocytic Lymphohistiocytosis Presenting as Hydrops Fetalis. Iwatani S, Uemura K, Mizobuchi M, Yoshimoto S, Kawasaki K, Kosaka Y, Hori M, Yasumi T, Nakao H. AJP Rep. 2015 Apr;5(1):e22-4. PMID: 26199792