News From the Genetics Lab
New Diagnostic Tests for HLH and XLP
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| Two new molecular diagnostic tests have been added to our armamentarium of clinical services in the Molecular Genetics Laboratory. |
Familial hemophagocytic lymphohistiocytosis (FHL or HLH) is an autosomal recessive disorder of immune regulation which typically presents in early childhood and has a rapidly fatal course unless aggressively treated with chemotherapy, immune suppression and bone marrow transplant. Perforin (PRF1) and MUNC13-4 are two causative genes of familial HLH. Mutations in the PRF1 and Munc13-4 genes are identified in approximately 50-60% of individuals with familial HLH worldwide. Syntaxin-11 (STX11) is the third gene, which has been linked to familial cases of HLH.
To date, mutations in STX11 have been identified in individuals of Turkish descent in which STX11 mutations may account for approximately 20% of cases of HLH. STX11 mutations have not yet been identified in Western European or other populations. NK-cell function, tested in vitro, may be normal: given the low number of HLH patients with STX11 mutations, this observation should be regarded with appropriate caution. At this time, there is no specific functional assay for the STX11 protein. Subjects with HLH, with normal PRF1 and MUNC13-4 mutational analyses are candidates for STX11 testing, particularly those from families with parental consanguinity, Turkish descent or families with multiple affected siblings.
The X-linked lymphoproliferative syndrome (XLP) is a rare, inherited immunodeficiency that is characterized by [EBV-driven] hemophagocytosis, often progressing into fatal infectious mononucleosis, hypogammaglobulinemia (common variable immunodeficiency disorder [CVID]) and lymphoproliferative disease (including lymphomas; typically of the extra-nodal non-Hodgkin variety). Disease manifestations of XLP are linked to EBV infections in about 50% of cases. Mutations in the signaling lymphocyte activation molecule (SLAM)-associated protein SAP (SH2D1A), a signaling adaptor molecule, underlie approximately 60% of cases of familial XLP.
Mutations in a second gene, BIRC4, were recently identified in an additional 20% of French patients with XLP. A thorough analysis of North American patients with a clinical phenotype consistent with XLP, but with normal SAP, is currently in progress. At this time, there is no specific functional assay for X-linked Inhibitor of Apoptosis Protein (XIAP), the protein encoded by BIRC4. Splenomegaly was noted in the few patients reported to date, while this is not a consistent feature of XLP secondary to mutations in SH2D1A. Males with clinical manifestations indicative of XLP and who have normal SAP expression or normal mutational analysis of SH2D1A are candidates for BIRC4 testing.
For further background information on HLH and XLP, please visit: www.genetest.org (search under Gene Reviews) or visit: www.cincinnatichildrens.org/dchi.
