Diagnosing XLP1 in patients with hemophagocytic lymphohistiocytosis.

Background: Hemophagocytic lymphohistiocytosis (HLH) is a
life-threatening, heterogeneous, hyperinflammmatory disorder.
Prompt identification of inherited forms resulting from
mutation in genes involved in cellular cytotoxicity can be
crucial. X-linked lymphoproliferative disease 1 (XLP1), due to
mutations in SH2D1A (Xq25) encoding signaling lymphocyte
activation molecule–associated protein (SAP), may present with
HLH. Defective SAP induces paradoxical inhibitory function of
the 2B4 coreceptor and impaired natural killer (NK) (and T)
cell response against EBV-infected cells.
Objective: To characterize a cohort of patients with HLH and
XLP1 for SAP expression and 2B4 function in lymphocytes,
proposing a rapid diagnostic screening to directmutation analysis.
Methods: We set up rapid assays for 2B4 function
(degranulation or 51Cr-release) to be combined with
intracellular SAP expression in peripheral blood NK cells. We
studied 12 patients with confirmed mutation in SH2D1A and
some family members.
Results: The combined phenotypic/functional assays allowed
efficient and complete diagnostic evaluation of all patients with
XLP1, thus directing mutation analysis and treatment. Nine
cases were SAP2, 2 expressed SAP with mean relative
fluorescence intensity values below the range of healthy controls
(SAPdull), and 1, carrying the R55L mutation, was SAP1. NK
cells from all patients showed inhibitory 2B4 function and
defective killing of B-EBV cells. Carriers with SH2D1A
mutations abolishing SAP expression and low percentage of
SAP1 cells showed neutral 2B4 function at the polyclonal NK
cell level. Three novel SH2D1A mutations have been identified.
Conclusions: Study of SAP expression is specific but may have
insufficient sensitivity for screening XLP1 as a single tool.
Combination with 2B4 functional assay allows identification of
all cases. (J Allergy Clin Immunol 2014;134:1381-7.)