Clinical flow cytometric screening of SAP and XIAP expression accurately identifies patients with<i>SH2D1A</i>and<i>XIAP/BIRC4</i>mutations

Gifford, Carrie; Weingartner, Elizabeth; Villanueva, Joyce; Johnson, Judith A.; Zhang, Kejian; Filipovich, Alexandra H.; Bleesing, Jack J.; Marsh, Rebecca

doi:10.1002/cyto.b.21166

Cited by 23 publications

(15 citation statements)

References 46 publications

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“…Further tests are necessary to characterize particular subgroups, such as those who develop the disease when they are younger than 2 years old, those with excessive autoimmunity, or those with severe perianal disease. Those tests include flow cytometry analysis of XIAP expression by lymphocytes and NK cells 129, 130 or FOXP3 expression in CD4 + T cells, which can diagnose a significant proportion of patients with XLP2 and IPEX. Flow cytometry can detect functional defects in MDP signaling in patients with XIAP deficiency 131 .…”

Section: Laboratory Tests and Functional Screensmentioning

confidence: 99%

The Diagnostic Approach to Monogenic Very Early Onset Inflammatory Bowel Disease

et al. 2014

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Patients with a diverse spectrum of rare genetic disorders can present with inflammatory bowel diseases (monogenic IBD). Patients with these disorders often develop symptoms during infancy or early childhood, along with endoscopic or histologic features of Crohn’s disease, ulcerative colitis or IBD unclassified. Defects in interleukin 10 signaling have a Mendelian inheritance pattern with complete penetrance of intestinal inflammation. Several genetic defects that disturb intestinal epithelial barrier function or affect innate and adaptive immune function have incomplete penetrance of the IBD-like phenotype. Several of these monogenic conditions do not respond to conventional therapy and are associated with high morbidity and mortality. Due to the broad spectrum of these extremely rare diseases, a correct diagnosis is frequently a challenge and often delayed. In many cases, these diseases cannot be categorized based on standard histologic and immunologic features of IBD. Genetic analysis is required to identify the cause of the disorder and offer the patient appropriate treatment options, which include medical therapy, surgery, or allogeneic hematopoietic stem cell transplantation. In addition, diagnosis based on genetic analysis can lead to genetic counseling for family members of patients. We describe key intestinal, extra-intestinal, and laboratory features of 50 genetic variants associated with IBD-like intestinal inflammation. We provide approaches for identifying patients likely to have these disorders. We discuss classical approaches to identify these variants in patients, starting with phenotypic and functional assessments that lead to analysis of candidate genes. As a complementary approach, we discuss parallel genetic screening using next-generation sequencing followed by functional confirmation of genetic defects.

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Section: Laboratory Tests and Functional Screensmentioning

confidence: 99%

The Diagnostic Approach to Monogenic Very Early Onset Inflammatory Bowel Disease

et al. 2014

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“…If perforin is normal or increased, girls should reflexively undergo flow cytometry for CD107a mobilization [14]. Boys should be tested for signaling lymphocyte activation molecule (SLAM)-associated protein (SAP) and X-linked inhibitor of apoptosis protein (XIAP) encoded by SH2D1A and BIRC4 and mutated in XLP-1 and XLP-2, respectively [15,16], and if SAP and XIAP are normal, CD107a mobilization should be performed next. CD107a (also known as lysosomal-associated membrane protein 1, or LAMP1) colocalizes with perforin in the lytic granules of both 5.…”

Section: Molecular Diagnosis Of Hlhmentioning

confidence: 99%

Deconstructing the diagnosis of hemophagocytic lymphohistiocytosis using illustrative cases

et al. 2015

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Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of extreme inflammation occurring in association with genetic defects involving the granule-dependent cytotoxic pathway of CD8+ T cells or NK cells and/or a wide variety of triggers including infections, malignancies, and rheumatologic disorders. Because of its relative rarity and the nonspecific nature of the individual clinical and laboratory abnormalities comprising the characteristic Bpattern^of HLH, the diagnosis can be elusive. Furthermore, some of the laboratory tests included in the diagnostic criteria are time-consuming or not widely available, and since many of these patients are critically ill, HLH must be considered early on so that the diagnosis can be established and potentially life-saving treatment initiated. Since the diagnosis of HLH is truly a clinicopathologic correlation, in this article, we as a team of pediatric clinical and laboratory physicians will use exemplary cases from our own institution with a variety of clinical presentations to illustrate the many Bfaces^of HLH; deconstruct the diagnosis; point out some of the challenges, limitations, pearls and pitfalls; and make it easier to understand the pathophysiology in context. However, while we may see relatively more cases working in a tertiary care children's hospital, HLH is a disease of both children and adults. Illustrative cases Case 1The patient was a previously healthy black 4-month-old girl transferred from an outside hospital. Two weeks prior, she had developed low-grade fever and a rash which was initially attributed to a viral exanthem, but because of worsening fever (to 40°C), she presented to the emergency department (ED), was found to have a platelet count of 70×10 3 /mL, admitted for further evaluation including a full septic work-up, and started on empiric antibiotics. Her white blood cell count, hemoglobin, and platelet count all progressively declined (with a nadir absolute neutrophil count of 0.2×10 3 /mL, hemoglobin dropping to 6.6 g/dL, and 21×10 3 /mL platelets) and she developed mild hepatosplenomegaly which was confirmed by abdominal ultrasonography, prompting bone marrow examination which showed no evidence of leukemia, neuroblastoma, or hemophagocytosis. Although initially her ferritin was 17 ng/dL, at the outside hospital it ultimately reached the 500 s, while fibrinogen decreased to <100 mg/ dL. Steroids were begun as treatment for HLH shortly after transfer to our institution and while an infectious etiology was not uncovered, additional testing revealed a ferritin of 4873 ng/mL, sCD25 level of 34,826 U/mL (age-specific reference range: 334-3026), absent NK cell function, and compound heterozygosity for two previously described mutations in PRF1 that are associated with familial HLH. Her initial cerebrospinal fluid (CSF) showed a minimally elevated protein without pleocytosis which normalized within 2 weeks of therapy and never exhibited neurologic symptoms. Three

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“…106 Confirmatory sequencing of the XIAP gene should be performed in patients with absent or low expression of XIAP and in cases of high clinical suspicion despite normal flow cytometric results, since missense mutations in XIAP can rarely result in expression of normal amounts of protein. 102 Unlike SAP deficiency, there are no additional flow cytometric or functional studies available to definitively guide decisions regarding whether or not novel missense variants that retain protein expression are truly disease-causing. Although iNKT cell numbers are typically low in XLP2 patients, they can also be normal, especially in EBV-naïve individuals.…”

Section: Xlp2/xiap Deficiencymentioning

confidence: 99%

“…It should also be performed in cases of high clinical suspicion despite normal flow cytometric results, as pathologic missense mutations occasionally result in normal levels of SAP protein. 102 In patients with SH2D1A sequence variants of uncertain significance (such as novel missense mutations that do not reduce the levels of SAP protein), additional laboratory studies can be performed to help determine whether the variants are pathogenic. For example, measurement of the percentage of peripheral blood invariant natural killer T cells (iNKTs) can be performed (Figure 22.6).…”

Section: Xlp1/sap Deficiencymentioning

confidence: 99%

“…In the authors' experience, the sensitivity and specificity of flow cytometric screening are approximately 90%. 102 In cases where flow cytometry is not available, analysis of SAP expression by Western blot can also be helpful. 85 Confirmatory sequencing of the SH2D1A gene should be performed in patients with reduced or absent SAP expression.…”

Section: Xlp1/sap Deficiencymentioning

confidence: 99%

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The X-Linked Lymphoproliferative Syndromes

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Marsh

2014

Stiehm's Immune Deficiencies

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Clinical flow cytometric screening of SAP and XIAP expression accurately identifies patients withSH2D1AandXIAP/BIRC4mutations

Cited by 23 publications

References 46 publications

The Diagnostic Approach to Monogenic Very Early Onset Inflammatory Bowel Disease

The Diagnostic Approach to Monogenic Very Early Onset Inflammatory Bowel Disease

Deconstructing the diagnosis of hemophagocytic lymphohistiocytosis using illustrative cases

The X-Linked Lymphoproliferative Syndromes

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