Rapid Gardos Hereditary Xerocytosis Diagnosis in 8 Families Using Reticulocyte Indices
Résumé
Gardos channelopathy (Gardos-HX) or type 2 stomatocytosis/xerocytosis is a hereditary hemolytic anemia due to mutations in the KCNN4 gene. It is rarer than inherited type 1 xerocytosis due to PIEZO1 mutations (Piezo1-HX) and its diagnosis is difficult given the absence of a specific clinical or biological phenotype. We report here that this diagnosis can be sped up using red blood cell (RBC) indices performed on an ADVIA 2120 (Siemens(R)) analyzer, which measures reticulocyte mean corpuscular volume (rMCV) and mean corpuscular hemoglobin concentration (rMCHC). We studied reticulocyte indices in 3 new and 12 described patients (8 families) with Gardos-HX, 11 subjects presented the recurrent p.Arg352His mutation, 4 cases (two families) carried a private KCNN4 mutation. They were compared to 79 described patients (49 families) with Piezo1-HX. Surprisingly, in Gardos-HX cases, rMCV revealed to be smaller than MCV and rMCHC higher than MCHC, in contrast with normal or Piezo1-HX RBC. Consequently, Delta MCV (rMCV-MCV) was -0.9 +/- 5 fL vs. 19.8 +/- 3 fL (p < 0.001) in Gardos compared with Piezo1-HX and Delta MCHC (rMCHC-MCHC) was 18.7 +/- 13 vs. -50 +/- 8.7 g/L (p < 0.001). A threshold of 8.6 fL for Delta MCV and -5.5 g/L for Delta MCHC could discriminate between Gardos and Piezo1-HX with 100% sensitivity and specificity, regardless of age, mutation or splenectomy status. Consequently, we showed that reticulocytes indices are useful to suggest Gardos-HX on blood count results, allowing to rapidly target these patients for gene analysis. In addition, these parameters may prove useful as a `functional tool' in interpreting new KCNN4 variants.