Clinical and biological features in PIEZO1-hereditary xerocytosis and Gardos channelopathy: a retrospective series of 126 patients

Abstract

We describe the clinical, hematologic and genetic characteristics of a retrospective series of 126 subjects from 64 families with hereditary xerocytosis. Twelve patients from six families carried a KCNN4 mutation, five had the recurrent p.Arg352His mutation and one had a new deletion at the exon 7-intron 7 junction. Forty-nine families carried a PIEZO1 mutation, which was a known recurrent mutation in only one-third of the cases and private sequence variation in others; 12 new probably pathogenic missense mutations were identified. The two dominant features leading to diagnosis were hemolysis that persisted after splenectomy and hyperferritinemia, with an inconstant correlation with liver iron content assessed by magnetic resonance imaging. PIEZO1-hereditary xerocytosis was characterized by compensated hemolysis in most cases, perinatal edema of heterogeneous severity in more than 20% of families and a major risk of post-splenectomy thrombotic events, including a high frequency of portal thrombosis. In KCNN4-related disease, the main symptoms were more severe anemia, hemolysis and iron overload, with no clear sign of red cell dehydration; therefore, this disorder would be better described as a 'Gardos channelopathy'. These data on the largest series to date indicate that PIEZO1-hereditary xerocytosis and Gardos channelopathy are not the same disease although they share hemolysis, a high rate of iron overload and inefficient splenectomy. They demonstrate the high variability in clinical expression as well as genetic bases of PIEZO1-hereditary xerocytosis. These results will help to improve the diagnosis of hereditary xerocytosis and to provide recommendations on the clinical management in terms of splenectomy, iron overload and pregnancy follow-up.

Figure 1.

Main clinical and biological features at diagnosis of the probands and their family members. (A) Repartition of age at diagnosis for the 64 index cases. The mean age was 32±18 years (range, 0-88). (B) Biological and clinical features at the time of diagnosis of hereditary xerocytosis (HX) in the 64 index cases and 62 family members; only post-splenectomy thromboses are shown; other: B19 parvovirus infection (n=1), persistent isolated jaundice after birth (n=1), systematic exploration in a context of familial porphyria leading to an “incidental” diagnosis of PIEZO1-related HX (n=1). The figure does not show one case of extramedullar hematopoiesis. NSCH: non-spherocytic chronic hemolysis; PNE: perinatal edema; NA: data not available (4 patients).

Figure 2.

Main hematologic data and red cell indices in PIEZO1 - and KCNN4-hereditary xerocytosis. (A) Hematologic features in the whole population of patients (index cases + family members positively tested): results are shown as mean hemoglobin (Hb, g/L), mean corpuscular volume (MCV, fL), reticulocyte count (Ret, x10⁹/L) and mean corpuscular hemoglobin concentration (MCHC, g/L). (B) Percentages of patients for each hemoglobin subgroup in the neonatal period (age <1 month, n=14, black boxes) in comparison with adults and infants after the age of 1 month (n=97, gray boxes). Forty-eight percent of neonates had a hemoglobin value under 100 g/L, while in 70% of adults and infants older than 1 month, hemoglobin level was in the normal range for the age. (C) Hemoglobin level was higher in PIEZO1-hereditary xerocytosis (HX) (n=80) than in KCNN4-HX (n=12): mean hemoglobin 134±19 g/L vs. 102±13, P<0.001. (D) Reticulocyte count in PIEZO1-HX vs. KCNN4-HX: 307.5±106 (×10⁹/L) vs. 178.1±63.1 (×10⁹/L), P<0.001. (E) MCHC in PIEZO1-HX vs. KCNN4-HX: 354±24.1 vs. 332 ±12.9 g/L, P<0.05. The MCHC value was obtained on an ADVIA2120 blood analyzer. (F) Frequency of typical stomatocytes on peripheral blood smear examination between PIEZO1-HX (n=63) and KCNN4-HX (n=10): +: rare, ++: few, +++: many.

Figure 3.

Hyperferritinemia and iron overload. (A, B) Ferritin level at diagnosis was correlated to the age of patients: the later in life the diagnosis was made, the higher the ferritin level was: the mean ferritin level was 273 ±141 ng/mL in patients < 20 years vs. 717±441 ng/mL in patients between 20-40 years (P<0.05) vs. 1409±653 ng/mL in those older than 40 years (P<0.05). (C) Percentages of patients receiving chelation therapy, depending on the age at diagnosis. (D) Efficiency of iron chelation on liver iron content (LIC), evaluated by magnetic resonance imaging (MRI), between patients at diagnosis (n=20) and patients at last follow-up (n=14): mean LIC: 200±103 μmol/g vs. 88±42 μmol/g, P<0.001. (E, F) Correlation between LIC assessed by liver MRI and ferritin level (< or > 1000 ng/mL) for patients for whom these two data were available simultaneously: LIC: 318±31 μmol/g for patients with ferritin >1000 ng/mL (n=7) vs. 113±68 μmol/g for patients with ferritin <1000 ng/mL (n=25), P<0.001. (E) Eight patients with a ferritin level below 1000 ng/mL already had a LIC >150 μmol/g, and (F) no clear correlation was found between LIC and ferritin below 1000 ng/mL.