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A retrospective series of 126 HX cases
was not available for four patients. Splenectomy was per- formed for persistent hemolysis and/or symptomatic splenomegaly before the diagnosis of HX was made, with a mean delay of 15 years between splenectomy and diag- nosis (range, 1-32 years). The mean age at splenectomy was 24 years (range, 4-41 years). Splenectomy did not abrogate hemolysis: the mean hemoglobin level and retic- ulocyte count were 112±19 g/L and 280±134 x109/L, respectively, in splenectomized patients.
Twelve (75%) splenectomized patients (8 patients with PIEZO1 mutation and 4 not genotyped) experienced 19 thrombotic events, including five portal thromboses (1 previously reported13), five cerebral strokes, six episodes of venous thromboembolism and three cases of chronic thromboembolic pulmonary hypertension (Online Supplementary Figure S2). Thrombotic events occured with a mean delay of 13±8.6 years after splenectomy. All splenectomized PIEZO1-HX subjects (8/8) developed thrombotic events and received long-term anticoagulation therapy (Online Supplementary Figure S2). None of the four KCNN4-HX splenectomized patients experienced throm- bosis, with a mean follow-up of 26.5 years (range, 2-44 years). One non-genotyped patient with severe thrombot- ic events after splenectomy (patient #5, Online Supplementary Figure S2) received anagrelide therapy for a JAK2V617F-negative essential thrombocythemia. Two patients presented heterozygous globin gene mutations in association with HX and experienced severe thrombosis after splenectomy: a woman with AS trait (patient #10, Online Supplementary Figure S2),24 and a male with PIEZO1- HX, β-thalassemia trait and α-globin gene triplication (patient #11, Online Supplementary Figure S2). Both experi- enced cerebral stroke and chronic thromboembolic pul- monary hypertension.
Occurrence of perinatal edema in hereditary xerocytosis
Twenty-two patients from 13 families had a known his- tory of perinatal edema. We focused on 19 patients, from 11 families, with well-documented records (Online Supplementary Table S3). In 13 cases, no family history of HX was known when the perinatal edema occurred. The diagnosis of HX was made at birth or in the first month in 12 cases, in utero in two cases, or retrospectively, later in life, in a context of non-spherocytic chronic hemolysis and/or recurrence of perinatal edema during a second pregnancy in five cases. Genetic data were available for ten families (18 patients) and revealed PIEZO1 mutations in all of them. Recurrent mutations were found in five families and private sequence variations in the other five. Five families had histories of recurrent perinatal edema. In family 1, the grandmother had a history of fetal loss due to edema. In families 2, 10 and 11, perinatal edema was noted in two siblings; no data were available for the other affected members. In family 4, all affected members had a history of perinatal edema. In the other families, recur- rence of perinatal edema could not be evaluated because of the absence of other HX cases and/or of other pregnan- cies. In terms of severity, we observed one death in utero at 27 weeks of gestation, one medical termination of preg- nancy due to severe hydrops at 28 weeks of gestation, and one death 15 days after birth with refractory effusions and cerebral edema. Five cases required in utero punctures, and five required post-natal punctures. The forms of perinatal edema were hydrops (n=6), pleural effusion (n=5), ascites (n=11), hydramnios (n=2), jugular cyst (n=1), subcuta-
neous edema (n=3), pericardial effusion (n=2) and hygro- ma (n=1). Anemia in a context of perinatal edema was documented in three cases, two of whom received in utero transfusions; the last one underwent ex sanguino transfu- sion at 23 weeks of gestation. The evolution was favor- able in 14 cases with complete resorption of the perinatal edema, except for one patient who still presented moder- ate lymphedema of the lower limbs at adult age.
Hyperferritinemia
Ferritin level at diagnosis was available for 49 patients. The mean ferritin level was 764±480 ng/mL and correlated with age (Figure 3A,B). The mean ferritin level at diagnosis was 1702±1048 ng/mL in adult KCNN4-HX (n=5) and 656±428 ng/mL in PIEZO1-HX (n=40). This hyperfer- ritinemia was not related to transfusions since no patient was transfused on a regular basis. Among these patients, HFE genotyping was available for 45 patients: 14 carried p.His63Asp heterozygous mutations, three were het- erozygous for the p.Cys282Tyr mutation and one was a composite heterozygous p.Cys282Tyr/ p.His63Asp. We did not find any difference in ferritin levels between wild- type and mutated patients (742±549 ng/mL vs. 874±534 ng/mL, respectively; P=NS). Diabetes mellitus was noted in three cases; one patient developed a hepatocarcinoma and underwent liver transplantation; hypogonadism was recorded in one case, hypothyroidism in one case and osteoporosis in three cases. The percentage of patients treated for iron overload increased with age (25% before the age of 20 years, 41% between 20 and 40 years, and 73% after the age of 40 years) (Figure 3C). Treatments included phlebotomy (n=15), deferasirox (n=9), deferox- amine (n=3) and deferiprone (n=1). Mean liver iron con- tent, evaluated using magnetic resonance imaging, was 200±103 μmol/g at diagnosis (n=20) vs. 88±42 (n=14) at the last follow-up (P<0.001), showing that iron chelation was efficient in decreasing iron content in the liver (Figure 3D). There was a strong difference in liver iron content between patients with a ferritin level above 1000 ng/mL (n=7) and under 1000 ng/mL (n=25): 318±31 μmol/g vs. 113±68 μmol/g, respectively (Figure 3E). However, focus- ing on patients with ferritin levels below 1000 ng/mL, the correlation was poor (Figure 3F). Therefore, even patients with a moderate ferritin increase should undergo an eval- uation of tissue iron content at diagnosis.
Pseudohyperkalemia
Among the 35 patients for whom data on potassium concentration at the same time as ektacytometry were available, the potassium level was above the upper range in 18 cases (51%). However, no specific potassium release test at room temperature was performed.
Discussion
Because of its heterogeneous presentation, HX is an underestimated condition, as suggested recently.25 The aim of our report is to describe precisely the mean pheno- typic and genotypic HX features, in order to facilitate the diagnosis. Our first conclusion is that most HX subjects have a mild hematologic phenotype, with two-thirds of patients having a fully compensated hemolysis; non-ery- throid features, including iron overload, perinatal edema and thrombotic events after splenectomy often deter-
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