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A retrospective series of 126 HX cases
observed severe thrombotic complications, including pul- monary hypertension in two patients carrying heterozy- gous globin gene mutations, one with A/S trait and the other with β-thalassemia trait + α-triplication, suggesting a synergistic deleterious effect of these conditions. Gene analysis was not available for the former, and the latter had two PIEZO1 missense sequence variations (p.Gln1519Pro and p.Glu1910Lys, scored as unknown sig- nificance and as a polymorphism, respectively), the role of these associated mutations on PIEZO1 function remains to be established.
Finally, perinatal edema was observed in PIEZO1-HX and not in KCNN4-mutated patients in this series. However, the low number of KCNN4-mutated families does not allow definitive conclusion to be drawn on this issue and we recommend that pregnancies should be monitored closely in both genotypes. The severity of peri- natal edema was heterogeneous, ranging from nuchal clar- ity to fetal loss or death after birth. This highlights the requirement for a careful pregnancy follow-up with at least monthly ultrasonography monitoring when one par- ent is affected. Whether severe perinatal edema is restrict- ed to a subset of PIEZO1 mutations is unclear, but we observed recurrent perinatal edema in all informative fam- ilies. Perinatal edema apparently did not involve the effect of PIEZO1 on red cells, since anemia was not present in most cases. The occurrence of chylous ascites and hygro- ma cysts evoked a primary defect in the lymphatic sys- tem.6,18,41,42 PIEZO1 is expressed in human embryo lym- phatic vessels11 and its bi-allelic loss of function is associ- ated with congenital lymphatic dysplasia.23,43 It is puzzling that gain-of-function mutations induced a similar pheno- type in the perinatal period. Morpholino PIEZO1-knock- down in zebrafish induced anemia;31 hemolysis with stomatocytes on the blood smear was seen in some patients with congenital lymphatic dysplasia.23 Moreover, one patient in our series carried a mutation associated with congenital lymphatic dysplasia, while another patient with a history of perinatal edema had persistent lymphedema in adulthood. Edema and hemolysis may
represent two features in the spectrum of PIEZO1-related diseases which may sometimes overlap. Again, functional studies are needed to decipher the pathophysiology of both entities.
In summary, we report here the clinical, biological and genetic features of the largest series of HX patients to date. We have uncovered the heterogeneous genetic bases of PIEZO1-HX reporting 12 novel mutations, and its varied clinical expression, characterized by a normal to high hemoglobin level, iron overload, occurrence of peri- natal edema, and the high thrombosis rate after splenec- tomy. Gardos channelopathy was characterized by more severe hemolysis, and less erythrocyte dehydration. Taken together, our results provide a better picture of this disorder and will help the diagnosis and clinical manage- ment of patients, particularly in terms of contraindica- tions of splenectomy, iron overload and pregnancy fol- low-up.
Acknowledgments
We particularly want to thank all the families, the patients and the French Registry of Hereditary Stomatocytosis. We thank all technicians and biologists of the Hematology Laboratory of Hôpital Bicêtre for their contribution and Mme Hélène Ponsin, for excellent resource management. We also thank the ARFH (Association Recherche et Formation en Hématopathologie) for its constant support. Finally, we thank all investigators and contrib- utors: Dr. Madeleine Fénéant-Thibault, Dr. Gérard Tertian, Pr. Gilles Tchernia, Dr. Philippe Agape, Dr. Nathalie Aladjidi, Dr. Yannick Bacq, Dr. Fiorenza Barraco, Dr. Sophie Bayart, Dr. Jean-Sébastien Blade, Pr. Photis Beris, Dr. Jean-Yves Boucher, Dr. Marie Pierre Castex, Dr. Denis Cléau, Dr. Luc Darnige, Dr. Xavier Delbrel, Dr. Valérie Mathieu, Dr.Vincent Di Martino, Dr. Valérie Doireau, Dr. Bernard Drenou, Pr. Cécile Goujard, Dr. Isabelle Grulois, Pr. Xavier Jeunemaitre, Dr. Marie- Françoise Le Coz, Dr. Nicolas Limal, Dr. Jean-Philippe Miguet, Dr. Laetitia Morel, Dr. Philippe Nicoud, Dr. Emmanuel Plouvier, Pr. Jacques Pouchot, Dr. Michel Renoux, Dr. Anne-Laure Suc, and Dr. Hacene Zerazhi. We thank the RFH association for its support.
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