Letter by Hernandez-Gonzalez et al Regarding Article, “Phenotypic Characterization of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension”
2018; Lippincott Williams & Wilkins; Volume: 137; Issue: 22 Linguagem: Inglês
10.1161/circulationaha.118.033641
ISSN1524-4539
AutoresIgnacio Hernández‐González, Paula Navas, Pilar Escribano Subías,
Tópico(s)PI3K/AKT/mTOR signaling in cancer
ResumoHomeCirculationVol. 137, No. 22Letter by Hernandez-Gonzalez et al Regarding Article, "Phenotypic Characterization of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension" Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBLetter by Hernandez-Gonzalez et al Regarding Article, "Phenotypic Characterization of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension" Ignacio Hernandez-Gonzalez, MD, Paula Navas, MD, PhD and Pilar Escribano-Subias, MD, PhD Ignacio Hernandez-GonzalezIgnacio Hernandez-Gonzalez Centro de Referencia Nacional de Hipertensión Pulmonar Compleja, Instituto de Investigación I+12, Hospital Universitario Doce de Octubre, Madrid, Spain (I.H.-G.). , Paula NavasPaula Navas Hospital General Universitario Gregorio Marañón, Madrid, Spain (P.N.). and Pilar Escribano-SubiasPilar Escribano-Subias Centro de Referencia Nacional de Hipertensión Pulmonar Compleja, Hospital Universitario Doce de Octubre, Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares, Madrid, Spain (P.E.-S.). Originally published29 May 2018https://doi.org/10.1161/CIRCULATIONAHA.118.033641Circulation. 2018;137:2411–2412To the Editor:We read with great interest the study by Hadinnapola et al1 evaluating the phenotype of eukaryotic translation initiation factor 2 alpha kinase 4 (EIF2AK4) mutation carriers in a nationwide cohort of pulmonary arterial hypertension patients.We were surprised by the small number of familial cases (1/14 patients) as compared with previous reports. There is no mention of known consanguinity, frequent in autosomal recessive diseases.Our group described a founder homozygote mutation in EIF2AK4 in 18 Iberian Romani patients among 5 unrelated families with hereditary pulmonary veno-occlusive disease (PVOD).2 Histological examinations of the lung were performed in 8 patients in 4 unrelated families. We found 2 different clinical-histological patterns. One presented better prognosis, higher tolerance to pulmonary vasodilators, longer event-free survival, and less venous involvement than the other, being the former pattern easily misdiagnosed as pulmonary arterial hypertension.In our experience,2–4 the prognosis of PVOD patients is by far poorer than in other forms of pulmonary arterial hypertension, with an event-free survival at 3 years of 40% for the overall population and 0% for nontolerant patients, and it is mainly determined by the tolerance to pulmonary vasodilator independently of the presence or absence of an underlying biallelic EIF2AK4 mutation.These results are consistent with the study by Montani et al,5 which describes 19 familial cases in 13 unrelated families over 27 biallelic EIF2AK4 mutations carriers, finding no differences in survival between EIF2AK4 mutations carriers and noncarriers (32% at 3 years).In the cohort of Hadinnapola and colleagues,1 64% of biallelic EIF2AK4 mutation carriers were initially misdiagnosed as having pulmonary arterial hypertension. They report a significantly greater overall survival of PVOD patients (>60% at 3 years), which might reflect a less aggressive and more tolerant form of the disease.It is necessary to highlight that PVOD is a rare disease that may present as a heritable condition, most frequently with a familial pattern. Genetic testing is the cornerstone to achieve a proper diagnosis but currently does not add any prognostic information. Moreover, there are no available data concerning the importance of being compound heterozygote versus homozygote for a pathogenic variant in EIF2AK4, and further investigations are needed. Genetic counseling helps to improve the management of heritable PVOD and to avoid new cases in future generations, of great importance in consanguineous populations.Current knowledge is based on small studies and must be interpreted with caution. PVOD may show a wide spectrum of severity and aggressivity, probably determined by the underlying venous involvement and the response to vasodilators. Early referral of eligible patients to a lung transplant center as soon as the diagnosis is confirmed should be warranted.DisclosuresNone.Footnoteshttp://circ.ahajournals.orgReferences1. Hadinnapola C, Bleda M, Haimel M, Screaton N, Swift A, Dorfmüller P, Preston SD, Southwood M, Hernandez-Sanchez J, Martin J, Treacy C, Yates K, Bogaard H, Church C, Coghlan G, Condliffe R, Corris PA, Gibbs S, Girerd B, Holden S, Humbert M, Kiely DG, Lawrie A, Machado R, MacKenzie Ross R, Moledina S, Montani D, Newnham M, Peacock A, Pepke-Zaba J, Rayner-Matthews P, Shamardina O, Soubrier F, Southgate L, Suntharalingam J, Toshner M, Trembath R, Vonk Noordegraaf A, Wilkins MR, Wort SJ, Wharton J, Gräf S, Morrell NW; NIHR BioResource–Rare Diseases Consortium; UK National Cohort Study of Idiopathic and Heritable PAH. Phenotypic characterization of EIF2AK4 mutation carriers in a large cohort of patients diagnosed clinically with pulmonary arterial hypertension.Circulation. 2017; 136:2022–2033. doi: 10.1161/CIRCULATIONAHA.117.028351.LinkGoogle Scholar2. Navas Tejedor P, Palomino Doza J, Tenorio Castaño JA, Enguita Valls AB, Rodríguez Reguero JJ, Martínez Meñaca A, Hernández González I, Bueno Zamora H, Lapunzina Badía PD, Escribano Subías P. Variable expressivity of a founder mutation in the EIF2AK4 gene in hereditary pulmonary veno-occlusive disease and its impact on survival.Rev Esp Cardiol (Engl Ed). 2016; 69:1011–1019. doi: 10.1016/j.rec.2016.03.029MedlineGoogle Scholar3. Quezada Loaiza CA, Velázquez Martín MT, Jiménez López-Guarch C, Ruiz Cano MJ, Navas Tejedor P, Carreira PE, Flox Camacho Á, de Pablo Gafas A, Delgado Jiménez JF, Gómez Sánchez MÁ, Escribano Subías P. Trends in pulmonary hypertension over a period of 30 years: experience from a single referral centre.Rev Esp Cardiol. 2017; 70:915–923. doi: 10.1016/j.rec.2016.12.044CrossrefMedlineGoogle Scholar4. Hernández González I, Ortiz Bautista C, de Pablo Gafas A, Pérez Núñez M, Ochoa Parra N, García-Aranda Domínguez B, Velázquez Martín MT, Escribano Subias MP. Clinical phenotype and outcomes of heritable and sporadic pulmonary venooclusive disease: experience from a single referral centre.Rev Esp Cardiol. 2017; 70(suppl 1):237.Google Scholar5. Montani D, Girerd B, Jaïs X, Levy M, Amar D, Savale L, Dorfmüller P, Seferian A, Lau EM, Eyries M, Le Pavec J, Parent F, Bonnet D, Soubrier F, Fadel E, Sitbon O, Simonneau G, Humbert M. Clinical phenotypes and outcomes of heritable and sporadic pulmonary veno-occlusive disease: a population based study.Lancet Respir Med. 2017; 5:125–134. doi: 10.1016/S2213-2600(16)30438-6.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Hernandez-Gonzalez I, Tenorio J, Palomino-Doza J, Martinez Meñaca A, Morales Ruiz R, Lago-Docampo M, Valverde Gomez M, Gomez Roman J, Enguita Valls A, Perez-Olivares C, Valverde D, Gil Carbonell J, Garrido-Lestache Rodríguez-Monte E, del Cerro M, Lapunzina P, Escribano-Subias P and West J (2020) Clinical heterogeneity of Pulmonary Arterial Hypertension associated with variants in TBX4, PLOS ONE, 10.1371/journal.pone.0232216, 15:4, (e0232216) Pérez Núñez M, Alonso Charterina S, Pérez-Olivares C, Revilla Ostolaza Y, Morales Ruiz R, Enguita Valls A, Tenorio J, Gallego Zazo N, De Pablo Gafas A, Lapunzina P, Rodríguez Chaverri A and Escribano Subías P (2021) Radiological Findings in Multidetector Computed Tomography (MDCT) of Hereditary and Sporadic Pulmonary Veno-Occlusive Disease: Certainties and Uncertainties, Diagnostics, 10.3390/diagnostics11010141, 11:1, (141) May 29, 2018Vol 137, Issue 22 Advertisement Article InformationMetrics © 2018 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.118.033641PMID: 29844074 Originally publishedMay 29, 2018 PDF download Advertisement SubjectsMortality/SurvivalPrognosisPulmonary Hypertension
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