Clinical Implications of the Genetic Background in Pediatric Pulmonary Arterial Hypertension: Data from the Spanish REHIPED Registry
Abstract
:1. Introduction
2. Methods
2.1. Study Population
2.2. Clinical Classification of Included Patients
2.3. Genetic Analyses
2.4. Outcomes
2.5. Statistics
3. Results
3.1. Genetic Findings in Idiopathic, Heritable PAH and TBX4 Forms
3.2. Findings in the PAH-CHD Population
3.3. Genetic Findings in the Pediatric PVOD Population
3.4. Genetic Analysis in Patients with Pulmonary Hypertension Associated with a Multisystemic Disorder
3.5. Differences in Survival Free of Death or Lung Transplantation according to the Clinical Classification and Genetics after Genetic Testing
4. Discussion
Limitations
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
References
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Total Cohort (n = 98) | Idiopathic (n = 28) | Heritable PAH (n = 18) | PVOD (n = 8) | PAH-CHD (n = 28) | TBX4 (n = 4) | PH-MSD (n = 12) | p Value | |
---|---|---|---|---|---|---|---|---|
Age—years (median—IQr) | 7.1 (1.5–14.7) | 6.3 (3.6–12.6) | 10.2 (5.6–17.7) | 15.7 (12.4–17.3) | 6.3 (2.1–10.5) | 0.4 (0.2–8.1) | 0.1 (0.1–0.4) | <0.001 |
Gender—male (n—%) | 43 (43.9) | 13 (46.4) | 6 (33.3) | 6 (75.0) | 10 (35.7) | 2 (50.0) | 6 (50.0) | 0.412 |
Descendance (n—%) | <0.001 * | |||||||
Arabic | 2 (2.1) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 2 (16.7) | |
Asiatic | 1 (1.0) | 0 (0.0) | 1 (5.6) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | |
Caucasian | 80 (81.6) | 27 (96.4) | 13 (72.2) | 2 (25.0) | 25 (89.3) | 4 (100.0) | 9 (75.0) | |
Romani | 8 (8.2) | 0 (0.0) | 2 (11.1) | 6 (75.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | |
Hispanic | 6 (6.1) | 1 (3.6) | 2 (11.1) | 0 (0.0) | 2 (7.1) | 0 (0.0) | 1 (8.3) | |
Black | 1 (1.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (3.6) | 0 (0.0) | 0 (0.0) | |
Mode of diagnosis—Index case vs. family screening (n—%) | 91 (92.9) | 28 (100.0) | 14 (77.8) | 5 (62.5) | 28 (100.0) | 4 (100.0) | 12 (100.0) | 0.001 * |
Baseline | ||||||||
hemodynamics | N = 82 | N = 27 | N = 16 | N = 7 | N= 21 | N = 3 | N = 8 | |
mPAP—mmHg (median—IQr) | 53.0 (40.0–63.0) | 54.0 (39.0–70.0) | 55.0 (42.5–68.5) | 44.0 (22.0–56.0) | 61.0 (46.0–65.0) | 39.0 (27.0–61.0) | 41.0 (32.0–49.5) | 0.081 |
RAP—mmHg (median—IQr) | 7.0 (5.0–10.0) | 7.0 (6.0–10.0) | 5.5 (2.0–11.5) | 7.0 (4.0–10.0) | 7.5 (6.0–10.0) | 11.0 (8.0–12.0) | 6.5 (5.0–12.0) | 0.814 |
iPVR—WU * m2 (median—IQr) | 11.3 (7.0–17.4) | 11.7 (7.9–16.9) | 15.6 (7.0–20.4) | 7.2 (3.2–13.7) | 11.8 (5.4–18.3) | 10.8 (3.8–16.2) | 8.6 (7.1–14.3) | 0.500 |
CI—L/m/m2 | 3.1 (2.0–4.0) | 3.1 (1.9–3.9) | 2.6 (2.0–3.2) | 2.3 (1.8–2.7) | 4.0 (3.1–4.8) | 6.4 (4.8–8.0) | 2.2 (1.6–3.1) | 0.007 |
(Median—IQr) | ||||||||
iPVR/ iSVR (median—IQr) | 0.9 (0.6–1.0) | 0.8 (0.6–0.9) | 0.8 (0.6–0.9) | N/A | 1.0 (0.6–1.3) | 0.8 (0.8–2.2) | 0.9 (0.8–1.0) | 0.178 |
Evaluated Genes | Number of Patients | PH Groups (IPAH, HPAH, PVOD, CHD, Others) | Diagnostic Yield of Genetic Analysis * | Results in IPAH/HPAH | Results in PVOD | Results in CHD-PAH | Age at Diagnosis of Mutation Carriers (Mean) | |
---|---|---|---|---|---|---|---|---|
Chida et al., 2012 [18] | BMPR2, ACVRL1, SMAD8, BMPR1B | 57 | 46/10/0/0/0 | 25/54 (46.3%) | BMPR2 n = 13/57 (33%) ALK1 n = 6/57 (13%) SMAD8 n = 1/57 (1.7%) BMPR1B n = 2 (3.5%) | NA | NA | 9.2 |
Levy et al., 2016 [19] | BMPR2, ACVRL1, TBX4, KCNK3, EIF2AK4 | 42 | 35/5/3/23 | 14/42 (33.3%) | BMPR2 n = 5/40 (12.5%) ACVRL1 n = 4/40 (10%) TBX4 n = 3/40 (7.5%) | EIF2AK4 2/3 (67.7%) | 0/23 (0%) | 8.3 |
Zhu et al., 2018 [9] | BMPR2, TBX4, ACVRL1, BMPR1B, CAV1, EIF2AK4, ENG, KCNK3, SMAD4, SMAD9 | 155 | 130/25 | 48/155 (31.0%) | BMPR2 n = 27/155 (17.7%) TBX4 n = 12/155 (7.4%) ACVRL1 n = 3/155 (1.9%), KCNK3 n = 2/155 (1.3%), SMAD9 n = 1/155 (0.6%) | N/A | N/A | |
Haarman et al., 2020 [20] | BMPR2, ACVRL1, CAV1, ENG, KCNK3, SMAD9, TBX4, EIF2AK4, VHL, MMACHC, CBLC, ACTA2 | 70 | 19/16/5/20/10 | 19/70 (27.1%) | BMPR2 n = 7/35 (20%) TBX4 n = 7/35 (20%) ACVRL1 n = 1/35 (2.8%), PTPN11 n = 2/35 (5.7%) KCNK3 n = 1/35 (2.8%) | EIF2AK4 2/5 (40.0%) | ACTA2 1/20 (5%) | 2.8 years TBX4 and14.0 years in BMPR2 carriers |
PPHNet Registry. 2021 [6] | BMPR2, ACVRL1, SMAD9, CAV1, KCNK3, TBX4, GDF2 | 40 FPAH | 0/40/0/0/0 | 36/40 heritable cases (90.0%) ** | BMPR2 n = 17/40 (43%) TBX4 n = 6/40 (15%) ALK/ENG n = 5/40 (5%) GDF2 n = 2 /40 (5%) CAV1 n = 1/40 (3%) KCNK3 n = 1 (3%) | N/A | N/A | N/A |
REHIPED registry (this study) | ABCC8, ACVRL1, BMPR1B, BMPR2, CAV1, CBLN2, CPS1, EIF2AK4, ENG, GDF2, KCNA5, KCNK3, MMACHC, NOTCH3, SARS2, SMAD1, SMAD4, SMAD5, SMAD9, TBX4, and TOPBP1 | 98 | 28/18/8/28/16 | 44/98 (44.9%) | BMPR2 n = 12/50 (24.0%) TBX4 n = 4/50 (8.0%) KCNK3 n = 2/50 (4.0%) ACVRL1 n = 1 (2.0%) BMPR1B n = 1 (2.0%) GDF2 n = 1 (2.0%) | EIF2AK4N = 8/8 (100.0%) | N = 7/28 (25.0%) - BMPR2 n = 3 - ENG n = 1 - CPS1 n = 1 - ABCC8/SMAD1 n = 1 - SOX17 n = 1 | 8.0 |
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Cruz-Utrilla, A.; Gallego-Zazo, N.; Tenorio-Castaño, J.A.; Guillén, I.; Torrent-Vernetta, A.; Moya-Bonora, A.; Labrandero, C.; Rodríguez-Monte, M.E.G.-L.; Rodríguez-Ogando, A.; Rey, M.d.M.R.V.D.; et al. Clinical Implications of the Genetic Background in Pediatric Pulmonary Arterial Hypertension: Data from the Spanish REHIPED Registry. Int. J. Mol. Sci. 2022, 23, 10433. https://doi.org/10.3390/ijms231810433
Cruz-Utrilla A, Gallego-Zazo N, Tenorio-Castaño JA, Guillén I, Torrent-Vernetta A, Moya-Bonora A, Labrandero C, Rodríguez-Monte MEG-L, Rodríguez-Ogando A, Rey MdMRVD, et al. Clinical Implications of the Genetic Background in Pediatric Pulmonary Arterial Hypertension: Data from the Spanish REHIPED Registry. International Journal of Molecular Sciences. 2022; 23(18):10433. https://doi.org/10.3390/ijms231810433
Chicago/Turabian StyleCruz-Utrilla, Alejandro, Natalia Gallego-Zazo, Jair Antonio Tenorio-Castaño, Inmaculada Guillén, Alba Torrent-Vernetta, Amparo Moya-Bonora, Carlos Labrandero, María Elvira Garrido-Lestache Rodríguez-Monte, Alejandro Rodríguez-Ogando, María del Mar Rodríguez Vázquez Del Rey, and et al. 2022. "Clinical Implications of the Genetic Background in Pediatric Pulmonary Arterial Hypertension: Data from the Spanish REHIPED Registry" International Journal of Molecular Sciences 23, no. 18: 10433. https://doi.org/10.3390/ijms231810433