Heterogeneous Pulmonary Phenotypes in Filamin A Mutation-Related Lung Disease
Publication: Pediatric Allergy, Immunology, and Pulmonology
Volume 34, Issue Number 1
Abstract
Background: Interstitial lung disease (ILD) has been recently reported in a few patients with pathogenic variants in the Filamin A (FLNA) gene with variable presentation and prognosis. This study evaluated the respiratory manifestations and clinical features in children with FLNA disease.
Methods: We conducted a retrospective review of pediatric patients with variants in FLNA in a tertiary children's hospital. The clinical features, genotype, management, and outcomes were analyzed.
Results: We identified 9 patients with variants in FLNA aged 15 months to 24 years, 4 females and 5 males. Six patients had abnormal chest imaging ranging from mild interstitial prominence to atelectasis, interstitial densities, and hyperinflation. Three patients with ILD presented during the neonatal period or early infancy with respiratory distress or respiratory failure requiring supplemental oxygen or assisted ventilation via tracheostomy. We report male twins with the same FLNA variant and lung disease, but different ages and clinical features at presentation eventually culminating in respiratory failure requiring assisted ventilation. All patients had FLNA variants identified by FLNA sequencing, had abnormal echocardiograms, and none of the patients underwent lung biopsy or lung transplantation. The outcomes were variable and could be as severe as chronic respiratory failure.
Conclusion: The wide spectrum of respiratory manifestations and abnormal chest imaging in our study highlights the importance of evaluation for lung disease in patients with variants in FLNA. FLNA sequencing in suspected cases with ILD may obviate the need for a lung biopsy, prompt surveillance for progressive lung disease, and evaluation for associated clinical features.
Get full access to this article
View all available purchase options and get full access to this article.
References
1. Sasaki E, Byrne AT, Phelan E, et al. A review of filamin A mutations and associated interstitial lung disease. Eur J Pediatr 2019; 178:121–129.
2. Shelmerdine SC, Semple T, Wallis C, et al. Filamin A (FLNA) mutation-A newcomer to the childhood interstitial lung disease (ChILD) classification. Pediatr Pulmonol 2017; 52:1306–1315.
3. Burrage LC, Guillerman RP, Das S, et al. Lung transplantation for FLNA-associated progressive lung disease. J Pediatr 2017; 186:118–123.e6.
4. Masurel-Paulet A, Haan E, Thompson EM, et al. Lung disease associated with periventricular nodular heterotopia and an FLNA mutation. Eur J Med Genet 2011; 54:25–28.
5. de Wit MCY, Tiddens HAWM, de Coo IFM, et al. Lung disease in FLNA mutation: confirmatory report. Eur J Med Genet 2011; 54:299–300.
6. Lord A, Shapiro AJ, Saint-Martin C, et al. Filamin A mutation may be associated with diffuse lung disease mimicking bronchopulmonary dysplasia in premature newborns. Respir Care 2014; 59:e171–e177.
7. Demirel N, Ochoa R, Dishop MK, et al. Respiratory distress in a 2-month-old infant: is the primary cause cardiac, pulmonary or both? Respir Med Case Rep 2018; 25:61–65.
8. Pelizzo G, Collura M, Puglisi A, et al. Congenital emphysematous lung disease associated with a novel Filamin A mutation. Case report and literature review. BMC Pediatr 2019; 19:86.
9. Yoshii K, Matsumoto H, Hirasawa K, et al. Microdeletion in Xq28 with a polymorphic inversion in a patient with FLNA-associated progressive lung disease. Respir Investig 2019; 57:395–398.
10. Lange M, Kasper B, Bohring A, et al. 47 patients with FLNA associated periventricular nodular heterotopia. Orphanet J Rare Dis 2015; 10:134.
11. Wade EM, Halliday BJ, Jenkins ZA, et al. The X-linked filaminopathies: synergistic insights from clinical and molecular analysis. Hum Mutat 2020; 41:865–883.
12. Gérard-Blanluet M, Sheen V, Machinis K, et al. Bilateral periventricular heterotopias in an X-linked dominant transmission in a family with two affected males. Am J Med Genet A 2006; 140:1041–1046.
13. Kurland G, Deterding RR, Hagood JS, et al. An official American Thoracic Society clinical practice guideline: classification, evaluation, and management of childhood interstitial lung disease in infancy. Am J Respir Crit Care Med 2013; 188:376–394.
14. Kremer TM, Lindsay ME, Kinane TB, et al. Case 28-2019: a 22-year-old woman with dyspnea and chest pain. N Engl J Med 2019; 381:1059–1067.
15. Calcaterra V, Avanzini MA, Mantelli M, et al. A case report on filamin A gene mutation and progressive pulmonary disease in an infant: a lung tissued derived mesenchymal stem cell study. Medicine (Baltimore) 2018; 97:e13033.
16. Eltahir S, Ahmad KS, Al-Balawi MM, et al. Lung disease associated with filamin A gene mutation: a case report. J Med Case Rep 2016; 10:97.
17. Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015; 17:405–424.
18. Karczewski KJ, Francioli LC, Tiao G, et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature 2020; 581:434–443.
19. Ren tzsch P, Witten D, Cooper GM, et al. CADD: predicting the deleteriousness of variants throughout the human genome. Nucleic Acids Res 2019; 47(D1):D886–D894.
20. Kinane TB, Lin AE, Lahoud-Rahme M, et al. Case 4-2017. A 2-month-old girl with growth retardation and respiratory failure. N Engl J Med 2017; 376:562–574.
21. Chen MH, Choudhury S, Hirata M, et al. Thoracic aortic aneurysm in patients with loss of function Filamin A mutations: clinical characterization, genetics, and recommendations. Am J Med Genet A 2018; 176:337–350.
22. MacCarrick G, Black JH 3rd, Bowdin S, et al. Loeys-Dietz syndrome: a primer for diagnosis and management. Genet Med 2014; 16:576–587.
23. Nurden P, Debili N, Coupry I, et al. Thrombocytopenia resulting from mutations in filamin A can be expressed as an isolated syndrome. Blood 2011; 118:5928–5937.
24. Chen MH, Walsh CA. FLNA-related periventricular nodular heterotopia. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews. Seattle: University of Washington, 2015. Available at https://www.ncbi.nlm.nih.gov/books/NBK1213/ (accessed December 7, 2020).
Information & Authors
Information
Published In
Pediatric Allergy, Immunology, and Pulmonology
Volume 34 • Issue Number 1 • March 2021
Pages: 7 - 14
PubMed: 33734874
Copyright
Copyright 2021, Mary Ann Liebert, Inc., publishers.
History
Published online: 17 March 2021
Published in print: March 2021
Accepted: 2 January 2021
Received: 16 September 2020
Topics
Authors
Author Disclosure Statement
No competing financial interests exist.
Funding Information
No funding was received for this article.
Metrics & Citations
Metrics
Citations
Export Citation
Export citation
Select the format you want to export the citations of this publication.
View Options
Get Access
Access content
To read the fulltext, please use one of the options below to sign in or purchase access.⚠ Society Access
If you are a member of a society that has access to this content please log in via your society website and then return to this publication.