Lung Transplantation for FLNA -Associated Progressive Lung Disease

Abstract

OBJECTIVE To review the outcome of patients with pathogenic variants in FLNA and progressive lung disease requiring lung transplantation. STUDY DESIGN We conducted a retrospective chart review of six female infants with heterozygous presumed loss of function pathogenic variants in FLNA whose initial presentation was early and progressive respiratory failure. RESULTS Each patient received lung transplantation at an average age of 11 months (range: 5 to 15 months). All patients had pulmonary arterial hypertension and chronic respiratory failure requiring tracheostomy and escalating levels of ventilator support prior to transplantation. All six patients survived initial lung transplantation; however, one patient died after a subsequent heart-lung transplant. The remaining five patients are living unrestricted lives on chronic immunosuppression at most recent follow-up (range: 19 months to 11.3 years post-transplantation). However, in all patients, severe ascending aortic dilation has been observed with aortic regurgitation. CONCLUSIONS Respiratory failure secondary to progressive obstructive lung disease during infancy may be the presenting phenotype of FLNA-associated periventricular nodular heterotopia. We describe the largest cohort of patients with progressive respiratory failure related to a pathogenic variant in FLNA and present lung transplantation as a viable therapeutic option for this group of patients.

Congenital emphysematous lung disease associated with a novel Filamin A mutation. Case report and literature review

“…Therapy with bronchodilatatorFemaleDeletion c.2190_2193delTTAC (p.Tyr731Alafs*10)Viral infectionsRight upper and middle, left upper lobe over-inflation; Coarse septal thickening; Lower lobe atelectasis383 monthsNoneNot performedAge 6 years. Supplementary oxygen supportBurrage et al, 2017 [14]FemaleDuplication c.4596dupG (p.Ser1533Glufs*12)Progressive lung diseaseIn all patients, severe pulmonary hyperinflation and hyperlucency with peripheral pulmonary vascular attenuation with parahilar and dependent lower lobe atelectasis and central pulmonary artery enlargement.In all patient, pulmonary arterial hypertension was also diagnosed.392–4 monthsPDA ligationYesLung transplantation in all.Five survivors at 19 months, 3 years, 4 years, 5.1 years, and 11.3 years respectively, post- follow-up. One died at 3 yearsFemaleMissense mutationc.5290G > A (p.Ala1764Thr)Progressive lung disease40neonatalPDA ligationYesFemaleDuplication c.4446_4447dupAT (p.Leu1483Tyrfs*19)Progressive lung disease38neonatalPDA ligationYesFemaleDuplication c.4617_4618delGC (p.Leu1540Alafs*4)Progressive lung disease34neonatalPDA ligationYesFemaleDuplication c.6585dupT (p.Pro2196Serfs*3)Progressive lung disease39neonatalPDA ligationYesFemaleMissense mutation c.2807A > G (p.Lys936Arg)Progressive lung disease38neonatalPDA ligationYesKinane et al 2017 [15]FemaleDeletion c.6577delC (p.Arg2193Alafs*14)Diffuse pulmonary abnormalitiesGround glass opacities, area of hyperacration, pulmonary hypertension3930 dayPDA ligationYesSasaki et al 2018 [16]FemaleDeletion c.1709_1712del (p.Val570Alafs*105)Progressive lung diseaseDiffuse bilateral groung-glass opacification throughout the lung, interstitial thickening, cystic changes371 monthNoneYesDied at 4 monthsMaleSplice site deletion c.6670-1delGSeveral episodes of profound desaturationBilateral dependent and subsegmental atelectasis, scattered opacity, interstitial thickening32day of live 1NoneYes…”

“…Perinatal lethality occured in six of these reported cases (24%; 5 females and 1 male); in all cases, cardiopathies were also found [2–10, 13–15, 18]. As reported in Table 1, a large spectrum of FLNA mutations are detected in patients with pulmonary disease, including missense mutations [9, 13, 14, 19], nonsense mutations [2, 20], deletions [13, 15, 16, 21], duplications [13, 14, 18, 21], truncating mutations [17, 21], and frameshift mutations [14].…”

“…However, one reported patient developed progressive obstructive lung disease at the age of 38 years [20]. The clinical presentation of lung involvement was variable, ranging from multiple episodes of intercurrent pulmonary infections [13], to progressive severe pulmonary disease [13, 14, 16–18, 20]. A variable outcome and management course were reported in the previously reported cases.…”

Case 28-2019: A 22-Year-Old Woman with Dyspnea and Chest Pain

“…There is emerging recognition of a respiratory phenotype of this genetic disorder that occurs in infancy and has unique features, including cardiovascular manifestations (aortic-valve disease and dilatation, patent ductus arteriosus, and pulmonary hypertension) and pulmonary manifestations (emphysema and lung cysts alternating with atelectasis and tracheobronchomalacia or stenosis). [14][15][16][17][18][19][20][21] A recent review summarizes the cases reported in the literature to date. 22 Thus far, at least 18 cases of FLNA-related disease with this respiratory phenotype have been identified in infancy.…”

“…20 Since then, 17 additional case reports of lung disease have been described in the literature, but more cases are being recognized in the clinic, particularly in lung transplantation centers. [15][16][17][18][19][20][21][22]27 Of the 18 patients, 15 were female, which suggests that males are more likely to be severely affected and are less likely to survive to birth. All but 1 of these patients were born at full term.…”