Where the congenital heart disease meets the pulmonary arterial hypertension, FLNA matters: a case report and literature review

Abstract

Background Pediatric patients with genetic disorders have a higher incidence of pulmonary arterial hypertension (PAH) regardless of their heart defects. Filamin A (FLNA) mutation is recently recognized to be associated with pediatric pulmonary disorders, however, the clinical courses of PAH related to the mutation were reported in limited cases. Here, we presented a case and pooled data for better understanding of the correlation between FLNA mutation and pediatric PAH. Case presentation The patient was a 8-month-old female with repeated episodes of pneumonia. Physical examination revealed cleft lip, cleft palate and developmental retardation. Imaging examination showed a small atrial septal defect (ASD), central pulmonary artery enlargement, left upper lobe of lung atelectasis, and pulmonary infiltration. Genetic test showed she carried a de novo pathogenic variant of FLNA gene (c.5417-1G > A, p.-). Oral medications didn’t slow the progression of PAH in the patient, and she died two years later. Conclusions FLNA mutation causes rare but progressive PAH in addition to a wide spectrum of congenital heart disease and other comorbidities in pediatric patients. We highly recommend genetic testing for pediatric patients when suspected with PAH. Given the high mortality in this group, lung transplantation may offer a better outcome.

Deficiency of filamin A in smooth muscle cells protects against hypoxia‑mediated pulmonary hypertension in mice

“…Mutations in FLNA can cause variable clinical features, including neurological, skeletal and cardiac dysfunction. Several reports have indicated that patients with FLNA mutations present with severe diffuse lung disease and severe pulmonary hypertension (23,24). Masurel-Paulet et al (25) reported that a male patient with a mosaic nonsense FLNA mutation presented with PAH and severe lung manifestations, and lung histology showed pan-pulmonary emphysema with a marked reduction of bronchial cartilage.…”

“…Hirashiki et al (9) reported that a family with heritable PAH carried a novel heterozygous splicing mutation in the FLNA gene. deng et al (23) summarized 19 pediatric cases with FLNA mutation; these patients presented with early onset PAH and all cases were complicated with congenital heart disease. Sasaki et al (26) summarized 18 cases of FLNA mutation and interstitial lung disease (ILD), 14 of which had PAH.…”

Microhomology-Mediated Nonhomologous End Joining Caused Rearrangement of EMD and FLNA in Emery-Dreifuss Muscular Dystrophy

“…It promotes orthogonal branching of actin filaments and links actin filaments to membrane glycoproteins with wide tissue expression. FLNA mutations can cause several severe syndromes, including periventricular nodular heterotopias, otopalatodigital syndromes, skeletal dysplasia, lung involvement, and cardiovascular abnormalities (Sankararaman et al, 2013;van der Werf et al, 2013;Deng et al, 2020;Meliota et al, 2021). In heterozygous females, the FLNA-related phenotype ranges from the absence of overall symptoms to severe manifestations.…”