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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.

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Background

Pediatric pulmonary arterial hypertension (PAH) is a rare disease with high mortality. Left-to-right shunting, lung diseases and genetic disorders are most common causes leading to PAH in children[1]. Filamin A (FLNA) is a 280-kD protein widely expressed in the body and regulating cell shape and migration. Among the broad range of diseases associated with FLNA mutation, lung diseases have been seen in most patients, such as pneumonia, and respiratory failure. In addition, PAH in pediatric patients with FLNA mutation was fatal despite of their congenital heart disease (CHD), and required early lung transplantation[2]. Here we report a female patient with FLNA mutation, who presented with recurrent pneumonia, arterial septal defect (ASD), mild developmental delay and rapidly progressive PAH.

Case presentation

An 8-month-old female patient was referred to our center due to severe cough, short of breath, fatigue and fever. The patient had nine episodes of pneumonia and cardiomegaly since she was two-month-old. Physical examination revealed cleft lip, which was surgical repaired when she was 6 months old, and cleft palate. Her finger oxygen saturation was 94%. Transthoracic echocardiography showed there was a 0.5 × 0.6 cm ASD with a 2.4 cm right atrium. Laboratory test showed NT-proBNP was 963 pg/ml. Some of autoimmune antibodies, including dsDNA-antibody, SSA/Ro 60kD antibody, anti-cardiolipid antibody, and anti-β2GPI antibody, were positive. Erythrocyte sedimentation rate (ESR) and C-reaction protein (CRP) were normal. IgG was slightly elevated at 18.40 g/L, and C3 was 0.83 g/L. Significantly increased pulmonary vascular resistance (PVR, 17 WU) was seen in her first right heart catheterization despite of the slightly increased pulmonary artery pressure (PAP, 38/17/24 mmHg). Oral furosemide and antisterone were given since then. She was also suggested to inhale oxygen at home even though she maintained her daily activities without additional requirement of oxygen. The patient was re-hospitalized several times because of recurrent pneumonia and heart failure thereafter. Her finger oxygen saturation dropped to 75% at lowest, and stayed at 95% or higher when given nasal catheter oxygen inhalation. Hemodynamic parameters turned worse in the second measurements, where PAP increased along with PVR (PAP, 100/50/67 mmHg; PVR, 42 WU). Further examination included chest computed tomography (CT) scan. CT showed infiltration in upper lobes at both sides (Fig. 1a, b), and lung atelectasis in left upper lobe (Fig. 1b). Pulmonary artery and right atrium were significantly dilated (Fig. 1b, star; d). No thrombosis was seen in pulmonary artery. The patient and her parents received whole exome sequencing test. A new splicing variant (exon34: c.5417-1G > A, p.-) in the FLNA gene was found only in the patient. Diuretics, dopamine, and oral Bosentan (12.5 mg twice daily) were used to relieve her symptoms. No intubation or other advanced life supports were required during hospitalizations. Patient’s family refused any further intervention during her last hospitalization at age of 2 years. She became significantly cyanosis after last discharge. Unfortunately, the patient didn’t response well to medication therapy, and she died from a severe pneumonia 5 months later.

Fig. 1
figure1

Chest CT. a Infiltration in both upper lobes of lung; b Main pulmonary artery was dilated (*). There was atelectasis in left upper lobe of lung; c Slightly infiltration in lower lobes; d Dilated right atrium. 

Discussion and conclusions

PAH is a clinical symptom characterized by increased pulmonary artery pressure more than 25 mmHg. Pediatric PAH shares similarities with adult PAH in some etiology. However, specialists have addressed that pediatric patients have higher prevalence of idiopathic PAH, PAH associated with congenital heart disease (CHD), and pulmonary disorders [3]. With the attempt to explore mechanism underlying, next generation sequencing reveals the genetic defects associated with pediatric PAH.

FLNA gene was firstly related to neurologic disorder defect periventricular heterotopia (PVNH) in 1998 [4]. A broad range of diseases were observed with FLNA mutation thereafter, such as otopalatodigital syndrome (OPD) [5], frontometaphyseal dysplasia (FMD) [6], and Melnick-Needles syndrome (MNS) [5], FG syndrome (FGS), chronic idiopathic intestinal pseudoobstruction (CIIP) [7], cardiac valvular disease (CVD) [8], and others. However, lung disease was noticed in patients with FLNA mutation first by de Wit MC, et al. in 2010 [9]. Patients with lung disease related to FLNA mutation had higher incidence of pneumonia, lung developmental defects and respiratory failure, however, PAH were uncommon [10,11,12]. Among the reported cases, there were 19 of them having early onset PAH (including this case). Their clinical characteristics are summarized in Table 1. Developmental delay was observed in 6 patients, while CHD were seen in all. Fourteen patients had surgical correction of CHD, 6 of which had lung transplantation at the same time. Only one patient died after lung transplantation, nonetheless, mortality among pediatric PAH patients with FLNA mutation is as high as 35%.

Table 1 Summary of pediatric PAH associated with FLNA mutation

Interstitial lung disease (ILD) may cause PAH in pediatric patients, and FLNA mutation has been called for attention in ILD [17], but pediatric PAH patients with FLNA mutation don’t always present with characteristically pulmonary pathologic changes of ILD. Moreover, high prevalence of CHD in patients with FLNA mutation may confuse the real cause of the rapidly progressive PAH [19]. In our experience, genetic testing is more helpful to offer early-stage and accurate diagnose. Moreover, lung transplantation would bring higher survival in these patients based on previous reports.

Availability of data and materials

The datasets used in current study are available from the corresponding author on reasonable request.

Abbreviations

FLNA:

Filamin A

CHD:

Congenital heart disease

ASD:

Atrial septal defect

VSD:

Ventricle septal defect

PDA:

Patent ductus arteriosus

PFO:

Patent foramen ovale

RHC:

Right heart catheterization

PAH:

Pulmonary arterial hypertension

NT-proBNP:

N-terminal prohormone of brain natriuretic peptide

ESR:

Erythrocyte sedimentation rate

CRP:

C-reaction protein

PVR:

Pulmonary vascular resistance

WU:

Wood unites

PAP:

Pulmonary artery pressure

CT:

Computed tomography

PVNH:

Periventricular heterotopia

OPD:

Otopalatodigital syndrome

FMD:

Frontometaphyseal dysplasia

MNS:

Melnick-Needles syndrome

FGS:

FG syndrome

CIIP:

Chronic idiopathic intestinal pseudoobstruction

CVD:

Cardiac valvular disease

References

  1. 1.

    Morrell NW, Aldred MA, Chung WK, Elliott CG, Nichols WC, Soubrier F, Trembath RC, Loyd JE. Genetics and genomics of pulmonary arterial hypertension. Eur Respir J. 2019;53(1).

  2. 2.

    Pelizzo G, Collura M, Puglisi A, Pappalardo MP, Agolini E, Novelli A, Piccione M, Cacace C, Bussani R, Corsello G, et al. Congenital emphysematous lung disease associated with a novel Filamin A mutation. Case report and literature review. BMC Pediatr. 2019;19(1):86.

    Article  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Rosenzweig EB, Abman SH, Adatia I, Beghetti M, Bonnet D, Haworth S, Ivy DD, Berger RMF. Paediatric pulmonary arterial hypertension: updates on definition, classification, diagnostics and management. Eur Respir J. 2019;53(1).

  4. 4.

    Fox JW, Lamperti ED, Eksioglu YZ, Hong SE, Feng Y, Graham DA, Scheffer IE, Dobyns WB, Hirsch BA, Radtke RA, et al. Mutations in filamin 1 prevent migration of cerebral cortical neurons in human periventricular heterotopia. Neuron. 1998;21(6):1315–25.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Robertson SP, Twigg SR, Sutherland-Smith AJ, Biancalana V, Gorlin RJ, Horn D, Kenwrick SJ, Kim CA, Morava E, Newbury-Ecob R, et al. Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans. Nat Genet. 2003;33(4):487–91.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Zenker M, Nahrlich L, Sticht H, Reis A, Horn D. Genotype-epigenotype-phenotype correlations in females with frontometaphyseal dysplasia. Am J Med Genet A. 2006;140(10):1069–73.

    Article  Google Scholar 

  7. 7.

    Gargiulo A, Auricchio R, Barone MV, Cotugno G, Reardon W, Milla PJ, Ballabio A, Ciccodicola A, Auricchio A. Filamin A is mutated in X-linked chronic idiopathic intestinal pseudo-obstruction with central nervous system involvement. Am J Hum Genet. 2007;80(4):751–8.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Kyndt F, Gueffet JP, Probst V, Jaafar P, Legendre A, Le Bouffant F, Toquet C, Roy E, McGregor L, Lynch SA, et al. Mutations in the gene encoding filamin A as a cause for familial cardiac valvular dystrophy. Circulation. 2007;115(1):40–9.

    CAS  Article  Google Scholar 

  9. 9.

    de Wit MC, Tiddens HA, de Coo IF, Mancini GM. Lung disease in FLNA mutation: confirmatory report. Eur J Med Genet. 2011;54(3):299–300.

    Article  PubMed  Google Scholar 

  10. 10.

    Shelmerdine SC, Semple T, Wallis C, Aurora P, Moledina S, Ashworth MT, Owens CM. Filamin A (FLNA) mutation-A newcomer to the childhood interstitial lung disease (ChILD) classification. Pediatr Pulmonol. 2017;52(10):1306–15.

    Article  PubMed  Google Scholar 

  11. 11.

    Eltahir S, Ahmad KS, Al-Balawi MM, Bukhamsien H, Al-Mobaireek K, Alotaibi W, Al-Shamrani A. Lung disease associated with filamin A gene mutation: a case report. J Med Case Rep. 2016;10:97.

    Article  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Lord A, Shapiro AJ, Saint-Martin C, Claveau M, Melancon S, Wintermark P. Filamin A mutation may be associated with diffuse lung disease mimicking bronchopulmonary dysplasia in premature newborns. Respir Care. 2014;59(11):e171–7.

    Article  PubMed  Google Scholar 

  13. 13.

    Masurel-Paulet A, Haan E, Thompson EM, Goizet C, Thauvin-Robinet C, Tai A, Kennedy D, Smith G, Khong TY, Sole G, et al. Lung disease associated with periventricular nodular heterotopia and an FLNA mutation. Eur J Med Genet. 2011;54(1):25–8.

    Article  PubMed  Google Scholar 

  14. 14.

    Reinstein E, Frentz S, Morgan T, Garcia-Minaur S, Leventer RJ, McGillivray G, Pariani M, van der Steen A, Pope M, Holder-Espinasse M, et al. Vascular and connective tissue anomalies associated with X-linked periventricular heterotopia due to mutations in Filamin A. Eur J Hum Genet. 2013;21(5):494–502.

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Burrage LC, Guillerman RP, Das S, Singh S, Schady DA, Morris SA, Walkiewicz M, Schecter MG, Heinle JS, Lotze TE, et al. Lung transplantation for FLNA-associated progressive lung disease. J Pediatr. 2017;186:118–123 e116.

    Article  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Kinane TB, Lin AE, Lahoud-Rahme M, Westra SJ, Mark EJ. Case 4-2017. A 2-month-old girl with growth retardation and respiratory failure. N Engl J Med. 2017;376(6):562–74.

    Article  PubMed  Google Scholar 

  17. 17.

    Sasaki E, Byrne AT, Phelan E, Cox DW, Reardon W. A review of filamin A mutations and associated interstitial lung disease. Eur J Pediatr. 2019;178(2):121–9.

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Cannaerts E, Shukla A, Hasanhodzic M, Alaerts M, Schepers D, Van Laer L, Girisha KM, Hojsak I, Loeys B, Verstraeten A. FLNA mutations in surviving males presenting with connective tissue findings: two new case reports and review of the literature. BMC Med Genet. 2018;19(1):140.

    Article  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Demirel N, Ochoa R, Dishop MK, Holm T, Gershan W, Brottman G. Respiratory distress in a 2-month-old infant: is the primary cause cardiac, pulmonary or both? Respir Med Case Rep. 2018;25:61–5.

    PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We would like to thank the patient’s family for their consent to publish this report. We also appreciated our medical team and their efforts to treat the patient.

Funding

The authors declare that they did not receive any source of funding for the preparation of the manuscript.

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Authors

Contributions

XD, SL, XZ management of the patient, drafting the article, critical revision of the article; QQ, BJ, MY literature review, critical revision of the article; H data collection; YW imaging evaluation; HZ, GZ critical revision of the article. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Xuan Zheng.

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The study was performed according to the Declaration of Helsinki. Written informed consent was obtained from the patient’s parents for publication of this case report and accompanying images.

Consent for publication

Written informed consent was obtained from the patient’s parents for publication of this case report and accompanying images.

Competing interests

The authors declare that they have no competing interests.

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Deng, X., Li, S., Qiu, Q. et al. Where the congenital heart disease meets the pulmonary arterial hypertension, FLNA matters: a case report and literature review. BMC Pediatr 20, 504 (2020). https://doi.org/10.1186/s12887-020-02393-2

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Keywords

  • Pulmonary arterial hypertension
  • Congenital heart disease
  • Filamin A