CASE 2:
A female neonate was born vaginally at 36 weeks’ gestation with right
full lip cleft. She was transported to our hospital due to cyanosis from
birth. Although the echocardiogram showed aortic valve regurgitation,
moderate pulmonary hypertension, and PDA; she was discharged without
desaturation at 11 days old. She was admitted with poor feeding at 4
weeks old, and her oxygen saturation in room air fell to 83%. Chest CT
showed partial atelectasis in dorsal predominance and most of the right
upper lobe. Lobular emphysematous changes with hyperinflation were
observed in both lungs. The echocardiogram revealed a 2.5-mm PDA with a
left-to-right shunt, and exacerbation of pulmonary hypertension.
Sildenafil was administered for pulmonary hypertension. Her respiratory
symptoms deteriorated, and she was intubated and ventilated. She was
briefly extubated, but she required reintubation due to respiratory
failure and ventilatory support. Cardiac catheterization revealed a
pulmonary artery pressure of 46/27 mmHg (mean, 36 mmHg). Pulmonary
hypertension was suspected as the cause of the recurring breathing
problems, so she underwent PDA ligation. She was successfully weaned off
the ventilator and discharged at 8 months old on 0.5 L/min of oxygen.
After the left-to-right shunt had closed, her NT-proBNP value reduced
from 8,973 pg/mL to 312 pg/mL. Whole exome sequencing analysis was
performed and detected a nonsense mutation
c.7231C>T:p.(Arg2411*) in the FLNA gene.
We report two girls with FLNA mutation and both ILD and left-to-right
shunts due to CHD who had difficulty in managing their respiration but
showed improved respiratory status after shunt closure. Partnership with
the cardiology, cardiovascular surgery, and intensive care departments
led to successful treatment.
Respiratory disorders associated with FLNA mutation can be lethal. Some
children have died of infection and respiratory failure, and others have
received lung transplantation in Europe and the United
States[2, 3].Our cases were primarily treated as
hypoxia due to lung disease and the patients initially were administered
with oxygen and pulmonary vasodilators. However, the respiratory status
of both patients worsened, which could be attributed to not only ILD but
also pulmonary over-circulation.
Pathological findings of the lung associated with FLNA mutations have
been reported in the lung parenchyma with alveolar simplification and
pulmonary artery curvature[3]. The increase in
volume loading for poor vascular beds is seen in ILD with pulmonary
hypertension. It is our opinion that as filamin A is capable of
repairing tissues, its mutation could result in lung damage. Both
patients showed improved breathing conditions after closing the small
left-to-right shunts and were consequently discharged.
Pulmonary hypertension is a common comorbidity with ILD and is
associated with a substantially increased mortality
risk[4]. Our cases were complicated by pulmonary
hypertension and CHD. High NT-proBNP levels are associated with a poor
prognosis in ILD patients[5]. The NT-proBNP value
of our cases decreased following shunt closure. The postoperative
reduction in the cardiac volume load caused by the shunt suggested that
pulmonary congestion improved, suggesting that NT-proBNP could also be
used as a biomarker in this disease.
Despite the seemingly unrelated treatment between respiratory failure
and heart failure, the outcome of our cases suggests that aggressive
shunt closure intervention, even if the shunt is small, can improve the
condition of lung damage and the prognosis of patients with lung disease
associated with FLNA mutation.
Acknowledgements: This work was supported by the Initiative on Rare and
Undiagnosed Diseases(19ek0109301) and MGeND (Medical Genomics Japan
Variant Database(19kk020514) from the Japan Agency for Medical Research
and Development and JSPS KAKENHI 20K08270(K.K.).
Conflict of interest: None
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Image legend: Axial chest computed tomography images of Case 1 of a) the
upper b) and lower at four months of age show partial atelectasis in the
bilateral dorsal region and hyperinflation in the upper lobe. Serial
chest radiographs at c) four months, d) eight months, and e) one year of
age reveal improvement in hyperinflation and atelectasis.