Rapid genetic diagnosis of neonatal persistent pulmonary hypertension with a novel FOXF1 mutation.

Abstract

A male baby weighing 2270 g was spontaneously delivered at term in a local hospital with Apgar score of 9–10 and normal prenatal examinations. The neonate developed respiratory distress with desaturation within 12 h after birth and received noninvasive positive pressure ventilation for progressive cyanosis. Due to increased oxygen requirement, persistent pulmonary hypertension of the newborn (PPHN) was confirmed by echocardiographic findings, including severe tricuspid valve regurgitation (TR) with dilations of the right atrium and ventricle. The newborn was then transferred to our hospital for severe hypoxemic shock under intubation with ventilatory support and inotrope use. After arrival, physical examination revealed a cyanotically distressed newborn with grade II systolic murmurs detected in the precordial area, and echocardiography showed normal cardiac structure, severe TR with pressure gradient of 70 mmHg, and a large patent ductus arteriosus (PDA) with left-to-right shunt. Immediately, the patient received venoarterial extracorporeal membrane oxygenation (VA ECMO) for unstable hemodynamics and inhaled NO, diuretics, and antibiotics for possible infection and PPHN. After meticulous care and removal of ECMO, he was extubated five days later. However, desaturation and bradycardia while crying were noted 6 h later, and reintubation was immediately performed due to the echocardiography finding of a large right-to-left shunt PDA. With inhaled NO and catecholamine use, the patient still experienced desaturation and bradycardia and was stabilized by cardiopulmonary resuscitation, followed by VA ECMO support. A rapid genetic study by whole-exome sequencing (WES) identified a novel de novo heterogeneous pathogenic variant in FOXF1 (NM_001451.2 c.320_322del, p.Ile107del) within five days after blood sampling (Fig. 1). The mutant allele was conserved evolutionarily and was predicted to be pathogenic by Mutation Tester (Fig. 1), implying a diagnosis of alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV). Further examination with whole-body computed tomography showed left-sided massive intracranial hemorrhage without gastrointestinal, genitourinary, or cardiovascular anomalies. After explanation of the poor prognosis to parents, ECMO was removed, and he died at the age of 18 days. Restricted autopsy was performed, and the pathologic finding confirmed the diagnosis of ACD/MPV (Fig. 1). ACD/MPV was first described in 1981 based on the autopsy of a term neonate with severe respiratory distress within 12 h after birth, who died at 40 h of life despite adequate treatment.1Janney C.G. Askin F.B. Kuhn C. 3rd. Congenital alveolar capillary dysplasia - an unusual cause of respiratory distress in the newborn.Am J Clin Pathol. 1981; 76: 722-727Crossref PubMed Google Scholar With an estimated incidence of 1/100,000–200,000 in western countries and 100% mortality, most ACD/MPV patients had respiratory distress with hypoxemia in the first day of life, and gastrointestinal, urogenital, or cardiovascular anomalies were identified in 80% of patients.2Slot E. Edel G. Cutz E. van Heijst A. Post M. Schnater M. et al.Alveolar capillary dysplasia with misalignment of the pulmonary veins: clinical, histological, and genetic aspects.Pulm Circ. 2018; 8 (2045894018795143)Crossref Scopus (25) Google Scholar In addition to the pathologic diagnosis, 60% of ACD/MPV patients harbored FOXF1 mutations, providing the genetic-based diagnosis.2Slot E. Edel G. Cutz E. van Heijst A. Post M. Schnater M. et al.Alveolar capillary dysplasia with misalignment of the pulmonary veins: clinical, histological, and genetic aspects.Pulm Circ. 2018; 8 (2045894018795143)Crossref Scopus (25) Google Scholar To our knowledge, rather than an invasive pathological diagnosis, this was the first genetic diagnosis of ACD/MVP in Taiwan, and a novel pathogenic mutation was identified in FOXF1. Our previous report showed that WES provided timely diagnosis with a 52.5% yield rate, which helps clinicians in shared decision-making to avoid unnecessary treatment.3Wu E.T. Hwu W.L. Chien Y.H. Hsu C. Chen T.F. Chen N.Q. et al.Critical trio exome benefits in-time decision-making for pediatric patients with severe illnesses.Pediatr Crit Care Med. 2019; 20: 1021-1026Crossref PubMed Scopus (16) Google Scholar In conclusion, this genetically and pathologically confirmed case of ACD/MPV reminds clinicians of the rare diagnosis for severe PPHN, and a rapid genetic study by WES can provide a timely diagnosis to guide clinical management.