Genotype–phenotype correlation in two Polish neonates with alveolar capillary dysplasia

Abstract

Background: Alveolar capillary dysplasia (ACD) is a rare cause of severe pulmonary hypertension and respiratory failure in neonates. The onset of ACD is usually preceded by a short asymptomatic period. The condition is refractory to all available therapies as it irreversibly affects development of the capillary bed in the lungs. The diagnosis of ACD is based on histopathological evaluation of lung biopsy or autopsy tissue or genetic testing of FOXF1 on chromosome 16q24.1. Here, we describe the first two Polish patients with ACD confirmed by histopathological and genetic examination. Case presentation: The patients were term neonates with high Apgar scores in the first minutes of life. They both were diagnosed prenatally with heart defects. Additionally, the first patient presented with omphalocele. The neonate slightly deteriorated around 12 th hour of life, but underwent surgical repair of omphalocele followed by mechanical ventilation. Due to further deterioration, therapy included inhaled nitric oxide (iNO), inotropes and surfactant administration. The second patient was treated with prostaglandin E1 since birth due to suspicion of aortic coarctation (CoA). After ruling out CoA in the 3 rd day of life, infusion of prostaglandin E1 was discountinued and immediately patient's condition worsened. Subsequent treatment included re-administration of prostaglandin E1, iNO and mechanical ventilation. Both patients presented with transient improvement after application of iNO, but died despite maximized therapy. They were histopathologically diagnosed post-mortem with ACD. Array comparative genomic hybridization in patient one and patient two revealed copy-number variant (CNV) deletions, respectively,~1.45 Mb in size involving FOXF1 and an~0.7 Mb in size involving FOXF1 enhancer and leaving FOXF1 intact. Conclusions: Both patients presented with a distinct course of ACD, extra-pulmonary manifestations and response to medications. Surgery and ceasing of prostaglandin E1 infusion should be considered as potential causes of this variability. We further highlight the necessity of thorough genetic testing and histopathological examination and propose immunostaining for CD31 and CD34 to facilitate the diagnostic process for better management of infants with ACD.

Role of nitric oxide in regulating epidermal permeability barrier function

“…6,7 Topical applications of a NO donor increase erythropoietin production in the kidney, 8 and inhalation of NO improves pulmonary hypertension in premature neonates. 9 In contrast, blockade of NO synthesis decreases T regulatory cells, worsens renal damage and increases blood pressure in rats. [10][11][12] Studies have also demonstrated an important regulatory role for NO in cutaneous functions.…”

Haploinsufficiencies of FOXF1, FOXC2 and FOXL1 genes originated from deleted 16q24.1q24.2 fragment related with alveolar capillary dysplasia with misalignment of pulmonary veins and lymphedema–distichiasis syndrome: relationship to phenotype

“…Combined with the abnormal results of multi-system malformations of the fetus such as congenital cardiac, lung, genitourinary and gastrointestinal anomalies, the diagnoses of ACD/MPV and LDS of the fetus were further de ned. In addition to our fetus, table 1 shows another 10 patients with a different fragment deletion in the 16q24.1q24.2 region and complete information, and the fragment sizes range from 0.9 Mb to 3.5 Mb, containing FOXF1, FOXL1 and FOXC2 genes, among which, two fetuses were from de novo mutation, four patients from maternal heredity, four patients from unknown origin, three females and seven males are enrolled from ve literatures [3,[9][10][11][12]. As is shown, the deleted sizes of 16q24.1q24.2 fragment are not proportional to phenotype severity and both the cardiac and renal anomalies are the two major symptoms during the fetal period, while the phenotypes of our fetus are the most serious, showing the changes of cardiopulmonary structure such as pulmonary artery dilatation, HLHS, complete AVSD, CAV, FOC, ASD, VSD; the upper pyloric obstruction manifestations; a hypodense mass in the left kidney.…”

“…In addition, about 50 to 75 percent of affected newborns have multiple-system abnormalities such as hypoplastic left heart syndrome (HLHS), intestinal malrotation (IM) [2]. In approximately 80-90% of ACD/MPV patients, heterozygous single nucleotide variants (SNVs) or copy number variant (CNV) deletions involving forkhead box F1 (FOXF1, OMIM 601089) and / or forkhead box C2 (FOXC2, OMIM 602402) at chromosome 16q24.1 have been found [3,4]. In this report, we describe a fetus featured as a series of diverse structural malformations.…”

Regulatory Role of Nitric Oxide in Cutaneous Inflammation

“…Conversely, inhibition of iNOS activity alleviates damage to both the liver and the kidneys in bile duct-ligated rats [8]. Moreover, inhalation of NO improves lung function in both humans and animals [9][10][11]. Likewise, supplemental NO can improve tolerance to aerobic and anaerobic exercise in untrained or moderately trained humans [12].…”