Pulmonary hypoplasia is a rare congenital lung disorder characterized by the incomplete development of lung tissue. This condition can be classified as primary or secondary to other congenital anomalies, with primary pulmonary hypoplasia being considerably rarer than the secondary form. Severe cases often manifest as respiratory failure in the immediate newborn period. While secondary pulmonary hypoplasia is often antenatally detected, primary cases-such as ours-may evade prenatal imaging, presenting as refractory neonatal respiratory distress. Secondary causes, such as oligohydramnios and intrathoracic space-occupying lesions, should always be actively looked for in a suspected case of pulmonary hypoplasia. We present a case of a 31-week preterm neonate (1620 g) from India with normal antenatal scans who developed severe respiratory distress at birth, requiring invasive ventilation (peak inspiratory pressure, 16; positive end-expiratory pressure, 6). Chest asymmetry and mediastinal shift on imaging suggested hypoplasia. The baby was initially managed for congenital pneumonia with no response to antibiotics. There was a restriction of chest movements on the right side. The baby had severe respiratory acidosis and was kept on invasive ventilation. A complete homogeneous lung opacity with an ipsilateral shift of the trachea on chest radiography clinched the diagnosis, and it was further confirmed with a chest computed tomography scan. Two-dimensional echocardiography and ultrasound of the whole abdomen were normal. Given the rarity of primary pulmonary hypoplasia, this condition is often missed by pediatricians, leading to injudicious use of antibiotics and failure to correctly inform the parents about the condition. This case underscores the need for early computed tomography imaging in preterm neonates with unexplained respiratory failure to differentiate hypoplasia from infections, mitigate futile treatments, and guide parental counseling. Clinical features, a negative sepsis workup, and nonresponse to antibiotics can provide clues to diagnosing pulmonary hypoplasia. Simple bedside investigations, such as chest radiographs, should be heavily relied upon, especially in resource-poor settings.

Lethal lung developmental disorders (LLDDs), histologically classified as alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV), congenital alveolar dysplasia (CAD), acinar dysplasia (AcDys), and primary pulmonary hypoplasia (PH), are rare diseases associated with high neonatal mortality due to refractory respiratory failure. Although ACDMPV mostly results from single nucleotide variants (SNVs) or copy-number variants (CNVs) involving FOXF1, AcDys, CAD, and PH are often associated with abnormalities within TBX4 or FGF10. These genes interact in the SHH-FOXF1 and TBX4-FGF10 signaling network and are known regulators of lung development. Recent studies conducted in TBX4-, FGF10-, or FOXF1-deficient LLDD lungs revealed decreased expression of TMEM100 at the transcriptomic and immunohistochemical levels. Here, we present four new patients with genetically and histopathologically confirmed LLDD, including ACDMPV (n = 2), AcDys (n = 1), and PH (n = 1), in whom we detected a heterozygous variants involving FOXF1 (n = 2) or TBX4 (n = 2). Additional immunohistochemical (TMEM100) and qPCR analyses (TMEM100, TBX4, FOXF1) performed in lung tissues of these newborns revealed a significant reduction in TMEM100, TBX4, and FOXF1 expression. Our results confirm previous findings indicating the possible involvement of TMEM100 in FOXF1-TBX4-FGF10 molecular signaling that, when disrupted, may lead to LLDD.

Acute respiratory distress in a neonate is a potentially critical condition with multiple possible causes. Developmental etiologies are particularly problematic by virtue of being refractory to routine modalities for enhancing ventilation and oxygen exchange. Some genetic causes of neonatal respiratory distress, such as surfactant protein deficiencies and alveolar capillary dysplasia with misalignment of pulmonary veins, are well known, and sequencing panels have been formulated to detect them. We present a case of fatal neonatal respiratory insufficiency in which the autopsy showed primary pulmonary hypoplasia and congenital alveolar dysplasia. A sequencing panel of genes associated with heritable pulmonary disorders gave a normal result; however, a chromosomal microarray identified a heterozygous deletion encompassing the TBX4 gene on chromosome 17. Haploinsufficiency for TBX4 is a known cause of disturbed pulmonary development. This case illustrates why work-up of pulmonary developmental disorders must look beyond standard sequencing panels in some instances, if rare causes of pulmonary maldevelopment such as deletions causing haploinsufficiency are not to be missed.

Congenital bronchopulmonary malformations are relatively common and arise during various periods of morphogenesis. Although some are isolated or sporadic occurrences, others may result from single gene mutations or cytogenetic imbalances. Single gene mutations have been identified, which are etiologically related to primary pulmonary hypoplasia, lung segmentation defects as well as pulmonary vascular and lymphatic lesions. Functional defects in cystic fibrosis, primary ciliary dyskinesias, alpha-1-antitrypsin deficiency, and surfactant proteins caused by gene mutations may result in progressive pulmonary disease. This article provides an overview of pediatric pulmonary disease from a genetic perspective.

Variants in the mitochondrial alanyl-tRNA synthetase 2 gene AARS2 (OMIM 612035) are associated with infantile mitochondrial cardiomyopathy or later-onset leukoencephalopathy with premature ovarian insufficiency. Here, we report two newborn siblings who died soon after birth with primary pulmonary hypoplasia without evidence of cardiomyopathy. Whole-exome sequencing detected the same compound heterozygous AARS2 variants in both siblings (c.1774C>T, p.Arg592Trp and c.647dup, p.Cys218Leufs*6) that have previously been associated with infantile mitochondrial cardiomyopathy. Segregation analysis in the family confirmed carrier status of the parents and an unaffected sibling. To our knowledge, this is the first report of primary pulmonary hypoplasia in the absence of cardiomyopathy associated with recessive AARS2 variants and further defines the phenotypic spectrum associated with this gene.