Pulmonary Hypoplasia, Primary

Description

Primary bilateral pulmonary hypoplasia is defined as quantitative and/or qualitative underdevelopment of bronchial and pulmonary tissue unrelated to an underlying disorder (Langer and Kaufmann, 1986).

Clinical Features

Boylan et al. (1977) reported the first seemingly familial instance of bilateral pulmonary hypoplasia. Male and female infants who died shortly after birth were described. Both infants had associated malformations, including prominent epicanthic folds, mild micrognathia, and low set ears; one had cleft palate. An older sib had a partial defect of the right diaphragm and rudimentary right lung.

Frey et al. (1994) reported a family in which 3 infants, 2 with definite and 1 with possible isolated pulmonary hypoplasia, died in the neonatal period.

Podlech et al. (1995) reported a newborn female who died immediately after birth and was found to have agenesis/aplasia of both lungs with a rudimentary right bronchus and distal tracheal atresia. No other malformations were observed. A later pregnancy was terminated at 21 weeks' gestation after ultrasound showed agenesis of both lungs. Postmortem examination of the second affected child showed bilateral absence of both lungs and a 5-mm solid round formation at the hilar region in the right thoracic cavity, which was shown histologically to be a rudimentary bronchus. No lung veins leading to the left atrium were observed, and there were no aortic ostia of bronchial arteries. The trachea was atretic in its distal part. No other abnormalities or malformations were observed.

Fokstuen and Schinzel (2000) described unilateral right pulmonary agenesis in a brother and sister born of healthy nonconsanguineous parents. The first child had respiratory symptoms from the age of 11 months with recurrent infections and asthma. These became more severe at the age of 24 years and she died at the age of 42 years, secondary to cor pulmonale. Autopsy showed agenesis of the middle lobe, aplasia of the upper lobe, and hypoplasia of the lower lobe of the right lung with hypoplasia of the right pulmonary artery. The second child had respiratory symptoms from early life. He died at the age of 9 months after severe asthmatic decompensation. Autopsy showed agenesis of the right upper lobe with severe hypoplasia of the right pulmonary artery and dextrocardia. In addition, he had bilateral stenosis of the ureters with hydroureters and hydronephrosis, and a small accessory spleen. Both patients also had dextrocardia.

Szafranski et al. (2016) described a term female neonate who developed apnea and cyanosis within minutes after delivery. She had persistent cyanosis and hypoxemia despite continuous positive airway pressure (CPAP). Chest x-ray showed abnormal shapes of the lungs and heart. Echocardiogram showed poor contractility, and at least one pulmonary vein and the pulmonary arteries appeared small. Care was withdrawn on the first day of life. Autopsy, limited to the heart and lungs, showed a secundum atrial septal defect. Lungs showed disorganized distal lung parenchyma. There was branching of the proximal conducting airways and bronchovascular bundles but maldevelopment of the terminal bronchioles, respiratory bronchioles, and alveoli. There were reduced numbers of sac-like airspaces lined with cuboidal cells with capillaries deep to the lining cells comparable to the pseudoglandular stage of fetal lung development. The findings were most consistent with acinar dysplasia.

German et al. (2019) reported a neonate with severe respiratory failure, bilateral clenched fists, posteriorly rotated and low-set ears, widely spaced and underdeveloped nipples, broad halluces, hypoplastic toenails, and bilateral clinodactyly of the second toes. By rapid exome sequencing, he was found to have a 2-Mb deletion (chr17:59,290,909-61,353,248, GRCh37) involving 14 genes, including TBX4. A lung biopsy on day 8 of life showed marked arrest of lung maturation consistent with acinar dysplasia.

Suhrie et al. (2019) reported 2 unrelated patients who presented with severe neonatal lung disease. The first patient (infant A) was a term female who presented with cyanosis and difficulty breathing that did not improve with CPAP and 100% oxygen. She had low lung volumes and a small right pneumothorax. After decompression and ventilation, her oxygen saturations remained low. Birth growth parameters were notable for weight (25th percentile), length (5th percentile), and head circumference (less than the 3rd percentile). Despite treatment, including inhaled nitric oxide and 3 weeks of extracorporeal membrane oxygenation (ECMO), started at 52 hours of age, she suffered seizures, intracranial hemorrhage, and left middle cerebral artery infarction. She died shortly after removal from ECMO. Autopsy showed no evidence of limb anomalies associated with small patella syndrome. Lungs had 3 lobes bilaterally and features of congenital alveolar dysplasia thought to represent growth arrest in the late canalicular/early saccular phase of lung development. No normally developed alveoli were present. The second patient (infant B) was a small-for-gestational age term male (weight, 5th percentile; length, less than 1st percentile; head circumference, 4th percentile) who presented at birth in respiratory distress. He had no obvious dysmorphic features, but radiographs were not available to assess for small patella syndrome. Echocardiogram showed a large secundum atrial septal defect. He had nonapneic hypoxia and tachypnea. He was able to be discharged home on day 25 of life on 0.25 liter oxygen by nasal cannula. He was readmitted at age 3 months for failure to thrive and was found to have persistent tachypnea and retractions. He was also noted to have bilateral undescended testes. CT showed interstitial pneumonia and aberrant lobular architecture with abnormal alveolar growth. Right lung upper and middle lobe biopsies showed an alveolar growth abnormality characterized by variably enlarged and simplified alveoli with focal cystically dilated airspaces. After several episodes of cardiopulmonary arrest, he was placed on ECMO for 4 days with prolonged pulseless arrest at the time of cannulation. He was discharged from the hospital at age 8 months with a tracheostomy and gastrostomy tube.

Karolak et al. (2019) studied a cohort of 26 deceased patients who had clinically and histopathologically diagnosed interstitial neonatal lung disorders: acinar dysplasia in 14, congenital alveolar dysplasia in 2, and other lethal lung hypoplasias in 10. One of the patients (P025) was the patient described by Szafranski et al. (2016). Another patient (P022) was born at term by cesarean section and developed respiratory distress immediately. There was no improvement following intubation, and he developed tension pneumothorax and required bilateral intercostal chest drains. At 2 hours of life, he became asystolic and died. Autopsy revealed acinar dysplasia.

Inheritance

Pulmonary hypoplasia occurs commonly in association with congenital diaphragmatic hernia, oligohydramnios (mostly related to renal dysfunction), skeletal dysplasias, fetal hydrops, malformations of the central nervous system, and neuromuscular diseases. Primary isolated bilateral pulmonary hypoplasia is rare and familial occurrence exceptional (summary by Frey et al., 1994).

In a series of 9 cases with isolated pulmonary hypoplasia, Langer and Kaufmann (1986) described 2 pairs of affected identical twins. Fraser (1988) observed pulmonary hypoplasia in 2 sibs, and Hamel (1995) described a family with 2 affected male sibs.

Frey et al. (1994) reported a family with 2 proven and 1 suspected case of isolated pulmonary hypoplasia. The parents were healthy and apparently nonconsanguineous; however, the 4 grandparents stemmed from the same rural region in the central part of Switzerland. Frey et al. (1994) suggested autosomal recessive inheritance.

Diagnosis

Langer and Kaufmann (1986) stated that the radiologic diagnosis of primary pulmonary hypoplasia is possible if the following findings are seen: clear, small lungs in the early postpartum period, bilaterally elevated diaphragms, early development of pneumothoraces, after mechanical ventilation or spontaneously, and 'bell shaped' thoracic configuration. The diagnosis is confirmed by the following clinical and laboratory findings: tachypnea, cyanosis, nasal flaring, intercostal retractions as signs of respiratory distress; hypercapnia, hypoxia, and acidosis.

Molecular Genetics

Associations Pending Confirmation

In a deceased child with severe lethal primary pulmonary hypoplasia and unilateral diaphragmatic defect (see, e.g., 142340 and 610187), Ackerman et al. (2005) identified a de novo heterozygous mutation in the ZFPM2 gene (603693.0003) on chromosome 8q23. Postmortem examination showed incomplete lung fissures bilaterally and a deep posterior left diaphragmatic eventration. The heart was grossly normal. Ackerman et al. (2005) suggested that mutations in the ZFPM2 gene may result in primary pulmonary and diaphragmatic defects.

Suhrie et al. (2019) reported 2 neonates with pulmonary hypoplasia. Infant A carried a de novo frameshift in the TBX4 gene (c.524_527del, Asn175ThrfsTer52) and a missense mutation in the ABCA3 gene (c.863G-A, R288K). Infant B had a 2.2-Mb deletion on chromosome 17q23.1-q23.2 (see 613355) that included the TBX4 gene and the identical ABCA3 variant. No functional studies were reported.

Karolak et al. (2019) studied a cohort of 26 deceased patients who had clinically and histopathologically diagnosed interstitial neonatal lung disorders: acinar dysplasia in 14 patients, congenital alveoloar dysplasia in 2, and other lethal lung hypoplasias in 10. The authors identified rare heterozygous copy number variants or deletions involving TBX4 (8 and 2, respectively) or FGF10 (602115) (2 and 2, respectively) in 16 (61%) of the 26 patients. Individuals with lung hypoplasia also harbored at least one noncoding single nucleotide variant (SNV) in the predicted lung-specific enhancer region. One patient (P025) was previously reported by Szafranski et al. (2016) to have a glu86-to-gln (E86Q; 601719.0005) variant in TBX4. Another infant (P022) carried a different change (E86K) at the same codon in TBX4.

Two sisters with isolated lung hypoplasia reported by Karolak et al. (2019) had a maternally inherited intragenic deletion of TBX4 and a paternally inherited missense mutation (D111Y) in TBX5 (601620). The authors argued that since TBX4 and TBX5 dimerize and are expressed in the developing lung that this is the cause of the pulmonary hypoplasia. Karolak et al. (2019) reported that they had identified a statistically significant enrichment of noncoding variants (either common or rare) in trans in subjects with acinar dysplasia, congenital alveolar dysplasia, or pulmonary hypoplasia and heterozygous SNVs or CNVs involving TBX4.

Karolak et al. (2019) also reported a family in which a mother and 2 daughters carried a deletion of 5p12 including the FGF10 gene. The mother and one daughter had LADD syndrome (149730). The other daughter (P040) had pulmonary hypoplasia and died at day 5 of age after intracranial hemorrhage on ECMO. She had a broad forehead but no other features of LADD syndrome. A second family had a father and daughter with LADD syndrome and another daughter (P076) who died at 5 days of age due to pulmonary hypoplasia. She also had dysplastic ears and hypoplastic toenails.