Pulmonary Agenesis and Aplasia

Pulmonary agenesis and pulmonary aplasia are both rare pulmonary developmental abnormalities.  In pulmonary agenesis, there is the complete absence of lung parenchyma, bronchi and vessels, while in pulmonary aplasia, there is presence of rudimentary bronchi with no associated lung parenchyma (1).

Given the rarity of both pulmonary malformations, the true incidence of agenesis or aplasia, either unilateral or bilateral, is difficult to ascertain.  The incidence of pulmonary agenesis has been estimated to be 1 in 10,000 (2). For pulmonary aplasia, the incidence is estimated to be 1 in 15,000 based on autopsies (3). 

Both the right and left lung are equally affected and incidence appears to be similar in both sexes. Unilateral lung agenesis is more common than bilateral agenesis, with unilateral cases occurring approximately 25 times more frequently (4, 5).

Approximately 50% of right sided pulmonary agenesis have associated abnormalities, including severe cardiac anomalies (6), while left sided agenesis is more often isolated. 

Pulmonary developmental lung anomalies are suspected to result from disruption of normal lung bud development that begins during the sixth week of gestation in the embryonic stage of lung development (7, 8). 

The human fetal respiratory system forms from a ventral diverticulum from the caudal end of the laryngotracheal groove of the foregut endoderm at the end of the fourth week of gestation. This laryngotracheal diverticulum progressively separates from the digestive tract and grows caudally to form the primitive trachea. The distal end of the diverticulum divides into 2 sacs, the lung buds (9). The lung buds then penetrate the neighbouring mesenchyme, with subsequent ramifications of bronchi and bronchioles ultimately forming pulmonary structures. The pulmonary structures are covered by blood vessels derived from the foregut mesoderm. Pulmonary agenesis or aplasia results from failure of the lung bud or the bronchial bud to develop properly respectively (6).

The etiology of lung agenesis is not well elucidated, although genetic factors, folic acid or vitamin A deficiencies have been identified as possible contributing factors (11).  

In an established classification system first proposed by Schneider in 1912, there are 3 different degrees of arrest of lung development that may occur: (a) pulmonary agenesis, where there is complete absence of one or both lungs, including complete absence of lung parenchyma, bronchi and vasculature; (b) pulmonary aplasia, where there is absence of lung tissue but with a rudimentary bronchus; and (c) pulmonary hypoplasia, where lung tissue and bronchi are present but underdeveloped (11).

Pulmonary agenesis can be associated with a broad range of structural abnormalities of other organ systems. The most commonly reported associated anomalies are cardiac and gastrointestinal abnormalities, followed by skeletal, vascular, cranial, facial and genitourinary anomalies (5). It has been reported as part of a syndrome (22q11 deletion spectrum, Goldenhar) (5, 12, 13) or an association such as VACTERL (vertebral defects, anal atresia, cardiac defects, tracheoesophageal fistula, renal anomalies, and limb abnormalities) sequence (14, 15). 

Unilateral or bilateral pulmonary agenesis does not appear to be associated with an underlying chromosomal abnormality and no familial tendency has been recognized (16), although parental consanguinity has been reported (2). This has also been reported in association with 22.q11 deletion and Trisomy 21, when the parents have balanced translocations for example (17).

Most patients with unilateral pulmonary agenesis present in the neonatal period with respiratory distress (7, 18), with some presenting in childhood with respiratory distress (19). Patients, however, may remain asymptomatic and the diagnosis is not made until adulthood (20) or as an incidental finding at time of autopsy (16).

Only a small number of unilateral pulmonary agenesis cases are detected prenatally (21%) (7), with prenatal diagnosis being challenging because of the potential difficulty in distinguishing this anomaly from others with a similar ultrasound appearance.

In the prenatal sonographic diagnosis of unilateral pulmonary agenesis or aplasia, the contralateral lung may appear enlarged and echogenic (21). There is typically a mediastinal shift to the side of the absent lung, with no identifiable lesion in the contralateral lung, including lack of ultrasound evidence of congenital diaphragmatic hernia (CDH), to explain the degree of mediastinal shift (22). 
Use of 2-dimensional color Doppler imaging is crucial in identifying pulmonary artery branches and delineating the pulmonary vasculature. A fundamental aspect of the diagnosis is the absence of the pulmonary artery bifurcation (18) and the pulmonary veins ipsilateral to the lesion or defect are not observed to reach the left atrium (23). Outflow  tract examination is therefore critical when there is a mediastinal shift (23).

Bilateral pulmonary agenesis can have the sonographic appearance of unilateral or bilateral CDH as the absence of lung tissue is thought to allow the diaphragm and abdominal organs to be displaced cephalad (10).

Fetal magnetic resonance imaging (MRI) is of great value in evaluating abnormalities of the thoracic cavity in detail as well as supporting the findings of the ultrasound examination (24, 25). In cases of bilateral agenesis, MRI may not be fully informative as the actual diaphragm can be difficult to visualize, especially if there is a lack of a fat or fluid interface between the pericardium, diaphragm and liver (10).

Bilateral pulmonary agenesis is not generally mistaken for other conditions (16), but may have the appearance of unilateral or bilateral CDH (10). 
The prenatal diagnosis of unilateral pulmonary agenesis is challenging because of inherent difficulty in differentiating this anomaly from others with similar sonographic appearances, especially those that result in a mediastinal shift (21, 23, 24). These include entities such as congenital diaphragmatic hernia, bronchopulmonary sequestration, fetal hyperechogenic lung masses and congenital pulmonary airway malformation (22). 

Bilateral cases of pulmonary agenesis are uniformly lethal, with all affected patients dying in utero or shortly after birth death (10, 16). 

For unilateral pulmonary agenesis, prognosis depends on primarily on the presence of other abnormalities that may carry a worse prognosis (7) as well as the amount of remaining pulmonary tissue. 
In the absence of associated abnormalities, unilateral lung agenesis with minimal mediastinal shift, particularly left sided agenesis, is compatible with long term survival (26, 27). Prognosis appears to be worse with right sided agenesis and is thought to be secondary to greater mediastinal shift with overexpansion of the left lung as well as higher incidence of other associated abnormalities (23). 

For left sided agenesis, most of the morbidity appears to be related to the presence of associated major cardiovascular anomalies and subsequent, postoperative complications and congestive heart failure. On the other hand, for right sided agenesis, airway complications secondary to tracheobronchial stenosis from vascular compression was a major contributing factor to morbidity and mortality (17). 

In cases where pulmonary agenesis is suspected, whether unilateral or bilateral, a detailed sonographic assessment, including 2-dimensional color Doppler imaging, should be undertaken to confirm the diagnosis, delineate pulmonary vasculature and exclude any associated abnormalities. 
Given the frequency of associated cardiac abnormalities, especially in unilateral cases, fetal echocardiography should also be performed in every patient. 
Fetal MRI may be particularly helpful in distinguishing agenesis from either aplasia or hypoplasia. MRI is also useful in detecting other associated fetal abnormalities, which would aid in determining prognosis and aid in counselling. 
Fetal karyotyping, microarray and specific 22q11 deletion tests may be offered, although pulmonary agenesis has not been associated with an increased incidence of chromosomal abnormalities (23).

If bilateral pulmonary agenesis is confirmed, extensive counselling should be undertaken regarding lethality and incompatibility with survival after delivery. Elective pregnancy termination is an option. If expectant management of the pregnancy is chosen, delivery should be undertaken without monitoring for fetal distress and no futile heroic resuscitation measures are undertaken (16).

With unilateral pulmonary agenesis, management depends on the presence of associated abnormalities. Parents should be counselled that the prognosis is guarded in cases with other associated anomalies. Even in isolated pulmonary agenesis, where the prognosis is very good, prenatal consultation with a pediatric surgeon and delivery in a tertiary care center is recommended so that appropriate care can be provided if complications arise (7).

After delivery, neonatal CT imaging with 2D and 3D multiplanar reformats is useful to distinguish pulmonary agenesis from aplasia or hypoplasia, while MR angiography is performed to define mediastinal vascular anatomy (28).

Management of unilateral pulmonary agenesis is essentially symptomatic, including surgical repair of associated cardiovascular malformations when they result in early airway complications as well as correction of significant mediastinal shift (13).

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