Overview of Prenatal Lung Development

Lung morphogenesis can be subdivided into distinct periods on the basis of the morphologic characteristics of the tissue ( Table 14-1 ).

Lung Agenesis and Pulmonary Hypoplasia

Primary pulmonary hypoplasia is occasionally reported as an isolated finding and has been described in many sibships, suggesting autosomal recessive inheritance in at least some cases. This serves as a reference point for some families who have given birth to one child with pulmonary hypoplasia because risks for recurrence may be 25% in subsequent pregnancies.

Tracheal atresia accompanied by bilateral agenesis of the lungs is most likely to arise as an isolated defect, possibly secondary to a vascular event occurring very early in the embryonic period. Variable degrees of pulmonary agenesis have been reported in many sibships, however, with and without consanguinity. Developmental anomalies of the lungs also have been described in association with other birth defects, as part of at least one possible mendelian disorder, and as an occasional finding in a microdeletion syndrome ( Table 14-2 ).

More often, pulmonary hypoplasia identified at birth in association with severe respiratory distress is found to be secondary to another underlying defect or disorder. These primary problems can be divided into three broad categories: (1) renal problems leading to oligohydramnios, (2) skeletal dysplasia resulting in thoracic cage limitation and pulmonary insufficiency, and (3) neuromuscular disorders leading to pulmonary hypoplasia owing to poor respiratory efforts in utero .

Any renal abnormality, developmental or obstructive, leading to decreased urine output in utero with concomitant oligohydramnios has the potential to cause pulmonary hypoplasia (see Chapter 6 ). The degree of oligohydramnios and length of time the fetus is exposed to limitation of movement likely determine the severity of pulmonary hypoplasia and potential for long-term survival. Most instances of oligohydramnios are not genetically determined, but instead are secondary to prolonged rupture of membranes. Late loss of amniotic fluid with a relatively short duration of fetal constriction is less likely to cause significant respiratory compromise. In contrast, prolonged, severe oligohydramnios secondary to renal agenesis or sirenomelia results in the Potter sequence with severe pulmonary hypoplasia and neonatal death.

In between these two extremes are variable findings and prognoses associated with decreased amniotic fluid volume. A common isolated birth defect in male fetuses, posterior urethral valves, may result in oligohydramnios, bladder distention, hydronephrosis, and ultimately renal damage. In severe cases, the bladder distention leads to anterior abdominal wall musculature hypoplasia and renal failure (prune-belly syndrome). These boys also may have respiratory compromise that tends to correlate with the duration and severity of the oligohydramnios.

Suboptimal urine output associated with many genetic conditions may be seen with varying degrees of pulmonary hypoplasia at birth. Table 14-3 lists some of these syndromes. Bilateral or unilateral renal agenesis may occur as an isolated (nonhereditary) defect during early fetal development.

In some instances, skeletal dysplasias with associated thoracic anomalies can result in secondary pulmonary hypoplasia. In addition to severe and universally fatal skeletal dysplasias, such as achondrogenesis, osteogenesis imperfecta type 2, a few short-rib polydactyly syndromes, and thanatophoric dysplasia, there are many less severe skeletal dysplasias that may result in pulmonary compromise and respiratory difficulties at or shortly after birth. The long-term prognosis for each depends on the extent of the pulmonary hypoplasia and ability for the lungs to grow within the confines of the thoracic cage over time. Table 14-4 lists some of the skeletal dysplasias associated with respiratory difficulties at birth, but with the possibility of long-term survival.

Severe neuromuscular disorders associated with lack of fetal movement (fetal akinesia) may cause a host of problems in addition to pulmonary hypoplasia. Prenatal history is often significant for polyhydramnios (believed to be secondary to decreased fetal swallowing), joint contractures, and clubfeet. Whether the fetal akinesia is secondary to an inherent muscle or peripheral nerve problem, or instead a central nervous system problem, the clinical presentations are similar. Severe, congenital forms of inborn errors of metabolism, myopathies, or neuropathies may be clinically indistinguishable, unless specific diagnostic tests are done. Table 14-5 summarizes genetic conditions with neuromuscular underpinnings that may result in secondary pulmonary hypoplasia.

Congenital Diaphragmatic Hernia

CDH is a common anomaly and frequently associated with secondary pulmonary hypoplasia. CHD is seen in approximately 1 in 2000 live-born infants. This birth defect occurs as an isolated event and in association with more than 15 genetic syndromes ( Table 14-6 ). CDH also is seen with numerous cytogenetic deletion and duplication syndromes as one of many congenital anomalies; 15% of infants with CDH have a structural or numeric cytogenetic abnormality. Prenatal or postnatal detection of a CDH would require a thorough evaluation to look for dysmorphic features or additional birth defects that may be diagnostic of a specific syndrome.

CDH arises early in gestation when the pleuroperitoneal membranes fail to seal the pleuroperitoneal canal completely. Of CDHs, 80% are left-sided and result in abdominal viscera sliding up into the pleural cavity ( Fig. 14-1 ). Postnatal survival reportedly ranges from 39% to 95% after repair of CDH. This large variation in mortality depends largely on the severity of the resulting pulmonary hypoplasia and abnormal pulmonary vasculature. If extracorporeal membrane oxygenation is required, the prognosis is not favorable. The overall outcome of CDH is recognized to be worse when it is found in association with certain syndromes, such as Fryns syndrome. A recurrence risk for sibs of a child with an isolated CDH, based on empiric data, is approximately 2%.

X-ray shows left sided diaphragmatic hernia with loops of bowel in the left hemithorax.

Isolated CDH is generally believed to be a sporadic occurrence, although autosomal dominant and autosomal recessive pedigrees have been described. Several loci and putative predisposition genes have been found in cases of CDH, with cytogenetic deletions, duplications, and translocations often uncovering a CDH locus (see Table 14-6 ).

Segmentation Defects and Heterotaxy

During the embryonic stage, the right and left bronchial buds begin to grow, subsequently dividing into secondary bronchi. Normally, the right lung bud divides into three segments, and the left lung bud divides into two segments. Rarely, segmentation or lobulation defects occur and may or may not be associated with other visceral heterotaxies. Nearly 80% of children with right isomerism (bilateral right lung) have asplenia, leading to a risk for overwhelming pneumococcal sepsis. A similar proportion with left isomerism (bilateral left lung) has multiple small spleens (polysplenia). A few genetic syndromes have been associated with these types of defects ( Table 14-7 ).

Cystic Adenomatoid Malformations

Cystic adenomatoid malformation of the lungs is a developmental abnormality that results from overgrowth of the terminal respiratory bronchioles modified by intercommunicating cysts. Cystic adenomatoid malformation encompasses variably sized cysts that, as they enlarge, compress adjacent lung tissue ( Fig. 14-2 ). The reported incidence is 1 in 25,000 to 35,000. It is useful to divide these cystic lesions into large cyst and small cyst types. The changes that have long been associated with the “adenomatoid” type now are recognized in various conditions with large airway obstruction and are more accurately called “pulmonary hyperplasia.”

A, X-ray shows right upper lung cystic area filled with air after resorption of fluid from congenital cystic adenomatoid malformation. B, CT scan shows septated cystic adenomatoid malformation in right upper lobe.

Bronchogenic Cysts and Other Cystic Lesions

Foregut cysts are closed epithelium-lined sacs developing abnormally in the thorax from the respiratory tract and primitive developing gut. When these structures differentiate toward airway and contain hyaline cartilage plates in the wall, they are called “bronchogenic cysts,” whereas structures developing toward the gut are termed “enterogenous cysts.” Bronchogenic cysts are the most common cysts in infancy, although many do not manifest until adolescence or adulthood. Most are situated in the middle mediastinum close to the carina, but do not communicate with the trachea or bronchi. Less frequently, they are adjacent to the esophagus. They are usually single, unilocular cystic structures that are filled with fluid or mucus, and more commonly are located on the right ( Fig. 14-3 ). Because of inadequate drainage, such cysts may be associated with recurrent infections and may appear as a consolidation or area of atelectasis on chest x-ray. Bronchogenic cysts also may be found within the lung hilum and parenchyma. When located within the lung, they are identical in their gross and histologic appearance to cysts in the mediastinum.

A and B, X-rays show thin-walled cyst in left lower lobe with air-fluid level. C, CT scan shows right upper lobe bronchogenic cyst.

Similarly located cysts with enteric-type mucosa, usually gastric or esophageal and without cartilage plates within their wall, are enteric duplication cysts. Esophageal cysts are more common. They are intramural and do not involve the mucosa. Gastroenteric cysts characteristically are not connected to the esophagus. In infants, they are a common cause of a posterior mediastinal mass. Neurenteric cysts are posterior mediastinal lesions, also lined by enteric-type mucosa, and with a pedicle that extends into the spinal canal. They are virtually always associated with vertebral defects in the region of this communication. Rarely, congenital cystic lesions may be seen in conjunction with genetic syndromes. There is a specific autosomal recessive disorder described with multiple peripheral lung cysts or fibrocystic pulmonary dysplasia as the primary feature ( Table 14-8 ).

Table 14-8

Genetic Conditions Associated with Pulmonary Cysts

SYNDROME	CLINICAL FEATURES	MODE OF INHERITANCE	GENE OR LOCUS IF KNOWN
Cystic disease of the lung	Cystic pulmonary lesions	Autosomal recessive (especially common in Yemenite and other non-Ashkenazi Jews)	Unknown
	Recurrent lung infections
	Spontaneous pneumothorax in the neonate
Proteus syndrome (encephalocraniocutaneous lipomatosis)	Cystic pulmonary lesions	Autosomal dominant (some cases may be due to somatic mosaicism for a gene mutation)	Gene = PTEN (only some cases)
	Macrocephaly
	Hemihypertrophy with localized overgrowth
	Variable cutaneous lesions, including lymphangiomas, lipomas, epidermal nevi, hemangiomas
	High risk of thrombosis
	Kyphoscoliosis
	CNS malformations
Down syndrome (trisomy 21)	Characteristic subpleural cysts	Cytogenetic	Extra copy of chromosome 21
	Facial dysmorphism
	Short, broad neck
	Cardiac, gastrointestinal, and genitourinary defects
	Brachydactyly, clinodactyly
	Single palmar crease

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