Perinatal/Neonatal Case Presentation

Alveolar capillary dysplasia with multiple congenital anomalies and bronchoscopic airway abnormalities


Alveolar capillary dysplasia is a rare and fatal disease of newborn infants. Here we describe a patient with alveolar capillary dysplasia, multiple congenital anomalies, a novel genetic mutation and previously undocumented airway findings on bronchoscopy. Knowledge of these associations may help diagnose this rare disorder in neonates with hypoxemic respiratory failure.


Alveolar capillary dysplasia (ACD) with misalignment of the pulmonary veins is a rare cause of hypoxemia and/or pulmonary hypertension in newborn infants. This developmental interstitial lung disorder is characterized by immature pulmonary lobular development, thickened alveolar septa, reduced pulmonary capillary density and abnormal location of the pulmonary veins.1 ACD usually presents within the first 48 h of life in term neonates, however it can rarely present in later months.1, 2, 3 This diagnosis is often suspected by clinicians in neonates with hypoxemic respiratory failure because of associated extrapulmonary anomalies including malformations of the gastrointestinal, cardiovascular and genitourinary systems. Here we present a case of ACD associated with previously undocumented airway anomalies and a new genetic mutation.


A Caucasian male was born at an outlying hospital after 32 weeks gestation. Prenatal history was significant for polyhydramnios, a single umbilical artery and increased nuchal thickness. At birth the patient was apneic, cyanotic and bradycardic requiring intubation and surfactant. Subsequently, he required ventilator support, fluid boluses and an epinephrine drip for hypotension. An echocardiogram performed at the outlying hospital showed possible aortic-arch narrowing. An alprostadil drip was started and he was transferred to our tertiary level children’s hospital.

On admission to the children’s hospital, physical exam was significant for microcephaly, down slanting palpebral fissures, low set crumpled ears, anteverted nostrils, short columella, short neck, hyperconvex fingernails and an imperforate anus. Chest radiograph showed bilateral diffuse granular opacities. Echocardiogram showed evidence of pulmonary hypertension, a right-sided aortic arch without narrowing and otherwise a normal cardiac anatomy. His arterial blood gas was significant for normocarbia and hypoxemia. At this time his hypoxemic respiratory failure was felt to be secondary to pulmonary hypertension; however, there was a suspicion of ACD because of the known association with imperforate anus. The patient did not respond to inhaled nitric-oxide or high-frequency oscillator. A trial of inhaled iloprost dramatically elevated his oxygen saturation and he was placed on scheduled dosing but quickly developed tachyphylaxis. As a result of the right-sided aortic arch a limited bedside bronchoscopy was performed to evaluate for a vascular ring. The scope showed asymmetry of the main-stem bronchi and an abnormal take-off of the right-sided secondary segments. Despite aggressive medical management, episodes of prolonged and severe desaturations continued. With parental permission aggressive medical support was withdrawn on day 4 of life and the patient expired.

Autopsy showed thick inter-lobular and inter-alveolar septa, centrally located septal blood vessels, markedly deficient peripheral alveolar capillaries and a misalignment of the pulmonary veins (Figure 1) consistent with ACD. Other findings included intestinal nonrotation and confirmation of a vascular ring around the trachea and esophagus formed by a left-sided ductus arteriosus.

Figure 1

Abnormal location of the pulmonary veins (V) that stain red crossing the path of the pulmonary artery branches (A), which stain blue on Masson–Trichrome stain. Inset shows a thickened inter-alveolar septum outlined by black lines (septum=S, alveoli=Al); reduced density of pulmonary capillaries and abnormal location of capillaries within the septum (black arrows). Image obtained at autopsy.

Chromosomal FISH analysis was normal. Gene sequencing was normal for ABCA3 and FOXF1; however, a DNA deletion/duplication array showed an interstitial deletion of 70 genes within the cytogenetic interval 16q23.2-16q24.3, which includes the FOX gene cluster.

Bronchoscopy was repeated post mortem to further evaluate the bronchial abnormalities. The left main bronchus was noted to be stenotic (Figure 2). The right upper lobe bronchus was visualized to have three segments. The bronchus intermedius demonstrated three secondary bronchi takeoffs at the same level rather than the more anterior and proximal positioning of the right middle lobe bronchus.

Figure 2

Left: normal carina; Right: stenosis of left main bronchus. Images obtained during bronchoscopy.


Over the years, case reports of ACD patients with various genetic mutations and cardiac, gastrointestinal and pulmonary anomalies have helped improve our understanding of this rare disorder.1 Although gastrointestinal, genitourinary and cardiovascular anomalies often aid in the diagnosis of ACD, airway anomalies are not typically considered. Our report, supported by one previous report,4 suggests that ACD patients not only have abnormalities of the alveoli and distal airway but some may also have abnormal development of the proximal airway. Advancements in fiberoptic technology now allow bedside proximal airway evaluation even in sick neonates. In neonates with pulmonary hypertension and hypoxemic respiratory failure, the presence of a proximal airway anomaly should increase suspicion of ACD.

Over 90% of infants with ACD reported in the literature were born at term,1 but our patient was born premature. We suspect ACD is underdiagnosed in premature infants because associated lung immaturity is often thought to explain the respiratory failure. Clinicians should consider the diagnosis of ACD in premature infants who die of respiratory failure despite surfactant therapy. A post-mortem lung biopsy would provide the answer.

Alveolar capillary dysplasia has been associated with congenital heart disease. An association with hypoplastic left heart, aortic coarctation, atrioventricular septal defects and valvular disease is well-documented.1, 5, 6 A tracheal ring formed by a right-sided aortic arch with a left-sided ductus arteriosus has not been previously reported with ACD.

Microdeletions involving the FOX gene cluster on 16q24.1 have been described in association with ACD and VACTERL association;7, 8 however, the specific deletion of 16q23.2-16q24.3, seen in our patient has not been previously documented. The FOXF1 gene sequencing had been ordered before our identification of the 16q23.2-16q24.3 deletion in our patient, and was reported to be normal. In addition to ACD, our patient had an imperforate anus, intestinal nonrotation, right-sided aortic arch and proximal airway anomalies. In murine models, FOXF1 is widely expressed in the mesoderm of the gastrointestinal tract9 and is known to have a role in the foregut and pulmonary patterning and development. In addition, cardiac defects have been associated with aberrant forkhead gene signaling and are believed to be related to this foregut signaling as the heart is derived from the visceral mesoderm.10, 11 The craniofacial dysmorphism seen in our patient was most likely due to the larger microdeletion disorder, but the primary phenotype can be ascribed to the deletion of the FOX gene cluster (FOXF1,FOXC & FOXL) as there are multiple similarities between our patient and those described by Stankiewicz et al., who reported ACD caused by the loss of function of FOXF1.7, 12, 13, 14

ACD should be considered in neonates of any gestational age presenting with pulmonary hypertension or hypoxemic respiratory failure, especially if associated with cardiovascular or gastrointestinal anomalies or mutations of the FOX gene cluster. Our description of bronchial abnormalities in association with ACD, as well as the documented association between ACD and subglottic stenosis by Shimizu et al., suggest that ACD should be a diagnostic consideration in neonates with pulmonary hypertension and/or hypoxemic respiratory failure and proximal airway anomalies. Given these findings, a thorough evaluation of neonates with hypoxemic respiratory failure or pulmonary hypertension is warranted.


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Correspondence to M A Basir.

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Bellamkonda-Athmaram, V., Sulman, C., Basel, D. et al. Alveolar capillary dysplasia with multiple congenital anomalies and bronchoscopic airway abnormalities. J Perinatol 34, 326–328 (2014).

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  • alveolar capillary dysplasia
  • newborn infant
  • anomaly
  • airway
  • bronchi

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