Alveolar Capillary Dysplasia With Misalignment Of Pulmonary Veins

A number sign (#) is used with this entry because of evidence that congenital alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is caused by heterozygous mutation in the FOXF1 gene (601089) on chromosome 16q24.

Description

Congenital alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is characterized histologically by failure of formation and ingrowth of alveolar capillaries that then do not make contact with alveolar epithelium, medial muscular thickening of small pulmonary arterioles with muscularization of the intraacinar arterioles, thickened alveolar walls, and anomalously situated pulmonary veins running alongside pulmonary arterioles and sharing the same adventitial sheath. Less common features include a reduced number of alveoli and a patchy distribution of the histopathologic changes. The disorder is associated with persistent pulmonary hypertension of the neonate and shows varying degrees of lability and severity (Boggs et al., 1994). Affected infants present with respiratory distress resulting from pulmonary hypertension in the early postnatal period, and the disease is uniformly fatal within the newborn period (Vassal et al., 1998). Additional features of ACDMPV include multiple congenital anomalies affecting the cardiovascular, gastrointestinal, genitourinary, and musculoskeletal systems, as well as disruption of the normal right-left asymmetry of intrathoracic or intraabdominal organs (Sen et al., 2004).

Clinical Features

MacMahon (1948) described 3 full-term infants with congenital alveolar dysplasia, who developed respiratory distress soon after birth and died within 2 days. The presentation was strikingly similar in all 3 infants: each cried and breathed promptly at birth, with no apparent impairment in respiration for a period varying from minutes to hours; then breathing became progressively distressed and cyanosis developed, with diminished to absent breath sounds on auscultation. At autopsy, microscopy of fresh lung tissue revealed 'too much stroma and too little air space,' with an excess of interstitial tissue that was rich in capillaries, surrounding a few isolated and sometimes overdistended pulmonary alveoli. Developmental anomalies in other organs included an almost complete atrial septal defect, multiple valvular hematomata, and hypoplasia of the brain in 1 infant, and an accessory spleen in the other 2, as well as bilateral ureteral valve-like constriction at the ureteropelvic junction in 1. MacMahon (1948) suggested that congenital alveolar dysplasia represents a retardation and disturbance in the normal development of pulmonary alveoli.

Shohet et al. (1984) reported 2 brothers and a sister with persistent pulmonary hypertension of the newborn who died at 4, 11, and 15 days of age. Pulmonary artery pressure in all was above systemic values, with a right-to-left shunt via the foramen ovale or ductus arteriosus or both. Histology showed extension of muscle into small pulmonary arteries which are normally nonmuscular. The parents, Tunisian Jews, were healthy first cousins. This abnormality of the pulmonary vasculature is also known as misalignment of the pulmonary vessels, or congenital alveolar capillary dysplasia.

McDonald-McGinn et al. (1992) stated that 7 infants with this condition had been reported. All were born at or near term, but died in the newborn period. McDonald-McGinn et al. (1992) described affected male and female sibs. The second-born, male sib died at 6 weeks of life, and postmortem examination showed malposition of pulmonary vein branches adjacent to pulmonary artery branches, increased muscularization of pulmonary arterioles, maldevelopment of pulmonary lobules, and deficient capillarization of airspace walls. The female sib died at 43 days with the same findings. The parents denied consanguinity; both, however, were of Ukrainian Jewish descent.

Boggs et al. (1994) described misalignment of pulmonary veins with alveolar capillary dysplasia and pulmonary hypertension in a male infant whose sister had previously died of the disease (Abdallah et al., 1993). The male infant deteriorated 12 hours after birth and died on the fortieth day of life; developmental anomalies observed at autopsy included bilateral ureteropelvic junction obstruction with hydronephrosis and bilateral cryptorchidism. In contrast, after an isolated episode of apnea and cyanosis shortly after birth, his sister had remained symptom-free until the age of 6 weeks, when she was readmitted in respiratory failure with severe, refractory pulmonary hypertension. Histologic examination revealed that while both sibs had malposition of the pulmonary veins, the capillary deficiency and abnormal development of distal air spaces were patchy in the sister but distributed evenly throughout the lung parenchyma in the brother. Review of 14 previously reported cases showed that more than 50% of affected infants had accompanying anomalies, the majority of which involved the genitourinary, gastrointestinal, and cardiovascular systems.

Manouvrier-Hanu et al. (1996) described 2 brothers in whom bilateral pelviureteric junction obstruction (PUJO) with secondary hydronephrosis was associated with misalignment of pulmonary veins with alveolar capillary dysplasia, leading to persistent pulmonary hypertension of the newborn. Both brothers died within 4 months after birth. Their parents were healthy and nonconsanguineous. No renal abnormalities were found in the mother, although a maternal uncle had PUJO and his daughter had vesicoureteral reflux. In 2 other families with pulmonary hypertension of the newborn in sibs, no renal abnormalities were reported (Manouvrier-Hanu et al., 1996). Manouvrier-Hanu et al. (1996) proposed that PUJO may be an important finding in patients with misalignment of pulmonary veins and congenital alveolar capillary dysplasia.

Vassal et al. (1998) reported a brother and sister with misalignment of the pulmonary vessels (congenital alveolar capillary dysplasia) and pulmonary hypertension who died at 20 days and 21 hours of life, respectively. Additional findings in the brother included secondary lymphangiectasia on histology, moderate hypertrophy of the right ventricle, patent ductus arteriosus, and severe bilateral hydronephrosis with ureters measuring about 8 cm in diameter and a hypertrophic bladder with 1-cm thick walls.

Witters et al. (2001) found congenital alveolar capillary dysplasia in 2 children, born of consanguineous Turkish parents. Both children died neonatally, and 1 child also had tibial agenesis and ectrodactyly (119100).

Sen et al. (2004) suggested that congenital alveolar dysplasia described by MacMahon (1948), and congenital alveolar capillary dysplasia may represent different entities: infants with congenital alveolar dysplasia have generally survived longer, do not uniformly have pulmonary hypertension, and do not have malposition of the pulmonary veins on pathologic examination. Sen et al. (2004) studied 23 patients with histologically confirmed alveolar capillary dysplasia, including the male infant previously reported by Boggs et al. (1994) and 2 sets of 2 sibs: diagnosis was based on the presence of dramatic pulmonary arterial medial thickening extending along the course of small pulmonary arteries well into air-space walls; pulmonary veins malpositioned adjacent to small pulmonary arteries in both their pre-acinar and intra-acinar course, rather than in their normal location at the lobular periphery and interlobular septa; and, frequently, maldevelopment of the acinus with reduction in volume and simplification in structure. Analysis of medical records showed that 90% of patients were born at term, 85% were appropriate for gestational age, and 82% expired within the first month of life despite aggressive intervention. Of 22 infants for whom autopsy reports were available, 18 (82%) had at least 1 additional major structural abnormality, affecting 1 or more of the cardiovascular (5 infants), gastrointestinal (4), genitourinary (4), or musculoskeletal (1) systems; and in 5 (28%) of the 18 infants with additional anomalies, disruption of the normal right-left asymmetry of intrathoracic or intraabdominal organs were noted.

Molecular Genetics

In 10 patients with alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) associated with multiple congenital anomalies, including 1 patient previously studied by Sen et al. (2004), Stankiewicz et al. (2009) identified 6 overlapping microdeletions encompassing the FOX transcription factor gene cluster on chromosome 16q24.1-q24.2, all but 1 of which included the FOXF1 gene (601089). Stankiewicz et al. (2009) sequenced the FOXF1 gene in 18 additional patients with ACDMPV and identified heterozygosity for 1 nonsense, 1 no-stop, and 2 frameshift mutations in 4 unrelated patients, respectively, including 1 previously studied by Sen et al. (2004) (601089.0001-601089.0004). Stankiewicz et al. (2009) noted that in contrast to the association of point mutations in FOXF1 with bowel malrotation, microdeletions of FOXF1 were associated with hypoplastic left heart syndrome and gastrointestinal atresias, which they suggested was due to haploinsufficiency for the neighboring FOXC2 (602402) and FOXL1 (603252) genes.

In a male infant with lethal alveolar capillary dysplasia and congenital heart disease, Yu et al. (2010) identified heterozygosity for a de novo 1.37-Mb deletion of chromosome 16q24.1-q24.2 (84,447,762-85,815,086; NCBI36.1) that encompassed 5 annotated genes, including FOXF1, FOXC2, and FOXL1. The infant died of irreversible pulmonary hypertension, respiratory failure, and cor pulmonale at 3 days of age. Autopsy showed alveolar capillary dysplasia with misalignment of pulmonary veins as well as cardiac anomalies, including hypoplasia of the left ventricle and mitral valve, pulmonary valve atresia and small main pulmonary artery, subaortic ventricular septal defect, overriding aorta, atrial septal defect, patent ductus arteriosus, and persistent left superior vena cava that drained to the coronary sinus. In addition, he had hydronephrotic urinary tract anomalies with urethral obstruction, and intestinal malrotation, with the cecum and appendix located in the left lower quadrant.

Sen et al. (2013) provided a comprehensive list of 42 identified FOXF1 variants in patients with ACDMPV. Twenty-five (60%) of the variants were located within the putative DNA-binding domain, indicating its plausible role in FOXF1 function. The majority of the ACDMPV cases were sporadic. Only 4 cases were familial, of which 3 showed maternal inheritance consistent with paternal imprinting of the gene.

Exclusion Studies

Sen et al. (2004) analyzed the BMPR2 (600799) and EMAPII (AIMP1; 603605) genes in DNA from 10 infants with alveolar capillary dysplasia but found no mutations.

Cytogenetics

Szafranski et al. (2014) reported a patient with severe neonatal-onset ACDMPV, resulting in death at 13 days of life, which was associated with a 194-kb deletion in 16q24.1 located about 272 kb upstream of the FOXF1 gene, leaving FOXF1 intact and disrupting LINC01081 (614977). An unrelated patient with later onset of ACDMPV at age 7 months had a 1.5-Mb deletion mapping 306 kb upstream of the FOXF1 gene, leaving both FOXF1 and LINC01081 intact, but removing part of LINC01082 (614978). Lung tissue in this patient showed a 70% reduction of FOXF1 expression compared to controls. Both deletions occurred de novo on the maternal chromosome, suggesting that FOXF1 is paternally imprinted. Knockdown of LINC01081 expression using 2 different siRNAs in fetal lung fibroblasts reduced FOXF1 transcript levels by 14 and 20%. These findings indicated that LINC01081 and LINC01082 are distant enhancers of FOXF1. Szafranski et al. (2014) concluded that the discordant phenotypes in these patients suggest that regulation of FOXF1 expression by LINC01081 contributes to the onset of ACDMPV symptoms.