Alveolar capillary dysplasia

Abstract: We observed two unrelated consanguineous families with malformation syndromes sharing anophthalmia and distinct eyebrows as common signs, but differing for alveolar capillary dysplasia or complex congenital heart defect in one and diaphragmatic hernia in the other family. Homozygosity mapping revealed linkage to a common locus on chromosome 15, and pathogenic homozygous mutations were identified in STRA6, a member of a large group of "stimulated by retinoic acid" genes encoding novel transmembrane proteins, transcription factors, and secreted signaling molecules or proteins of largely unknown function. Subsequently, homozygous STRA6 mutations were also demonstrated in 3 of 13 patients chosen on the basis of significant phenotypic overlap to the original cases. While a homozygous deletion generating a premature stop codon (p.G50AfsX22) led to absence of the immunoreactive protein in patient's fibroblast culture, structural analysis of three missense mutations (P90L, P293L, and T321P) suggested significant effects on the geometry of the loops connecting the transmembrane helices of STRA6. Two further variations in the C-terminus (T644M and R655C) alter specific functional sites, an SH2-binding motif and a phosphorylation site, respectively. STRA6 mutations thus define a pleiotropic malformation syndrome representing the first human phenotype associated with mutations in a gene from the "STRA" group.

Abstract: Alveolar capillary dysplasia with misalignment of the pulmonary veins (ACD/MPV) is a rare, fatal developmental lung disorder of neonates and infants. This review aims to address recent findings in the etiology and genetics of ACD/MPV and to raise awareness of this poorly known disease, which may also present as milder, unclassified forms. Successively discussed are what is known about the epidemiology, pathogenesis, pathophysiology, diagnostic indicators and approaches, genetic testing, treatment, and cases of delayed onset. The review concludes with suggestions for future directions to answer the many unknowns about this disorder.

Abstract: Decreased pulmonary expression of Forkhead Box f1 (Foxf1) transcription factor was associated with lethal alveolar hemorrhage in 55% of the Foxf1 +/− newborn mice. The severity of the pulmonary abnormalities correlates with the levels of Foxf1 mRNA. Defects in alveolarization and vasculogenesis were observed in subsets of the Foxf1 +/− mice with relatively low levels of expression from the normal Foxf1 allele. Lung hemorrhage was coincident with disruption of the mesenchymal–epithelial cell interfaces in the alveolar and bronchiolar regions of the lung parenchyma and was associated with increased apoptosis and reduced surfactant protein B (SP-B) expression. Finally, the lung defect associated with the Foxf1 +/− mutation was accompanied by reduced expression of vascular endothelial growth factor (VEGF), the VEGF receptor 2 (Flk-1), bone morphogenetic protein 4 (Bmp-4), and the transcription factors of the Brachyury T-Box family (Tbx2–Tbx5) and Lung Kruppel-like Factor. Reduction in the level of Foxf1 caused neonatal pulmonary hemorrhage and abnormalities in alveologenesis, implicating this transcription factor in the regulation of mesenchyme–epithelial interaction critical for lung morphogenesis.

Abstract: Pulmonary surfactant is required for adaptation to air breathing after birth, reducing surface tension at the air-liquid interface in the alveolus to maintain lung volumes during the respiratory cycle. Disorders of pulmonary surfactant homeostasis are associated with acute and chronic respiratory disease in infants and adults. Mutations in the surfactant protein genes encoding SP-B and SP-C cause severe respiratory failure in infancy and chronic interstitial lung disease in older individuals.

Abstract: We report the use of inhaled prostacyclin (PGI 2 ) in 4 neonates with persistent pulmonary hypertension and hypoxemia refractory to inhaled nitric oxide. Oxygenation rapidly improved after inhalation of PGI 2 in all infants. The condition of one infant subsequently deteriorated, and alveolar capillary dysplasia was found at autopsy. The surviving infants were discharged with normal oxygen saturations in room air. (J Pediatr 2002;141:830-32)