Definition: complex vascular abnormality in the lungs causing progressive hypoxemia in the newborn.
Congenital alveolar capillary dysplasia is a rare cause of irreversible pulmonary hypertension with 100% mortality.
Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare, neonatally lethal developmental disorder of the lung with defining histologic abnormalities typically associated with multiple congenital anomalies (MCA).
Alveolar capillary dysplasia should be considered with a high index of suspicion in an infant who presents with pulmonary hypertension beyond the neonatal period and for which no anatomical cause can be found.
Early consideration of open lung biopsy may prevent using costly, invasive, and probably ineffective procedures such as extracorporeal membrane oxygenation.
Synopsis
possible familial occurence (3721495)
macroscopicla examination
- bulky stiff lungs
- focal pulmonary hemorrhages
- prominent interlobular septa
- areas of dilated vessels
persistent pulmonary hypertension of newborn
dilated veins around pulmonary arteries
pulmonary arteriole showing marked thickening of the medial musculature
broad alveolar septa containing centrally located large alveolar capillaries
artery is surrounded by an anomalous venous ring derived from branches of septal veins
interstitial thickening
markedly decreased septal capillaries
poor development of the capillary-alveolar interface
muscularized pulonary arteries within aleolar septa away from bronchioles
centrally placed capillaries beneath the basement membrane of the alveolar lining cells and surrounded by loose mesenchyme
ectatic veinswithin bronchovascular bundles, or within the adventia of the pulmonary arteries
intermittent venous ring auround bronchioles
small muscularized arteries in the acini, extending to the precapillary area
severe pulmonary capillary hypoplasia
normal anatomical and biochemical parenchymal maturation
intractable pulmonary hypertension
deficient capillaries in airspace walls
anomalous small pulmonary veins in bronchiolar-arterial rays
medial thickening in small pulmonary arteries
peripheral arterial muscularization
abnormally immature parenchymal development in the lungs
underdevelopment of alveoli
pulmonary interstitial fibrosis
misalignment of lung vessels
- the pulmonary veins joined the pulmonary arteries, rather than following a course away from them.
Associations
phocomelia
trisomy 21 (Down syndrome) (16944970, 16235130)
duodenal atresia (17060189)
cardiac malformations (congenital heart disease)
- atrioventricular septal defect (16331469)
- atrial septal defect
- ventricular septal defect
- quadricuspid pulmonary valve (16331469)
asplenia
fetal ureteric obstruction
fetal urethral obstruction
anorectal anomaly (17060189)
intestinal malrotation (17060189)
total colonic Hirschsprung disease (17060189)
familial microphthalmia (17036407)
anterior segment dysgenesis of the eye (11536028)
hypoplastic left heart syndrome (HLH) (11178633)
persistent pulmonary hypertension (PPH) (11178633)
intestinal malrotation (11178633)
intestinal obstruction (11178633)
congenital pulmonary alveolar proteinosis (MIM.265120) (10378403)
bilateral tibial agenesis with ectrodactyly (MIM.119100) (11754046)
Physiopathology
The primary pulmonary vascular anomaly is likely to be a failure of fetal lung vascularization dating from the second trimester and to be due to action of an unknown teratogen.
centroacinar veins may represent bronchial veins that do not normally develop beyond the ends of cartilaginous bronchi.
Pulmonary arterial occlusive changes are interpreted as reactive to obstruction at the level of pulmonary arterioles.
Associations
omphalocele (20453609)
trisomy 21 (16235130)
Etiology
germline mutations in STRA6 gene (17273977)
trisomy 21 (16235130)
genomic and genic deletions of the FOX gene cluster on 16q24.1 (19500772)
inactivating mutations of FOXF1 (19500772)
haploinsufficiencies of FOXF1 (20425831)
haploinsufficiencies of FOXC2 (20425831)
Using array CGH analysis, six overlapping microdeletions have been identified, encompassing the FOX transcription factor gene cluster in chromosome 16q24.1q24.2 in patients with ACD/MPV and MCA. (19500772)
Four different heterozygous mutations (frameshift, nonsense, and no-stop) have been identified in the candidate FOXF1 gene in unrelated patients with sporadic ACD/MPV and MCA. (19500772)
Custom-designed, high-resolution microarray analysis of additional ACD/MPV samples revealed one microdeletion harboring FOXF1 and two distinct microdeletions upstream of FOXF1, implicating a position effect. (19500772)
DNA sequence analysis revealed that in six of nine deletions, both breakpoints occurred in the portions of Alu elements showing eight to 43 base pairs of perfect microhomology, suggesting replication error Microhomology-Mediated Break-Induced Replication (MMBIR)/Fork Stalling and Template Switching (FoSTeS) as a mechanism of their formation. (19500772)
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, probably due to haploinsufficiency for the neighboring FOXC2 and FOXL1 genes. These differences reveal the phenotypic consequences of gene alterations in cis. (19500772)
See also
congenital alveolar capillary dysplasia with misalignment of pulmonary veins
progressive hypoxemia
persistent fetal circulation
pulmonary capillary maturation
References
Haploinsufficiencies of FOXF1 and FOXC2 genes associated with lethal alveolar capillary dysplasia and congenital heart disease. Yu S, Shao L, Kilbride H, Zwick DL. Am J Med Genet A. 2010 May;152A(5):1257-62. PMID: 20425831
Genomic and genic deletions of the FOX gene cluster on 16q24.1 and inactivating mutations of FOXF1 cause alveolar capillary dysplasia and other malformations. Stankiewicz P, Sen P, Bhatt SS, Storer M, Xia Z, Bejjani BA, Ou Z, Wiszniewska J, Driscoll DJ, Maisenbacher MK, Bolivar J, Bauer M, Zackai EH, McDonald-McGinn D, Nowaczyk MM, Murray M, Hustead V, Mascotti K, Schultz R, Hallam L, McRae D, Nicholson AG, Newbury R, Durham-O’Donnell J, Knight G, Kini U, Shaikh TH, Martin V, Tyreman M, Simonic I, Willatt L, Paterson J, Mehta S, Rajan D, Fitzgerald T, Gribble S, Prigmore E, Patel A, Shaffer LG, Carter NP, Cheung SW, Langston C, Shaw-Smith C. Am J Hum Genet. 2009 Jun;84(6):780-91. PMID: 19500772
Profound hypoxemia and pulmonary hypertension in a 7-month-old infant: late presentation of alveolar capillary dysplasia. Ahmed S, Ackerman V, Faught P, Langston C. Pediatr Crit Care Med. 2008 Nov;9(6):e43-6. PMID: 18997591
Eulmesekian P, Cutz E, Parvez B, Bohn D, Adatia I. Alveolar capillary dysplasia: a six-year single center experience. J Perinat Med. 2005;33(4):347-52. PMID: 16207122
Shehata BM, Abramowsky CR. Alveolar capillary dysplasia in an infant with trisomy 21. Pediatr Dev Pathol. 2005 Nov-Dec;8(6):696-700. PMID: 16235130
Eulmesekian P, Cutz E, Parvez B, Bohn D, Adatia I.Alveolar capillary dysplasia: a six-year single center experience.J Perinat Med. 2005;33(4):347-52. PMID: 16207122
Hugosson CO, Salama HM, Al-Dayel F, Khoumais N, Kattan AH.Primary alveolar capillary dysplasia (acinar dysplasia) and surfactant protein B deficiency: a clinical, radiological and pathological study.Pediatr Radiol. 2005 Mar;35(3):311-6. PMID: 15490144
Rabah R, Poulik JM. Congenital alveolar capillary dysplasia with misalignment of pulmonary veins associated with hypoplastic left heart syndrome. Pediatr Dev Pathol. 2001 Mar-Apr;4(2):167-74. PMID: 11178633
Gutierrez C, Rodriguez A, Palenzuela S, Forteza C, Rossello JL. Congenital misalignment of pulmonary veins with alveolar capillary dysplasia causing persistent neonatal pulmonary hypertension: report of two affected siblings. Pediatr Dev Pathol. 2000 May-Jun;3(3):271-6. PMID: 10742415
Haraida S, Lochbühler H, Heger A, Nerlich A, Diebold J, Wiest I, Müller-Höcker J, Löhrs U.Congenital alveolar capillary dysplasia: rare cause of persistent pulmonary hypertension.Pediatr Pathol Lab Med. 1997 Nov-Dec;17(6):959-75. PMID: 9353836
Cullinane C, Cox PN, Silver MM. Persistent pulmonary hypertension of the newborn due to alveolar capillary dysplasia. Pediatr Pathol. 1992 Jul-Aug;12(4):499-514. PMID: 1409149
Langston C. Misalignment of pulmonary veins and alveolar capillary dysplasia. Pediatr Pathol. 1991 Jan-Feb;11(1):163-70. PMID: 2014189
Khorsand J, Tennant R, Gillies C, Phillipps AF. Congenital alveolar capillary dysplasia: a developmental vascular anomaly causing persistent pulmonary hypertension of the newborn. Pediatr Pathol. 1985;3(2-4):299-306. PMID: 4095026
Wagenvoort CA. Misalignment of lung vessels: a syndrome causing persistent neonatal pulmonary hypertension. Hum Pathol. 1986 Jul;17(7):727-30. PMID: 3721495
Janney CG, Askin FB, Kuhn C 3rd. Congenital alveolar capillary dysplasia—an unusual cause of respiratory distress in the newborn. Am J Clin Pathol. 1981 Nov;76(5):722-7. PMID: 7293984