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alveolar capillary dysplasia

Monday 24 October 2005

Digital cases

- Case 80 (HPC:80) : Alveolar capillary dysplasia
- Case 84 (HPC:84) : Alveolar capillary dysplasia
- Case 204 (HPC:204) : Alveolar capillary dysplasia
- Case 249 (HPC:249) : Alveolar capillary dysplasia

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.

Epidemiology

- possible familial occurence (#3721495#)

Macroscopy

- bulky stiff lungs
- focal pulmonary hemorrhages
- prominent interlobular septa
- areas of dilated vessels

Microscopy

- 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

- Expression of angiogenic and vasculogenic proteins in the lung in alveolar capillary dysplasia/misalignment of pulmonary veins: an immunohistochemical study. Sen P, Choudhury T, Smith EO, Langston C. Pediatr Dev Pathol. 2010 Sep-Oct;13(5):354-61. PMID: #20331367#

- 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#