Alveolar capillary dysplasia

Alveolar capillary dysplasia
Classification and external resources
OMIM 265380

Alveolar capillary dysplasia (ACD, also congenital alveolar dysplasia) is a very rare congenital malformation involving abnormal development of the capillary vascular system around the alveoli of the lungs. It is a rare cause of persistent pulmonary hypertension in infants.[1] It also may be a rare cause of pulmonary hypoplasia.[2] Until mid-2012, the only possible outcome was neonatal death, with one of the longest surviving infants living 2 months.[3]

Babies with ACD may appear normal at birth but within minutes or hours they develop respiratory distress with persistent pulmonary hypertension.[4] ACD does not respond to standard therapies that resolve simple pulmonary hypertension. The lack of response is an important diagnostic clue.

Cause

It is now well established that Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins (ACDMPV) is a genetic disease. This means that ACDMPV occurs due to abnormalities in the DNA. However, this doesn't mean that ACDMPV is familial in most cases. In almost all cases the genetic abnormalities (mutations and deletions) that are found in infants with ACD are not present in either of their parents and thus the risk of other children being affected by ACD is very low.

Two broad types of genetic abnormality have been found to cause ACDMPV, a mutation of the FOXF1 gene on chromosome 16, or other genetic abnormalities such as deletions in areas of chromosome 16 that regulate the expression of the FOXF1 gene. New genetic abnormalities are being found regularly, but at present around 80-90% of infants with confirmed ACDMPV can be found to have one of these abnormalities.

Based on the cases described so far, the FOXF1 gene seems to be subject to paternal imprinting. The FOXF1 gene that an infant inherits from his/her father is inactive and not expressed, thus all cases of ACDMPV arise by the genetic abnormalities arising on the chromosome inherited from an infant's mother. In approximately 98% of cases of ACDMPV, the genetic abnormality appears to have arisen de novo and is not familial. The abnormality arises in the mother's ovary early in her life, often before the she was born. One case of ACDMPV due to gonadal mosaicism has been described. The risk of having more than one infant with ACDMPV if neither parent carries the genetic abnormality is thus approximately 1%.

Three cases of familial ACDMPV have been described so far. There might not be a family history of ACDMPV as a result of paternal imprinting. This means that the genetic abnormality only results in ACDMPV when it is inherited from an infant's mother. In familial ACDMPV, the genetic abnormality detectable in the infant can also be found in his/her mother.

This means that overall, considering familial ACDMPV and gonadal mosaicism, the risk of having more than one child affected by ACD is around 2%.

The best way to detect genetic abnormalities is using a blood sample from an infant. If this is not possible, DNA can also be extracted from tissue, for example a lung biopsy or autopsy (post mortem). It is important to test such material for mutations in FOXF1. This test is performed in Baylor College of Medicine, in Houston, Texas, USA by Professor Stankiewicz's laboratory. Some other centres are now able to do this test (for example Great Ormond Street Hospital, London, UK). It is also important to test for other genetic abnormalities in chromosome 16 close to the FOXF1 gene. This can be done using a widely-available genetic test called array CGH (Comparative Genomic Hybridisation).

If an infant has a genetic abnormality detected, this can be used to test future siblings when the mother is pregnant (or after birth) to look for ACDMPV if so desired. DNA can be taken from the fetus when in the womb by one of two procedures known as chorionic villus sampling and amniocentesis. This test is offered by the clinical diagnostic laboratories at Baylor College of Medicine.

Diagnosis

The best way to detect genetic abnormalities is using a blood sample from an infant. If this is not possible, DNA can also be extracted from tissue, for example a lung biopsy or autopsy (post mortem). It is important to test such material for mutations in FOXF1. This test is performed in Baylor College of Medicine, in Houston, Texas, USA by Professor Stankiewicz's laboratory. Some other centres are now able to do this test (for example Great Ormond Street Hospital, London, UK). It is also important to test for other genetic abnormalities in chromosome 16 close to the FOXF1 gene. This can be done using a widely-available genetic test called array CGH (Comparative Genomic Hybridisation).

If an infant has a genetic abnormality detected, this can be used to test future siblings when the mother is pregnant (or after birth) to look for ACDMPV if so desired. DNA can be taken from the fetus when in the womb by one of two procedures known as chorionic villus sampling and amniocentesis. This test is offered by the clinical diagnostic laboratories at Baylor College of Medicine.

Sometimes ACD is diagnosed clinically.[5] This is common when there is a family history of ACD, but rare otherwise. A clinical differential diagnosis of ACD excludes fetal atelectasis.[4]

ACD is not detectable by prenatal imaging. However, some babies with ACD have associated congenital malformations that are detectable by imaging, particularly of the cardiovascular, gastrointestinal, and genitourinary systems. The identification of genes involved in ACD offers the potential for prenatal testing and genetic counseling.

Treatment

Most babies with ACD have normal Apgar scores at 1 and 5 minutes, but within minutes or hours present with hypoxia and upon investigation are found to have hypoxemia and pulmonary hypertension. Initial treatments address the hypoxia, usually beginning with supplemental oxygen and arrangements for urgent transport to a neonatal intensive care unit.

Therapies that have been tried to extend life include extracorporeal membrane oxygenation and nitric oxide. These are supportive therapies for persistent pulmonary hypertension; they do not treat the ACD. The objective of therapy is to keep the baby alive long enough to obtain a lung transplant.[3] To date no such case has been reported except as set forth in "Advance in experimental treatment" below.

Research

Since 2001, the ACD Association has been supporting ACD research at Baylor College of Medicine in Houston, Texas through donations of blood samples, tissue samples and funding. In order to enhance the chances for successful research grants and improve the outcomes of the studies in the future, the ACD Association encourages families to donate their baby's tissue and blood samples to the ACD research team based at Baylor. Every sample is critical because there are such a small number of samples. Please contact Dr. Pawel Stankiewicz at Baylor to participate in the study.

The Baylor study is funded with grants from the National Organization for Rare Disorders (NORD) that are the result of contributions to the ACD account at NORD. Research through NORD's grant process does two things: 1) the request for proposal publicizes NORD in the medical community, and 2) research brings us closer to non-invasive diagnostics, more information, treatment, and a cure. It is easy to make a tax deductible donation through NORD. Please click here and be sure to choose "Alveolar Capillary Dysplasia" (ACD) from the "research fund" pull down menu. If you are making an international (outside of the U.S.) donation, (1) you may want to first contact NORD, or (2) all UK & Europe based families are welcome to use The David Ashwell Foundation as a means of fundraising for ACD Research.

Advance in experimental treatment

According to the St. Louis Children's Hospital (the Level I pediatric trauma center and pediatric teaching hospital for the Washington University School of Medicine), which is noted worldwide for its record in pediatric pulmonary transplantation, a type of artificial lung device, the Quadrox, was used after ECMO as a bridge to a dual lung transplant in ten-month-old Eleni Scott of the St. Louis suburb of Florissant, Missouri, who after transplantation returned to her home. Doctors have said it is too early to presume it will continue to work here or work in other pediatric patients as an experiment, much less a successful, curative standard therapy, but the infant has survived thus far, meaning that there might be hope for sufferers of this rare condition. For more information, please see the link to the news release.[6]

History

ACD was first described in 1948.[4][7] A familial association of ACD/MPV was first reported in 1994.[8]

References

  1. ↑ Cater G, Thibeault DW, Beatty EC, Kilbride HW, Huntrakoon M (February 1989). "Misalignment of lung vessels and alveolar capillary dysplasia: a cause of persistent pulmonary hypertension". The Journal of Pediatrics 114 (2): 293–300. doi:10.1016/S0022-3476(89)80800-5. PMID 2915290.
  2. ↑ Sirkin W, O'Hare BP, Cox PN, Perrin D, Cutz E, Silver MM (1997). "Alveolar capillary dysplasia: lung biopsy diagnosis, nitric oxide responsiveness, and bronchial generation count". Pediatric Pathology & Laboratory Medicine : Journal of the Society for Pediatric Pathology, Affiliated with the International Paediatric Pathology Association 17 (1): 125–32. doi:10.3109/15513819709168352. PMID 9050066.
  3. ↑ 3.0 3.1 Kitayama Y, Kamata S, Okuyama H, Usui N, Sawai T, Kobayashi T, Fukui Y, Okada A (January 1997). "Nitric oxide inhalation therapy for an infant with persistent pulmonary hypertension caused by misalignment of pulmonary veins with alveolar capillary dysplasia". Journal of Pediatric Surgery 32 (1): 99–100. doi:10.1016/s0022-3468(97)90105-6. PMID 9021581.
  4. ↑ 4.0 4.1 4.2 MacMahon HE (July 1948). "Congenital alveolar dysplasia of the lungs". The American Journal of Pathology 24 (4): 919–31. PMC 1942746. PMID 18874417.
  5. ↑ Liet JM, Joubert M, Gournay V, Godon N, Godde F, Nomballais MF, Roze JC (January 1998). "[Neonatal hypoxemia due to misaligned pulmonary vessels with alveolar capillary dysplasia]". Archives De Pédiatrie : Organe Officiel De La Sociéte Française De Pédiatrie (in French) 5 (1): 27–30. doi:10.1016/s0929-693x(97)83463-x. PMID 10223108.
  6. ↑ http://www.stlouischildrens.org/articles/features/2012/new-medical-approach-helps-baby-with-rare-disease
  7. ↑ MacMahon HE (July 1948). "Congenital alveolar dysplasia; a developmental anomaly involving pulmonary alveoli". Pediatrics 2 (1): 43–57. PMID 18874463.
  8. ↑ Boggs S, Harris MC, Hoffman DJ, Goel R, McDonald-McGinn D, Langston C, Zackai E, Ruchelli E (January 1994). "Misalignment of pulmonary veins with alveolar capillary dysplasia: affected siblings and variable phenotypic expression". The Journal of Pediatrics 124 (1): 125–8. doi:10.1016/S0022-3476(94)70267-5. PMID 8283361.

External links