Alveolar capillary dysplasia

Alveolar capillary dysplasia

Alveolar Capillary Dysplasia with misalignment of the pulmonary veins (ACDMPV) is a very rare congenital malformation involving abnormal development of the capillary vascular system around the alveoli of the lungs. Capillaries are the smallest blood vessels in the body and the microscopic capillaries around the air sacs fail to develop normally in cases of ACDMPV. There are fewer capillaries, and the ones that are present are not positioned correctly within the walls of the alveoli. This makes gas exchange (the delivery of oxygen from the lungs to the bloodstream) very difficult and ineffective. It is a rare cause of persistent pulmonary hypertension in infants. It also may be a rare cause of pulmonary hypoplasia. Babies with classical cases of ACDMPV may appear normal at birth but within the first days of life they develop respiratory distress with persistent pulmonary hypertension. Limited reports have begun to emerge of presentation beyond the neonatal period in patients with a “patchy” distribution of disease. ACDMPV does not respond to standard therapies that resolve simple pulmonary hypertension. The lack of response is an important diagnostic clue. ACDMPV is considered a fatal diagnosis, however, some patients have survived with atypical or “patchy ACDMPV” long enough to receive lung transplants.

The ACD Association has grown to close to 200 registered families from around the world and there are more than 100 cases of ACDMPV reported in medical literature worldwide. For several reasons, these case reports almost certainly underestimate the true prevalence of ACDMPV. First, the definitive diagnosis of ACDMPV currently depends on histological examination of lung tissue on autopsy or ante mortem lung biopsy, and neither of these diagnostic modalities is universally pursued in the setting of a critically ill or dying newborn. Second, many infants born with ACDMPV have associated malformations in other organ systems that may allow the lung pathology to go undetected. Third, the diagnosis may be missed by pathologists unfamiliar with the disorder. Last, evidence is mounting to suggest that a less severe phenotype compatible with prolonged survival might exist, although definitive diagnostic criteria for this group are yet to be established.

If your family has been affected by ACDMPV, please click here to register with the ACD Association. Please also connect with the ACD Association on Facebook and Twitter.

Cause

It is now well established that ACDMPV is a genetic disease. This means that ACDMPV occurs due to abnormalities in the DNA. Humans carry DNA in all of our cells that make us up and it acts as the blueprint to make us who we are. 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 ACDMPV are not present in either of their parents and thus the risk of other children being affected by ACDMPV is low.

Two broad types of genetic abnormality have been found to cause ACDMPV: (1) a mutation of the FOXF1 gene on chromosome 16, or (2) 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. The genetic abnormalities responsible for ACDMPV in the remaining 10-20% of cases are currently being investigated including testing for deletions farther away from the FOXF1 gene on chromosome 16 and whole exome testing.

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 90% of cases of ACDMPV where a genetic abnormality has been found it appears to have arisen de novo and is not familial. The abnormality arises in the mother’s ovary early in her life, often before she was born. Four families with more than one child affected by ACDMPV have been described in research conducted at the Baylor College of Medicine 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 three of these families, there was a mutation in FOXF1 found in the mother’s blood sample. One case of ACDMPV due to gonadal mosaicism (see term below) has been described.

This means that overall, considering familial ACDMPV and gonadal mosaicism, the risk of having more than one child affected by ACDMPV is around 10%. The risk of having more than one infant with ACDMPV if neither parent carries the genetic abnormality is 1-2% (due to gondadal mosaicism).

Note: Gonadal Mosaicism occurs when a person (in this case the mother of an infant with ACDMPV) has two or more populations of cells in her ovary. One population of cells contains normal genetic material while the others contain genetic abnormalities. The genetic abnormality is confined to cells in the ovary, however, and is not present in the DNA from the mother’s other tissues. If two eggs with the genetic abnormality were released and fertilized, then both children would have ACDMPV even though a sample of the mother’s blood would not show a genetic abnormality.

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 the following:

1. FOXF1 gene sequencing to detect a mutation 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);

2. Other genetic abnormalities such as deletions in chromosome 16 close to the FOXF1. 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. A blood sample for genetic testing can be collected prior to or after an infant is placed on ECMO as the donor blood used for ECMO is depleted of the white blood cells that are used in genetic testing before it is given to the infant and therefore there is no chance of contamination.

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

The diagnosis of ACDMPV should be considered in infants who present with severe hypoxemia and idiopathic pulmonary hypertension, and who do not respond appropriately after 7 to 10 days of neonatal intensive care treatment as described below. The majority of patients with ACDMPV (up to 80%) will have other associated anomalies of the cardiovascular, gastrointestinal, urogenital, or musculoskeletal systems. The initial chest radiograph is usually normal. If a cardiac catheterization is performed, there may be absence of the capillary blush phase. The diagnosis can only be confirmed by lung biopsy or autopsy. Consulting a pathologist with experience in making this diagnosis may be helpful. Pathological features include a paucity of alveolar capillaries, widened alveolar septae, and increased muscularization of pulmonary arterioles. There is usually malpositioning (“misalignment”) of pulmonary veins in the bronchovascular bundle, but this is not required for the diagnosis. A focal distribution of disease has been described, which makes it necessary to examine multiple lung sections if ACDMPV is suspected.

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

Treatment

Most babies with ACDMPV have normal Apgar scores at 1 and 5 minutes, but within the first days of life 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 ACDMPV. The objective of therapy is to keep the baby alive long enough to obtain a lung transplant.

Because none of the supportive therapies described above has changed the expected mortality due to ACDMPV, lung transplantation is currently the only option that might prolong survival. Achieving early diagnosis by lung biopsy is an essential first step, followed by strategies that sufficiently prolong survival. Lung transplantation may provide effective treatment for carefully selected affected infants. Donor availability continues to limit the utilization of lung transplantation for neonatal diseases. See “Advance in Experimental Treatment” below for further discussion on lung transplantation.

Research

Since 2001, the ACD Association has been supporting ACDMPV 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 ACDMPV 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 ACDMPV 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" dropdown list. All UK & Europe based families are also welcome to use The David Ashwell Foundation as a means of fundraising for ACDMPV Research.

Advance in experimental treatment

Several patients have survived with atypical or “patchy ACDMPV” long enough to receive lung transplants. According to a 2013 case series conducted by St. Louis Children’s Hospital, four ACDMPV patients (ages 4 months, 5 months, 9 months and 20 months of age at time of transplant) with atypical presentations of ACDMPV each underwent a successful bilateral lung transplantation (BLT). As stated in the case study, “If they survive to BLT, patients with ACDMPV can have successful outcomes” and the ACDMPV patients “are alive at last follow-up at 1, 8, 9 and 12 years of age” (as of May 2013).

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.

History

ACDMPV was first described in 1948. A familial association of ACDMPV was first reported in 1994.

External links

• "ACD Association: "Searching for answers...hoping for a cure."". Retrieved 14 January 2011.

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