Alveolar capillary dysplasia with misalignment of the pulmonary veins (ACDMPV, OMIM# 265380) is a rare disorder present at birth (congenital). Infants experience severe, life-threatening breathing problems (respiratory distress) and high blood pressure in the blood vessels of the lungs (pulmonary hypertension). These problems may occur within a few hours or a couple of days after birth. Almost all infants pass away within the first month of life. Very rarely, the disorder presents later (late-onset form). Infants often have additional symptoms, involving the gastrointestinal tract, cardiovascular system, or genitourinary system. In the vast majority of infants, AVDMPV is caused by point mutations (single nucleotide variants) involving the FOXF1 gene or by a loss of genetic material (copy-number variant (CNV) deletions or genomic deletion) that includes the FOXF1 gene or its distant regulatory genomic region (lung-specific enhancer). The disorder is usually not inherited but has in specific instances been seen to run in families.
Alveolar capillary dysplasia (ACD) is a rare, congenital diffuse lung disease characterized by abnormal blood vessels in the lungs that cause highly elevated pulmonary blood pressure and an inability to effectively oxygenate and remove carbon dioxide from the blood.
Symptoms
Within the first few days after birth, infants with ACDMPV develop severe breathing problems and lack of oxygen in the blood (hypoxemia). They experience shortness of breath and cyanosis, a condition marked by abnormal bluish discoloration of the skin that occurs because of low levels of circulating oxygen in the blood. High blood pressure in the blood vessels of the lungs (pulmonary hypertension) also occurs. Breathing issues become progressively worse and most infants experience respiratory failure. Very rarely, infants may not show signs of the disorder until weeks or even months after birth, usually when pulmonary hypertension of various severity is noted.
Affected infants often have additional symptoms including gastrointestinal symptoms such as twisting of the large intestines, genitourinary symptoms such as swelling of the kidneys because of urine backing up (hydronephrosis), or cardiovascular symptoms such as underdevelopment of the left side of the heart.
Causes
In some instances, ACDMPV is caused by a point mutation in the FOXF1 gene, or by a loss of genetic material on chromosome 16q24.1 that includes the FOXF1 gene or non-coding elements that regulate the expression of FOXF1. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty or inefficient. Depending upon the functions of the particular protein, this can affect many organ systems of the body. For a minority of infants (~10-20%) with ACDMPV, the molecular cause is unknown. In most instances the disorder is sporadic, which means that the genetic changes occur at the time of fertilization and are not inherited from the parents. There are very rare instances where ACDMPV has run in families and can be inherited.
The FOXF1 gene creates a protein that is a type of transcription factor. Transcription factors are proteins that help to control which genes are turned on and which genes are turned off. They do this by binding with DNA and other proteins. When the FOXF1 gene is altered it does not produce enough of the transcription factor that it is supposed to (or it creates a damaged or inefficient version of it). The lack of this protein causes many problems, particularly affecting the small blood vessels within the lungs.
In infants with ACDMPV, the alveolar capillaries fail to develop properly. They are described as being misaligned or malpositioned. Alveolar refers to the alveoli, the millions of tiny air sacs that are scattered throughout the lungs. The capillaries are very tiny blood vessels that connect the alveoli to larger blood vessels. When a person breathes in air, oxygen travels to the lungs and into the alveoli. It passes through the walls of the alveoli into the capillaries and into the bloodstream to be carried throughout the body. In addition, carbon dioxide passes from the bloodstream into the alveoli to be sent out of the body when a person breathes out. Because the alveoli capillaries do not develop properly in infants with ACDMPV, sufficient levels of oxygen cannot be delivered to the tissues of the body and not all of the carbon dioxide can be expelled from the body.
A specific process that may be associated with ACDMPV is genomic imprinting. Everyone has two copies of every gene – one received from the father and one received from the mother. In most cases, both genes are “turned on” or active. However, some genes are preferentially silenced or “turned off” based upon which parent that gene came from (genomic imprinting). Usually, genomic imprinting is controlled by chemical switches in DNA through a process called methylation. Proper genetic imprinting is necessary for normal development. Defective imprinting has been associated with several disorders. In defective imprinting, the wrong gene is turned on or the wrong one is turned off.
ACD/MPV can be caused by mutations in the FOXF1 gene. The protein produced from the FOXF1 gene is a transcription factor, which means that it attaches (binds) to specific regions of DNA and helps control the activity of many other genes. The FOXF1 protein is important in development of the lungs and their blood vessels. The FOXF1 protein is also involved in the development of the gastrointestinal tract. Mutations in the FOXF1 gene that cause ACD/MPV result in an inactive protein that cannot regulate development, leading to abnormal formation of the pulmonary blood vessels and gastrointestinal tract.
ACD/MPV can also be caused by a deletion of genetic material on the long arm of chromosome 16 in a region known as 16q24.1. This region includes several genes, including the FOXF1 gene. Deletion of one copy of the FOXF1 gene in each cell reduces the production of the FOXF1 protein. A shortage of FOXF1 protein affects the development of pulmonary blood vessels and causes the main features of ACD/MPV. Researchers suggest that the loss of other genes in this region probably causes the additional abnormalities, such as heart defects, seen in some infants with this disorder. Like FOXF1, these genes also provide instructions for making transcription factors that regulate development of various body systems before birth.
Diagnosis
ACDMPV may be suspected in any infant who presents with severe cyanosis (hypoxemia) and high pulmonary blood pressure (pulmonary hypertension) that is unresponsive to treatment in the neonatal intensive care unit (NICU). The diagnosis is confirmed through an examination of lung tissue by an experienced pathologist for characteristic tissue changes. The characteristics that a pathologist will look for can include a relative lack of capillaries near the alveoli, thickening of the walls (septa) of alveoli, and increased “muscularization” of the small arteries of the lungs (arterioles).
Molecular genetic testing can confirm a diagnosis of ACDMPV in approximately 80-90% of cases. This testing should also be done on parents to determine whether the parents carry the genetic abnormality. Molecular genetic testing can detect changes in the FOXF1 gene or changes affecting the function of the FOXF1 gene that are known to cause this disorder.
Treatment
Various treatments have been tried in infants with ACDMPV, including mechanical ventilation, nitric oxide, and extracorporeal membrane oxygenation (ECMO). These are standard treatments for infants with other disorders that cause respiratory distress, but they have been ineffective in treating infants with ACDMPV. In few older infants with milder or late-onset ACDMPV, lung transplantations have been successful.
Initial treatments attempt to improve low blood oxygenation and high pulmonary blood pressures. Because blood oxygen content is usually very low, babies with ACD are often intubated, sedated, and mechanically ventilated with pure oxygen. Pulmonary vasodilators like sildenafil or inhaled nitric oxide can be used to reduce pulmonary blood pressure.[rx] For those with severe ACD, these measures offer only momentary improvement. As symptoms worsen, ECMO can be used, but it also offers only brief improvement. There are no effective treatments for severe ACD.[rx]
For infants with atypical ACD who initially had milder symptoms and were present at months of life, there can be a better response to therapy. There have been reports of infants with ACD surviving to 20 or 36 months without lung transplantation. Bilateral lung transplantation may be the definitive treatment.
Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is essential as well.
References
