• Disease Overview
  • Synonyms
  • Signs & Symptoms
  • Causes
  • Affected Populations
  • Disorders with Similar Symptoms
  • Diagnosis
  • Standard Therapies
  • Clinical Trials and Studies
  • References
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Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins

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Last updated: 7/18/2023
Years published: 2003, 2016, 2019, 2023


Acknowledgment

NORD gratefully acknowledges Pawel Stankiewicz, MD, PhD, Professor and Przemyslaw Szafranski, PhD, Associate Professor in the Department of Molecular & Human Genetics, Baylor College of Medicine, for assistance in the preparation of this report.


Disease Overview

Summary


Alveolar capillary dysplasia with misalignment of the pulmonary veins (ACDMPV) is a rarely diagnosed lethal lung developmental disorder in newborns (neonates) that is present at birth (congenital). Infants experience severe, life-threatening breathing problems (respiratory distress) and high blood pressure in the arterial 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 with this condition die 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 most affected children, AVDMPV is caused by point mutations (single nucleotide variants in DNA) involving the FOXF1 gene or by a loss of genetic material (copy-number variant (CNV) deletions (or genomic deletion) that include the FOXF1 gene or its distant regulatory genomic region (lung-specific enhancer). The disorder is usually not inherited but there are very rare instances where ACDMPV has been reported to run in families and can be inherited.

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Synonyms

  • ACDMPV
  • alveolar capillary dysplasia
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Signs & 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 oxygen in the blood. High blood pressure in the arterial 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 variable 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.

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Causes

In most affected children, 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 (promoter and lung-specific enhancer) 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 protein, this can affect many organ systems of the body. For a minority of infants (~10-20%) with ACDMPV, the molecular cause remains 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. However, there are very rare instances where ACDMPV has been reported to 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, other protein factors and RNA polymerase. 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. 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. The pulmonary veins are described as being misaligned or mispositioned.

A specific process that may be associated with ACDMPV is the parental chromosome on which genetic defect arises. In contrast to point mutations within FOXF1, the ACDMPV-causative CNV deletions arise de novo almost exclusively on the maternal chromosome 16q24.1. Thus far, 50 de novo CNV deletions have been reported that arose on maternal chromosome 16 and only five de novo CNV deletions arose on paternal chromosome 16q24.1. Recently, a bimodal structure and parental functional dimorphism of the FOXF1 enhancer has been proposed as responsible for this phenomenon.

Very rare cases of late onset or mild ACDMPV have been associated with non-coding single nucleotide variants (SNVs) in the lung specific FOXF1 enhancer on the other chromosome 16. They may function as so-called modifiers that up-regulate the other unaffected copy of the FOXF1 gene.

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Affected populations

ACDMPV is a very rare disorder. The incidence and prevalence are unknown. More than 200 people with this disorder have been reported in the medical literature. However, many infants may go misdiagnosed or undiagnosed, so determining the true frequency of ACDMPV in the general population is difficult.

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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 a histopathological examination of lung tissue at biopsy or autopsy 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, misalignment of pulmonary veins 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 children. 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. This testing should also be done on parents to determine whether the parents carry the genetic abnormality.

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Standard Therapies

Treatment
Various treatments have been tried in infants with ACDMPV, including mechanical ventilation, nitric oxide and extra corporeal 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 a few older infants with milder or late onset ACDMPV, lung transplantations have been successful.

Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is essential as well.

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Clinical Trials and Studies

As researchers learn more about the underlying genetic factors that cause ACDMPV (e.g., genetic changes affecting the FOXF1 gene), new avenues for developing treatments are beginning to emerge. Researchers are currently studying the disorder in the hope of developing effective treatments.

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/

For information about clinical trials sponsored by private sources, in the main, contact:
www.centerwatch.com

For more information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

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References

JOURNAL ARTICLES
Szafranski P, Majewski T, Yıldız Bölükbaşı E, Gambin T, Karolak JA, Cortes-Santiago N, Bruckner M, Amann G, Weis D, Stankiewicz P. Ultra-conserved non-coding sequences within the FOXF1 enhancer are critical for human lung development.
Genes Dis. 2022 May 18;9(6):1423-1426. doi: 10.1016/j.gendis.2022.05.002. eCollection 2022 Nov. PMID: 36157490
https://pubmed.ncbi.nlm.nih.gov/36157490/

Szafranski P, Liu Q, Karolak JA, Song X, de Leeuw N, Faas B, Gerychova R, Janku P, Jezova M, Valaskova I, Gibbs KA, Surrey LF, Poisson V, Bérubé D, Oligny LL, Michaud JL, Popek E, Stankiewicz P. Association of rare non-coding SNVs in the lung-specific FOXF1 enhancer with a mitigation of the lethal ACDMPV phenotype.
Hum Genet. 2019 Dec;138(11-12):1301-1311. doi: 10.1007/s00439-019-02073-x. Epub 2019 Nov 4. PMID: 31686214
https://pubmed.ncbi.nlm.nih.gov/31686214/

Yıldız Bölükbaşı E, Karolak JA, Gambin T, Szafranski P, Deutsch GH, Stankiewicz P. Do paternal deletions involving the FOXF1 locus on chromosome 16q24.1 manifest with more severe non-lung anomalies?. Eur J Med Genet. 2022;65(6):104519. doi:10.1016/j.ejmg.2022.104519

Towe CT, White FV, Grady RM, Sweet SC, Eghtesady P, Wegner DJ, Sen P, Szafranski P, Stankiewicz P, Hamvas A, Cole FS, Wambach JA. Infants with atypical presentations of alveolar capillary dysplasia with misalignment of the pulmonary veins who underwent bilateral lung transplantation. J Pediatr. 2018; Mar;194:158-164.e1 https://www.ncbi.nlm.nih.gov/pubmed/29198536

Szafranski P, Gambin T, Dharmadhikari AV. Pathogenesis of alveolar capillary dysplasia with misalignment of pulmonary veins. Hum Genet. 2016;135:569-586. https://www.ncbi.nlm.nih.gov/pubmed/27071622

Dharmadhikari AV, Szafranski P, Kalinichenko VV, Stankiewicz P. Genomic and epigenetic complexity of the FOXF1 locus in 16q24.1: implications of development and disease. Curr Genomics. 2015;16:107-116. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4467301/

Szafranski P, Dharmadhikari AV, Wambach JA, et al. Two deletions overlapping a distant FOXF1 enhancer unravel the role of IncRNA LINC01081 in etiology of alveolar capillary dysplasia with misalignment of pulmonary veins. Am J Med Genet A. 2014;164:2013-2019. https://www.ncbi.nlm.nih.gov/pubmed/24842713

Sen P, Yang Y, Navarro C, et al. Novel FOXF1 mutations in sporadic and familial cases of alveolar capillary dysplasia with misaligned pulmonary veins imply a role for its DNA binding domain. Hum Mutat. 2013;34(6):801-11. https://www.ncbi.nlm.nih.gov/pubmed/23505205

Szafranski P, Dharmadhikari AV, Brosens E, et al. Small noncoding differentially methylated copy-number variants, including lncRNA genes, cause a lethal lung developmental disorder. Genome Res. 2013;23(1):23-33. https://www.ncbi.nlm.nih.gov/pubmed/23034409

Sen P, Gerychova R, Janku P, et al. A familial case of alveolar capillary dysplasia with misalignment of pulmonary veins supports paternal imprinting of FOXF1 in human. Eur J Hum Genet. 2013;21:474-477. https://www.ncbi.nlm.nih.gov/pubmed/22990143

Bishop NB, Stankiewicz P, Steinhorn RH. Alveolar capillary dysplasia. Am J Respir Crit Car Med. 2011;184:172-179. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3172887/

Sen P, Choudhury T, Smith EO, Langston C. Expression of angiogenic and vasculogenic proteins in the lung in alveolar capillary dysplasia/misalignment of pulmonary veins: an immunohistochemical study. Pediatr Dev Pathol. 2010;13:354-361. https://pubmed.ncbi.nlm.nih.gov/20331367/

Stankiewicz P, Sen p, Bhatt SS. Genomic and genic deletions of the FOX gene cluster on 16q24.1 and inactivating mutations of FOXF1 cause alveolar capillary dysplasia and other malformations. Am J Hum Genet. 2009;84:780-791. https://pubmed.ncbi.nlm.nih.gov/19500772/

INTERNET
Genetics Home Reference. Alveolar capillary dysplasia with misalignment of pulmonary veins. Reviewed Aug. 2015. Available at: https://ghr.nlm.nih.gov/condition/alveolar-capillary-dysplasia-with-misalignment-of-pulmonary-veins Accessed July 18, 2023.

McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:265380; Last Update:06.04/2020. Available at: omim.org/entry/265380 Accessed July 18, 2023.

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