July 2023 | Case of the Month Answer for Residency Program

July 2023 – Presented by Dr. Jasper X. Zheng (Mentored by Drs. Bokhari and Tovar)

Introduction

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare developmental disorder of the lung that causes early postnatal respiratory distress and persistent pulmonary hypertension.

Clinical Presentation

Infants with ACD/MPV will experience early postnatal persistent respiratory distress and persistent pulmonary hypertension (PPHN).

PPHN is characterized by abnormally elevated pulmonary vascular resistance (PVR) that persists after birth, resulting in right-to-left shunting of blood through fetal circulatory pathways. This in turn leads to severe hypoxia which rarely responds to conventional respiratory support.

Majority of the infants with ACD/MPV have additional malformations that includes cardiovascular (hypoplastic left heart), gastrointestinal malrotations/atresia, and renal/urogenital abnormalities.

Diagnosis

ACD/MPV is clinically indistinguishable from other possible causes of PPHN. The diagnosis of ACD/MPV can only be established and supported at autopsy examination of pulmonary tissue or adequate invasive lung biopsies.

Histomorphologic Features

The characteristic histological features are paucity of adjacent capillaries near alveolar epithelium, muscular hypertrophy of pulmonary arterioles, and the sharing of adventitial sheath by pulmonary arterioles and venules within the broncho-arterial bundles (1). Variable deficient pulmonary alveolar development is often noted. Pulmonary lymphangiectasia can be seen in 30% of the cases.

Prognosis

Unfortunately, the current medical knowledge offers no effective treatment for ACD/MPV. The current available medical interventions are directed mainly at relieving the pulmonary hypertension and the reductions, if successful, is only transient. Extracorporeal membrane oxygenation (ECMO) is at times used to support the neonates, but it contributes nothing to patient survival. The only prospect of therapeutic intervention for this grim diagnosis is lung transplant; however, the survival rates are still very disappointing.

Genetics

ACD/MPV is usually not inheritable. There are a few cases of familial occurrence of ACD/MPV being reported but without any documented genetic changes. In other studies, transcription factor FOXF1 gene mutation or deletion have been detected in 40% of cases of ACD/MPV (3). Nonetheless, negative genetic testing does not preclude this grim disorder. Histomorphologic recognition of pertinent neonate pulmonary pathology is still the current gold standard for rendering the diagnosis of ACD/MPV.

References

Sihoe AD, Lee AT, To KF, Thung KH, Lee TW, Yim AP. "Alveolar capillary dysplasia with congenital misalignment of pulmonary vessels". Asian Cardiovasc Thorac Ann. 2005 Mar;13(1):82-4. doi: 10.1177/021849230501300121. PMID: 15793061.
Slot E, Edel G, Cutz E, van Heijst A, Post M, Schnater M, Wijnen R, Tibboel D, Rottier R, de Klein A. "Alveolar capillary dysplasia with misalignment of the pulmonary veins: clinical, histological, and genetic aspects". Pulm Circ. 2018 Jul-Sep;8(3):2045894018795143. doi: 10.1177/2045894018795143. Epub 2018 Jul 30. PMID: 30058937; PMCID: PMC6108021.
Bishop NB, Stankiewicz P, Steinhorn RH. "Alveolar capillary dysplasia". Am J Respir Crit Care Med. 2011 Jul 15;184(2):172-9. doi: 10.1164/rccm.201010-1697CI. Epub 2011 Mar 11. PMID: 21471096; PMCID: PMC3172887.
Kamp JC, Neubert L, Ackermann M, Stark H, Plucinski E, Shah HR, Janciauskiene S, Bergmann AK, Schmidt G, Welte T, Haverich A, Werlein C, Braubach P, Laenger F, Schwerk N, Olsson KM, Fuge J, Park DH, Schupp JC, Hoeper MM, Kuehnel MP, Jonigk DD. "A Morphomolecular Approach to Alveolar Capillary Dysplasia". Am J Pathol. 2022 Aug;192(8):1110-1121. doi: 10.1016/j.ajpath.2022.05.004. Epub 2022 May 29. PMID: 35649494.
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 Jun;65(6):104519. doi: 10.1016/j.ejmg.2022.104519. Epub 2022 May 6. PMID: 35533956; PMCID: PMC10022888.
Alturkustani M, Li D, Byers JT, Szymanski L, Parham DM, Shi W, Wang LL. "Histopathologic features of alveolar capillary dysplasia with misalignment of pulmonary veins with atypical clinical presentation". Cardiovasc Pathol. 2021 Jan-Feb;50:107289. doi: 10.1016/j.carpath.2020.107289. Epub 2020 Sep 16. PMID: 32949727.