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Chest. 2018 Feb;153(2):404-413. doi: 10.1016/j.chest.2017.09.023. Epub 2017 Sep 28.

Nonsyndromic Peripheral Pulmonary Artery Stenosis Is Associated With Homozygosity of RNF213 p.Arg4810Lys Regardless of Co-occurrence of Moyamoya Disease.

Author information

1
Division of Cardiology, Department of Medicine, Heart Vascular Stroke Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
2
Departments of Laboratory Medicine and Genetics, Heart Vascular Stroke Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
3
Departments of Radiology, Heart Vascular Stroke Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
4
Departments of Nuclear Medicine and Molecular Imaging, Heart Vascular Stroke Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
5
Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
6
Departments of Pediatrics, Heart Vascular Stroke Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
7
Division of Cardiology, Department of Medicine, Heart Vascular Stroke Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. Electronic address: dukkyung.kim@gmail.com.

Abstract

BACKGROUND:

Peripheral pulmonary arterial stenosis (PPAS) in childhood is frequently associated with other syndromes; however, PPAS in adolescents and adults is rare and its etiology is not well understood. We report the clinical characteristics of adult-onset nonsyndromic PPAS associated with the p.Arg4810Lys variant of the RNF213 gene.

METHODS:

We recently encountered an index case of severe pulmonary hypertension with multiple PPAS and intra- and extracranial arteriopathy. Because of a family history of Moyamoya disease (MMD), genetic analysis was performed, and revealed that this patient was homozygous for RNF213 p.Arg4810Lys. We searched for PPAS by reviewing the pulmonary hypertension registry and the MMD registry, and found four more cases of PPAS. Clinical features of the five patients and their families were analyzed.

RESULTS:

Mean age at diagnosis of pulmonary hypertension was 26 years, and the male to female ratio was 4:1. Genetic analysis of four patients revealed that all these patients were homozygous for the RNF213 p.Arg4810Lys variant. Pulmonary angiograms showed a string of beads pattern and/or diffuse stenosis of peripheral pulmonary arteries. Notably, three patients had MMD, whereas two patients did not. The three MMD patients had multiple stenoses of extracranial arteries other than the pulmonary artery.

CONCLUSIONS:

PPAS in segmental or subsegmental arteries in adulthood with multiple extracranial vasculopathies was found to be associated with homozygosity for RNF213 p.Arg4810Lys. RNF213 variant-associated vasculopathy should be categorized as a discrete disease entity of adulthood-onset PPAS regardless of the presence of MMD.

KEYWORDS:

Moyamoya disease; homozygote; peripheral pulmonary arterial stenosis; pulmonary hypertension

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