title: Homozygosity for moyamoya disease risk allele leads to moyamoya disease with extracranial systemic and pulmonary vasculopathy.
abstract: Moyamoya disease is characterized by diffuse distal intracranial stenosis. Recently, RNF213 has been identified as a susceptibility gene in the development of this condition. Pulmonary hypertension is a rare progressive vasculopathy with an unknown etiology. The co-occurrence of pulmonary hypertension and Moyamoya disease has been described in four patients; however, whether this co-occurrence represents a chance association or a common vascular pathology has remained unknown. Here, we report two unrelated male patients who presented during their childhood with dyspnea on exertion. Systemic vascular imaging studies revealed the presence of pulmonary hypertension and Moyamoya disease in both patients. Medical exome sequencing revealed that both patients had a homozygous mutation for p.Arg4810Lys in RNF213. We suggest that homozygosity in RNF213 may lead to a novel entity involving the brain and lung. Interestingly, when present in a heterozygous state, this mutation causes a classic cerebral vascular disease, Moyamoya disease. In the homozygous state, the exact same mutation led to Moyamoya disease with extracranial systemic vasculopathy in at least two patients. From a clinical standpoint, cerebrovascular or pulmonary vascular investigations may be warranted in patients with pulmonary hypertension or Moyamoya disease, respectively. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Fukushima
authors.affiliation: Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan.|Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Toshiki
authors.initials: T
authors.lastname: Takenouchi
authors.affiliation: Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Kosaki
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics; D000483:Alleles; D002533:Cerebral Angiography; D002648:Child; D059472:Exome; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D006720:Homozygote; D006801:Humans; D018810:Magnetic Resonance Angiography; D008297:Male; D009072:Moyamoya Disease / Q000175:diagnosis* / Q000235:genetics*; D010641:Phenotype; D044767:Ubiquitin-Protein Ligases / Q000235:genetics
chemical_list: C557998:RNF213 protein, human; D044767:Ubiquitin-Protein Ligases; D000251:Adenosine Triphosphatases
keywords: Moyamoya disease; RNF213; brain; exome sequencing; lung; pulmonary hypertension; vasculopathy