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Table of Contents    
Year : 2019  |  Volume : 67  |  Issue : 1  |  Page : 312-314

A case of delayed-onset hereditary hemorrhagic telangiectasia with a frameshift ENG mutation

1 Department of Neurosurgery, Tokyo Women's Medical University Medical Center East; Tokyo Women's Medical University Institute for Integrated Medical Sciences (TIIMS), Tokyo, Japan
2 Department of Neurosurgery, Tokyo Women's Medical University Medical Center East; Division of Neurosurgery, Kofu Neurosurgical Hospital, Kofu, Japan
3 Tokyo Women's Medical University Institute for Integrated Medical Sciences (TIIMS); Department of Neurosurgery, Tokyo Women's Medical University, Tokyo, Japan
4 Division of Neurosurgery, Kofu Neurosurgical Hospital, Kofu, Japan
5 Department of Neurosurgery, Tokyo Women's Medical University Medical Center East, Tokyo, Japan

Date of Web Publication7-Mar-2019

Correspondence Address:
Dr. Hiroyuki Akagawa
Tokyo Women's Medical University Institute for Integrated Medical Sciences (TIIMS), 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0028-3886.253633

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How to cite this article:
Akagawa H, Onda H, Nomura S, Shinohara T, Kasuya H. A case of delayed-onset hereditary hemorrhagic telangiectasia with a frameshift ENG mutation. Neurol India 2019;67:312-4

How to cite this URL:
Akagawa H, Onda H, Nomura S, Shinohara T, Kasuya H. A case of delayed-onset hereditary hemorrhagic telangiectasia with a frameshift ENG mutation. Neurol India [serial online] 2019 [cited 2022 May 18];67:312-4. Available from: https://www.neurologyindia.com/text.asp?2019/67/1/312/253633


Hereditary hemorrhagic telangiectasia (HHT) is a genetic disorder characterized by multi-systemic vascular dysplasia and hemorrhage. Clinical diagnosis of HHT is made according to Curaçao criteria.[1] Patients who fulfill two or more of the following criteria are regarded as “probable” and “definite” patients with HHT, respectively: (a) spontaneous recurrent nose bleeds, (b) mucocutaneous telangiectasias, (c) visceral arteriovenous malformations, and (d) a positive family history reflecting HHT inherited in an autosomal dominant manner. Mutations in the two major causative genes, endoglin (ENG, 9q34.1) and activin A receptor type II-like 1 (ACVRL1, 12q31), produce HHT1 and HHT2 subtypes, respectively. Pulmonary arteriovenous fistulas (PAVFs) are predominantly observed in patients with HHT1, and nose bleeds almost always appear in patients with HHT1 before the age of 40 years.[2],[3] We herein report a patient with elderly-onset HHT1.

A 72-year old woman presented with disturbed consciousness and left hemiplegia. Diffusion-weighted magnetic resonance (MR) imaging of the brain showed white matter hyperintensities in the region supplied by the right posterior cerebral artery (PCA), which was occluded at the P2 segment and partially recanalized during repeated MR angiographies of the brain [Figure 1]a and [Figure 1]b, suggesting a cerebral embolism. Although atrial fibrillation was not observed in a Holter electrocardiogram, the patient did have a family history of HHT. Her daughter, her elder sister, and the sister's daughter had been clinically diagnosed with HHT due to the presence of PAVFs. A PAVF was detected in the left pulmonary apex by cervical MR angiography, and confirmed by computed tomography (CT) of the chest [Figure 1]c and [Figure 1]d. Thrombosis was found in a soleal vein by ultrasonography of the lower limb, leading to paradoxical cerebral embolism. Until then, she had not experienced spontaneous and recurrent nose bleeds or gastrointestinal hemorrhage associated with mucocutaneous telangiectasias, and the PAVFs had not caused hemorrhage or heart failure. After acute-phase treatment, she was transferred to a regional medical center for resection of the PAVF considered untreatable by coil embolization. The patient's disability was scored as 4 on the modified Rankin scale, indicating a moderately severe disability.
1: (a) Diffusion-weighted MR images of the brain show acute-stage cerebral infarctionsin the right PCA.(b) MR angiographies of the brain show the right PCA occlusion at the P2 segment (left panel), partially recanalized a day after onset (right panel). (c) Cervical MR angiography results indicate a venous reflux from an arteriovenous fistula, at the left pulmonary apex. (d) Contrast-enhanced CT of the chest confirms the abnormal venous reflux was from a PAVF. (e) Chromatograms of a heterozygous c. 685delG mutation in ENG (NM_001114753.2, NM_001278138.1) and a wild-type control

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Genetic analysis of patients with HHTwas approved by the ethics committees of Tokyo Women's Medical University. After obtaining written informed consent, genomic DNA was extracted from her peripheral blood sample. Polymerase chain reaction (PCR)-based, direct Sanger sequencing was performed in all coding exons and their exon–intron junctions for the ENG (NM_001114753.2 and NM_001278138.1) and ACVRL1 (NM_000020.2 and NM_001077401.1) genes. We identified a heterozygous c. 685delG mutation resulting in immediate premature termination (p. Ala229ProfsTer6) in ENG [Figure 1]e. This frameshift mutation was not listed in the NCBI ClinVar database (http://www.ncbi.nlm.nih.gov/clinvar/) or the HHT Mutation Database (http://arup.utah.edu/database/HHT/). However, it was reported in a family that was part of a large series of Japanese patients with HHT [Table 1].[4],[5],[6],[7],[8],[9],[10],[11],[12],[13] Therefore, we concluded that this mutation caused the disease in the present HHT family, although DNA samples from other family members were not available.
Table 1: Pathogenic point mutations and indels in ENG not reported in the ClinVar and the HHT Mutation Database

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Among various Mendelian disorders, HHT is a rare example for which effective treatments for each major clinical manifestation have been established.[14] Therefore, a severe outcome, as seen in this case, could have been prevented by an earlier genetic diagnosis. It is necessary to identify the causative mutations of HHT with in families to improve clinical outcomes and prevent the development of serious conditions. Recent advances in DNA sequencing allow rapid and accurate genetic testing using small amounts of biological samples, such as buccal swabs, simultaneously covering all genes responsible for causing HHT and its related disorders. To date, ENG, ACVRL1, SMAD4, GDF2, and RASA1 are genes known to be involved.[3] Genetic testing for HHT will become an essential diagnostic modality for the clinical management of patients with HHT and their families.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

The Funds for the Development of Human Resources in Science and Technology and the Program to Disseminate Tenure Tracking System (Akagawa H) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT, FY2011).

Conflicts of interest

There are no conflicts of interest.

  References Top

Shovlin CL, Guttmacher AE, Buscarini E, Faughnan ME, Hyland RH, Westermann CJ, et al. Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome). Am J Med Genet 2000;91:66-7.  Back to cited text no. 1
Berg J, Porteous M, Reinhardt D, Gallione C, Holloway S, Umasunthar T, et al. Hereditary haemorrhagic telangiectasia: A questionnaire based study to delineate the different phenotypes caused by endoglin and ALK1 mutations. J Med Genet 2003;40:585-90.  Back to cited text no. 2
Patrick C, McIntyre K, Ramidial J, Joa S, Zaveri VD, Hansra D. Novel ACLV1 mutation identified in late onset hereditary hemorrhagic telangiectasia. Int J Otolaryngol Head Neck Surg 2016;5:157-73.  Back to cited text no. 3
Albinana V, Zafra MP, Colau J, Zarrabeitia R, Recio-Poveda L, Olavarrieta L, et al. Mutation affecting the proximal promoter of Endoglin as the origin of hereditary hemorrhagic telangiectasia type 1. BMC Med Genet 2017;18:20.  Back to cited text no. 4
Heimdal K, Dalhus B, Rodningen OK, Kroken M, Eiklid K, Dheyauldeen S, et al. Mutation analysis in Norwegian families with hereditary hemorrhagic telangiectasia: Founder mutations in ACVRL1. Clin Genet 2016;89:182-6.  Back to cited text no. 5
Canzonieri C, Centenara L, Ornati F, Pagella F, Matti E, Alvisi C, et al. Endoscopic evaluation of gastrointestinal tract in patients with hereditary hemorrhagic telangiectasia and correlation with their genotypes. Genet Med 2014;16:3-10.  Back to cited text no. 6
Mallet C, Lamribet K, Giraud S, Dupuis-Girod S, Feige JJ, Bailly S, et al. Functional analysis of endoglin mutations from hereditary hemorrhagic telangiectasia type 1 patients reveals different mechanisms for endoglin loss of function. Hum Mol Genet 2015;24:1142-54.  Back to cited text no. 7
Lux A, Muller R, Tulk M, Olivieri C, Zarrabeita R, Salonikios T, et al. HHT diagnosis by mid-infrared spectroscopy and artificial neural network analysis. Orphanet J Rare Dis 2013;8:94.  Back to cited text no. 8
Komiyama M, Ishiguro T, Yamada O, Morisaki H, Morisaki T. Hereditary hemorrhagic telangiectasia in Japanese patients. J Hum Genet 2014;59:37-41.  Back to cited text no. 9
Bertoli LF, Lee PL, Lallone L, Barton JC. Intravenous bevacizumab therapy in a patient with hereditary hemorrhagic telangiectasia, ENG E137K, alcoholic cirrhosis, and portal hypertension. Case Rep Gastroenterol 2017;11:293-304.  Back to cited text no. 10
Tørring PM, Kjeldsen AD, Ousager LB, Brusgaard K. ENG mutational mosaicism in a family with hereditary hemorrhagic telangiectasia. Mol Genet Genomic Med 2018;6:121-5.  Back to cited text no. 11
Chen KH, Lin CH. Brain abscess as an initial presentation in a patient of hereditary haemorrhagic telangiectasia caused by a novel ENG mutation. BMJ Case Rep 2013:pii: bcr2013008802.  Back to cited text no. 12
Lu Y, Zhu Y, Shi L, Zhen H, Sun Z, Cheng L. A novel endoglin mutation in hereditary hemorrhagic telangiectasia type 1: A case report. Mol Med Rep 2015;12:510-2.  Back to cited text no. 13
McDonald J, Bayrak-Toydemir P, Pyeritz RE. Hereditary hemorrhagic telangiectasia: An overview of diagnosis, management, and pathogenesis. Genet Med 2011;13:607-16.  Back to cited text no. 14


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