Current Status of Clinical Diagnosis and Genetic Analysis of Hereditary Hemorrhagic Telangiectasia in South Korea: Multicenter Case Series and a Systematic Review

Abstract

Purpose: Hereditary hemorrhagic telangiectasia (HHT), a rare genetic vascular disorder, has been rarely reported in South Korea. We investigated the current prevalence and presenting patterns of genetically confirmed HHT in South Korea. Materials and Methods: We defined HHT patients as those with proven mutations on known HHT-related genes (ENG, ACVRL1, SMAD4, and GDF2) or those fulfilling 3 or 4 of the Curaçao criteria. A computerized systematic search was performed in PubMed and KoreaMed using the following search term: ("hereditary hemorrhagic telangiectasia" AND "Korea") OR ("Osler-Weber-Rendu" AND "Korea"). We also collected government health insurance data. HHT genetic testing results were collected from three tertiary hospitals in which the genetic tests were performed. We integrated patient data by analyzing each case to obtain the prevalence and presenting pattern of HHT in South Korea. Results: We extracted 90 cases from 52 relevant articles from PubMed and KoreaMed. An additional 22 cases were identified from the three Korean tertiary hospitals after excluding seven cases that overlapped with those in the published articles. Finally, 112 HHT patients were identified (41 males and 71 females, aged 4-82 years [mean±standard deviation, 45.3±20.6 years]). The prevalence of HHT in South Korea is about 1 in 500,000, with an almost equal prevalence among men and women. Forty-nine patients underwent genetic testing, of whom 28 had HHT1 (ENG mutation) and 19 had HHT2 (ACVRL1 mutation); the other two patients were negative for ENG, ACVRL1, and SMAD4 mutations. Conclusion: The prevalence of HHT is underestimated in Korea. The rate of phenotypic presentation seems to be similar to that found worldwide. Korean health insurance coverage is limited to representative genetic analysis to detect ENG and ACVRL1 mutations. Further genetic analyses to detect HHT3, HHT4, and other forms of HHT should be implemented.

Mutational and clinical spectrum of Japanese patients with hereditary hemorrhagic telangiectasia

“…In our cohort of Japanese patients, the ENG mutations were dominant ( ENG / ACVRL1 ratio at 1.35) although the difference was smaller as compared with our own previous smaller series [ 19 ]. Previous reports showed a considerable difference in the incidence of ENG - vs ACVRL1 -HHT with the ENG dominance in the US ( ENG / ACVRL1 at 1.58) [ 27 ], Netherlands (3.40) [ 17 ], Denmark (4.05) [ 15 ], and Korea (1.47) [ 17 ] as opposed to the ACVRL1 dominance in France and Italy (0.37) [ 28 ], Germany (0.89) [ 29 ], and China (0.41) [ 18 ]. The founder effects could be one of the explanations for these differences although it is unclear whether the previously identified, small-sized founder effects could account for all these differences [ 30 ].…”

“…So far, more than 1000 different mutations have been identified as associated with ENG -HHT and ACVRL1 -HHT [ 12 , 13 ]. However, most of the large-scale studies have been conducted on Caucasians [ 1 , 14 – 16 ], and only limited, relatively small studies have been reported for other populations [ 17 – 19 ]. Moreover, even within Caucasians, the reported mutational spectrum has been different depending on the countries so does the clinical presentation [ 14 – 16 , 20 ].…”

Case report of juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome: first report in Korea with a novel mutation in the SMAD4 gene

“…However, no features of HHT were reported in these patients (14,15). Meanwhile, a recent multicenter case series investigating the genetic analysis of HHT in Korea reported that among 49 patients who had underwent genetic testing, 28 had ENG mutations and 19 had ACVRL1 mutations, while the other two patients were all negative for ENG, ACVRL1, and SMAD4 mutations (16). Similarly, a study in Chinese families with HHT revealed variants in ACVRL1 and ENG, while no SMAD4 mutations were detected (17).…”

Rare Neurovascular Diseases in Korea: Classification and Related Genetic Variants

“…AVMs can also be associated with inherited genetic disorders such as HHT and capillary malformation–AVM (CM–AVM) [ 21 22 23 ]. All HHT mutations ( ENG , ACVRL1 , SMAD4 , and GDF2 ) appear to cause decreased BMP-Smad signaling that may lead in turn to increased angiogenesis, otherwise CM–AVM has loss-of-function mutations in RASA1 (CM–AVM1) and EPHB4 (CM–AVM2) genes, leading to activation of Ras-MAPK pathway [ 22 24 25 ]. Cerebral AVMs can also occur as a component of syndrome-associated malformations, such as the Parkes–Weber syndrome, which is characterized by multifocal CMs, high-flow shunt lesion, and limb overgrowth, or congenital lipomatous overgrowth, vascular malformations, epidermal nevis, spinal/skeletal anomalies/scoliosis (CLOVES) syndrome [ 12 ].…”

“…F, G. A pulmonary arteriovenous fistula (arrows) was demonstrated on the chest CT (F) and confirmed on the pulmonary arteriography (G) in the proband's father. The pedigree (A) is adapted from Kim et al Neurointervention 2019;14:91–98 [ 25 ]. AVF = arteriovenous fistula, AVM = arteriovenous malformation, DM = diabetes mellitus, ICH = intracranial hemorrhage…”