Current Status of Clinical and Genetic Screening of Hereditary Hemorrhagic Telangiectasia Families in Hungary

Abstract

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal-dominant, multisystemic vascular disease with a prevalence of 1:5000–1:10,000. Approximately 85% of HHT cases have heterozygous, family-specific mutations in the ENG or ACVRL1 genes. We present the results of systematic genetic and clinical screenings of Hungarian HHT families over a 10-year period. Probands were diagnosed with HHT through otorhinolaryngological and internal physical examinations of characteristic telangiectasis sites using visceral arteriovenous malformation screening and ENG/ACVRL1/SMAD4/RASA1/GDF2 Sanger or next-generation sequencing analysis. At-risk individuals underwent physical examinations and testing for the family-specific mutation followed by AVM screening as needed. Eighteen ENG, 16 ACVRL1 and 1 SMAD4 mutations were identified in 21, 26 and 1 families, respectively, with 117 individuals carrying the family-specific mutation (92 of them with clinically definite and 20 with suspected disease). In 65 family members from the HHT1 and HHT2 families, wild-type ENG/ACVRL1 alleles were detected. Two additional probands with definite HHT showed wild-type alleles in all tested HHT loci. The majority of tested individuals came from Northeast Hungary. Systematic family screening is the best way to recruit HHT patients. The significance of genetic testing is its confirmation or exclusion of HHT in young, asymptomatic family members.

Pharmacogenomic Considerations for Anticoagulant Prescription in Patients with Hereditary Haemorrhagic Telangiectasia

“…The 2020 Second International Guidelines [7] recommended obtaining a genetic diagnosis of the HHT-causative mutation to facilitate targeted screening for internal AVMs. HHT gene testing pathways are now in place in multiple countries worldwide [7,8,[18][19][20][21][22][23][24][25] and facilitate the diagnosis of HHT, targeted AVM screening programmes, and direction of SMAD4 families to SMAD4-specific preventative measures [26][27][28][29][30][31].…”

Pathogenic Variant Frequencies in Hereditary Haemorrhagic Telangiectasia Support Clinical Evidence of Protection from Myocardial Infarction

“…GDF2 heterozygous variants were initially described as causing an HHT-like syndrome [ 36 ] and, more recently, in a family meeting full Curaçao Criteria clinical designation [ 37 ]. Genetic testing for ACVRL1 , ENG , SMAD4, and GDF2 is widely performed as part of HHT diagnostics [ 21 , 22 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 ]. Genotyped patients and families are commonly referred to as HHT type 1 ( ENG , OMIM #187300), HHT type 2 ( ACVRL1 , OMIM #600376), JPHT ( SMAD4 , (OMIM ##175050), and HHT type 5 ( GDF2 , OMIM # 615506).…”

Hereditary Hemorrhagic Telangiectasia: Diagnosis and Management

“…Major, T. et al assert that society is lacking in knowledge of HHT disease and that this is related to the unawareness of HHT within the medical community [ 4 ]. I would only add that, as seen in this SI, those physicians who are aware of rare diseases such as HHT they never let their patients down and always do their best to help them.…”

“…This Special Issue (SI), with nine original articles and one review, focuses on “Diagnosis and Management.” Management is not possible without a correct diagnosis. However, this obvious statement ignores the fact that the average time taken for a diagnosis of HHT to be established is 27 years, as noted by Major, T. et al, with the average diagnosis in Hungary being obtained over periods between 22.6 and 29.1 years [ 4 ].…”