Objective: To explore the diagnostic significance of the combination of clinical and genetic detection of hereditary hemorrhagic telangiectasia (HHT) by analyzing the clinical and genetic diagnosis of a family with HHT. Methods: Medical history data of the probands and their family members were collected, and the sequence analyses of coding regions of ENG, ACVRL1, SMAD4 and GDF2 genes were performed by PCR-sequencing method, and a comprehensive diagnosis was made based on the clinical features and gene detection results. After the pathogenic gene variation was identified, 11 members of 3 generations of the family were tested for pathogenic gene mutation. Results: There was an ACVRL1 c.715_716delAG mutation in the proband and 9 other family members, which caused p.S239C. Based on the clinical and genetic findings, the 7 suspected were diagnosed and 2 asymptomatic patients were found to carry the mutation site. Conclusion: The combination of clinical features and gene detection can determine the etiology and classification of HHT, which is convenient for the early diagnosis and prevention of the disease.
Activin Receptors, Type II/genetics* ; Endoglin/genetics* ; Genetic Testing ; Humans ; Mutation ; Sequence Analysis ; Telangiectasia, Hereditary Hemorrhagic/genetics*

OBJECTIVES: Hereditary hemorrhagic telangiectasia (HHT) is a rare autosomal dominant genetic disorder characterized by pathogenic blood vessel development and maintenance. HHT type 1 (HHT1) and type 2 (HHT2) are caused by variants in endoglin (ENG) and activin receptor-like kinase-1 (ACVRL1), respectively. The aim of this study was to identify the spectrum of pathogenic variants in ENG and ACVRL1 in Austrian HHT families. METHODS: In this prospective study, eight Austrian HHT families were screened for variants in ENG and ACVRL1 by polymerase chain reaction amplification and sequencing of DNA isolated from peripheral blood. RESULTS: Heterozygous variants were identified in all families under study. HHT1 was caused by a novel c.816+1G>A splice donor variant, a novel c.1479C>A nonsense (p.Cys493X) variant and a published c.1306C>T nonsense (p.Gln436X) variant in ENG. Variants found in ACVRL1 were novel c.200G>C (p.Arg67Pro) and known c.772G>A (p.Gly258Ser) missense variants in highly conserved residues, a known heterozygous c.100dupT frameshift (p.Cys34Leufs*4) and the known c.1204G>A missense (p.Gly402Ser) and c.1435C>T nonsense (p.Arg479X) variants as causes of HHT2. CONCLUSION: Novel and published variants in ENG (37.5%) and ACVRL1 (62.5%) were exclusively identified as the cause of HHT in an Austrian patient cohort. Identification of novel causative genetics variants should facilitate the development of tailored therapeutical applications in the future treatment of autosomal dominant HHT.
Activins ; Blood Vessels ; Cohort Studies ; DNA ; Genetics ; Humans ; Polymerase Chain Reaction ; Prospective Studies ; Telangiectasia, Hereditary Hemorrhagic ; Telangiectasis ; Tissue Donors

OBJECTIVETo carry out genetic testing for a family affected with pulmonary hypertension (PH) as the initial sign of hereditary hemorrhagic telangiectasia (HHT).

METHODSHigh throughput sequencing was performed to detect potential mutation in the coding regions of endoglin (ENG), activin receptor-like kinase 1 (ACVRL1) and mothers against decapentaplegic homolog 4 (SMAD4) genes.

RESULTSA pathogenic heterozygous c.814C>T (p.Gln272Ter) mutation of the ACVRL1 gene was identified in the proband. Her mother and two sons have carried the same mutation.

CONCLUSIONThe c.814C>T (p.Gln272Ter) mutation of the ACVRL1 gene probably underlies the disease in this family. Genetic testing should be recommended to HHT patient, in particular those with pulmonary hypertension.

Activin Receptors, Type II ; genetics ; Child ; Endoglin ; genetics ; Female ; Genetic Testing ; High-Throughput Nucleotide Sequencing ; Humans ; Hypertension, Pulmonary ; etiology ; genetics ; Male ; Middle Aged ; Mutation ; Telangiectasia, Hereditary Hemorrhagic ; complications

BACKGROUNDHereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease characterized by recurrent epistaxis, mucocutaneous telangiectasia, and arteriovenous malformations. The efficacy of traditional treatments for HHT is very limited. The aim of this study was to investigate the therapeutic role of thalidomide in HHT patients and the effect in FLI-EGFP transgenic zebrafish model.

METHODSHHT was diagnosed according to Shovlin criteria. Five HHT patients were treated with thalidomide (100 mg/d). The Epistaxis Severity Score (ESS), telangiectasia spots, and hepatic computed tomography angiography (CTA) were used to assess the clinical efficacy of thalidomide. The Fli-EGFP zebrafish model was investigated for the effect of thalidomide on angiogenesis. Dynamic real-time polymerase chain reaction assay, ELISA and Western blotting from patient's peripheral blood mononuclear cells and plasma were used to detect the expression of transforming growth factor beta 3 (TGF-β3) messenger RNA (mRNA) and vascular endothelial growth factor (VEGF) protein before and after 6 months of thalidomide treatment.

RESULTSThe average ESS before and after thalidomide were 6.966 ± 3.093 and 1.799 ± 0.627, respectively (P = 0.009). The "telangiectatic spot" on the tongue almost vanished; CTA examination of case 2 indicated a smaller proximal hepatic artery and decreased or ceased hepatic artery collateral circulation. The Fli-EGFP zebrafish model manifested discontinuous vessel development and vascular occlusion (7 of 10 fishes), and the TGF-β3 mRNA expression of five patients was lower after thalidomide therapy. The plasma VEGF protein expression was down-regulated in HHT patients.

CONCLUSIONSThalidomide reverses telangiectasia and controls nosebleeds by down-regulating the expression of TGF-β3 and VEGF in HHT patients. It also leads to vascular remodeling in the zebrafish model.

Animals ; Animals, Genetically Modified ; Female ; Green Fluorescent Proteins ; genetics ; metabolism ; Humans ; Middle Aged ; Telangiectasia, Hereditary Hemorrhagic ; drug therapy ; metabolism ; Thalidomide ; therapeutic use ; Transforming Growth Factor beta3 ; genetics ; Vascular Endothelial Growth Factor A ; metabolism ; Zebrafish

A case of hereditary hemorrhagic telangiectasia was reported. Repeated hemorrhage in nasal and digestive system are main clinical manifestation. Capillary expanded on tongue and finger is the main physical sign. Main clinical manifestation and typical physical signs, combined with family history, can help to establish a diagnosis.
Humans ; Male ; Middle Aged ; Pedigree ; Telangiectasia, Hereditary Hemorrhagic ; genetics

OBJECTIVETo analyze clinical features of 4 families with hereditary hemorrhagic telangiectasia (HHT) and potential mutations of ENG, ACVRL1 and SMAD4 genes.

METHODSFour unrelated HHT patients and their affected family members were analyzed. All exons and flanking regions of ENG, ACVRL1 and SMAD4 genes were analyzed with PCR and direct sequencing and multiplex ligation-dependent probe amplification (MLPA) methods.

RESULTSEleven patients from the 4 families were enrolled in this study. Two ENG and 1 ACVRL1 mutations were identified, among which an ENG mutation (c.207G>A; p.L69L) and an ACVRL1 mutation (c.817C>T; p.L273L) have been previously reported. In addition, a novel ENG mutation (c.1004A>T; p.Q335L) has been found in 3 different families. Similar mutations were not detected in 200 healthy individuals. No mutations of ENG, ACVRL1 and SMAD4 were found in the fourth family.

CONCLUSIONA novel mutation c.1004A>T (p. Q335L) of ENG has been identified in patients with HHT. And there is significant phenotypic variability and genetic heterogeneity with the disease.

Activin Receptors, Type II ; genetics ; Adolescent ; Adult ; Amino Acid Sequence ; Antigens, CD ; genetics ; Endoglin ; Female ; Genetic Testing ; Humans ; Male ; Molecular Sequence Data ; Mutation ; Receptors, Cell Surface ; genetics ; Smad4 Protein ; genetics ; Telangiectasia, Hereditary Hemorrhagic ; diagnosis ; genetics

OBJECTIVE: To study the early gene diagnosis of hereditary hemorrhagic telangiectasia (HHT) induced severe nosebleed. METHOD: Clinical features of 23 family members in two HHT pedigrees were examined. Genomic DNA was extracted from peripheral blood samples. PCR amplification was conducted to screen ENG and ACVRL-1 genes with their specific primers. Direct sequencing was performed to detect the mutation. Mutation analysis was carried out to evaluate its significance. RESULT: A heterozygous c. 263A > G mutation was identified in exon 3 of ACVRL-1 in 6 out of 11 members in NMG-1 pedigree. In GD-2 pedigree, 5 of 11 members carried c. 199C > G mutation. Mutation detection rate was 100% in subjects with nosebleed history and 25% in family members without epistaxis. CONCLUSION Gene diagnosis characterized by high sensitivity and specificity is of great practi-cal significance and early genetic screening should be a clinical routine test for HHT induced severe nosebleed.
Activin Receptors, Type II ; genetics ; Adolescent ; Adult ; Antigens, CD ; genetics ; DNA Mutational Analysis ; Endoglin ; Epistaxis ; diagnosis ; etiology ; genetics ; Exons ; Female ; Genetic Testing ; Humans ; Male ; Middle Aged ; Pedigree ; Receptors, Cell Surface ; genetics ; Telangiectasia, Hereditary Hemorrhagic ; complications ; diagnosis ; genetics ; Young Adult

This is a case report of a 68-year-old man with hepatocellular carcinoma (HCC) accompanied by hereditary hemorrhagic telangiectasia (HHT), also known as Osler-Weber-Rendu disease, and hepatic vascular malformation. HHT is an autosomal dominant disorder of the fibrovascular tissue that is characterized by recurrent epistaxis, mucocutaneous telangiectasias, and visceral arteriovenous malformations. HHT is caused by mutation of the genes involved in the signaling pathway of transforming growth factor-beta, which plays an important role in the formation of vascular endothelia1. Hepatic involvement has been reported as occurring in 30-73% of patients with HHT. However, symptomatic liver involvement is quite rare, and the representative clinical presentations of HHT in hepatic involvement are high-output heart failure, portal hypertension, nodular regenerative hyperplasia, and symptoms of biliary ischemia. Some cases of HCC in association with HHT have been reported, but are very rare. We present herein the characteristic radiologic and genetic findings of HHT that was diagnosed during the evaluation and treatment of HCC.
Activin Receptors, Type II/genetics ; Aged ; Angiography ; Carcinoma, Hepatocellular/*complications/*therapy ; Chemoembolization, Therapeutic ; Exons ; Gene Deletion ; Humans ; Liver Neoplasms/*complications/*therapy ; Male ; Mutation ; *Telangiectasia, Hereditary Hemorrhagic/complications/genetics/pathology/radiography ; Tomography, X-Ray Computed

Hereditary hemorrhagic telangiectasia (HHT) is an inherited disorder that is characterized by abnormal communication between the arteries and veins in the skin, mucosa, and various organs. HHT has been reported to show significant phenotypic variability and genetic heterogeneity with wide ethnic and geographic variations. Although mutations in the endoglin (ENG) and activin A receptor type II-like 1 (ACVRL1) genes have been known to cause HHT for more than 10 yr, little is known about the clinical features or genetic background of Korean patients with HHT. In addition, mutations in mothers against decapentaplegic homolog 4 (SMAD4) are also seen in patients with the combined syndrome of juvenile polyposis and HHT. This study examined five Korean patients with the typical manifestations of HHT such as frequent epistaxis and pulmonary arteriovenous malformations. Direct sequencing of the ENG and ACVRL1 genes revealed one known mutation, ENG c.277C>T, in one patient and two novel mutations, ENG c.992-1G>C and ACVRL1 c.81dupT in two patients, respectively. The remaining two patients with negative results were screened for SMAD4 mutations as well as gross deletions of ENG and ACVRL1 using multiple ligation-dependent probe amplification, but none was detected. Despite the small number of patients investigated, we firstly report Korean patients with genetically confirmed HHT, and show the genetic and allelic heterogeneity underlying HHT.
Activin Receptors, Type II/*genetics ; Adult ; Alleles ; Angiography ; Antigens, CD/*genetics ; Asian Continental Ancestry Group/*genetics ; Base Sequence ; Female ; Genetic Predisposition to Disease ; Humans ; Korea ; Male ; Middle Aged ; *Mutation ; Pedigree ; Receptors, Cell Surface/*genetics ; Smad4 Protein/*genetics ; Telangiectasia, Hereditary Hemorrhagic/diagnosis/*genetics/pathology ; Tomography, X-Ray Computed ; Young Adult

OBJECTIVETo identify the activin A receptor type II-like 1 gene (ACVRL1) mutations in a Chinese family with hereditary hemorrhagic telangiectasia (HHT2).

METHODSThe exons 3, 7 and 8 of ACVRL1 gene of the proband and her five family members were amplified by polymerase chain reaction (PCR), and the PCR products were sequenced.

RESULTSThe proband had obvious telangiectasis of gastric mucosa, and small arteriovenous fistula in the right kidney. All the patients in the HHT2 family had iterative epistaxis or bleeding in other sites, and had telangiectasis of nasal mucosa, tunica mucosa oris and finger tips. ACVRL1 gene analysis confirmed that there is frameshift mutation caused by deletion of G145 in exon 3 in the 4 patients, but the mutation is absent in 2 members without HHT2.

CONCLUSIONThe HHT2 family is caused by a 145delG mutation of ACVRL1 gene, resulting in frameshift and a new stop codon at codon 53.

Activin Receptors, Type II ; genetics ; Exons ; genetics ; Female ; Frameshift Mutation ; genetics ; Humans ; Male ; Mutation ; Polymerase Chain Reaction ; Telangiectasia, Hereditary Hemorrhagic ; genetics ; pathology