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

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 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

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

Abdomen, Acute ; etiology ; Child ; Family Health ; Female ; Gastrointestinal Diseases ; etiology ; Genes, Dominant ; genetics ; Humans ; Male ; Nausea ; etiology ; Pedigree ; Telangiectasia, Hereditary Hemorrhagic ; complications ; genetics ; pathology ; Time Factors ; Vomiting ; etiology

OBJECTIVETo identify the gene mutations in a pedigree with hereditary hemorrhagic telangiectasia.

METHODSGenomic DNA was extracted from the peripheral blood of the propositus. All of the exons, intron/exon boundaries and the 5' untranslation regions (UTR) of the ALK-1 and endoglin gene were amplified by polymerase chain reaction (PCR). The PCR products were screened by direct sequencing.

RESULTSThe mutation is a C1437T substitution in exon 10 of the ALK-1 gene, resulting in Arg 479 Stop.

CONCLUSIONThe hereditary hemorrhagic telangiectasia propositus is caused by a heterozygous Arg 479 Stop mutation in the ALK-1 gene which has not been identified previously.

Activin Receptors, Type II ; genetics ; Aged ; Antigens, CD ; genetics ; Base Sequence ; Codon, Nonsense ; DNA Mutational Analysis ; Exons ; genetics ; Female ; Humans ; Male ; Pedigree ; Point Mutation ; Receptors, Cell Surface ; genetics ; Telangiectasia, Hereditary Hemorrhagic ; genetics ; pathology

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

BACKGROUNDWe determined the diagnosis of hereditary hemorrhagic telangiectasis (HHT) in a suspected HHT family, identified ALK1 gene mutation and established a gene diagnosis method of HHT. The level of related plasma proteins (transforming growth factor beta and thrombomodulin) were also analyzed.

METHODSBleeding history and family history were collected; Dilatant nasal mucosal capillaries in proband were observed under nasal cavity endoscope; exons 3, 7, 8 of ALK1 gene in proband and her family members were amplified with polymerase chain reaction (PCR), and the PCR products were analyzed. Using enzyme-linked immunosorbent assay (ELISA), plasma TGF-beta1 and TGF-beta2 concentrations were measured. Plasma thrombomodulin (TM) level was detected by Western blotting.

RESULTSOf all family members, four had epstaxis, two had evident telangiectases on skin or mucosa. Gene screening results showed that C to T substitution at position 1231 in exon 8 of ALK1 gene (CGG-->TGG) existed in proband, her affected brother and their father. The mutation did not exist in proband's sister-in-law and nephew. Plasma TGF-beta1 concentrations in the affected HHT was 20,538, 17,194, 13,131 pg/ml, while that of normal control and unaffected family members was 15,950, 20,297, 12,836 pg/ml, respectively. Plasma TGF-beta2 in HHT patients was 14,502, 9550, 10,592 and that of normal controls 8579, 20,297, 7680 pg/ml respectively. Level of plasma TM was in HHT subjects significantly lower than in normal subjects.

CONCLUSIONSChinese HHT individuals have mutant ALK1 gene, a C1231T variation on exon 8 of ALK1 is responsible for HHT clinical phenotypes in this family. ALK1 gene analysis, together with special clinical phenotypes and family history, provides a reliable method in diagnosing HHT. In affected HHT subjects, plasma TGFbeta levels were not obviously different from those of normal subject; while plasma TM concentration was significantly lower than that in normal subjects. The significance and mechanism remain to be elucidated.

Activin Receptors, Type I ; genetics ; Activin Receptors, Type II ; Aged ; Asian Continental Ancestry Group ; genetics ; China ; Female ; Humans ; Male ; Middle Aged ; Mutation ; Telangiectasia, Hereditary Hemorrhagic ; blood ; genetics ; Thrombomodulin ; blood ; Transforming Growth Factor beta ; blood