Clinical genetic analysis and diagnosis of a family with hereditary hemorrhagic telangiectasia / 中华耳鼻咽喉头颈外科杂志

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.

Effects of bevacizumab on familial epistaxis caused by hereditary hemorrhagic telangiectasia / 中华耳鼻咽喉头颈外科杂志

Objective: To observe the clinical effects of bevacizumab in the treatment of familial epistaxis caused by hereditary hemorrhagic telangiectasia (HHT). Methods: The data of 27 patients with familial epistaxis caused by HHT who were treated with bevacizumab intravenously from Beijing Anzhen Hospital, the First Clinical Center of Chinese People's Liberation Army General Hospital and Binzhou Central Hospital between December 2016 and December 2019 were retrospectively analyzed. There were 14 males and 13 females, aged (55.3±11.2) years. The dose of bevacizumab was calculated according to the body weight of 5 mg/kg. The curative effect was observed one month after the first treatment. Visual analogue scale (VAS) was used to compare patients' self-scores of systemic symptoms before and after treatment. Epistaxis severity score (ESS) was used to compare and analyze the six problems (including the frequency, duration, intensity, treatment demand, anemia and blood transfusion) of the patients before and after treatment. The changes of hemoglobin levels before and after treatment were compared. SPSS 20.0 statistical software was used to process the data. Results: Among the 27 patients at one month after the first bevacizumab treatment, 22 cases reported that the severity of epistaxis was improved significantly, and 5 cases reported that the treatment effect was not significant. The effective rate was 81.5% (22/27). The significant effect in 22 patients lasted for 5-24 months, with a median duration of 11.23 months. The VAS score of systemic symptoms decreased significantly compared with that before treatment (2.41±2.55 vs 8.19±1.47, t=9.708, P<0.01). The scores of six aspects and standardized scores of ESS were significantly decreased after treatment (epistaxis frequency: 1.78±1.22 vs 3.44±0.80, t=6.814, P<0.01; epistaxis duration: 0.85±0.91 vs 3.00±0.73, t=8.845, P<0.01; epistaxis intensity: 0.19±0.40 vs 1.00±0.00, t=10.696, P<0.01; treatment demand: 0.22 ± 0.42 vs 1.00±0.00, t=9.539, P<0.01; anemia: 0.41±0.50 vs 0.89±0.32, t=4.914, P<0.01; blood transfusion: 0.11±0.32 vs 0.41±0.50, t=3.309, P<0.01; ESS standardized score: 2.50±2.45 vs 7.60±1.30, t=9.344, P<0.01). The hemoglobin level after treatment was significantly higher than that before treatment ((105.48±24.31) g/L vs (73.07±23.71) g/L, t=6.864, P<0.01). Among the 27 patients, there were 8 cases of HHT1 (ENG gene) and 19 cases of HHT2 (ACVRL1 gene). The improvement duration of epistaxis in group HHT1 and group HHT2 was (4.76±5.12) months and (7.60±10.84) months, respectively, which was in group HHT2 longer than that of group HHT1, but there was no significant difference between the two groups (P>0.05). There was no significant difference in ESS scores between the two groups before and after treatment (P>0.05). Two female patients had amenorrhea after the first medication. All patients had no other adverse reactions and complications. Conclusion: Intravenous bevacizumab is significantly effective and safe in the treatment of familial epistaxis caused by HHT.

Genetic analysis of a family affected with pulmonary hypertension secondary to hereditary hemorrhagic telangiectasia / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To carry out genetic testing for a family affected with pulmonary hypertension (PH) as the initial sign of hereditary hemorrhagic telangiectasia (HHT).</p><p><b>METHODS</b>High 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.</p><p><b>RESULTS</b>A 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.</p><p><b>CONCLUSION</b>The 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.</p>

TGF-beta receptor mediated telomerase inhibition, telomere shortening and breast cancer cell senescence

Human telomerase reverse transcriptase (hTERT) plays a central role in telomere lengthening for continuous cell proliferation, but it remains unclear how extracellular cues regulate telomerase lengthening of telomeres. Here we report that the cytokine bone morphogenetic protein-7 (BMP7) induces the hTERT gene repression in a BMPRII receptor- and Smad3-dependent manner in human breast cancer cells. Chonic exposure of human breast cancer cells to BMP7 results in short telomeres, cell senescence and apoptosis. Mutation of the BMPRII receptor, but not TGFbRII, ACTRIIA or ACTRIIB receptor, inhibits BMP7-induced repression of the hTERT gene promoter activity, leading to increased telomerase activity, lengthened telomeres and continued cell proliferation. Expression of hTERT prevents BMP7-induced breast cancer cell senescence and apoptosis. Thus, our data suggest that BMP7 induces breast cancer cell aging by a mechanism involving BMPRII receptor- and Smad3-mediated repression of the hTERT gene.

Clinical features and genetic screening of hereditary hemorrhagic telangiectasia / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To analyze clinical features of 4 families with hereditary hemorrhagic telangiectasia (HHT) and potential mutations of ENG, ACVRL1 and SMAD4 genes.</p><p><b>METHODS</b>Four 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.</p><p><b>RESULTS</b>Eleven 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.</p><p><b>CONCLUSION</b>A 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.</p>

Early genetic diagnosis in patients with HHT induced severe nosebleed / 临床耳鼻咽喉头颈外科杂志

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.

Osler-Weber-Rendu disease presenting with hepatocellular carcinoma: radiologic and genetic findings / 대한간학회지

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.

Inhibitory effect of transforming growth factor-β(1) on oral squamous cell carcinoma brain metastasis Tb cell line / 中华口腔医学杂志

<p><b>OBJECTIVE</b>To investigate the inhibitory effect of transforming growth factor (TGF)-β₁ on oral squamous cell carcinoma (OSCC) Tb cell line.</p><p><b>METHODS</b>Cell counting method was used to examine the inhibitory effect of TGF-β₁ on Tb cell and flow cytometry (FCM) assay performed to measure the changes of cell cycle. Superarray was used to screen the changing expression of genes in TGF-β₁/Smads signaling pathway.RT-PCR method was used to detect the results of Superarray.</p><p><b>RESULTS</b>TGF-β₁ showed significant inhibiting effect on OSCC Tb cell line. TGF-β₁ blocked the cell cycle at G₁ phase. The expression level of activin receptor-like kinase-1 (ACVRL-1), anti-mullerian hirmine (AMH), cyclim-dependent kinase inhibitor-2B (CDKN-2B) and transforming growth factor-beta-indnced factor (TGIF) was higer in the cells treated with TGF-β₁ than in control, while TDGF-1 expression was down-regulated. ACVRL-1 and CDKN-2B gene expression was consistent with the results of Superarray.</p><p><b>CONCLUSIONS</b>TGF-β₁ can inhibit the growth of OSCC Tb cell line. The mechanism may be related to the regulation of cell cycle and the expression of ACVRL-1 and CDKN-2B in TGF-β₁-Smads signaling pathway.</p>

Clinical Features and Mutations in the ENG, ACVRL1, and SMAD4 genes in Korean Patients with Hereditary Hemorrhagic Telangiectasia

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.

Mutations of ACVRL1 gene in a pedigree with hereditary hemorrhagic telangiectasia / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To identify the activin A receptor type II-like 1 gene (ACVRL1) mutations in a Chinese family with hereditary hemorrhagic telangiectasia (HHT2).</p><p><b>METHODS</b>The 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.</p><p><b>RESULTS</b>The 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.</p><p><b>CONCLUSION</b>The HHT2 family is caused by a 145delG mutation of ACVRL1 gene, resulting in frameshift and a new stop codon at codon 53.</p>

Anaplastic large cell lymphoma (ALCL) presenting as primary bone and soft tissue sarcoma--a study of 12 cases.

This study highlights the rare presentation of anaplastic large cell lymphoma as primary bone and soft tissue tumour. Twelve cases were studied. Clinical impression was non Hodgkin's lymphoma in 4 cases, sarcoma in 6 (osteosarcoma-2, Ewing's/primitive neuroectodermal tumour-1, and sarcoma NOS-3), and tuberculosis of thoracic spine in 1 and the last case involving the rib had a differential diagnosis of tuberculosis and NHL. Histology revealed round cells with eosinophilic cytoplasm and pleomorphic nuclei. Immunohistochemically all tumours were CD30 positive and 8 of 9 cases (88.9%) showed ALK-1 positivity. The pleomorphic cytomorphology ofALCL leads to confusion with the more frequent bone and soft tissue sarcomas affecting the musculoskeletal system. A high index of suspicion is necessary to initiate the correct panel of immunohistochemical markers to first confirm the lymphomatous nature of this tumour and to subsequently subclassify. This alone will lead to an accurate recognition of ALCL and the appropriate chemotherapy.

Expression of TGFbeta1 and its type I receptors ALK1 and ALK5 mRNA in brain arteriovenous malformation / 南方医科大学学报

<p><b>OBJECTIVE</b>To explore the expression of transforming growth factor beta1 (TGFbeta1) and its type I receptors activin-like kinase 1 (ALK1) and ALK5 mRNA in the development of brain arteriovenous malformation (BAVM).</p><p><b>METHODS</b>The mRNA expressions of TGFbeta1, ALK1and ALK5 were detected with semiquantitative RT-PCR in patients with BAVM.</p><p><b>RESULTS</b>The expressions of TGFbeta1 and ALK5 mRNA increased significantly in BAVM, and their relative expression quantity were 0.777-/+0.047 and 0.585-/+0.074, respectively. However, ALK1 mRNA expression declined significantlies with a relative expression of 0.173-/+0.044 in comparison with the control group (0.720-/+0.098, P<0.01).</p><p><b>CONCLUSION</b>The balance of TGFbeta1 and its type I receptors ALK1 and ALK5 mRNA expressions may play important role in the development of BAVM.</p>

Linfoma anaplásico de células grandes ALK-1 positivo, primario de pulmón: Informe de un caso pediátrico / ALK-1 positive anaplastic large cell lymphoma of the lung: Report of a pediatric case

El linfoma no Hodgkin anaplásico de células grandes, positivo al antígeno Ki-1, es una entidad bien reconocida. La característica clínica usual es la linfadenopatía con extensión mediastinal y en la enfermedad extranodal, que ocurre en la mitad de los casos, es la piel el sitio más común, con afección poco frecuente a médula ósea, pulmón y sistema nervioso. La mayor frecuencia de presentación del linfoma anaplásico de células grandes es en la población joven, con pronóstico más favora ble que en la población adulta. El linfoma anaplásico de células grandes primario de pulmón es una entidad clínica rara. Su comportamiento clínico corresponde a un linfoma de alto grado y en la mayoría de los casos se presentan al diagnóstico como una enfermedad en estadio avanzado. Se informa un caso pediátrico de linfoma anaplásico de células grandes primario de pulmón, ALK 1 positivo, que es un marcador pronóstico y específico de esta entidad.

Ki 1 anaplastic large cell non Hodgkin lymphoma is a well recognized clinical entity. The main clinical feature includes lymphadenopathy with mediastinal sparing. In the extranodal disease, which occurs in approximately half of the cases, the skin is the most common site; bone marrow, lung and central nervous system are generally not involved. Anaplastic large cell lymphoma is more common among young people, in whom the prognosis is more favorable. Primary anaplastic large cell lymphoma of the lung is a rare clinical entity. Its clinical expression is similar to a high grade malignant lymphoma, and in most cases the diagnosis is made in advanced stages. We present a pediatric case with ALK1 positive anaplastic large cell lymphoma of the lung.

Hereditary hemorrhagic telangiectasia resulted from a nonsense mutation Arg479 Stop in the ALK-1 gene / 中华血液学杂志

<p><b>OBJECTIVE</b>To identify the gene mutations in a pedigree with hereditary hemorrhagic telangiectasia.</p><p><b>METHODS</b>Genomic 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.</p><p><b>RESULTS</b>The mutation is a C1437T substitution in exon 10 of the ALK-1 gene, resulting in Arg 479 Stop.</p><p><b>CONCLUSION</b>The hereditary hemorrhagic telangiectasia propositus is caused by a heterozygous Arg 479 Stop mutation in the ALK-1 gene which has not been identified previously.</p>

Clinical phenotypes, ALK1 gene mutation and level of related plasma proteins in Chinese hereditary hemorrhagic telangiectasia / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>We 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.</p><p><b>METHODS</b>Bleeding 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.</p><p><b>RESULTS</b>Of 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.</p><p><b>CONCLUSIONS</b>Chinese 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.</p>