Hereditary hemorrhagic telangiectasia (HHT), also known as Rendu-Osler-Weber syndrome, is a rare autosomal dominant hereditary disorder characterized by multisystem vascular malformations, including mucocutaneous telangiectasia and arteriovenous malformations. This paper reports a case of a male patient with HHT admitted to the Second Xiangya Hospital of Central South University who presented with hemoptysis, an uncommon manifestation in HHT. Imaging revealed bilateral bronchial artery dilatation and tortuosity, as well as bilateral pulmonary artery enlargement. Whole-exome sequencing for monogenic disorders ultimately identified an <i>ACVRL1i> gene mutation, confirming a diagnosis of HHT type 2. Diagnosis of HHT is primarily based on clinical manifestations, imaging findings, and family history, while genetic testing facilitates definitive diagnosis and subtyping. Anti-angiogenic therapy has proven to be an effective and safe treatment approach for controlling hemoptysis, epistaxis, and gastrointestinal bleeding in HHT patients. This case highlights the importance of early genetic screening in suspected cases to enable timely etiological clarification and intervention.
Humans ; Telangiectasia, Hereditary Hemorrhagic/diagnosis* ; Hemoptysis/etiology* ; Male ; Activin Receptors, Type II/genetics* ; Mutation

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder characterized by congenital bilateral malformation of the large toe and progressive, extensive, and irreversible heterotopic ossification (HO) of soft tissues throughout the body, leading to severe disabilities. FOP is caused primarily by mutations in activin A receptor type 1 (<i>ACVR1i>), also known as activin-like kinase 2 (<i>ALK2i>), which encodes a receptor belonging to the bone morphogenetic protein (BMP) type I family. However, the continuous and complex process of HO in FOP is not yet fully understood, which has impeded the development of therapeutic drugs. Despite surgical removal of HO, which often results in recurrence and expansion of ossification, there is currently no definitive drug treatment available to completely prevent, halt, or reverse the progression of HO in FOP. Currently, researchers are intensively studying the pathogenesis of FOP at various stages and developing promising drug candidates, including saracatinib, palovarotene, and rapamycin. This review provides an overview of progress in understanding the mechanism of FOP and the development of therapeutic drugs, with the goal of providing insights for further research and the development of new treatment methods.
Myositis Ossificans/genetics* ; Humans ; Activin Receptors, Type I/genetics* ; Ossification, Heterotopic ; Mutation ; Sirolimus/therapeutic use* ; Quinolones/therapeutic use* ; Benzodioxoles/therapeutic use* ; Animals ; Quinazolines/therapeutic use*

The three-day-old female infant was admitted to the hospital due to respiratory distress after birth. She was born premature at 36⁺² weeks gestational age. Prenatal ultrasound suggested abnormal development of the fetal liver vessels, and she had dyspnea that required respiratory support after birth. Chest X-ray indicated an enlarged cardiac silhouette, and cardiac ultrasound revealed enlargement of the right atrium and right ventricle. Diagnosis of hepatic hemangioma with arteriovenous fistula was confirmed through liver ultrasound and abdominal enhanced CT. At 19 days old, she underwent ligation of the hepatic artery under general anesthesia, which led to an improvement in cardiac function and she was subsequently discharged. Genetic testing revealed a mutation in the <i>ACVRL1i> gene, which was inherited from the mother. The article primarily introduces a case of neonatal heart failure caused by hepatic hemangioma with arteriovenous fistula, and multi-disciplinary diagnosis and treatment of this disease.
Female ; Humans ; Infant, Newborn ; Pregnancy ; Activin Receptors, Type II ; Arteriovenous Fistula/complications* ; Dyspnea ; Heart Failure/etiology* ; Hemangioma/complications* ; Liver

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 <i>vsi> 8.19±1.47, <i>ti>=9.708, <i>Pi><0.01). The scores of six aspects and standardized scores of ESS were significantly decreased after treatment (epistaxis frequency: 1.78±1.22 <i>vsi> 3.44±0.80, <i>ti>=6.814, <i>Pi><0.01; epistaxis duration: 0.85±0.91 <i>vsi> 3.00±0.73, <i>ti>=8.845, <i>Pi><0.01; epistaxis intensity: 0.19±0.40 <i>vsi> 1.00±0.00, <i>ti>=10.696, <i>Pi><0.01; treatment demand: 0.22 ± 0.42 <i>vsi> 1.00±0.00, <i>ti>=9.539, <i>Pi><0.01; anemia: 0.41±0.50 <i>vsi> 0.89±0.32, <i>ti>=4.914, <i>Pi><0.01; blood transfusion: 0.11±0.32 <i>vsi> 0.41±0.50, <i>ti>=3.309, <i>Pi><0.01; ESS standardized score: 2.50±2.45 <i>vsi> 7.60±1.30, <i>ti>=9.344, <i>Pi><0.01). The hemoglobin level after treatment was significantly higher than that before treatment ((105.48±24.31) g/L <i>vsi> (73.07±23.71) g/L, <i>ti>=6.864, <i>Pi><0.01). Among the 27 patients, there were 8 cases of HHT1 (<i>ENGi> gene) and 19 cases of HHT2 (<i>ACVRL1i> 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 (<i>Pi>>0.05). There was no significant difference in ESS scores between the two groups before and after treatment (<i>Pi>>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.
Activin Receptors, Type II ; Adult ; Aged ; Bevacizumab/therapeutic use* ; Epistaxis/etiology* ; Female ; Humans ; Male ; Middle Aged ; Retrospective Studies ; Telangiectasia, Hereditary Hemorrhagic/drug therapy*

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 <i>ENG, ACVRL1, SMAD4i> and <i>GDF2i> 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 <i>ACVRL1i> 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*

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

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.
Actin-Related Protein 2 ; genetics ; metabolism ; Activin Receptors, Type II ; genetics ; metabolism ; Bone Morphogenetic Protein 7 ; genetics ; metabolism ; Bone Morphogenetic Protein Receptors, Type II ; genetics ; metabolism ; Breast Neoplasms ; genetics ; metabolism ; Cellular Senescence ; Female ; HeLa Cells ; Humans ; MCF-7 Cells ; Neoplasm Proteins ; genetics ; metabolism ; Protein-Serine-Threonine Kinases ; genetics ; metabolism ; Receptor, Transforming Growth Factor-beta Type II ; Receptors, Transforming Growth Factor beta ; genetics ; metabolism ; Smad3 Protein ; genetics ; metabolism ; Telomerase ; genetics ; metabolism ; Telomere Homeostasis

OBJECTIVETo study the clinicopathologic features, differential diagnosis and prognosis of primary bone anaplastic large cell lymphoma(ALCL).

METHODSTwelve patients diagnosed with primary bone ALCL were retrospectively reviewed. The clinicopathologic features, immunohistochemic findings and results of in situ hybridization for EB virus were analyzed.

RESULTSOf the 12 patients, the male-to-female was 7: 5 with a median age of 17.5 years (range from 9 to 64 years). Bone pain was the presenting symptom in all patients. Radiographic examination demonstrated solitary osteolytic lesion in 8 patients and multiple lesions in the rest 4 patients. Spine (7 cases) was the most common site to be involved, followed by ilium (5 cases), sacrum (2 cases), humerus (1 case) and collarbone (1 case). Ten patients were available with the follow-up data including 5 ALK-positive and 5 ALK-negative patients, and the follow-up time was 2 to 47 months. Interestingly, the 3 dead patients were ALK-negative whereas 5 of 7 ALK-positive patients achieved remission.

CONCLUSIONSPrimary bone ALCL is a rare type of non-Hodgkin lymphoma and it more frequently involves the axial skeleton. Boys and young males are more commonly affected. Patients usually present at an early stage and have a relatively favorable prognosis. Expression of ALK protein may be associated with a favorable prognosis in primary bone ALCL.

Activin Receptors, Type I ; Adolescent ; Adult ; Alkaline Phosphatase ; Bone Diseases ; etiology ; Bone Neoplasms ; diagnostic imaging ; enzymology ; mortality ; Child ; Female ; Humans ; Lymphoma, Large-Cell, Anaplastic ; diagnostic imaging ; enzymology ; mortality ; Male ; Middle Aged ; Pain ; etiology ; Prognosis ; Radiography ; Receptor Protein-Tyrosine Kinases ; Retrospective Studies ; Young Adult

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