Factors associated with dysglycemia and its post-surgical resolution in patients with pheochromocytomas.

A Novel Frame-Shift Mutation in SCNN1B Identified in a Chinese Family Characterized by Early-Onset Hypertension.

Background:Liddle syndrome is a form of monogenic hypertension caused by mutations in the three homologous subunits of the epithelial sodium channels (ENaCs), α, β, and γ. It is characterized by early-onset refractory hypertension, hypokalemia, low renin activity, and hypoaldosteronism. In this study, we report a novel frame-shift mutation in SCNN1B responsible for Liddle syndrome in a Chinese family.Methods:DNA samples were collected from all participants. Whole-exome sequencing was performed in the proband to detect possible causative variants. Sanger sequencing was then conducted in the other family members to verify the candidate variant, and in 100 patients with hypertension and 100 normotensive controls to exclude population genetic polymorphism.Results:We identified a novel frame-shift mutation (c.1691_1693delinsG) in SCNN1B that was responsible for Liddle syndrome in this family. This mutation leads to the substitution of Arg in place of Gln at codon site 564 and generates a new stop codon at 592, influencing the crucial PY motif and resulting in reduced inactivation of the ENaCs. Aside from the proband, eight family members carried the mutation. Intra-familial phenotypic heterogeneity was observed in the blood pressure and serum potassium levels. Amiloride therapy combined with a low sodium diet is effective to alleviate the symptoms of patients with Liddle syndrome.Conclusion:c.1691_1693delinsG, a novel frame-shift mutation in the β subunit of ENaC, was identified in a Chinese family with Liddle syndrome by whole-exome sequencing. Phenotypic heterogeneity can make diagnosis of Liddle syndrome difficult on the basis of clinical or biochemical characteristics alone. Genetic analysis is a useful tool allowing timely and accurate diagnosis of Liddle syndrome and playing a guiding role in precise treatment of the disease.

Concurrent Primary Aldosteronism and Renal Artery Stenosis: An Overlooked Condition Inducing Resistant Hypertension.

To explore the clinical features of coexisting primary aldosteronism (PA) and renal artery stenosis (RAS), we retrospectively analyzed records from 71 patients with PA with RAS and a control group of 121 patients with PA without RAS. Aldosterone-to-renin concentration ratio tests and computerized tomography (CT) scanning of the adrenal and renal arteries were routinely conducted to screen for PA and RAS. Color Doppler flow and/or magnetic resonance imaging were used as substitute testing of patients for whom CT was contraindicated. Standard percutaneous renal arteriography (PTRA) was considered for patients with RAS exceeding 70% based on non-invasive tests and for those without PTRA contraindications. The patients with PA with RAS were further divided into severe (RAS>70%) and moderate (50% < RAS <70%) RAS groups. The prevalence of RAS among PA patients was 6.9% (71/1,033), including 3.2% (33/1,033) with severe RAS. Compared with the PA without RAS group, the severe RAS group showed higher levels of systolic blood pressure (SBP) (171.82 ± 18.24 vs. 154.11 ± 18.96 mmHg; P < 0.001) and diastolic BP(DBP) (110.76 ± 15.90 vs. 91.73 ± 12.85 mmHg; P < 0.001) and prevalence of resistant hypertension (RH) (90.9 vs. 66.9%; P = 0.008), whereas the moderate RAS group merely showed higher DBP (98.63 ± 14.90 vs. 91.73 ± 12.85 mmHg; P = 0.006). The direct renin concentrations (DRCs) (5.37 ± 3.94 vs. 3.71 ± 2.10 μU/mL; P < 0.001) and false-negative rate (33.8 vs. 3.3%; P < 0.01) of PA screening tests were significantly higher in the PA with RAS group than in the control group, but only in severe RAS group, in subgroup analysis. Among patients who underwent successful treatment for severe RAS, mean DRC decreased from 11.22 ± 9.10 to 3.24 ± 2.69 μIU/mL (P < 0.001). Overall, the prevalence of RH decreased from 81.7 to 2.8% (P < 0.001) when both PA and RAS were treated with standard methods. PA with concurrent severe RAS is a condition that induces RH. PA can be easily missed in patients with coexisting RAS. RAS patients with RH after successful revascularization for RAS should be evaluated for coexisting PA.

Prognostic value of plasma big endothelin-1 in left ventricular non-compaction cardiomyopathy.

OBJECTIVE:To determine the prognostic role of big endothelin-1 (ET-1) in left ventricular non-compaction cardiomyopathy (LVNC).METHODS:We prospectively enrolled patients whose LVNC was diagnosed by cardiac MRI and who had big ET-1 data available. Primary end point was a composite of all-cause mortality, heart transplantation, sustained ventricular tachycardia/fibrillation and implanted cardioverter defibrillator discharge. Secondary end point was cardiac death or heart transplantation.RESULTS:Altogether, 203 patients (median age 44 years; 70.9% male) were divided into high-level (≥0.42 pmol/L) and low-level (<0.42 pmol/L) big ET-1 groups according to the median value of plasma big ET-1 levels. Ln big ET-1 was positively associated with Ln N-terminal pro-brain natriuretic peptide, left ventricular diameter, but negatively related to age and Ln left ventricular ejection fraction. Median follow-up was 1.9 years (IQR 0.9-3.1 years). Kaplan-Meier analysis showed that, compared with patients with low levels of big ET-1, those with high levels were at greater risk for meeting both primary (p<0.001) and secondary (p<0.001) end points. The C-statistic estimation of Ln big ET-1 for predicting the primary outcome was 0.755 (95% CI 0.685 to 0.824, p<0.001). After adjusting for confounding factors, Ln big ET-1 was identified as an independent predictor of the composite primary outcome (HR 1.83, 95% CI 1.27 to 2.62, p=0.001) and secondary outcome (HR 1.93, 95% CI 1.32 to 2.83, p=0.001).CONCLUSIONS:Plasma big ET-1 may be a valuable index to predict the clinical adverse outcomes in patients with LVNC.

Clinical characteristics and outcomes of chronic heart failure in adult Takayasu arteritis: A cohort study of 163 patients.

BACKGROUND:Chronic heart failure (CHF) is a serious complication and a major cause of mortality in patients with Takayasu arteritis (TA). We aimed to explore the clinical features and long-term outcomes in TA patients with CHF.METHODS AND RESULTS:Adult TA patients admitted to our hospital between January 2009 to April 2018 were classified as HF and non-HF group. The adverse events were defined as a composite of all-cause mortality and hospitalization for HF. The outcome of the HF-group was further analyzed. A total of 61 HF patients and 102 non-HF patients were identified. In the HF group, the median age at assessment was 41.9 years, and female was predominant (82.0%). The multivariable logistic regression model revealed that pulmonary hypertension, aortic regurgitation, mitral regurgitation, level albumin, and uric acid were independently associated with CHF. After a median follow-up of 1347 days, 25 adverse events occurred in HF patients, and the 5-year event-free rate was 54.7%. The Cox model showed that coronary artery involvement, aortic regurgitation, without interventional treatment were related to adverse events.CONCLUSIONS:The 5-year event-free rate was not satisfying. Aggressive intervention may decreased the likelihood of adverse events in patients with CHF.

Apparent mineralocorticoid excess caused by novel compound heterozygous mutations in HSD11B2 and characterized by early-onset hypertension and hypokalemia.

PURPOSE:Apparent mineralocorticoid excess (AME) is an ultrarare autosomal recessive disorder resulting from deficiency of 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2) caused by mutations in HSD11B2. The purpose of this study was to identify novel compound heterozygous HSD11B2 mutations in a Chinese pedigree with AME and conduct a systematic review evaluating the AME clinical features associated with HSD11B2 mutations.METHODS:Next-generation sequencing was performed in the proband, and Sanger sequencing was used to identify candidate variants in family members, 100 hypertensives, and 100 healthy controls. A predicted structure of 11βHSD2 was constructed by in silico modeling. A systematic review was used to identify cases of HSD11B2-related AME. Data for genotyping and clinical characterizations and complications were extracted.RESULTS:Next-generation sequencing showed novel compound heterozygous mutations (c.343_348del and c.1099_1101del) in the proband with early-onset hypertension and hypokalemia. Sanger sequencing verified the monoallelic form of the same mutations in five other relatives but not in 100 hypertensives or 100 healthy subjects. In silico structural modeling showed that compound mutations may simultaneously perturb the substrate and coenzyme binding pocket. A systematic review of 101 AME patients with 54 HSD11B2 mutations revealed early-onset hypertension, hypokalemia and homozygous mutations as common features. The homozygous HSD11B2 mutations correlated with low birth weight (r = 0.285, P = 0.02).CONCLUSIONS:We report novel compound heterozygous HSD11B2 mutations in a Chinese teenager with early-onset hypertension, and enriched genotypic and phenotypic spectrums in AME. Genetic testing helps early diagnosis and treatment for AME patients, which may avoid target organ damage.

Hypertension and Brachydactyly Syndrome Associated With Vertebral Artery Malformation Caused by a PDE3A Missense Mutation.

BACKGROUND:Hypertension and brachydactyly syndrome (HTNB), also called Bilginturan syndrome, is a rare autosomal dominant disorder characterized by severe salt-independent hypertension, a short stature, brachydactyly, and death from stroke before the age of 50 years when untreated. The purpose of the present study was to identify a PDE3A mutation leading to HTNB associated with vertebral artery malformation in a Chinese family.METHODS:Peripheral blood samples were collected from all subjects for DNA extraction. Next-generation sequencing and Sanger sequencing were performed to identify the PDE3A mutation. A comparative overview was performed in the probands with HTNB caused by PDE3A mutations.RESULTS:Genetic analysis identified a missense mutation in PDE3A, c.1346G>A, in the proband with HTNB. This mutation, resulting in p.Gly449Asp, was located in a highly conserved domain and predicted to be damaging by different bioinformatics tools. Cosegregation analyses showed that the proband inherited the identified mutation from her father. Antihypertensive therapy was effective for the proband. Comparative overview of HTNB probands with 9 different PDE3A mutations revealed phenotypic heterogeneity.CONCLUSIONS:Genetic screening can significantly improve the diagnosis of HTNB patients at an early age. Our study not only adds to the spectrum of PDE3A mutations in the Chinese population and extends the phenotype of HTNB patients to include vertebral malformation but also improves the awareness of pathogenesis in HTNB patients. We emphasize the importance of antihypertensive treatment and long-term follow-up to prevent stroke and adverse cardiovascular events.

Is primary aldosteronism a potential risk factor for aortic dissection? A case report and literature review.

BACKGROUND:Primary aldosteronism (PA) increases the risk of cardiovascular morbidity, including stroke, coronary artery disease, atrial fibrillation, and heart failure. The relationship between primary aldosteronism and aortic dissection has rarely been reported. We report a case of aortic dissection caused by secondary hypertension from PA and review similar cases in the literature.CASE PRESENTATION:A 56-year-old woman with a history of surgery for aortic dissection presented for follow-up of hypertension and a left adrenal mass. She had been diagnosed with hypertension and hypokalemia in 2003. Blood pressure had been controlled by antihypertensive medications. In 2009, she presented with chest and back pain; she was diagnosed with aortic dissection by computed tomography (CT). She underwent placement of an endovascular aortic stent graft. CT at that time showed a left adrenal mass with a diameter of 1 cm. In 2017, CT reexamination revealed that the left adrenal mass had grown to 3 cm in diameter. Laboratory data showed blood potassium 2.4 mmol/L (reference range: 3.5-5.3 mmol/L). The plasma aldosterone/renin ratio was elevated because of suppressed plasma renin and elevated serum aldosterone levels. Plasma aldosterone levels were not suppressed after taking captopril. Positron emission tomography/CT showed that the left adrenal tumor radiographic uptake was slightly increased (maximum standardized uptake value of 2.2), and metastasis was not detected. Laparoscopic adrenalectomy was performed, and an adrenocortical adenoma was confirmed histopathologically. After surgery, blood pressure and laboratory findings were within their reference ranges without any pharmacological treatment.CONCLUSIONS:Our patient and the literature suggest that PA is a potential cause of aortic dissection. Diagnosing PA in the early stages of the disease and early treatment are important because affected patients may be at increased risk of aortic dissection.

Pediatric Liddle Syndrome Caused by a Novel SCNN1G Variant in a Chinese Family and Characterized by Early-Onset Hypertension.

BACKGROUND:Liddle syndrome (LS), an autosomal dominant disorder, is a common monogenic hypertension in pediatrics. In this study, we reported a novel SCNN1G variant in a Chinese family with pediatric LS, and conduct a systematic review of epithelial sodium channel (ENaC)-gene-positive LS cases to conclude the clinical genetic features of LS in childhood.METHODS:Next-generation sequencing and in silico analysis were performed in the proband to discover candidate variants. Sanger sequencing was used to identify the predicted likely pathogenic variant. LS patients in this family were treated with amiloride. The Medline database was searched to summarize clinical features of pediatric LS cases whose age at genetic diagnosis was not more than 18 years.RESULTS:Genetic analysis identified a novel SCNN1G missense variant (c.1874C>T, p.Pro625Leu) in the proband with LS in childhood. In silico analysis revealed this heterozygous variant was highly conserved and deleterious. A total of 38 publications described pediatric LS associated with 25 pathogenic variants in SCNN1B and SCNN1G in 54 children. Despite the phenotypic heterogeneity, early-onset hypertension is the most common feature. All LS patients in this family or the reviewed cases showed significantly improvements in hypertension and hypokalemia after treatment with ENaC inhibitors.CONCLUSIONS:This study identified a novel SCNN1G missense variant in a patient with pediatric LS, expanding the genetic spectrum of SCNN1G and demonstrating the PY motif of γ-ENaC as a potential mutant region. Early identification and specific management of LS in children and adolescents are important to prevent the development of hypertensive end-organ disease.

Whole exome sequencing identified a pathogenic nonsense mutation in LMNA in a family with a progressive cardiac conduction defect: A case report.

Progressive cardiac conduction defect (PCCD) is an inherited autosomal dominant cardiac disorder characterized by an age‑dependent cardiac electrical conduction block. Several genes have been associated with the genetic pathogenesis of PCCD. The present study aimed to identify the causal mutation of PCCD and to investigate the association between genotype and phenotype in a Chinese family with PCCD. A total of 39 family members were included in the present study. All subjects participated in physical, biochemical, electrocardiography and echocardiography examinations. Whole‑exome sequencing was performed for four individuals from the same generation, including three patients with PCCD and one normal control with no cardiovascular disease. Sanger sequencing and in silico analysis were used to identify the causal mutation. Whole‑exome sequencing and variant identification revealed a candidate nonsense mutation (c.1443C>A, p.Tyr481*) in lamin A/C (LMNA). The mutation was identified in seven patients (including the proband) and two asymptomatic mutation carriers, but it was not detected in 100 control subjects of matched ancestry. Clinical examinations identified typical symptoms in patients with PCCD, including bradycardia and various types of conduction defect, and excluded other phenotypes related to the LMNA mutation. The genotype and phenotype were co‑associated among all participants. In the present study, the c.1443C>A mutation in the LMNA gene was identified as a potential cause of PCCD. In silico analysis predicted that the identified mutation was damaging through its effect on the lamin tail domain of LMNA. From the present study, it could be suggested that genetic screening and family counseling, early pacemaker implantation or a sudden death in the family may be essential for risk stratification and treatment of patients with PCCD.

Factors associated with dysglycemia and its post-surgical resolution in patients with pheochromocytomas.

A Novel Frame-Shift Mutation in SCNN1B Identified in a Chinese Family Characterized by Early-Onset Hypertension.

Background:Liddle syndrome is a form of monogenic hypertension caused by mutations in the three homologous subunits of the epithelial sodium channels (ENaCs), α, β, and γ. It is characterized by early-onset refractory hypertension, hypokalemia, low renin activity, and hypoaldosteronism. In this study, we report a novel frame-shift mutation in SCNN1B responsible for Liddle syndrome in a Chinese family.Methods:DNA samples were collected from all participants. Whole-exome sequencing was performed in the proband to detect possible causative variants. Sanger sequencing was then conducted in the other family members to verify the candidate variant, and in 100 patients with hypertension and 100 normotensive controls to exclude population genetic polymorphism.Results:We identified a novel frame-shift mutation (c.1691_1693delinsG) in SCNN1B that was responsible for Liddle syndrome in this family. This mutation leads to the substitution of Arg in place of Gln at codon site 564 and generates a new stop codon at 592, influencing the crucial PY motif and resulting in reduced inactivation of the ENaCs. Aside from the proband, eight family members carried the mutation. Intra-familial phenotypic heterogeneity was observed in the blood pressure and serum potassium levels. Amiloride therapy combined with a low sodium diet is effective to alleviate the symptoms of patients with Liddle syndrome.Conclusion:c.1691_1693delinsG, a novel frame-shift mutation in the β subunit of ENaC, was identified in a Chinese family with Liddle syndrome by whole-exome sequencing. Phenotypic heterogeneity can make diagnosis of Liddle syndrome difficult on the basis of clinical or biochemical characteristics alone. Genetic analysis is a useful tool allowing timely and accurate diagnosis of Liddle syndrome and playing a guiding role in precise treatment of the disease.

Concurrent Primary Aldosteronism and Renal Artery Stenosis: An Overlooked Condition Inducing Resistant Hypertension.

To explore the clinical features of coexisting primary aldosteronism (PA) and renal artery stenosis (RAS), we retrospectively analyzed records from 71 patients with PA with RAS and a control group of 121 patients with PA without RAS. Aldosterone-to-renin concentration ratio tests and computerized tomography (CT) scanning of the adrenal and renal arteries were routinely conducted to screen for PA and RAS. Color Doppler flow and/or magnetic resonance imaging were used as substitute testing of patients for whom CT was contraindicated. Standard percutaneous renal arteriography (PTRA) was considered for patients with RAS exceeding 70% based on non-invasive tests and for those without PTRA contraindications. The patients with PA with RAS were further divided into severe (RAS>70%) and moderate (50% < RAS <70%) RAS groups. The prevalence of RAS among PA patients was 6.9% (71/1,033), including 3.2% (33/1,033) with severe RAS. Compared with the PA without RAS group, the severe RAS group showed higher levels of systolic blood pressure (SBP) (171.82 ± 18.24 vs. 154.11 ± 18.96 mmHg; P < 0.001) and diastolic BP(DBP) (110.76 ± 15.90 vs. 91.73 ± 12.85 mmHg; P < 0.001) and prevalence of resistant hypertension (RH) (90.9 vs. 66.9%; P = 0.008), whereas the moderate RAS group merely showed higher DBP (98.63 ± 14.90 vs. 91.73 ± 12.85 mmHg; P = 0.006). The direct renin concentrations (DRCs) (5.37 ± 3.94 vs. 3.71 ± 2.10 μU/mL; P < 0.001) and false-negative rate (33.8 vs. 3.3%; P < 0.01) of PA screening tests were significantly higher in the PA with RAS group than in the control group, but only in severe RAS group, in subgroup analysis. Among patients who underwent successful treatment for severe RAS, mean DRC decreased from 11.22 ± 9.10 to 3.24 ± 2.69 μIU/mL (P < 0.001). Overall, the prevalence of RH decreased from 81.7 to 2.8% (P < 0.001) when both PA and RAS were treated with standard methods. PA with concurrent severe RAS is a condition that induces RH. PA can be easily missed in patients with coexisting RAS. RAS patients with RH after successful revascularization for RAS should be evaluated for coexisting PA.

Prognostic value of plasma big endothelin-1 in left ventricular non-compaction cardiomyopathy.

OBJECTIVE:To determine the prognostic role of big endothelin-1 (ET-1) in left ventricular non-compaction cardiomyopathy (LVNC).METHODS:We prospectively enrolled patients whose LVNC was diagnosed by cardiac MRI and who had big ET-1 data available. Primary end point was a composite of all-cause mortality, heart transplantation, sustained ventricular tachycardia/fibrillation and implanted cardioverter defibrillator discharge. Secondary end point was cardiac death or heart transplantation.RESULTS:Altogether, 203 patients (median age 44 years; 70.9% male) were divided into high-level (≥0.42 pmol/L) and low-level (<0.42 pmol/L) big ET-1 groups according to the median value of plasma big ET-1 levels. Ln big ET-1 was positively associated with Ln N-terminal pro-brain natriuretic peptide, left ventricular diameter, but negatively related to age and Ln left ventricular ejection fraction. Median follow-up was 1.9 years (IQR 0.9-3.1 years). Kaplan-Meier analysis showed that, compared with patients with low levels of big ET-1, those with high levels were at greater risk for meeting both primary (p<0.001) and secondary (p<0.001) end points. The C-statistic estimation of Ln big ET-1 for predicting the primary outcome was 0.755 (95% CI 0.685 to 0.824, p<0.001). After adjusting for confounding factors, Ln big ET-1 was identified as an independent predictor of the composite primary outcome (HR 1.83, 95% CI 1.27 to 2.62, p=0.001) and secondary outcome (HR 1.93, 95% CI 1.32 to 2.83, p=0.001).CONCLUSIONS:Plasma big ET-1 may be a valuable index to predict the clinical adverse outcomes in patients with LVNC.

Clinical characteristics and outcomes of chronic heart failure in adult Takayasu arteritis: A cohort study of 163 patients.

BACKGROUND:Chronic heart failure (CHF) is a serious complication and a major cause of mortality in patients with Takayasu arteritis (TA). We aimed to explore the clinical features and long-term outcomes in TA patients with CHF.METHODS AND RESULTS:Adult TA patients admitted to our hospital between January 2009 to April 2018 were classified as HF and non-HF group. The adverse events were defined as a composite of all-cause mortality and hospitalization for HF. The outcome of the HF-group was further analyzed. A total of 61 HF patients and 102 non-HF patients were identified. In the HF group, the median age at assessment was 41.9 years, and female was predominant (82.0%). The multivariable logistic regression model revealed that pulmonary hypertension, aortic regurgitation, mitral regurgitation, level albumin, and uric acid were independently associated with CHF. After a median follow-up of 1347 days, 25 adverse events occurred in HF patients, and the 5-year event-free rate was 54.7%. The Cox model showed that coronary artery involvement, aortic regurgitation, without interventional treatment were related to adverse events.CONCLUSIONS:The 5-year event-free rate was not satisfying. Aggressive intervention may decreased the likelihood of adverse events in patients with CHF.

Apparent mineralocorticoid excess caused by novel compound heterozygous mutations in HSD11B2 and characterized by early-onset hypertension and hypokalemia.

PURPOSE:Apparent mineralocorticoid excess (AME) is an ultrarare autosomal recessive disorder resulting from deficiency of 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2) caused by mutations in HSD11B2. The purpose of this study was to identify novel compound heterozygous HSD11B2 mutations in a Chinese pedigree with AME and conduct a systematic review evaluating the AME clinical features associated with HSD11B2 mutations.METHODS:Next-generation sequencing was performed in the proband, and Sanger sequencing was used to identify candidate variants in family members, 100 hypertensives, and 100 healthy controls. A predicted structure of 11βHSD2 was constructed by in silico modeling. A systematic review was used to identify cases of HSD11B2-related AME. Data for genotyping and clinical characterizations and complications were extracted.RESULTS:Next-generation sequencing showed novel compound heterozygous mutations (c.343_348del and c.1099_1101del) in the proband with early-onset hypertension and hypokalemia. Sanger sequencing verified the monoallelic form of the same mutations in five other relatives but not in 100 hypertensives or 100 healthy subjects. In silico structural modeling showed that compound mutations may simultaneously perturb the substrate and coenzyme binding pocket. A systematic review of 101 AME patients with 54 HSD11B2 mutations revealed early-onset hypertension, hypokalemia and homozygous mutations as common features. The homozygous HSD11B2 mutations correlated with low birth weight (r = 0.285, P = 0.02).CONCLUSIONS:We report novel compound heterozygous HSD11B2 mutations in a Chinese teenager with early-onset hypertension, and enriched genotypic and phenotypic spectrums in AME. Genetic testing helps early diagnosis and treatment for AME patients, which may avoid target organ damage.

Hypertension and Brachydactyly Syndrome Associated With Vertebral Artery Malformation Caused by a PDE3A Missense Mutation.

BACKGROUND:Hypertension and brachydactyly syndrome (HTNB), also called Bilginturan syndrome, is a rare autosomal dominant disorder characterized by severe salt-independent hypertension, a short stature, brachydactyly, and death from stroke before the age of 50 years when untreated. The purpose of the present study was to identify a PDE3A mutation leading to HTNB associated with vertebral artery malformation in a Chinese family.METHODS:Peripheral blood samples were collected from all subjects for DNA extraction. Next-generation sequencing and Sanger sequencing were performed to identify the PDE3A mutation. A comparative overview was performed in the probands with HTNB caused by PDE3A mutations.RESULTS:Genetic analysis identified a missense mutation in PDE3A, c.1346G>A, in the proband with HTNB. This mutation, resulting in p.Gly449Asp, was located in a highly conserved domain and predicted to be damaging by different bioinformatics tools. Cosegregation analyses showed that the proband inherited the identified mutation from her father. Antihypertensive therapy was effective for the proband. Comparative overview of HTNB probands with 9 different PDE3A mutations revealed phenotypic heterogeneity.CONCLUSIONS:Genetic screening can significantly improve the diagnosis of HTNB patients at an early age. Our study not only adds to the spectrum of PDE3A mutations in the Chinese population and extends the phenotype of HTNB patients to include vertebral malformation but also improves the awareness of pathogenesis in HTNB patients. We emphasize the importance of antihypertensive treatment and long-term follow-up to prevent stroke and adverse cardiovascular events.

Is primary aldosteronism a potential risk factor for aortic dissection? A case report and literature review.

BACKGROUND:Primary aldosteronism (PA) increases the risk of cardiovascular morbidity, including stroke, coronary artery disease, atrial fibrillation, and heart failure. The relationship between primary aldosteronism and aortic dissection has rarely been reported. We report a case of aortic dissection caused by secondary hypertension from PA and review similar cases in the literature.CASE PRESENTATION:A 56-year-old woman with a history of surgery for aortic dissection presented for follow-up of hypertension and a left adrenal mass. She had been diagnosed with hypertension and hypokalemia in 2003. Blood pressure had been controlled by antihypertensive medications. In 2009, she presented with chest and back pain; she was diagnosed with aortic dissection by computed tomography (CT). She underwent placement of an endovascular aortic stent graft. CT at that time showed a left adrenal mass with a diameter of 1 cm. In 2017, CT reexamination revealed that the left adrenal mass had grown to 3 cm in diameter. Laboratory data showed blood potassium 2.4 mmol/L (reference range: 3.5-5.3 mmol/L). The plasma aldosterone/renin ratio was elevated because of suppressed plasma renin and elevated serum aldosterone levels. Plasma aldosterone levels were not suppressed after taking captopril. Positron emission tomography/CT showed that the left adrenal tumor radiographic uptake was slightly increased (maximum standardized uptake value of 2.2), and metastasis was not detected. Laparoscopic adrenalectomy was performed, and an adrenocortical adenoma was confirmed histopathologically. After surgery, blood pressure and laboratory findings were within their reference ranges without any pharmacological treatment.CONCLUSIONS:Our patient and the literature suggest that PA is a potential cause of aortic dissection. Diagnosing PA in the early stages of the disease and early treatment are important because affected patients may be at increased risk of aortic dissection.

Pediatric Liddle Syndrome Caused by a Novel SCNN1G Variant in a Chinese Family and Characterized by Early-Onset Hypertension.

BACKGROUND:Liddle syndrome (LS), an autosomal dominant disorder, is a common monogenic hypertension in pediatrics. In this study, we reported a novel SCNN1G variant in a Chinese family with pediatric LS, and conduct a systematic review of epithelial sodium channel (ENaC)-gene-positive LS cases to conclude the clinical genetic features of LS in childhood.METHODS:Next-generation sequencing and in silico analysis were performed in the proband to discover candidate variants. Sanger sequencing was used to identify the predicted likely pathogenic variant. LS patients in this family were treated with amiloride. The Medline database was searched to summarize clinical features of pediatric LS cases whose age at genetic diagnosis was not more than 18 years.RESULTS:Genetic analysis identified a novel SCNN1G missense variant (c.1874C>T, p.Pro625Leu) in the proband with LS in childhood. In silico analysis revealed this heterozygous variant was highly conserved and deleterious. A total of 38 publications described pediatric LS associated with 25 pathogenic variants in SCNN1B and SCNN1G in 54 children. Despite the phenotypic heterogeneity, early-onset hypertension is the most common feature. All LS patients in this family or the reviewed cases showed significantly improvements in hypertension and hypokalemia after treatment with ENaC inhibitors.CONCLUSIONS:This study identified a novel SCNN1G missense variant in a patient with pediatric LS, expanding the genetic spectrum of SCNN1G and demonstrating the PY motif of γ-ENaC as a potential mutant region. Early identification and specific management of LS in children and adolescents are important to prevent the development of hypertensive end-organ disease.

Whole exome sequencing identified a pathogenic nonsense mutation in LMNA in a family with a progressive cardiac conduction defect: A case report.

Progressive cardiac conduction defect (PCCD) is an inherited autosomal dominant cardiac disorder characterized by an age‑dependent cardiac electrical conduction block. Several genes have been associated with the genetic pathogenesis of PCCD. The present study aimed to identify the causal mutation of PCCD and to investigate the association between genotype and phenotype in a Chinese family with PCCD. A total of 39 family members were included in the present study. All subjects participated in physical, biochemical, electrocardiography and echocardiography examinations. Whole‑exome sequencing was performed for four individuals from the same generation, including three patients with PCCD and one normal control with no cardiovascular disease. Sanger sequencing and in silico analysis were used to identify the causal mutation. Whole‑exome sequencing and variant identification revealed a candidate nonsense mutation (c.1443C>A, p.Tyr481*) in lamin A/C (LMNA). The mutation was identified in seven patients (including the proband) and two asymptomatic mutation carriers, but it was not detected in 100 control subjects of matched ancestry. Clinical examinations identified typical symptoms in patients with PCCD, including bradycardia and various types of conduction defect, and excluded other phenotypes related to the LMNA mutation. The genotype and phenotype were co‑associated among all participants. In the present study, the c.1443C>A mutation in the LMNA gene was identified as a potential cause of PCCD. In silico analysis predicted that the identified mutation was damaging through its effect on the lamin tail domain of LMNA. From the present study, it could be suggested that genetic screening and family counseling, early pacemaker implantation or a sudden death in the family may be essential for risk stratification and treatment of patients with PCCD.