ABSTRACT
Aortic aneurysms, which may dissect or rupture acutely and be lethal, can be a part of multisystem disorders that have a heritable basis. We report four patients with deficiency of selenocysteine-containing proteins due to selenocysteine Insertion Sequence Binding Protein 2 (SECISBP2) mutations who show early-onset, progressive, aneurysmal dilatation of the ascending aorta due to cystic medial necrosis. Zebrafish and male mice with global or vascular smooth muscle cell (VSMC)-targeted disruption of Secisbp2 respectively show similar aortopathy. Aortas from patients and animal models exhibit raised cellular reactive oxygen species, oxidative DNA damage and VSMC apoptosis. Antioxidant exposure or chelation of iron prevents oxidative damage in patient's cells and aortopathy in the zebrafish model. Our observations suggest a key role for oxidative stress and cell death, including via ferroptosis, in mediating aortic degeneration.
Subject(s)
Aortic Aneurysm , Zebrafish , Humans , Male , Mice , Animals , Selenocysteine , Muscle, Smooth, Vascular/metabolism , Aortic Aneurysm/genetics , Aortic Aneurysm/metabolism , Selenoproteins/genetics , Myocytes, Smooth Muscle/metabolismABSTRACT
BACKGROUND: Deletions in the SHOX gene are the most frequent genetic cause of Leri-Weill syndrome and Langer mesomelic dysplasia, which are also present in idiopathic short stature. AIM: To describe the molecular and clinical findings observed in 23 of 45 non-consanguineous Chilean patients with different phenotypes related to SHOX deficiency. METHODS: Multiplex ligation-dependent probe amplification was used to detect the deletions; the SHOX coding region and deletion-flanking areas were sequenced to identify point mutations and single-nucleotide polymorphisms (SNPs). RESULTS: The main genetic defects identified in 21 patients consisted of deletions; one of them, a large deletion of >800 kb, was found in 8 patients. Also, a smaller deletion of >350 kb was observed in 4 patients. Although we could not precisely determine the deletion breakpoint, we were able to identify a common haplotype in 7 of the 8 patients with the larger deletion based on 22 informative SNPs. CONCLUSION: These results suggest that the large deletion-bearing allele has a common ancestor and was either introduced by European immigrants or had originated in our Amerindian population. This study allowed us to identify one recurrent deletion in Chilean patients; also, it contributed to expanding our knowledge about the genetic background of our population.
Subject(s)
Gene Deletion , Growth Disorders/genetics , Homeodomain Proteins/genetics , Mutation , Osteochondrodysplasias/genetics , Adolescent , Adult , Child , Child, Preschool , Chile , Female , Haplotypes , Humans , Infant , Male , Phenotype , Short Stature Homeobox Protein , Young AdultABSTRACT
OBJECTIVE: To describe the percentile distribution of waist circumference (WC) by sex and age in a representative sample of children and adolescents of lower-middle and low socioeconomic status in Santiago, Chile. METHODS: A cross-section of 3022 primary-school students between the ages of 6 and 14 from middle-low and low-class schools of Santiago. Ten schools from the Primary Education Society (SIP) in Santiago, Chile, were selected at random. WC was measured under standardized procedures as instructed by the WHO (midpoint between lower costal margin and iliac crest). The population was categorized between percentiles 10 and 90 and divided by sex and age. RESULTS: WC tends to increase with age in both males and females, but no significant differences were found in the percentiles by age for boys and girls at any age range (p>0.05). In our sample, comparing Chilean children with other populations (British, Australian, European-American, African-American, Mexican - American and Colombian), Chilean children have shown a significantly greater WC (p<0.05). CONCLUSIONS: We present new WC reference values for Chilean children according to sex and age from a representative sample of Chilean population. These can be considered as a new anthropometric assessment tool for estimating cardiometabolic risk in Chilean children.
Subject(s)
Waist Circumference , Adolescent , Body Height , Body Mass Index , Body Weight , Cardiovascular Diseases/epidemiology , Child , Chile/epidemiology , Cross-Sectional Studies , Female , Humans , Male , Metabolic Syndrome/epidemiology , Obesity, Abdominal/epidemiology , Risk Factors , Sampling StudiesABSTRACT
CONTEXT: Low birth weight has been independently associated with adult hypertension, and renin-angiotensin system (RAS) plays a role in this connection. OBJECTIVE: To characterize the associations between birth weight (BW) and serum aldosterone (SA), serum cortisol, plasma renin activity (PRA) and blood pressure (BP). DESIGN: Cross-sectional study. SUBJECTS: Children from the community born at a gestational age >32 weeks. METHODS: Systolic and diastolic BP indices (SBPi and DBPi) were calculated using the observed BP/50th percentile BP for gender, age and stature. BW was transformed to a standard deviation score (SDS) for gestational age, whereas SA, serum cortisol and PRA were transformed using the natural log. RESULTS: We selected 288 subjects between the ages of 4·9 and 15·5 years (Females, 50%). After adjusting for body mass index (BMI) SDS and Tanner, multiple regression analysis revealed that BW (SDS) was both independently and inversely associated with the natural log of SA (ß = -0·065; P = 0·039), the natural log of serum cortisol (ß = -0·064; P = 0·009), SBPi (ß = -0·012; P = 0·020) and DBPi (ß = -0·023; P = 0·002). An association was not observed with PRA (P = 0·178) and aldosterone renin ratio (ARR) (P = 0·452). Serum cortisol levels were positively associated with SA (r = 0·125; P = 0·034), while an association with PRA (P = 0·251) and ARR (P = 0·052) was not observed. CONCLUSIONS: The results of this study demonstrate an inverse association between birth weight and blood pressure and serum aldosterone and cortisol levels. This association is independent of BMI and Tanner, suggesting foetal programming of the hypothalamic-pituitary-adrenal axis.
Subject(s)
Aldosterone/blood , Birth Weight/physiology , Blood Pressure/physiology , Hydrocortisone/blood , Adolescent , Child , Child, Preschool , Cross-Sectional Studies , Female , Gestational Age , Humans , Infant, Newborn , Linear Models , MaleABSTRACT
Familial hyperaldosteronism type 1 is an autosomal dominant disorder attributed to a chimeric CYP11B1/CYP11B2 gene (CG). Its prevalence and manifestation in the pediatric population has not been established. We aimed to investigate the prevalence of familial hyperaldosteronism type 1 in Chilean hypertensive children and to describe their clinical and biochemical characteristics. We studied 130 untreated hypertensive children (4 to 16 years old). Blood samples for measuring plasma potassium, serum aldosterone, plasma renin activity, aldosterone/renin ratio, and DNA were collected. The detection of CG was performed using long-extension PCR. We found 4 (3.08%) of 130 children with CG who belonged to 4 unrelated families. The 4 patients with CG had very high aldosterone/renin ratio (49 to 242). In addition, we found 4 children and 5 adults who were affected among 21 first-degree relatives. Of the 8 affected children, 6 presented severe hypertension, 1 presented prehypertension, and 1 presented normotension. High serum aldosterone levels (>17.7 ng/dL) were detected in 6 of 8 subjects (range: 18.6 to 48.4 ng/dL) and suppressed plasma renin activity (≤0.5 ng/mL per hour) and high aldosterone/renin ratio (>10) in 8 of 8 children (range: 49 to 242). Hypokalemia was observed in only 1 of 8 children. We demonstrated that the prevalence of familial hyperaldosteronism type 1 in a pediatric hypertensive pediatric population was surprisingly high. We found a high variability in the clinical and biochemical characteristics of the affected patients, which suggests that familial hyperaldosteronism type 1 is a heterogeneous disease with a wide spectrum of presentations even within the same family group.
Subject(s)
Blood Pressure/physiology , Hyperaldosteronism/genetics , Hypertension/physiopathology , Adolescent , Adult , Aldosterone/blood , Child , Child, Preschool , Chile/epidemiology , Comorbidity , Cross-Sectional Studies , Cytochrome P-450 CYP11B2/genetics , Family Health , Gene Fusion/genetics , Humans , Hyperaldosteronism/epidemiology , Hyperaldosteronism/pathology , Hypertension/blood , Hypertension/epidemiology , Polymerase Chain Reaction , Potassium/blood , Prevalence , Renin/blood , Steroid 11-beta-Hydroxylase/geneticsABSTRACT
Primary aldosteronism is an important cause of secondary hypertension and is suspected in adults with an aldosterone/renin ratio > or =25. The normal aldosterone/renin ratio is unknown in children. The aim was to establish serum aldosterone, plasma renin activity, and aldosterone/renin ratio values in a healthy pediatric population. A cross-sectional study was performed in 211 healthy normotensive children (4 to 16 years old). Two subgroups of normotensive children were obtained: with hypertensive parents (NH) (n=113) and normotensive parents (n=98). Blood samples for measuring serum aldosterone, plasma renin activity, aldosterone/renin ratio, and DNA were collected. In subjects with aldosterone/renin ratio > or =25, the chimeric CYP11B1/CYP11B2 gene was investigated by long-extension PCR. Results are expressed as median [Q(1)-Q(3)]. NH and normotensive parents groups were similar in serum aldosterone (6.5 [3.6 to 9.0] ng/dL versus 6.5 [2.9 to 9.7] ng/dL; P=0.968) and plasma renin activity (2.3 [1.6 to 3.1] versus 2.4 [1.7 to 3.7] ng/mL per hour; P=0.129). The aldosterone/renin ratio was higher in the NH group, but this difference did not reach statistical significance (2.8 [1.9 to 4.1] versus 2.5 [1.4 to 4.0], P=0.104). In one subject of the NH group, the chimeric CYP11B1/CYP11B2 gene was detected. We demonstrated that normal aldosterone/renin ratio values in a healthy pediatric population without NH were lower than those reported for an adult normotensive population.