Hernán García

An XRCC4 splice mutation associated with severe short stature, gonadal failure, and early-onset metabolic syndrome

CONTEXT Severe short stature can be caused by defects in numerous biological processes including defects in IGF-1 signaling, centromere function, cell cycle control, and DNA damage repair. Many syndromic causes of short stature are associated with medical comorbidities including hypogonadism and microcephaly. OBJECTIVE To identify an underlying genetic etiology in two siblings with severe short stature and gonadal failure. DESIGN Clinical phenotyping, genetic analysis, complemented by in vitro functional studies of the candidate gene. SETTING An academic pediatric endocrinology clinic. PATIENTS OR OTHER PARTICIPANTS Two adult siblings (male patient [P1] and female patient 2 [P2]) presented with a history of severe postnatal growth failure (adult heights: P1, -6.8 SD score; P2, -4 SD score), microcephaly, primary gonadal failure, and early-onset metabolic syndrome in late adolescence. In addition, P2 developed a malignant gastrointestinal stromal tumor at age 28. INTERVENTION(S) Single nucleotide polymorphism microarray and exome sequencing. RESULTS Combined microarray analysis and whole exome sequencing of the two affected siblings and one unaffected sister identified a homozygous variant in XRCC4 as the probable candidate variant. Sanger sequencing and mRNA studies revealed a splice variant resulting in an in-frame deletion of 23 amino acids. Primary fibroblasts (P1) showed a DNA damage repair defect. CONCLUSIONS In this study we have identified a novel pathogenic variant in XRCC4, a gene that plays a critical role in non-homologous end-joining DNA repair. This finding expands the spectrum of DNA damage repair syndromes to include XRCC4 deficiency causing severe postnatal growth failure, microcephaly, gonadal failure, metabolic syndrome, and possibly tumor predisposition.

Sulfonylurea Treatment in Young Children With Neonatal Diabetes: Dealing with hyperglycemia, hypoglycemia, and sick days

Recently, heterozygous activating mutations in the genes forming the ATP-sensitive K+ channel (KATP channel), KCNJ11 and ABCC8 , have been shown to cause neonatal diabetes (1–4). Sulfonylurea treatment restores insulin secretion in these patients (3,5,6), but information on the practical management of children with mutated KATP channels taking this medication is limited. We report clinical aspects of the successful transfer to oral treatment in three cases of young children with KCNJ11 and ABCC8 mutations (Table 1). All parents gave written consent. In case 1, a girl was transferred from insulin to glibenclamide at 17 months (7) and had been on this treatment for 2 years. During this period, blood glucose testing decreased …

Birth weight is inversely associated with blood pressure and serum aldosterone and cortisol levels in children

Context  Low birth weight has been independently associated with adult hypertension, and renin‐angiotensin system (RAS) plays a role in this connection.

Frequency of Familial Hyperaldosteronism Type 1 in a Hypertensive Pediatric Population: Clinical and Biochemical Presentation

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.

Prevalencia de hipertensión arterial y su asociación con la obesidad en edad pediátrica

Background: Hypertension in children is a frequently overlooked problem that is an important cardiovascular risk factor. Aim: To determine the prevalence of hypertension among school age children. Material and Methods: Cross-sectional study of 2980 children aged 10 ± 2years (48% females) from 10 schools of middle and lower class in Metropolitan Santiago. Blood pressure (BP) was measured in the sitting position on three occasions after a rest period, using a mercury sphygmomanometer with appropriate cuff arm diameter, averaging the results of the measurements. Systolic and diastolic hypertension were defined as blood pressure values over 95percentilefor age, sex and height. Results: The overall prevalence of hypertension was 12.2% in women and 15% in men (p < 0.05). According to nutritional status, the prevalence was 6.7, 8.9,13.6 and 26% in underweight, eutrophic, overweight and obese children, respectively (p < 0.01). Compared with normal weight children, the risk of being hypertensive for overweight children was 1.6 (95% confidence intervals (CI) 1.2-2.3) and for obese children was 3.6 (95% CI 2.8-4.7). Conclusions: The studied children had a high prevalence of hypertension, that was directly related to a higher body mass index.

Age-Related Changes in 11β-Hydroxysteroid Dehydrogenase Type 2 Activity in Normotensive Subjects

BACKGROUND Impairment in 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) activity results in inefficient inactivation of cortisol to cortisone, and it can trigger hypertension through activation of the mineralocorticoid receptor. Information about age-related changes in 11β-HSD2 activity and its physiological consequences is scarce. Our aim was to investigate whether 11β-HSD2 activity is age dependent in normotensive subjects. METHODS We recruited 196 healthy, normotensive subjects. Of these, 93 were children (Group 1: aged 5-15 years), and 103 were adults who were divided according to their ages: Group 2: aged 30-41 years (n = 10); Group 3: aged 42-53 years (n = 72); and Group 4: aged 54-65 years (n = 21). Fasting serum cortisol, cortisone, aldosterone, and plasma renin activity (PRA) were measured. The 11β-HSD2 activity was estimated by the cortisol/cortisone ratio. The results were expressed as median (interquartile range (IQR)) values and compared using Kruskal-Wallis and Dunns multiple-comparison tests. RESULTS As subject age increased, cortisol concentrations increased (Group 1 median = 8.6, IQR = 6.3-10.8 µg/dl; Group 4 median = 12.4, IQR = 10.7-14.7 µg/dl; P < 0.001), and cortisone concentrations showed a gradual decrease (Group 2 median = 4.0, IQR = 3.3-4.2 µg/dl; Group 4 median =2.8, IQR = 2.6-3.3 µg/dl; P < 0.01). As a consequence, the cortisol/cortisone ratio was higher in the oldest subjects (Group 4) than in the subjects from the other 3 groups; the ratios from Group 4 to Group 1 were 4.4 (IQR = 3.7-5.1) µg/dl, 3.3 (IQR = 2.7-3.8) µg/dl, 2.5 (IQR = 2.3-3.8) µg/dl, and 2.7 (IQR = 2.1-3.4) µg/dl, respectively (P < 0.01). The PRA decreased with age. Blood pressure levels increased with age but stayed within the normal range. CONCLUSIONS Cortisol and the cortisol/cortisone ratio increased with age, but cortisone decreased, suggesting a decrease in 11β-HSD2 activity. These results suggest that the cortisol-mediated activation of the mineralocorticoid receptor may explain the blood pressure increase in elderly subjects.

Aldosterone, Plasma Renin Activity, and Aldosterone/Renin Ratio in a Normotensive Healthy Pediatric Population

Primary aldosteronism is an important cause of secondary hypertension and is suspected in adults with an aldosterone/renin ratio ≥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 ≥25, the chimeric CYP11B1/CYP11B2 gene was investigated by long-extension PCR. Results are expressed as median [Q1–Q3]. 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.

Prevalence of components of the metabolic syndrome according to birthweight among overweight and obese children and adolescents

Abstract Background/objectives: Extremes of birthweight (BW) have been associated with increased rates of metabolic risks. The objective was to study the prevalence of metabolic risks markers among obese and overweight (OW) subjects according to BW. Subjects/methods: A cross-sectional study was performed in a cohort of 1002 patients (2–18 years, 40.6% male) evaluated for OW or obese subjects in two private clinics. Anthropometrics, fasting lipids, glycemia, and insulin were obtained. Results: Of the subjects, 76.1% were born appropriate for gestational age (AGA), 10.9% small for gestational age (SGA), and 13% large for gestational age (LGA). Children born LGA presented a more severe degree of obesity compared with those born AGA and SGA (p<0.0001). No differences in glycemia, insulin, and lipid levels were detected among the groups. Abnormal glucose was found in 37 subjects: one with type 2 diabetes mellitus (from the previously glucose-intolerant subjects), 10 with glucose intolerance, and 27 with impaired fasting glucose. According to Boney criteria, 6.6% of the patients (6–18 years old) exhibited metabolic syndrome (MS) (69.4% AGA, 12.9% SGA, and 17.7% LGA). Conclusions: Being born LGA represents a higher risk of severe obesity. At this age, the most frequent component of MS was an abnormal lipid profile with low high-density lipoprotein and high triglycerides. Finally, the most frequent finding associated with abnormalities of glucose tolerance was a family history of diabetes. Thus, BW, lipid profile, and family history are mandatory when these patients are evaluated.

Prevalencia de síndrome metabólico en niños y adolescentes que consultan por obesidad

BACKGROUND The higher prevalence of childhood obesity has led to search for metabolic syndrome (MS) in this age group. AIM To study the prevalence of MS in obese children and adolescents. MATERIAL AND METHODS Cross sectional study of 255 obese children and adolescents aged 11.3 ± 2.4 years, 45% males, 60% pubertal, with a body mass index (BMI) z score of 2.7 ± 0.6, who were evaluated for obesity. MS was defined as the presence of at least three of the following criteria, according to Ferranti: fasting glucose (FG) ≥ 100 mg/dl, triglycerides (TG) ≥ 100 mg/dl, HDL < 50 mg/dl, waist circumference (WC) > percentile (p) 75 and blood pressure (BP) > p90. Patients were also classified using Cook criteria: FG ≥ 100 mg/dl, TG ≥ 110 mg/dl, HDL < 40 mg/dl, WC > p 90, BP > p 90. RESULTS MS was observed in 45 and 22.7% of patients, according to Ferranti and Cook definitions, respectively. WC was the most frequent criteria and glucose was the most uncommon. Males had higher body mass index, WC and TG levels than females. According to Ferranti and Cook definitions, MS prevalence was 53.5 and 28% in males and 37.6 and l8.4% in females (p < 0.05). Fifty and 26.1% of pubertal patients exhibited MS vs 36.9 and 17.5% in pre-pubertal subjects (p < 0.05) using Ferranti and Cook criteria, respectively. The frequency of MS increased along with a higher BMI. CONCLUSIONS MS is a prevalent condition in obese children and adolescents, especially in males and pubertal children. It is necessary to have a better and universal definition for MS in pediatrics including all ages, in order to be focused in obesity prevention and treatment.

La razón cintura estatura en escolares no varía con el género, la edad ni la maduración puberal

Background: Waist-to-height ratio (WHtR) is a cardiometabolic risk indicator in children. A value greater than or equal to 0.55 is an effective screening tool for identifying obese children with metabolic syndrome. However, it is unclear whether this cutoff can be applied equally to any age or gender. Aim: To analyze the variability of WHtR by age, gender and pubertal stage in elementary school children. Patients and methods: Cross-sectional study in 2,980 school children (6-14 years old, 51% male) of Santiago, Chile. We measured weight, height and waist circumference and calculated body mass index and WHtR. Pubertal stage was assessed and classified as peripubertal (Tanner I and II) and pubertal (Tanner III, IV and V). Results: The mean age was 9.9 ± 2.3 years, with no gender difference (p = 0.5). Eighty one percent of boys and 59.4 % of girls were peripubertal (p<0.001). The association between age- adjusted WHtR by gender and pubertal stage was not significant (p= 0.409). Therefore mean, standard deviation and percentiles of WHtR were calculated without sex and pubertal stage segmentations. Conclusions: Since WHtR does not vary with age, gender and pubertal status in elementary school children, it is possible to use a single cutoff value, previously defined in this population, to identify children with cardiometabolic risk.