[Rat bite fever in children]. / Rattenbeetziekte bij kinderen.

BACKGROUND: Worldwide, disease in children due to exposure to rats is increasing, also in the Netherlands. Not only the generally known pathogen Leptospira should be considered, also S. moniliformis, Yersinia pestis, Lymphocytic choriomeningitis virus, Hantavirus, Francisella tularensis and Pasteurella multocida are also known rat-associated zoonosis. CASE DESCRIPTION: An 12-year-old boy visited the pediatrician with fever, headache and nausea, followed by generalized erythema and arthritis. The boy had a pet rat. The patient's blood culture was positive for S. moniliformis. The patient was treated with antibiotics and made a full recovery. CONCLUSION: Just like many rat-associated diseases have 'rat-bite fever' caused by S. moniliformis an nonspecific clinical presentation. It is not necessary to have had a rat bite, to develop rat-bite fever. Better awareness and knowledge about rat related diseases should contribute to earlier diagnosis and treatment. Which is of great importance because of increased morbidity and mortality associated to rat related diseases.

Copy number variants in patients with short stature.

Height is a highly heritable and classic polygenic trait. Recent genome-wide association studies (GWAS) have revealed that at least 180 genetic variants influence adult height. However, these variants explain only about 10% of the phenotypic variation in height. Genetic analysis of short individuals can lead to the discovery of novel rare gene defects with a large effect on growth. In an effort to identify novel genes associated with short stature, genome-wide analysis for copy number variants (CNVs), using single-nucleotide polymorphism arrays, in 162 patients (149 families) with short stature was performed. Segregation analysis was performed if possible, and genes in CNVs were compared with information from GWAS, gene expression in rodents' growth plates and published information. CNVs were detected in 40 families. In six families, a known cause of short stature was found (SHOX deletion or duplication, IGF1R deletion), in two combined with a de novo potentially pathogenic CNV. Thirty-three families had one or more potentially pathogenic CNVs (n=40). In 24 of these families, segregation analysis could be performed, identifying three de novo CNVs and nine CNVs segregating with short stature. Four were located near loci associated with height in GWAS (ADAMTS17, TULP4, PRKG2/BMP3 and PAPPA). Besides six CNVs known to be causative for short stature, 40 CNVs with possible pathogenicity were identified. Segregation studies and bioinformatics analysis suggested various potential candidate genes.

Absence of clinically relevant growth acceleration in untreated children with non-classical congenital adrenal hyperplasia.

BACKGROUND/AIMS: In classical congenital adrenal hyperplasia (CAH), elevation of adrenal androgens leads to accelerated growth and bone maturation with compromised adult height. In untreated children with non-classical CAH (NC-CAH), in which adrenal androgens are generally only slightly increased, growth velocity may not be significantly elevated. METHODS: Twenty-four patients were included and divided into a symptomatic and an asymptomatic group. Height was expressed as height standard deviation scores (HSDS) and corrected for target height (HSDS-THSDS). Bone maturation was expressed as bone age acceleration (BA(c) = bone age - calendar age). Linear mixed models with random factor patient were used for the analysis of growth and bone age. RESULTS: In symptomatic patients (n = 17), HSDS-THSDS only slightly increased by 0.06 SDS per year (95% CI 0.02-0.10). Mean BA(c) was 2.21 years (SDS 0.66, p < 0.0001). In asymptomatic patients (n = 7), no significant growth acceleration or BA(c) was found. CONCLUSIONS: In untreated NC-CAH children, growth acceleration is small and generally not visible on their growth charts. BA(c) is more pronounced. Therefore, the absence of an increase in growth velocity does not exclude the diagnosis of NC-CAH. When considering this diagnosis, bone age acceleration should also be taken into account.

Estrogen receptor-alpha gene polymorphisms and body composition in children and adolescents.

BACKGROUND/AIMS: Gender differences in body composition are largely explained by differences in sex hormones, such as estrogens. Associations between 2 polymorphisms in the estrogen receptor-α gene (ESR1) and body composition in children and adolescents were investigated. METHODS: Two comparable Dutch cohorts with a generational difference of about 20 years were investigated. The first consisted of 350 subjects (184 girls) and the second of 316 subjects (155 girls). Associations between height, weight, BMI, fat mass (FM) and fat-free mass and two polymorphisms in the ESR1 gene were investigated. RESULTS: In girls in the recent cohort, the PvuII-XbaI haplotype 2 polymorphism in the ESR1 gene was associated with a lower body weight, BMI, and FM. These associations were not observed in the older cohort. The younger cohort had a significantly higher total FM, body weight and BMI compared to the older cohort. CONCLUSION: Because the associations between the PvuII-XbaI haplotype 2 polymorphism and body FM in girls were only found in the recent cohort, but not in a comparable, generally leaner cohort from an older generation, it is suggested that non-carriers of this polymorphism are likely to be more vulnerable to fat accumulation in today's obesity promoting environment, than carriers.

Androgen receptor gene CAG repeat polymorphism in longitudinal height and body composition in children and adolescents.

OBJECTIVE: The number of CAG repeats within the CAG repeat polymorphism of the androgen receptor (AR) gene correlates inversely with the transactivation of the receptor. We investigated the relationship between the AR CAG repeat polymorphism and longitudinal growth, puberty and body composition from prepuberty until young adult age. DESIGN: Observational study with repeated measurements. SUBJECTS: Two comparable young Dutch cohorts. The first cohort consisted of 226 subjects. Measurements were performed from 13 until 36 years of age. The second cohort consisted of 244 subjects. Measurements in this cohort were performed from 8 until 14 years of age. MEASUREMENTS: Associations between height, height velocity, weight, BMI, fat mass, fat-free mass and pubertal development and CAG repeat length were measured. RESULTS: Height-standard deviation scores (SDS) were inversely associated with AR CAG repeat length in boys at young, prepubertal and early pubertal age. This association diminishes in the following years and completely disappears after the age of 16 years. No associations were found with pubertal stage or any of the other parameters for body composition. CONCLUSIONS: AR CAG repeat length is inversely associated with longitudinal height in young boys, before the onset of puberty. During puberty, these differences disappear, possibly overruled by a strongly developing hypothalamic-pituitary-gonadal axis.

Glucocorticoid receptor gene variant is associated with increased body fatness in youngsters.

OBJECTIVE: Sensitivity to glucocorticoids is known to be highly variable between individuals and is partly determined by polymorphisms in the glucocorticoid receptor (GR) gene. We investigated the relationship between four GR gene polymorphisms and body composition during puberty and at young adult age. DESIGN: An observational study with repeated measurements. PATIENTS: Two comparable young Dutch cohorts with a generational difference of about 20 years were investigated. The first cohort consisted of 284 subjects born between 1961 and 1965. Measurements were performed from 13 to 36 years of age. The second cohort consisted of 235 subjects born between 1981 and 1989. Measurements were performed from 8 to 14 years of age. MEASUREMENTS: Associations between height, weight, BMI, fat mass (FM) and fat-free mass and four well-known functional polymorphisms were investigated. Results In boys in the younger cohort, the G-allele of the BclI polymorphism (haplotype 2) was associated with a higher body weight, weight-SDS, BMI, BMI-SDS and FM. These associations were not observed in the older cohort. Irrespective of genotype, the younger cohort showed a significantly higher total FM, body weight and BMI compared with the older cohort. CONCLUSIONS: Because the associations between the G-allele of the BclI polymorphism in the GR gene and body FM in boys were only found in a healthy young population, but not in a comparable, generally leaner cohort from an older generation, it is suggested that carriers of this polymorphism are likely to be more vulnerable to fat accumulation in today's obesity promoting environment, than noncarriers.

Glucocorticoid receptor gene polymorphism is less frequent in children born small for gestational age without catch-up growth.

BACKGROUND/AIMS: Glucocorticoids are important regulators of many processes involved in embryonal growth and development and fat and glucose metabolism. Glucocorticoids exert their effect through the glucocorticoid receptor (GR). The aim of this study was to investigate possible associations between 4 well-known GR gene haplotypes and size at birth. METHODS: We investigated associations between GR haplotypes and size at birth in a Dutch reference cohort. This reference cohort consisted of 222 young healthy Caucasian subjects. Associations between size at birth and glucocorticoid receptor gene haplotypes were tested. Furthermore, we investigated a group of 119 children born small for gestational age (SGA), without catch-up growth. Prevalence of the different GR haplotypes was compared between the SGA group and the reference cohort. RESULTS: No associations were found between any of the GR haplotypes and birth weight or birth length in the reference group. The prevalence of GR haplotype 2 (Bcl1) was significantly lower in the SGA group compared to controls. CONCLUSION: Genetic variance in the GR seems not to be associated with intrauterine growth in the general population. However, GR haplotype might play a role in growth of children born SGA, reflected by the decreased prevalence of GR haplotype 2 (Bcl1) in this group.

Association between an IGF-I gene polymorphism and body fatness: differences between generations.

OBJECTIVE: A polymorphism near the promoter region of the IGF-I gene has been associated with serum IGF-I levels, body height and birth weight. In this study, we investigated whether this polymorphism is associated with body composition in young healthy subjects in two cohorts of different generations. DESIGN: Observational study with repeated measurements. METHODS: The study group consisted of two comparable young Dutch cohorts with a generational difference of around 20 years. The older cohort consisted of 359 subjects born between 1961 and 1965. Measurements were performed from 13 until 36 years of age. The younger cohort consisted of 258 subjects born between 1981 and 1989. Measurements were performed from 8 until 14 years of age. Height, body mass index (BMI), fat mass, fat-free mass, waist and hip circumference were compared between wild-type carriers and variant type carriers of the IGF-I polymorphism. RESULTS: In the younger cohort, body weight, BMI, fat mass and waist circumference were significantly higher in female variant carriers of the IGF-I polymorphism. A similar trend was observed in male variant carriers. In contrast, these differences were not observed in the older cohort. Irrespective of genotype, the younger cohort showed a significantly higher total fat mass, body weight and BMI compared with the older cohort. CONCLUSIONS: Because the differences between both genotypes were small, it seems likely that the genetic variability due to this IGF-I polymorphism impacts only slightly on body composition. Importantly, our study suggested that associations between this IGF-I promoter polymorphism and body composition possibly reflect a gene-environmental interaction of this polymorphism and that an environment that promotes obesity leads to a slightly more pronounced fat accumulation in variant carriers of this IGF-I polymorphism.

An IGF-I promoter polymorphism modifies the relationships between birth weight and risk factors for cardiovascular disease and diabetes at age 36.

OBJECTIVE: To investigate whether IGF-I promoter polymorphism was associated with birth weight and risk factors for cardiovascular disease (CVD) and type 2 diabetes (T2DM), and whether the birth weight--risk factor relationship was the same for each genotype. DESIGN AND PARTICIPANTS: 264 subjects (mean age 36 years) had data available on birth weight, IGF-I promoter polymorphism genotype, CVD and T2DM risk factors. Student's t-test and regression analyses were applied to analyse differences in birth weight and differences in the birth weight--risk factors relationship between the genotypes. RESULTS: Male variant carriers (VCs) of the IGF-I promoter polymorphism had a 0.2 kg lower birth weight than men with the wild type allele (p = 0.009). Of the risk factors for CVD and T2DM, solely LDL concentration was associated with the genotype for the polymorphism. Most birth weight--risk factor relationships were stronger in the VC subjects; among others the birth weight--systolic blood pressure relationship: 1 kg lower birth weight was related to an 8.0 mmHg higher systolic blood pressure CONCLUSION: The polymorphism in the promoter region of the IGF-I gene is related to birth weight in men only, and to LDL concentration only. Furthermore, the genotype for this polymorphism modified the relationships between birth weight and the risk factors, especially for systolic and diastolic blood pressure.

The ER22/23EK polymorphism in the glucocorticoid receptor gene is associated with a beneficial body composition and muscle strength in young adults.

Glucocorticoids play an important role in determining body composition. A polymorphism of the glucocorticoid receptor gene (in codons 22 and 23) has previously been found to be associated with relative glucocorticoid resistance, low cholesterol levels, and increased insulin sensitivity. In this study, we investigated whether this ER22/23EK polymorphism is associated with differences in body composition and muscle strength. We studied a cohort of 350 subjects who were followed from age 13 until 36 yr. We compared noncarriers and carriers of the ER22/23EK variant in anthropometric parameters, body composition, and muscle strength, as measured by arm pull tests and high jump from standing. We identified 27 (8.0%) heterozygous ER22/23EK carriers. In males at 36 yr of age, we found that ER22/23EK carriers were taller, had more lean body mass, greater thigh circumference, and more muscle strength in arms and legs. We observed no differences in body mass index or fat mass. In females, waist and hip circumferences tended to be smaller in ER22/23EK carriers at the age of 36 yr, but no differences in body mass index were found. Thus, the ER22/23EK polymorphism is associated with a sex-specific, beneficial body composition at young-adult age, as well as greater muscle strength in males.