Two novel mutations in the human thyroid peroxidase (TPO) gene: genetics and clinical findings in four children.

UNLABELLED: We report four children originating from two unrelated German families with congenital hypothyroidism (CH) due to mutations in the thyroid peroxidase (TPO) gene. Three female siblings (family 1) were found to be compound heterozygous for two mutations, a known mutation in exon 9 (W527C), and a mutation in exon 8 (Q446H), which has not been described before. In the second family we identified a boy with goitrous CH, who had a novel homozygous mutation in the TPO gene in exon 16 (W873X). All children of family 1 were diagnosed postnatally by newborn screening. The case of the boy of family 2 has already been reported for the in utero treatment of a goiter with hypothyroidism. CONCLUSION: Our results confirm existing data on the phenotypic variability of patients with TPO gene mutations.

Adiponectin levels are high in children with classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency.

OBJECTIVE: It has been shown that adiponectin serves as an insulin-sensitizing adipokine. Serum concentrations of adiponectin are low in children with obesity, and increase with fat mass loss, indicating that adiponectin can serve as a biomarker. Since the prevalence of overweight and obesity is increased in children with congenital adrenal hyperplasia (CAH), our study aimed to evaluate serum levels of adiponectin in a cohort of CAH children and adolescents, and their associations with clinical parameters such as chronological age (CA), body mass index (BMI), Tanner stage (TS), medication and metabolic control. PATIENTS AND METHODS: We studied 51 patients, aged between 5.6 and 19.6 years (median 11.8; 30 females, 21 males), cross-sectionally. All patients had genetically confirmed CAH and received standard steroid substitution therapy. Adiponectin was measured by an enzyme linked immunoassay. Since BMI SDS of the CAH cohort were significantly higher compared to the reference population, we built matched pairs with healthy Caucasian subjects from a normal representative cohort for sex, Tanner stage, chronologic age and BMI. RESULTS: Adiponectin concentrations were significantly higher in CAH patients (median 11 microg/L) compared to the matched controls (6.7 microg/L, p < 0.0001). Correlation analyses in CAH patients revealed a significant inverse relationship between adiponectin and CA, TS, BMI, serum DHEAS and serum testosterone, but no correlation with hydrocortisone and fludrocortisone dosage. CONCLUSION: Currently, the importance of the elevated adiponectin concentrations in CAH children for risk assessment is not clear. However, our data imply that besides adequate metabolic control of glucocorticoid substitution, a long-term follow-up of other metabolic markers of insulin resistance should be conducted in CAH patients.

Does an altered leptin axis play a role in obesity among children and adolescents with classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency?

OBJECTIVE: Congenital adrenal hyperplasia (CAH) patients are at a higher risk to develop obesity. The role of leptin in CAH is still controversial. Our study aimed to evaluate serum levels of leptin, the soluble leptin receptor (sOB-R), and the sOB-R: leptin molar ratios in a cohort of CAH children and adolescents, and their associations with clinical and metabolic parameters. METHODS: We studied 51 CAH patients, aged 5.6-19.6 years (median 11.8, n=30 females) cross-sectionally. All patients had genetically proven CAH and received standard steroid substitution therapy. Blood specimens were taken after overnight fasting between 0800 and 1000 h. For the analyses of leptin and sOB-R, matched pairs were built with healthy Caucasian patients for sex, Tanner stage (TS), chronologic age (CA), and body mass index (BMI). RESULTS: BMI and SDS were significantly elevated compared with the reference population. Leptin levels were not different between matched pairs, whereas sOB-R levels were significantly lower in CAH. Consequently, the sOB-R: leptin molar ratios were significantly decreased in CAH. Correlation analyses in CAH patients revealed significant relationship between leptin and CA, TS, BMI, and homeostasis model assessment of insulin resistance. Similar results were obtained for the matched control group. For sOB-R, we found no significant correlation for CA, TS, or BMI in CAH, but we did in the controls. There were significant correlations for androgens within the CAH group. Additional analyses revealed no correlation with steroid medication or metabolic control. CONCLUSIONS: Our data show that an altered leptin axis with normal serum leptin concentrations but decreased sOB-R serum levels may contribute to the increased risk of overweight and obesity in CAH.

Altered 24-hour blood pressure profiles in children and adolescents with classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

OBJECTIVE: Children and adolescents with classical congenital adrenal hyperplasia have been shown to be at risk for obesity associated with higher insulin and leptin levels. Because these factors are also known to cause hypertension, the aim of this study was to analyze 24-h blood pressure profiles and their relation to different clinical and laboratory parameters. DESIGN: Fifty-five subjects, aged between 5.3 and 19.0 yr, were enrolled in a prospective, cross-sectional study. All patients had genetically proven 21-hydroxylase deficiency and underwent ambulatory 24-h blood pressure monitoring during a period off school/work. RESULTS (MEDIAN, RANGE): The median body mass index of the cohort was significantly elevated [1.09 sd score (SDS), -2.45 to 3.77]. Daytime and nighttime systolic blood pressures were also significantly elevated (0.67 SDS, -1.5-4.1; 0.63 SDS, -0.91 to 3.3), whereas daytime diastolic blood pressure was significantly lowered (-0.81 SDS, -2.6 to 3.2) and normal during the night (0.11 SDS, -2.0 to 2.0). Overall, there was a normal nocturnal drop of systolic (12.8%, 2.1-22.8) but not diastolic blood pressure (17.2%, 0.90-25.8). The different parameters of systolic and diastolic blood pressures were significantly correlated with body mass index and skinfold thickness (r(s) = 0.271-0.486). There was no correlation with equivalent hydrocortisone and fludrocortisone dosage and laboratory parameters except for serum leptin and insulin. CONCLUSIONS: Our data show altered 24-h blood pressure profiles with elevated systolic levels correlated with the degree of overweight and obesity, whereas normal-weight patients tended to diastolic hypotension.

Catch-down growth during infancy of children born small (SGA) or appropriate (AGA) for gestational age with short-statured parents.

OBJECTIVE: We analyzed postnatal growth in children with familial short stature (FSS) with regard to small (SGA) or appropriate (AGA) for gestational age status at birth. STUDY DESIGN: We studied 96 otherwise healthy short-statured children (58 males; SGA: n = 41, AGA: n = 55). At least one of the parents was short-statured. Cross-sectional data for length/height and weight for the first 4 years of age were collected retrospectively. RESULTS: AGA children had a mean length of 0.09 +/- 1.02 standard deviation score (SDS) at birth, -1.57 +/- 1.16 SDS after 1 year of age, and -2.36 +/- 0.72 SDS after 4 years. SGA children had a mean length of -2.04 +/- 1.06 SDS at birth, -2.70 +/- 1.12 SDS at 1 year of age, and -3.05+/-0.86 SDS at 4 years. The loss of length SDS within the first 2 years of life was greater in AGA than in SGA children. SGA children were significantly shorter than AGA children at all of the study points (p <.001). CONCLUSIONS: Children with an FSS background born AGA show catch-down growth to their lower familial range during the first 2 years of life. SGA children did not catch up to their AGA peers at any time.

Obesity among children and adolescents with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

OBJECTIVES: Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is the most common inherited disorder of adrenal steroid biosynthesis. Patients with the classic form of CAH show androgen excess, with or without salt wasting. There are few studies reporting on higher rates of overweight and obesity among children with CAH. In addition to its role in the regulation of energy balance, leptin is involved in various endocrine and metabolic pathways. In this context, elevated serum leptin levels were reported recently for patients with CAH and were thought to be involved in the development of obesity among these patients. Therefore, the aim of this study was to analyze BMI values, compared with population-based references, for children and adolescents with CAH. Possible contributing factors, such as glucocorticoid therapy, skeletal maturation, birth weight and length, and parental BMI, were correlated with current BMI SD scores (SDS). In addition, the implications of serum leptin levels, corrected for BMI, gender, and Tanner stage, were investigated. METHODS: We performed a cross-sectional retrospective study of 89 children and adolescents with cah (48 female and 41 male subjects; age: 0.2-17.9 years) who presented in our outpatient department during 1 year. All individuals had classic cah, confirmed with molecular genetic analyses, and received substitution therapy (glucocorticoids and mineralocorticoids, if necessary). The quality of therapy was monitored in follow-up visits every 3 to 6 months, on the basis of clinical presentation and laboratory measurement findings according to current guidelines. We grouped the patients into salt wasting and simple virilizing groups, as well as according to current metabolic control. Leptin levels were measured with a commercial radioimmunoassay and calculated as sds. For statistical analyses, standard parametric and nonparametric methods were used. RESULTS: The chronologic ages of the children with CAH were between 0.20 and 17.9 years (mean +/- SD: 8.9 +/- 4.6 years). The BMI SDS of the whole group ranged from -2.7 to 4.3 (mean +/- SD: 0.88 +/- 1.3) and was significantly elevated above 0. Fifteen subjects (16.8%) had BMI SDS of >2.0, which indicated a significantly greater frequency of obesity among patients with CAH than expected for the normal population (expected: 2.27%). There was no significant difference in age and BMI between genders and clinical forms (salt wasting versus simple virilizing). BMI SDS was correlated positively with chronologic age. The BMI SDS did not differ significantly between children receiving hydrocortisone, prednisone, or dexamethasone. Hydrocortisone dosages (including equivalent dosages of prednisone and dexamethasone) ranged from 6.2 to 30.1 mg/m2 body surface area (mean +/- SD: 14.7 +/- 4.8 mg/m2 body surface area). Hydrocortisone dosages were correlated positively with BMI SDS. The relative risk of having a BMI SDS of >2.0 was not significantly elevated among children with prednisone/dexamethasone medication, compared with those with hydrocortisone treatment. In contrast to this, fludrocortisone dosage was not correlated with BMI SDS. Bone age delay, as calculated from the difference of bone age and chronologic age, ranged from -2.9 years to 5.6 years (mean +/- SD: 1.11 +/- 1.8 years) and was significantly elevated; it was correlated positively with BMI SDS. The BMI of parents ranged from 17.8 to 39.0 kg/m2 (median: 24.2 kg/m2). Median BMI values did not differ significantly between fathers and mothers. The relative risk for obesity among our children (BMI SDS of >2.0) was significantly elevated for children with obese parents, compared with those with nonobese parents (relative risk: 4.86). There was no significant correlation of birth length, birth weight, or gestational age with BMI SDS. Serum leptin values ranged from 0.10 to 32 microg/L (median: 4.4 microg/L); they were correlated positively with BMI SDS, chronologic age, and Tanner stage. After transformation into leptin concentration SDS values, the median SDS of 0.42 (range: -5.4 to 3.1) did not differ significantly from 0. CONCLUSIONS: Children and adolescents with CAH have a higher risk of obesity. Glucocorticoid dosage, chronologic age, advanced bone age maturation, and parental obesity contributed to elevated BMI SDS, whereas birth weight and length, serum leptin levels, used glucocorticoid, and fludrocortisone dosage were not associated with obesity. Therefore, children with CAH who become obese should be tightly monitored and should participate concurrently in weight management programs that include obese family members.

Cardiovascular anomalies in children and young adults with Ullrich-Turner syndrome the Erlangen experience.

BACKGROUND: Females with Ullrich-Turner syndrome (UTS) have typical clinical features such as short stature, ovarian failure, visible dysmorphic stigmata, and abnormalities in different organs such as kidney or heart. HYPOTHESIS: The aim of the present study was to analyze the distribution, prevalence, and relative risk of cardiovascular anomalies (CVA) in females with Ullrich-Turner syndrome (UTS) seen at one single center compared with that of the regional Bavarian population. METHODS: The associations between CVA and karyotype were determined. In all, 117 girls and women with UTS, aged between 3 and 43 years (median 17.4 years) were studied retrospectively. The detailed cardiologic status including echocardiography was available in all patients. The prevalences of each cardiovascular anomaly were determined. On the basis of published epidemiologic data of CVA in Bavarian children, we assessed the relative risks of each CVA. RESULTS: Thirty-five (29.9%) girls with UTS had at least one CVA. In all of these CVAs, coarctation of the aorta and bicuspid aortic valve occurred most often (18.5% each). The aortic malformations represented over two-thirds of all CVA (72.8%), whereas anomalies of the septum (8.6%), mitral valve (6.2%), pulmonary veins (4.9%), and other locations together accounted for the other third. Bicuspid aortic valve and partial anomalous pulmonary venous drainage were associated with the highest relative risk (RR) (3603 and 1293, respectively) compared with the Bavarian population. The overall RR of CVA was 48.7. Of the 117 girls and women examined, 64 (54.7%) had complete monosomy 45 X. CONCLUSIONS: Our data demonstrate that about every third female with UTS is affected with at least one CVA, mainly left sided and associated with aortic structures. Our results underline the necessity of thorough cardiologic evaluation.

Spontaneous growth hormone secretion and IGF1:IGFBP3 molar ratios in children born small for gestational age (SGA).

OBJECTIVE: To analyze spontaneous nocturnal GH profiles, IGF1 and IGFBP3 serum levels, as well as IGF1:IGFBP3 molar ratios in SGA children without postnatal catch-up growth. METHODS: Short statured prepubertal SGA children (n = 24) were matched retrospectively for sex, age and BMI to short statured children born appropriate for gestational age (AGA), who underwent the same diagnostic program. GH deficiency was excluded in all children by a normal increase of GH in 2 stimulation tests (>8 microg/L). For assessment of spontaneous nocturnal GH secretion, GH serum levels were measured every 20 min for 10 h. Pulsatility was analyzed with Pulsar. RESULTS: None of the Pulsar derived descriptive parameters showed a significant difference between SGA and AGA children. Overall, median IGF1 levels were approximately one SDS below zero SDS (p < 0.001), whereas IGFBP3 levels were normal in both groups. Thus, the IGF1:IGFBP3 molar ratios were significantly lower from zero (p < 0.01) in SGA as well as in AGA children. However, IGF1- and IGFBP3-SDS levels related either to chronological or to bone age did not differ significantly between SGA and AGA children. CONCLUSIONS: Building matched pairs of short statured children born either SGA or AGA for sex, age and BMI we did not find any significant differences in spontaneous nocturnal GH secretion, IGF1, IGFBP3, and IGF1:IGFBP3 molar ratios.