Interaction of Pubertal Development and Metabolic Control in Adolescents with Type 1 Diabetes Mellitus.

BACKGROUND: In T1DM, delayed pubertal development and reduced final height are associated with inadequate metabolic control. OBJECTIVE: To assess whether T1DM affects pubertal growth spurt and whether metabolic control during puberty is gender-related. METHODS: Using a large multicentre database, longitudinal data from 1294 patients were analysed. Inclusion criteria: complete records of height and HbA1c from the age of seven to 16 years. Exclusion criteria: other significant chronic diseases and medications, T1DM duration less than three months, and initial BMI < 3rd or >97th percentile. RESULTS: Growth velocity (GV) was impaired with a significant reduction of peak GV by 1.2 cm in boys. HbA1c increase during male puberty was lower except for a period of 1.5 years. The highest HbA1c increase in boys coincided with maximum growth spurt. In girls, the highest HbA1c increase was observed during late puberty. Even though there is impaired GV, both sexes reach a height at 16 years of age which corresponds to the background population height. CONCLUSION: Worsening of metabolic control is sex-discordant and associated with gender-specific alterations of GV. However, the vast majority of boys and girls with T1DM seems to reach normal height at the age of 16 years.

[Is the Intrahepatic Sound Speed an Indicator of the Fat Content of the Liver in Children?]. / Die intrahepatische Schallgeschwindigkeit als möglicher Parameter zur Abschätzung der Steatosis hepatis bei Kindern?

PURPOSE: Can the sonographically estimated intrahepatic sound speed give hints on the hepatic fat content in children? MATERIALS AND METHODS: In 75 children and adolescents the intrahepatic sound speed was estimated during routine sonography of the liver as a result of an image reconstruction algorithm. It was correlated with weight, age, size, and body mass index (BMI) oft he children, respectively. RESULTS: The average hepatic sound speed in children of normal weight was 1 566 m/s (standard deviation (STD) 29 m/s, in overweight or obese children it was 1 501 m/s (STD 22 m/s), and in obese children it was 1 497 ms (STD 24 m/s). The strongest correlation was found between sound speed and BMI of the children, respectively. The difference of sound speed in normal weighing subjects and overweight/obese children was statistically significant. CONCLUSION: There is a good correlation between the estimated intrahepatic sound speed and the fat content of the liver. Further examinations are encouraged.

Adult height and epigenotype in children with Silver-Russell syndrome treated with GH.

AIMS: To compare adult heights of GH-treated and GH-untreated patients with Silver-Russell syndrome (SRS) who were epigenotyped. METHODS: This was a nonrandomized retrospective study with matched controls at a single center. Molecular analysis of 32 out of 37 GH-treated patients (16 females) revealed IGF2-H19 epimutations in 12 and maternal uniparental disomy of chromosome 7 (matUPD7) in 5 patients; 15 were negative. At start of GH, mean age was 7.2 years and mean height -3.34 standard deviation score (SDS). Mean GH dose used was 51 µg/kg·day, mean duration of therapy was 5.6 years. Puberty was blocked by GnRH analogs in 16 patients. The untreated group comprised 13 individuals (5 females, mean age 6.8 years and mean height -3.34 SDS). End points were adult height and overall height gain. RESULTS: GH-treated patients reached an adult height of -2.12 ± 0.98 SDS gaining 1.22 SDS in comparison to baseline. Adult height SDS of the untreated was -3.13 ± 1.37 SDS. The matched treated patients were significantly taller than their untreated counterparts. Outcome was dependent on height at start of GH and duration of therapy. Height gain was highest in the shortest patients. CONCLUSIONS: GH improved adult height in SRS to a comparable degree as reported in nonsyndromic SGA children. A trend toward a better outcome in matUPD7 needs confirmation in larger cohorts.

[Pediatric hyperglycemic hyperosmolar coma diabeticum: diagnostic evaluation and therapeutic concept]. / Das hyperglykämisch-hyperosmolare Coma diabeticum im Kindesalter: Diagnostische Abgrenzung und Therapiekonzept.

Hyperglycemic hyperosmolar coma diabeticum (HHS) is a rare phenomenon in pediatric patients. It causes major morbidity and significant mortality. It is characterized by the trias of hyperglycemia, hyperosmolality and absent or mild metabolic acidosis. Major complications include cerebral edema and rhabdomyolysis. Evidence based guidelines for HHS in children are lacking. Based on a literature review we discuss treatment options in pediatric HHS und suggest a therapeutic concept. Appropriate treatment consists of adequate fluid administration and a cautious lowering of the serum glucose level. Patients should be treated on an intensive care unit and monitored closely to avoid complications. Low-dose and late insulin administration seems to be favourable.

TCF7L2 polymorphism rs7903146 and predisposition for type 2 diabetes mellitus in obese children.

Polymorphism RS7903146 in transcription factor 7-like2 gene ( TCF7L2) is associated with type 2-diabetes mellitus (T2DM) in adults. Concerned with predisposition for diabetes mellitus in obese children, we tested if risk genotypes TC and TT of rs7903146 are more common in obese children with increased homeostasis model assessment insulin resistance index (HOMA-IR) compared to obese controls with normal HOMA-IR. As exploratory analysis, we also calculated beta-cell function for these risk genotypes and measured glucagon-like peptide 1 (GLP-1) in a subgroup. The cohort was 401 obese children (BMI > 2SDS; 211 female; 59% presenting increased HOMA-IR) from two German outpatient obesity referral centers. Genotype distributions in patients presenting increased HOMA-IR (TT: 10.18%, CT: 35.65%, CC: 54.17%) and in patients with normal HOMA-IR (TT: 8.66%, CT: 42.67%, CC: 48.67%) provided no significant effect of these two risk genotypes (p > 0.2). Correction for possible confounder's gender, age, pubertal stage, and BMI revealed no association with glucose metabolism parameters including GLP-1. However, exploratory HOMA-B% index was comparatively higher in TT-homozygotes (p=0.021) as compared to CC-homozygotes. We conclude that even though TT and CT genotypes were not higher in patients presenting elevated HOMA-IR, the higher HOMA-B% index in TT-homozygotes indicates TCF7L2 to be a susceptibility gene for the development of impaired glucose tolerance in obese children as demonstrated in several adult cohort studies.

[Postnatal consequences of intrauterine development: pubertal development in children born small for gestational age]. / Postnatale Konsequenzen fetaler Entwicklung: Einfluss der Geburtsmasse auf spätere Pubertätsentwicklung und potentielle Interaktion mit einer Wachstumshormontherapie.

Five to ten percent of all children are born small for gestational age (SGA). SGA children are not only at risk of remaining small as an adult in case of lacking catch-up growth, but may develop several metabolic disturbances which might have a serious impact on the future health of these children. In this context, several studies described abnormalities of the pubertal development in SGA children, especially in SGA children demonstrating rapid postnatal weight gain. This review highlights the current knowledge of the relationship between auxiological birth para-meters and subsequent pubertal course, and the interrelationships between puberty and growth in SGA children with and without growth hormone therapy.

Modulation of circulating IGF-I and IGFBP-3 levels by hormonal regulators of energy homeostasis in obese children.

UNLABELLED: Growth hormone (GH) and insulin-like growth factor-I (IGF-I) are key factors in the control of somatic growth. Recent work revealed a critical role for the transcription factor STAT5b in GH stimulated IGF-I gene expression. In obesity, the normal regulation of the GH/IGF-I axis is disturbed, with normal levels of circulating IGF-I despite blunted GH secretion. We hypothesized that leptin or other hormonal regulators of energy homeostasis, which can activate Stat5b-regulated gene expression or exert an effect on GH secretion, might be able to substitute for GH in terms of IGF-I synthesis. Thus, the aim of this study was to identify potential regulators of IGF-I serum levels in obesity with a particular focus on the interaction of leptin and IGF-I. In a cross-sectional study, we measured hormonal and auxiological parameters in 99 obese children who were referred to our obesity outpatient clinic and analysed correlations between unadjusted hormone levels and between hormone concentrations expressed as SDS values, adjusted for sex, age, and/or puberty and BMI. Serum concentrations of IGF-I correlated highly significant with IGFBP-3, leptin, fasting ghrelin and insulin (p<0.001). However, when expressing hormone levels as SDS values, only leptin SDS and IGFBP-3 SDS correlated significantly with IGF-I SDS (p<0.01). This correlation between leptin SDS and IGF-I SDS was more pronounced in prepubertal and in male subjects, with increasing IGF-I SDS values paralleling an increase in leptin SDS tertiles in prepubertal subjects. In linear regression analyses, leptin SDS, IGFBP-3 SDS and BMI SDS contributed significantly to the variation of IGF-I SDS values, and explained 53.3% of the variability of IGF-I SDS levels in male subjects. SUMMARY AND CONCLUSIONS: In summary, we demonstrated a strong correlation of age and sex-adjusted standard deviation scores (SDS) for IGF-I and leptin in obese children, which is modulated by sex, pubertal stage and body weight. Whether this association results from a direct induction of hepatic IGF-I gene expression by leptin or reflects a more complex interrelationship between IGF-I and obesity-related factors should be subject of future research.

Complete virilization in congenital adrenal hyperplasia: clinical course, medical management and disease-related complications.

OBJECTIVE: In girls with congenital adrenal hyperplasia (CAH), genital ambiguity usually leads to a rapid neonatal diagnosis. Rarely, CAH causes complete virilization and male sex assignment with a delayed diagnosis. After being confronted with very specific problems in two of such patients, we collected data of patients with CAH and complete virilization in a nationwide study to delineate specific problems of these rare patients in order to improve their management. DESIGN AND PATIENTS: Through the German Working Group of Paediatric Endocrinology (Arbeitsgemeinschaft Pädiatrische Endokrinologie, APE), questionnaires were sent to all members caring for patients with CAH and complete virilization in their endocrine clinics. Data from 16 patients from 10 paediatric endocrine centres were assessed by questionnaire. RESULTS: The following problems have been encountered. (1) Sex assignment/gender identity: initially all patients had a male sex assignment. Six patients were diagnosed during the first month of life. Five were reassigned to female sex immediately, one at the age of 19 months. Except in one girl demonstrating some tomboyish behaviour, gender role behaviour in these patients did not differ from unaffected girls. Ten patients were diagnosed late at 3.4--7 years of age. In seven patients with a late diagnosis, male sex assignment was maintained; one of them expressed some concerns about living as a male. In three patients late sex reversal was performed, gender identity is very poor in one and new sex assignment is currently under consideration. (2) SURGERY: irrespective of the sex assigned, all patients had between one and three surgical procedures, including clitoris reduction and (repeated) vaginoplasties in patients with female sex assignment. Hysterectomy and ovarectomy were performed in patients with male sex assignment. (3) Short stature: patients with a late diagnosis of CAH had extremely advanced bone ages of +6.3 to +9.5 years, leading to severely reduced final height of 137 to 150 cm in adult patients. Patients tended to follow height percentiles of genetic females. One pubertal patient was suicidal due to short stature. (4) Central precocious puberty (CPP): prolonged exposition to adrenal androgens led to CPP in one patient. He was treated with GnRH analogues until gonadectomy. CONCLUSIONS: Patients with CAH and complete virilization have a high risk of being diagnosed late. There are major problems and uncertainties of the patients' families and the treating physicians concerning gender assignment. Gender identity is disturbed in some patients. In addition, multiple surgical procedures are necessary and short stature as well as central precocious puberty might be important to avoid late sequelae. While some surgical interventions are probably unavoidable, most of these issues could be resolved with an early diagnosis. Thus, especially for these patients, a neonatal screening programme for CAH would be of paramount importance.

GB virus C/hepatitis G virus infection in HIV infected patients with haemophilia despite treatment with virus inactivated clotting factor concentrates.

AIM: To determine the frequency of GB virus C (GBV-C)/hepatitis G virus (HGV) infection before and after switch to the use of virus inactivated concentrates in haemophiliac patients infected with human immunodeficiency virus (HIV). PATIENTS AND METHODS: Initial and follow up sera from 49 children with haemophilia were analysed for the presence of GBV-C/HGV RNA and antibodies to HGV (anti-HGV). All patients had been infected with HIV while receiving concentrates without virus inactivation before 1984 and were subsequently treated with virus inactivated concentrates. RESULTS: In the first available serum sample (1987 or later), two of 49 patients were GBV-C/HGV RNA positive and two further patients were anti-HGV positive. During follow up (mean, 6 years), 14 patients developed markers of GBV-C/HGV infection. Eleven of these had received no blood products except clotting factor concentrates that had been prepared with virus inactivation. CONCLUSIONS: Despite being treated with virus inactivated clotting factor concentrates, HIV positive patients with haemophilia are at an increased risk of manifesting GBV-C/HGV infection. We hypothesise that GBV-C/HGV is transmitted by these clotting factor concentrates. However, we cannot rule out the emergence of markers of GBV-C/HGV infection as a result of the progression of immune impairment in the course of HIV infection.

Persistent hepatitis G virus infection after neonatal transfusion.

BACKGROUND: Recently two Flaviviridae-like viruses have been discovered and named GB virus C and hepatitis G virus. Molecular characterization showed them to be different subtypes of the same virus. An association with posttransfusion hepatitis and with sporadic and fulminant hepatitis was reported, but most infected people remain asymptomatic. Data concerning hepatitis G virus infection in infants and children have not been reported to date. The prevalence of hepatitis G virus infection in children after transfusion of blood products in the neonatal period was studied. METHODS: Serum samples from 251 children, who had received blood products in the first 4 weeks of life and who had been reexamined as part of another study at a mean interval of 37 months (range, 10-70) after last transfusion, were analyzed for hepatitis G virus infection. Follow-up examinations were performed in 14 of 19 hepatitis G virus-positive children 12 to 17 years after the last transfusion. Presence of hepatitis G virus RNA in serum was determined by a reverse transcription polymerase chain reaction assay with nested primers from the helicase region of the hepatitis G virus. To prove specificity of the hepatitis G virus, reverse transcription polymerase chain reaction assay and compare follow-ups with initial sequences, direct sequencing of the NS3 and NS5 regions of the hepatitis G virus was performed. RESULTS: Hepatitis G virus RNA was detected in 19 of 251 patients (7.6%); sequence analysis showed the isolates to be of hepatitis G virus type. None of the patients with hepatitis G virus infection had evidence of liver disease, although 3 patients were coinfected with hepatitis C virus. Four of 14 patients who were reinvestigated after a mean of 15 years showed persistent hepatitis G virus infection. Each of the 4 children was healthy. In none were clinical signs of liver disease observed; liver function test results were within the normal range. CONCLUSIONS: Children receiving blood transfusions in the neonatal period are at increased risk of hepatitis G virus infection with a high rate of chronic infection. However, as in the findings in several studies of adult transfusion recipients, in the current results, no association between hepatitis G virus infection and clinical or biochemical signs of hepatitis or extrahepatic disease could be seen.

Subdural hemorrhage as an initial sign of glutaric aciduria type 1: a diagnostic pitfall.

The case of a 9-month-old girl with glutaric aciduria type 1 (GA 1) is reported. On initial presentation at 6 months of age, the patient demonstrated bilateral subdural hemorrhages and widening of the basal cisterns. After neurosurgical intervention the subdural effusions regressed; their etiology remained unclear. At the age of 9 months the patient presented again because of progressive loss of psychomotor abilities and a dystonic movement disorder. Cerebral MRI revealed regressive subdural hematoma, but marked frontotemporal atrophy as well. Because of a suspected metabolic disorder, urinary analysis of organic acids was performed. This repeatedly showed marked excretion of glutaric acid, 3-hydroxyglutaric acid and glutaconic acid, indicating a diagnosis of GA 1. Considering our patient's history, we recommend the inclusion of GA 1 in the differential diagnosis of patients with unexplained subdural hematoma and neurological deficits.