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.

Long-term Surveillance of Children with Congenital Hypothyroidism: Data from the German Registry for Congenital Hypothyroidism (AQUAPE "Hypo Dok").

BACKGROUND: The German study group for quality assurance in pediatric endocrinology and the University of Ulm have established a software ("Hypo Dok") for the documentation of longitudinal data of patients with congenital primary hypothyroidism (CH). Aim of this study was to analyse the long-term follow-up of patients with CH and to compare treatment with current guidelines. METHODS/PATIENTS: Anonymised data of 1,080 patients from 46 centres were statistically analysed. RESULTS: Newborn screening result was available at a mean age of 7.3 days. Confirmation of the diagnosis was established at 8.4 days and therapy was started at 11 days. The average screening TSH was 180.0 mIU/L. During the first 3 months mean levothyroxine (LT4) dose was 10.7 µg/kg/day or 186.0 µg/m²/day. Weight-, BMI- and height-SDS did not differ significantly from the normal population. Only 25% of the patients (n=262) underwent formal EQ/IQ-testing. Their average IQ was 98.8 ± 13.2 points. DISCUSSION: In Germany screening, confirmation and start of treatment of CH are within the recommended time frame of 14 days. Initial LT4-doses are adequate. The auxological longterm outcome of young CH patients is normal. The implementation of standardized IQ testing has to be improved in routine patient care. CONCLUSION: Longitudinal data of patients with CH was analysed and compared to current guidelines. Confirmation and start of treatment are according to the recommendations. However standardised IQ testing requires improvement.

BK polyomavirus-specific cellular immune responses are age-dependent and strongly correlate with phases of virus replication.

BK polyomavirus (BKPyV) infection is widespread and typically asymptomatic during childhood, but may cause nephropathy in kidney transplant recipients. However, there is only limited knowledge on BKPyV-specific immunity in children and adults, and its role in BKPyV-replication and disease posttransplant. We therefore characterized BKPyV-specific immunity from 122 immunocompetent individuals (1-84 years), 38 adult kidney recipients with (n = 14) and without BKPyV-associated complications (n = 24), and 25 hemodialysis (HD) patients. Blood samples were stimulated with overlapping peptides of BKPyV large-T antigen and VP1 followed by flow-cytometric analysis of activated CD4 T cells expressing interferon-γ, IL-2 and tumor necrosis factor-α. Antibody-levels were determined using enzyme-linked immunosorbent assay. Both BKPyV-IgG levels and BKPyV-specific CD4 T cell frequencies were age-dependent (p = 0.0059) with maximum levels between 20 and 30 years (0.042%, interquartile range 0.05%). Transplant recipients showed a significantly higher BKPyV-specific T cell prevalence (57.9%) compared to age-matched controls (21.7%) or HD patients (28%, p = 0.017). Clinically relevant BKPyV-replication was associated with elevated frequencies of BKPyV-specific T cells (p = 0.0002), but decreased percentage of cells expressing multiple cytokines (p = 0.009). In conclusion, BKPyV-specific cellular immunity reflects phases of active BKPyV-replication either after primary infection in childhood or during reactivation after transplantation. Combined analysis of BKPyV-specific T cell functionality and viral loads may improve individual risk assessment.

HDR syndrome: a follow-up genotype-phenotype analysis of a de novo missense Thr272Ile mutation in exon 4 of GATA3.

Hypoparathyroidism, sensorineural deafness and renal dysplasia (HDR) syndrome (MIM 146255) is a rare autosomal dominant disorder caused by mutations in the gene encoding GATA3, a dual zinc-finger transcription factor involved in vertebrate embryonic development. In this clinical case study we report on a follow-up of a phenotype associated with a GATA3 mutation. HDR syndrome was clinically diagnosed at age of 1.5 years in a boy with a de novo heterozygous missense (c.815C→T) mutation, Thr272Ile, in exon 4 of the GATA3 gene. Both parents were negative for Thr272Ile.At age of 17 months, the patient had a weight of 10.7, a body length of 78 cm, and a head circumference of 47.5 cm. By the age of 7 years, growth is age-appropriate, severe bilateral hearing loss (dB 60) was corrected by hearing aids. However, cognitive development (auditory sensory me-mory and language abilities) is at the lower ends of the test scores.In conclusion, a mildly impaired clinical course was achieved by the age of 7 years in a patient with HDR syndrome; this report adds to the body of data on genotype-phenotype analysis in HDR syndrome. ·

Diabetes mellitus in children and adolescents with genetic syndromes.

BACKGROUND: Several genetic syndromes are associated with diabetes mellitus (DM). This study aimed to analyse data from the DPV database with regard to frequency, treatment strategies and long-term complications in paediatric DM patients with genetic syndromes, including Turner syndrome (TS), Prader-Willi syndrome (PWS), Friedreich ataxia (FA), Alström syndrome (AS), Klinefelter syndrome (KS), Bardet-Biedl syndrome (BBS), Berardinelli-Seip syndrome (BSS) and Down syndrome (DS). METHODS: Longitudinal data for 43 521 patients with DM onset at age < 20 years were collected from 309 treatment centres in Germany and Austria using the DPV software. Data included anthropometric parameters, type of diabetes, mean age, age at diabetes onset, daily insulin dose, HbA 1c , micro- and macroalbuminuria, retinopathy and dyslipidaemia. Descriptive statistics and standard statistical tests were used for data analysis. RESULTS: In total, 205 DM patients had one of the following syndromes: DS (141 patients), TS (24), PWS (23), FA (5), AS (5), KS (4), BBS (2) and BSS (1). Diabetes-specific antibodies were positive in the majority of patients with DS, TS and FA. CONCLUSION: Despite the well-known association between DM and certain syndromic disorders, the number of affected patients in the German and Austrian paediatric diabetic population is very low. Nevertheless, physicians should be aware of syndromic forms of diabetes. Joint multicentre analyses are needed to draw relevant conclusions.

Down's syndrome in diabetic patients aged <20 years: an analysis of metabolic status, glycaemic control and autoimmunity in comparison with type 1 diabetes.

AIMS/HYPOTHESIS: Intellectual impairment in individuals with Down's syndrome and diabetes mellitus potentially limits the quality of diabetic control. In addition, these patients are at risk of having immunological abnormalities. The present study compared metabolic status and concomitant diseases in young (<20 years old) Down's syndrome patients with diabetes vs young type 1 diabetic patients. METHODS: The Diabetes-Patienten-Verlaufsdaten is a longitudinal follow-up database, which collects data from 298 German and Austrian diabetes centres. Data available on diabetic patients aged <20 years were analysed statistically. RESULTS: We compared data for 159 Down's syndrome patients with diabetes and 41,983 type 1 diabetic patients. The former used less insulin, but showed better glycaemic control (HbA1c). Diabetes onset during the first 3 years of life occurred in 18.9% of Down's syndrome patients with diabetes and in 6.4% of type 1 diabetic patients. Antibody titres indicative of coeliac disease and thyroid peroxidase antibodies were more frequent in Down's syndrome patients with diabetes. No significant differences were found regarding the beta cell autoantibodies studied. CONCLUSIONS/INTERPRETATION: The age-of-onset distribution showed a shift towards younger ages and was bimodal in the Down's syndrome group. The better metabolic control found, despite intellectual impairment, in young Down's syndrome patients with diabetes cannot be conclusively explained by our data, but is likely to be due to a less complex lifestyle. Our data provide further confirmation that coeliac and thyroid antibodies are more prevalent in Down's syndrome. The presence of beta cell autoantibodies supports an autoimmune cause of diabetes in some children with Down's syndrome.

Noonan syndrome: introduction and basic clinical features.

Noonan syndrome (NS) is a fairly common (1 per 1,000-2,500 live births) autosomal dominantly inherited disorder and the most common syndromal cause of congenital heart disease after Down's syndrome. The clinical features vary with age, but typical signs of NS include characteristic facial features with hypertelorism, down-slanting palpebral fissures, low-set posteriorly rotated ears, chest and spinal deformities, short stature, specific heart defects, learning disabilities and mild mental retardation. This article gives a brief introduction to NS and its basic clinical features using the established and generally accepted NS scoring system based on family history and facial, cardiac, growth, chest wall and other criteria. Aspects discussed include the definition, epidemiology, etiology, diagnosis and genetics of NS, as well as growth, skeletal and gonadal anomalies, pubertal development, ophthalmic and cutaneous abnormalities and the incidence of cancer in patients with NS.

[Cranial birth trauma]. / Kraniales Geburtstrauma.

Injuries to an infant that result during the birth process are categorized as birth trauma. Cranial injuries due to mechanical forces such as compression or traction include caput succedaneum, cephalhematoma, subgaleal hematoma and intracranial hemorrhaging. Hypoxic ischemic encephalopathy is the consequence of systemic asphyxia occurring during birth.

[Shaken baby syndrome]. / Shaken-baby-Syndrom.

Shaken baby syndrome (SBS) describes the coincidence of subdural hematoma, retinal bleeding and, disadvantageous for the prognosis, diffuse brain damage caused by powerful shaking of the infant. The clinical symptoms include irritability, difficulty with drinking, somnolence, apathy, cerebral cramp attacks, apnoea, temperature regulation disorders and vomiting due to cranial pressure. Milder symptoms of SBS are often not diagnosed and the number of unregistered cases is probably much greater. The diagnosis of SBS is made through the typical symptom constellation, but the lack of retinal bleeding does not exclude the diagnosis. Normally the infants are held by the thorax or upper arms and shaken in a sagittal direction during which the head falls backwards and forwards and is stopped abruptly at each extreme position. The injurious mechanism is considered to be caused by rotational forces which force tissue layers in the brain against each other and also lead to rupture of bridging veins between the skull and the brain. The prognosis is poor and approximately 25% of infants die of SBS within days or weeks. Approximately 75% of survivors suffer from long term damage with physical handicaps, limitations in hearing, visual disturbances up to blindness and mental disorders or combinations of these conditions. Prevention is therefore the most important aspect.

[Clinical assessment of suspected child physical abuse]. / Klinischer Verdacht auf Kindesmisshandlung.

Violence against children has many faces. Child physical abuse, neglect, sexual abuse and interparental violence can cause acute and permanent damage and affect children's development and their life plans in the long term. In industrialized nations almost 1 child in 10 is affected. Up to 10% of child physical abuse cases involve the central nervous system with 80% of these cases occurring during the first year of life. Worldwide more than 50,000 children die as a result of violence, abuse and neglect every year, according to the United Nations Children's Fund UNICEF. In Germany, there are about 120 cases of non-accidental head injury per year. In addition to the officially known cases there is a large grey area for all forms of violence. Recognition of these cases and the provision of help for the victims require an appropriate suspicion and understanding of the pertinent pathophysiology. Suspicion must be based on a well-documented medical history and multidisciplinary diagnostic assessment. Medical confidentiality prevents the disclosure of such information making early detection networks and guidelines for collaboration absolutely indispensable.

Is the response to growth hormone in short children born small for gestational age dependent on genetic or maternal factors?

BACKGROUND/AIMS: We investigated whether genetic or maternal/environmental risk factors for being born small for gestational age (SGA), e.g. Silver-Russell syndrome, congenital heart defects, infections of mothers or smoking during pregnancy, explain the variation in the first-year growth response to GH therapy. METHODS: Secondary analysis was made of growth response in 135 short prepubertal German children (66% males) enrolled in a SGA phase III trial. Initial mean patient age was 6.8 +/- 2.6 years; mean patient height SDS -3.8 +/- 1.2, and GH treatment dose was 0.066 mg/kg body weight per day. RESULTS: Growth velocity increased by 4.5 +/- 2.0 cm/year and height SDS by 1.0 +/- 0.5 SDS. Although patient number was limited and variation was high, both growth response (cm/year) and change in height SDS did not appear to differ between subgroups which also did not differ in terms of Studentized residuals set up in the KIGS growth prediction model for SGA. Likewise, in a step-forward multivariate analysis, the variables Silver-Russell syndrome, congenital heart defects, infections of mothers and smoking were not identified as independent factors influencing growth velocity. CONCLUSION: The retrospectively analyzed genetic and maternal/environmental risk factors for SGA do not appear to explain the observed patient variance in response to GH. Larger prospective studies are needed, however, to substantiate these preliminary findings.

Late endocrine sequelae after radiotherapy of pediatric brain tumors are independent of tumor location.

INTRODUCTION: Irradiation of brain tumors (BT) in children can lead to the loss of pituitary function, predominantly manifesting as deficiencies in GH and ACTH. OBJECTIVE: To assess the incidence and nature of pituitary deficiency in relation to initial tumor location in children after radiotherapy of BT. METHODS: Twenty survivors (16 males and 4 females) of radiation-treated BT aged 1.4-10.9 (median 3.6) yr at diagnosis were studied, 10 with supratentorial and 10 with infratentorial BT. Radiation doses to the hypothalamus- pituitary (HP) area ranged from 30 to 54 (median 45) Gray. Follow-up was 9.4-16.9 (median 12.2) yr. Basal pituitary hormone levels were measured every 6 months. When growth failure became evident or pituitary deficiency was suspected, provocation tests of the HP axis were performed to assess GH, ACTH, and TSH function. RESULTS: GH deficiency (GHD) developed in 17/20 (85%) children. In 10 patients, it occurred 4 yr after radiotherapy and in 2, 11 and 12 yr after radiotherapy. Six (30%) patients developed secondary hypothyroidism and 4 (20%) developed ACTH deficiency. Precocious puberty occurred in 2 girls. The course of development and the severity of hormone deficiencies were similar for supratentorial and infratentorial tumors. CONCLUSION: The major hormonal effect of BT irradiation in children is GHD, which may sometimes take more than 10 yr to manifest. We confirm findings by others that ACTH insufficiency occurs less frequently in children than reported for adults. Tumor location has no prognostic significance regarding the loss of HP function.

[Sonographic diagnosis of caudal regression syndrome]. / Sonografische Diagnose eines kaudalen Regressionssyndroms.

Caudal regression sequence (CRS) is a rare developmental defect of the lower spinal segments and the neural tube. Motor and sensory neurological deficits of the lower extremities as well as a reduced control of bowel and bladder functions are the main symptoms. Etiology and pathogenesis are widely unknown. This article discusses a newborn male with postnatal anomalies of the lower extremities. Sonographically, the spinal cord ended in the lumbar region. NMR confirmed the suspected sonographic finding of CRS. Sonographic examination of the abdominal vessel system depicted a common origin and junction of the hepatic artery, splenic artery and superior mesenteric artery from one common truncus. This points to a possible relict of a persisting vitelline artery. As previously described in sirenomelia, the findings in the present case indicate a possible vascular etiology of CRS.

Novel flaps for lip reconstruction.

Reconstruction of the lips requires careful attention to aesthetic and functional goals. We describe our approach to lip repair and present novel methods to maintain symmetry and function, and optimize cosmetic results.

Craniopharyngioma in a female adolescent presenting with symptoms of anorexia nervosa.

BACKGROUND: Tumours of the central nervous system mostly present with neurological symptoms and signs of intracranial hypertension. Several reports of cerebral tumors in adolescents outline initial symptoms of anorexia and emaciation, leading to the diagnosis of anorexia nervosa. PATIENT: We report on a 15.5-year-old girl with a craniopharyngioma. The girl had a 2 year history of weight loss, dystrophy, no onset of puberty, and a 6 year history of headache. These symptoms had led initially to the clinical diagnoses of migraine and anorexia nervosa, since unenhanced computed tomography of the brain was normal. At presentation, physical examination showed short stature (height SDS - 3.6) and Tanner stage I. Bone age delay was about four years. Laboratory analyses showed hypopituitarism. The diagnosis of craniopharyngioma was made by repeated imaging, depicting an intrasellar and parasellar mass, which was totally removed by neurosurgery. Hormonal substitution with hGH, L-thyroxine, hydrocortisone, and estrogens led to normal physiological development and final height within upper target height. CONCLUSIONS: The reported case illustrates that the diagnosis of craniopharyngioma is often delayed due to unspecific clinical symptoms. Careful evaluation of anthropometrics, ophthalmologic, and endocrine data in patients with suspected eating disorders may give additional clues to the diagnosis of a craniopharyngioma.

Growth of heterokaryotic monozygotic twins discordant for Ullrich-Turner syndrome during the first years of life.

The rare observation of different karyotypes in monozygotic (MZ) twins, i.e., heterokaryotic monozygosity, occurs due to chromosomal aberration in one of the twins after separation of the embryos. We report on the differences of heterokaryotic MZ Turkish twins who are discordant for Ullrich-Turner syndrome. Chromosomal analyses from peripheral lymphocytes revealed a 45,X/46,XX mosaicism in both twins. FISH analyses of buccal smears showed 99% of nuclei 45,X in twin A and 98% of nuclei 46,XX in twin B. These results are consistent with a non-mosaic 45,X and 46,XX karyotype, respectively. The girls showed a different growth pattern in the first years. As their genotype should be identical except for the number of X chromosomes, the difference in phenotype may be a pure result of loss of one X chromosome in the affected girl. Special interest is set on the spontaneous and growth hormone induced growth of the twins.

Tall stature as presenting symptom in a girl with triple X syndrome.

An 11 year-old girl presented with 47,XXX karyotype. Our report emphasizes the fact that triple X syndrome has also to be considered in girls presenting with tall stature that is not explained by parental heights.

[Clinical symptoms in 35 children and adolescents with craniopharyngeoma at the time of diagnosis]. / Klinische Symptome und Befunde zum Zeitpunkt der Diagnosestellung bei Kindern und Jugendlichen mit Kraniopharyngeom.

AIM: Hormonal deficiencies, visual disturbances, or cerebral symptoms are often the symptoms through which craniopharyngiomas (CP) first become clinically manifest. As these symptoms can exist for a long period of time various specialists are often consulted before the final diagnosis is made. PATIENTS AND METHODS: Between the years 1970 and 1998, 37 children and adolescents with CP were treated in Erlangen. The documents of 35 patients (22 male, 13 female) were evaluated retrospectively. RESULTS: The median age of the children at diagnosis was 9,3 years (1,3 - 15,6 years). The most frequently documented symptoms were: headache 57 % (median duration 7 months; varying from 1 week to 6 years), visual disturbances 45 % (median duration 2 months, range 2 weeks to 10 years), and reduced growth 40 % (median duration 1 year, range 3 months to 5 years). On average the reported symptoms were present for 15 months (median 5 months, time span 1 week to 10 years). CONCLUSION: The clinical symptoms of CP are non-specific and highly varied. Endocrine disturbances are the primary objective finding. Correct interpretation of the symptoms are required for the early diagnosis of CP.

[Resistance to thyroid hormone - goiter and attention deficit-hyperactivity disorder as main manifestation]. / "Familiäre Schilddrüsenhormonresistenz" - Struma und Hyperaktivitätssyndrom als Leitsymptome.

HISTORY AND CLINICAL FINDINGS: Two siblings with goiter and attention deficit-hyperactivity disorder were presented. Earlier laboratory tests showed increased serum levels of thyroid hormones in association with non-suppressed serum levels of thyrotropin (TSH) in both children. Because hyperthyroidism caused by inappropriate secretion of thyrotropin was suspected, a cerebral MRI was performed. A pituitary adenoma was excluded in both children. Before antithyroid drug treatment was initiated, both patients were referred to our hospital. Careful medical history, clinical examination of the patients and careful interpretation of the laboratory results finally led to the diagnosis resistance to thyroid hormone (RTH). INVESTIGATIONS: Thyroid hormone serum levels were elevated in both children, while serum TSH was within the normal range. Molecular analysis confirmed the diagnosis of RTH. COURSE: Thyrostatic treatment was not initiated. CONCLUSION: Careful medical history, correct interpretation of laboratory results, comprehensive clinical examination and molecular genetic analysis are important in the diagnosis of RTH.