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.

Functional and total IGFBP3 for the assessment of disorders of the GH/IGF1 axis in children with chronic kidney disease, GH deficiency, or short stature after SGA status at birth.

OBJECTIVE: IGFBP3 immunoreactivity may appear elevated in patients with chronic kidney disease (CKD), in part due to accumulation of low molecular fragments. The importance of these IGFBP3 variants for binding and inactivation of IGF1 and their relevance for the impaired growth of uremic children are unclear. Nevertheless, IGFBP3, measured as total (t-)IGFBP3, is frequently used as a diagnostic parameter in pediatric CKD patients. A new assay for functional (f-)IGFBP3 exclusively detects IGFBP3 capable of IGF binding. The aim of the study was to evaluate the significance of f-IGFBP3 measurements for the assessment of uremic abnormalities of the GH/IGF1 axis. DESIGN: Prospective cross-sectional study. METHODS: t-IGFBP3, f-IGFBP3, and IGF1 were measured in pediatric CKD patients, including patients with CKD stage 3-4 not on dialysis (CKD, n=33), on dialysis treatment (DT, n=26), patients after renal transplantation (RTx, n=89), healthy children (n=29), children with GH deficiency (GHD, n=42), and small for gestational age (SGA) children (SGA, n=34). RESULTS: Mean t-IGFBP3 SDS was elevated in CKD, DT, and RTx children compared with controls and GHD patients (P≤0.0004). Highest values were reached in DT (P<0.0001 vs all groups). In contrast, mean f-IGFBP3 was similar in all groups (P=0.30). CONCLUSIONS: Pediatric CKD patients displayed elevated serum concentrations of t-IGFBP3 but not f-IGFBP3, supporting the hypothesis that IGFBP3 fragments not binding IGF1 accumulate during uremia. f-IGFBP3 is an indicator of IGFBP3 fragmentation and seems to reflect IGF1 binding in CKD better than t-IGFBP3. However, the role of f-IGFBP3 for the diagnosis of disturbances of the GH/IGF hormonal axis appears to be limited.

Impact of overweight on effectiveness of treatment with human growth hormone in growth hormone deficient children: analysis of German KIGS data.

BACKGROUND: We hypothesized that overweight children with growth hormone deficiency (GHD) demonstrate a lower response to growth hormone (GH) as a result of a misclassification since obesity is associated with lower GH peaks in stimulation tests. METHODS: Anthropometric data, response, and responsiveness to GH in the first year of treatment were compared in 1.712 prepubertal children with GHD from the German KIGS database according to BMI (underweight=group A, normal weight=group B, overweight=group C) (median age: group A, B, C: 7.3, 7.28, and 8.4 years). RESULTS: Maximum GH levels to tests (median: group A, B, C: 5.8, 5.8, and 4.0 µg/ml) were significantly lower in group C. IGF-I SDS levels were not different between the groups. Growth velocity in the first year of GH treatment was significantly lower in the underweight cohort (median: group A, B, C: 8.2, 8.8, and 9.0 cm/yr), while the gain in height was not different between groups. The difference between observed and predicted growth velocity expressed as Studentized residuals was not significantly different between groups. Separating the 164 overweight children into obese children (BMI>97th centile; n=71) and moderate overweight children (BMI>90th to 97th centile, n=93) demonstrated no significant difference in any parameter. CONCLUSIONS: Overweight prepubertal children with idiopathic GHD demonstrated similar levels of responsiveness to GH treatment compared to normal weight children. Furthermore, the IGF-I levels were low in overweight children. Therefore, a misclassification of GHD in overweight prepubertal children within the KIGS database seems unlikely. The first year growth prediction models can be applied to overweight and obese GHD children.

Monitoring medical treatment in adolescents and young adults with congenital adrenal hyperplasia: utility of salivary 17α-hydroxyprogesterone day profiles.

INTRODUCTION: Efficacy of medical treatment in patients with 21-hydroxylase deficiency is usually monitored by measurement of 17α-hydroxyprogesterone (17OHP). Saliva instead of serum sampling offers some advantages, such as painless handling and measurement of the bioactive free hormone. This study evaluated the diagnostic validity of salivary 17OHP for monitoring medical treatment, with samples collected at 7 time points throughout a day. SUBJECTS AND METHODS: Day profiles were performed in 23 adolescents and young adults with 21-hydroxylase deficiency and 43 healthy volunteers. During each profile, saliva and serum samples for 17OHP were simultaneously collected. RESULTS: With regard to the initial day profiles, samples were pathological in 63% (saliva) and 41% (serum). After the first day profile 14 patients underwent adjustment of medical treatment, either because of highly elevated 17OHP levels or with the aim of dose reduction. When comparing the best with the first day profile fewer samples were pathological (saliva: 32% vs. 71%; p<0.05; serum: 21% vs. 47%; n. s.), while the mean hydrocortisone equivalent dose was significantly reduced (20.09 mg vs. 27.27 mg; p<0.01). In 53% of profiles with controlled salivary 17OHP levels at 0700 h, the necessity for a treatment modification became only apparent when analyzing the whole day profile. CONCLUSION: A single 0700 h value within the reference range does not allow for a reliable assessment of therapeutic efficacy. We therefore suggest 17OHP day profiles for monitoring medical treatment. In this context, saliva analysis appears to be more sensitive in identifying patients who are inadequately treated.

[Management of adolescents with childhood onset growth hormone deficiency in the transition--results of a field based study in Germany]. / Im Kindesalter diagnostizierter und behandelter Wachstumshormonmangel: Umgang mit den Patienten in der Transitionsphase. Ergebnisse einer Umfrage unter Pädiatrischen und Internistischen Endokrinologen.

BACKGROUND: Discontinuation of growth hormone (GH) treatment upon attainment of final height has been associated with impaired somatic development and altered body composition. Therefore, optimal care of patients with GH deficiency (GHD) in the transition phase from adolescence to adulthood is a challenge for all parties involved. We analyzed the current clinical practice in Germany. METHODS: In 2008, 124 endocrinologists (69 pediatric, 55 adult endocrinologists) in Germany were interviewed using a structured questionnaire. RESULTS: Overall, 67 % of pediatric endocrinologists (PE) and adult endocrinologists (AE) declared to have a contact physician for their patients. 13 endocrinologists declared to have a common transition clinic with their corresponding colleague. 74 % of PE stated to transfer their patients after the end of GH therapy to an AE. 62 % of the patients were transferred at the age of 18 years. 70 % of the PE stated to retest their patients themselves, while 70 % of the AE answered that the patients had not been retested when they first came to the adult clinic. For the evaluation of GH-secretion, PE most frequently used the arginine (86 %), ITT (35 %) and clonidine test (33 %), whereas AE utilized the GHRH/arginine test (71 %), and the ITT (67 %). The level of patient's information about his disease status was considered as "good" by 44 % of AE (77 % by AE having established a transition clinic). The quality of patient files transferred from the PE was considered as "good" by 54 % of all AE (100 % by AE with transition clinic). CONCLUSION: To a significant extent, there is an inconsistence in diagnostic methods and treatment modalities performed by PE and AE compared to recently published consensus guidelines. Only 13 PE interviewed in this study transfer their GHD patients in a transition clinic setting. Communication and transfer of information between both groups appears to be impaired in centres without a transition clinic. In those clinics having established transition clinics, patient's status of information and quality of patient files is considered to be much better.

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.

Recommendations for the diagnosis and management of Prader-Willi syndrome.

OBJECTIVE: The objective of the study was to provide recommendations for the diagnosis and management of Prader-Willi syndrome throughout the life span to guide clinical practice. PARTICIPANTS: An open international multidisciplinary expert meeting was held in October 2006 in Toulouse, France, with 37 invited speakers and session chairs (see Acknowledgments) and 85 additional registered participants. The meeting was supported by an unrestricted educational grant from Pfizer. EVIDENCE: Invited participants with particular expertise reviewed the published evidence base for their specialist topic and unpublished data from personal experience, previous national and international PWS conferences, and PWS Association clinical advisory groups. Sessions covered epidemiology, psychiatric, and behavioral disorders; breathing and sleep abnormalities; genetics; endocrinology; and management in infancy, childhood, transition, and adulthood. CONSENSUS PROCESS: This included group meetings including open discussion after each session. The guidelines were written by the Scientific Committee (authors), using the conclusions provided by the sessions chairs and summary provided by each speaker, including incorporation of changes suggested after review by selected meeting participants (see Acknowledgments). CONCLUSIONS: The diagnosis and management of this complex disorder requires a multidisciplinary approach with particular emphasis on the importance of early diagnosis using accredited genetic testing, use and monitoring of GH therapy from early childhood, control of the food environment and regular exercise, appropriate management of transition, consideration of group home placement in adulthood, and distinction of behavioral problems from psychiatric illness.

Mutations in the amino-terminal domain of the human androgen receptor may be associated with partial androgen insensitivity and impaired transactivation in vitro.

The majority of genetic variations in the androgen receptor (AR) gene are point mutations leading to impairment of the DNA- or hormone-binding domains. The N-terminus encoded by the first exon of the AR-gene usually harbors disruptive mutations associated with complete androgen insensitivity syndrome (CAIS) while missense mutations related with partial androgen insensitivity syndrome (PAIS) are seemingly rare. We present a 46,XY male with scrotal hypospadias in whom we detected a S432 F point mutation within the N-terminus. Transient transfections of an AR expression plasmid carrying the S432 F mutation using Chinese Hamster Ovary (CHO) cells revealed a significant partial reduction in transactivation of the co-transfected androgen responsive (ARE) (2)TATA luciferase reporter gene thus confirming PAIS. In two further 46, XY patients with slight to moderate virilization defects, we detected an S411 N mutation, and a 9 base pair deletion leading to the loss of amino acids 409 to 411 (L-A-S), respectively. These mutations did not compromise AR-function under the chosen experimental settings. The S432 F-patient supports particular significance of the AR-N-terminus for mild forms of AIS while the functional role of the two further mutations remains unclear. The N-terminus is a species-specific AR-domain possibly also involved in contributing to target tissue selectivity of AR-actions via mediating co-regulator interactions. Therefore, mild molecular defects of the AR-N-terminus may not necessarily inhibit general transactivation properties using currently established reporter gene models.

Leydig cell hypoplasia: absent luteinizing hormone receptor cell surface expression caused by a novel homozygous mutation in the extracellular domain.

Leydig cell hypoplasia is a rare autosomal recessive condition that interferes with normal development of male external genitalia in 46,XY individuals. We have studied a family with a 46,XY girl due to a new homozygous mutation (V144F) in the extracellular ligand-binding domain. HEK 293 cells transfected with the mutant LH receptor exhibited a marked impairment of human chorionic gonadotropin binding. Using Western blotting of the expressed V144F mutant LH receptor protein showed the absence of the glycosylated cell surface form. Treatment of the mutant LH receptor with N-glycosidase F or endoglycosidase-H demonstrated that the mutant receptor is retained in the endoplasmic reticulum. Expression and study of enhanced green fluorescent protein-tagged receptors confirmed that the mutant LHR-V144F receptors do not migrate to the cell surface, and the fluorescence remains intracellular and colocalizes with an endoplasmic reticulum marker, ER-tracker Blue-white DPX. Comparison of the theoretical molecular models of the extracellular domain of the wild-type and the mutant receptor suggests that the mutation LHR-V144F, located in the outer circumference in a alpha-helix of the leucine-rich repeat 4, may induce a conformational strain on the molecule. F144 of the mutant LH receptor has overlapping interactions with F119, which V144 in the wild-type receptor has not.

Behavioural and emotional disturbances in people with Prader-Willi Syndrome.

BACKGROUND: The study of the behaviour profile in subjects with Prader-Willi Syndrome (PWS). METHODS: A total of fifty-eight 3- to 29-year-old subjects with PWS were studied using a standardized parent report of behavioural and emotional disturbances. RESULTS: There was an increase of behavioural and emotional disturbances for the adolescent and young adult age range, whereas gender and intelligence were not significant. Increasing body mass index (BMI) was also associated with more behavioural and emotional disturbances. There was no significant relation between genetic status and behavioural abnormalities. CONCLUSIONS: This systematic study supports single case observations of a heightened psychiatric vulnerability of adolescent and young adult PWS subjects.

Association of morphological characteristics with precocious puberty and/or gelastic seizures in hypothalamic hamartoma.

The pathogenesis of central precocious puberty (PP) and/or gelastic seizures due to a hypothalamic hamartoma (HH) is still under debate. We evaluated the association of clinical symptoms with morphology and localization of the HH in 34 patients. The majority (86.4%) of HHs in patients with isolated PP (n = 22; 68.2% females) revealed a parahypothalamic position without affecting the third ventricle (91%). Half of them were pedunculated, and 40.9% showed a diameter less than 10 mm. In contrast, 11 of 12 patients with seizures, eight of whom were male, presented with a sessile intrahypothalamic hamartoma, 10 of which distorted the third ventricle. Logistic regression analysis revealed an increased relative risk (RR) for epilepsy in males (RR, 4.3; 95% confidence interval, 0.96-19). However, combination of the risk factor gender with intrahypothalamic position (RR, 19; 1.3-285) and distortion of the third ventricle (RR, 10; 0.6-164) reduced the risk associated with male gender to 1.1. The position of a HH and involvement of the third ventricle are likely to be more predictive for clinical characteristics than size and shape. Male gender was associated with an intrahypothalamic HH and epilepsy, suggesting a sexually dimorphic developmental pattern of this heterotopic mass.

Adult height after GH therapy in 188 Ullrich-Turner syndrome patients: results of the German IGLU Follow-up Study 2001.

OBJECTIVES: We aimed to evaluate the factors influencing true adult height (HT) after long-term (from 1987 to 2000) GH treatment in Ullrich-Turner syndrome (UTS) based on modalities conceived in the 1980s. DESIGN: Out of 347 near-adult (>16 Years) patients from 96 German centres, whose longitudinal growth was documented within KIGS (Pharmacia International Growth Database), 188 (45, X=59%; bone age >15 Years) were available for further anthropometric measurements. RESULTS: At a median GH dose of 0.88 (10th/90th percentiles: 0.47/1.06) IU/kg per week, a gain of 6.0 (-1.3/+13) cm above the projected adult height was recorded. Variables were recorded at GH start, after 1 Year GH, puberty onset, and last visit on GH therapy. At these visits, the median ages were 11.7, 12.7, 14.2, 16.6 and 18.7 Years; and median heights, 0.4, 1.1, 1.7, 1.7 and 1.3 SDS (UTS) respectively. Height gain (DeltaHT) after GH discontinuation was 1.5 cm. Total DeltaHT correlated (P<0.001) negatively with bone age and HT SDS at GH start, but positively with DeltaHT after the first Year, DeltaHT at puberty onset, and GH duration. Final HT correlated (P<0.001) positively with HT at GH start, first-Year DeltaHT, and HT at puberty onset. Body mass index increased slightly (P<0.05), with values at start and adult follow-up correlating highly (R=0.70, P<0.001). No major side effects of GH occurred. CONCLUSIONS: GH dosages conceived in the 1980s are safe but too low for most UTS patients. HT gain and height are determined by age and HT at GH start. Height gain during the first Year on GH is indicative of overall height gain. After spontaneous or induced puberty, little gain in height occurs.

McCune-Albright syndrome--the German experience.

The classical McCune-Albright syndrome (MAS) consists of peripheral precocious puberty (PPP), fibrous bone dysplasia and café-au-lait spots. We conducted a survey among pediatric endocrinologists in Germany, Austria and Switzerland, most of them participating in the German Working Group for Pediatric Endocrinology (APE). Thirty-three physicians reported 58 patients. A detailed questionnaire yielded extensive data from 41 patients. Patients (36 females, 5 males) were diagnosed between the 4th week of life and 8 years. Symptoms included precocious puberty (37 patients), café-au-lait spots (35), fibrous bone dysplasia (32), hyperthyroidism (5), liver disease (5), phosphate wasting (4), GH hypersecretion (3), anemia in infancy (2), hyperprolactinemia (1), and Cushing's disease (1). Therapy of PPP included testolactone (15), tamoxifen (7), cyproterone acetate (CPA) (5), anastrozole (1) and exemestane (1). Testolactone, tamoxifen and CPA showed varying degrees of clinical remission; none was unanimously effective, but side effects were very rare. New aromatase inhibitors were not well validated in MAS. Eleven children received bisphosphonate therapy (pamidronate i.v. q 3 months) for fibrous bone dysplasia. Pamidronate was well tolerated, and pain improved when present, but data on preventive effects are not yet available. In conclusion, this survey describes a large cohort of patients with MAS, many with severe clinical problems, including major physical handicaps. Our results show that there is no 'gold standard' for the therapy of PPP; tested treatment regimens are not ideal, and new aromatase inhibitors need to be evaluated in controlled studies. Pamidronate was well tolerated, but preventive effects on bone dysplasia have not yet been proven.

Sexual precocity and recurrent beta-human chorionic gonadotropin upsurges preceding the diagnosis of a malignant mediastinal germ-cell tumor in a 9-year-old boy.

Numerous disorders are known to cause sexual precocity. Beta-human chorionic gonadotropin (beta-HCG)-secreting germ-cell tumors are one of the sources that have to be considered in the differential diagnosis of processes inducing a peripheral precocious puberty. Germ-cell tumors might be located in the ovaries or testes, retroperitoneum, mediastinum or the cranium. We present the case of a 9-year-old boy with sexual precocity and a recurrent transient beta-HCG elevation. After an interval of 2 years with repeated radiological examinations including the mediastinum, a mediastinal tumor was identified by magnetic resonance imaging. To our knowledge, this is the first case of a diagnosis of a mediastinal choriocarcinoma with a recurrent serum beta-HCG elevation. So far, factors that might be responsible for the repeated spontaneous beta-HCG decline are unknown.

Male LH-independent sexual precocity in a 3.5-year-old boy caused by a somatic activating mutation of the LH receptor in a Leydig cell tumor.

We describe the clinical features of severe sexual precocity in a 3.5-yr-old boy. Hormonal evaluation showed LH-independent T hypersecretion. Initial examination of the adrenals and testes revealed no evidence of congenital adrenal hyperplasia, hCG- or androgen-secreting tumors, or McCune-Albright syndrome. In the coding sequence of the LH receptor gene no activating mutation was found. Spironolactone (5.7 mg/kg x d) and testolactone (40 mg/kg x d) were unsuccessful in suppressing the elevated concentration of T. To further determine the origin of the elevated serum T, a selective venous sampling procedure was planned. However before the sampling procedure, high resolution ultrasound examination showed a small tumor in the left testis, which was removed. Histology proved the tumor to be a Leydig cell adenoma. Sequencing of the tumor LH receptor gene revealed a heterozygous mutation in exon 11 encoding a replacement of aspartic acid at position 578 with histidine, which has been shown to be a constitutively activating mutation. These findings indicate that in male patients with gonadotropin-independent sexual precocity, the presence of small testicular Leydig cell tumors harboring a somatic mutation of the LH receptor gene should be considered.

Clinical implications of pulsatile hormone signals.

In all biological systems, the information content of hormonal signals is conveyed by the modalities of pulsatile hormone secretion. New mathematical tools for the analysis of pulsatile behaviour and increasing knowledge of the sources of signal variability have enabled us to recognize altered hormonal pulsatility associated with human disease. Its consequences for our understanding of disease mechanisms, for diagnostic procedures and for therapeutic decisions are discussed at the level of single hormones. Increased disorderliness of hormone secretion is a hallmark of pituitary adenomas, indicating functional subsystem autonomy. The effects on target tissues of changing growth hormone therapy from low-frequency administration to long-acting preparations are still incompletely understood. In contrast, the gonadotropic axis is a paradigm for the successful therapeutic use of induced pulsatility changes, where therapy with long-acting gonadotropin-releasing hormone (GnRH) agonists suppresses endogenous gonadotropin pulses and gonadal function, and pulsatile GnRH administration is used to restore normal gonadal function. Future development of endocrine therapies will depend on our knowledge of hormonal pulsatility.

Adiposity indices in German children and adolescents with genetically confirmed Prader-Willi syndrome (PWS).

BACKGROUND: Morbid obesity develops as a result of hyperphagia and compulsive eating behavior in patients with Prader-Willi syndrome (PWS), if caloric intake is not rigorously controlled. PWS-specific centile curves for adiposity indices constructed in the past were based on clinically diagnosed patients. With the advent of molecular genetic methods, allowing for an unequivocal diagnosis, new PWS curves based exclusively on molecularly diagnosed patients are becoming available, eliminating a potential diagnostic bias. OBJECTIVE: To compare fat distribution in molecularly confirmed German PWS patients to that of clinically diagnosed American PWS patients and a healthy reference population. DESIGN: Cross-sectional anthropometric study. SUBJECTS: One hundred German patients (49 F) with molecularly confirmed PWS (age: <30 y). MEASUREMENTS: Triceps (subscapular) skinfold thickness, waist and hip circumference. RESULTS: Skinfold thickness was massively elevated in the majority of the molecularly confirmed German PWS patients compared to a healthy reference population. Whereas triceps skinfold thickness was in good agreement with American PWS patients, subscapular skinfold thickness in German girls rose earlier than in American PWS girls, indicating possible differences between caloric intake or the proportion of patients entering puberty spontaneously. Waist circumference and waist-hip ratio (n=89) were elevated in a relative small proportion of patients only and did not reflect lower abdominal fat. This may be due to the peculiar shape of many patients with a typical fat accumulation around the buttocks. CONCLUSIONS: In addition to body mass index, use of skinfold thickness is recommended for follow-up of dietary interventions in PWS.