Different relationships between the first 2 years on growth hormone treatment and the d3-growth hormone receptor polymorphism in short small-for-gestational-age (SGA) children.

BACKGROUND: There has been controversy in recent years on whether the d3 polymorphism of the GH receptor is associated with a better growth response to GH in idiopathic short children born small for gestational age (SGA). METHODS: In this prospective study, we evaluated exon 3-GHR polymorphisms in 142 (62 f, 80 m) short prepubertal children born SGA (birth length and/or weight of ≤-2 SD for GA) and treated with rhGH (mean dose of 0·30 mg/kg/week) in 24 centres in Germany. A growth prediction for the first year of therapy was calculated for each child according to Ranke and co-workers. The index of responsiveness (IOR) was calculated by dividing the response (observed growth minus predicted growth) by the standard error of the prediction. All analyses were performed in one centre on samples collected and shipped on filter paper. The DNA fragment containing or missing exon 3 of the GHR was amplified by multiplex PCR. RESULTS: The fl-GHR isoform was most common with a frequency of 47·8%, followed by the d3/fl isoform with 38% and the d3-GHR isoform with 14·2%. There were no significant differences regarding gestational age, birth weight and birth length, mid parental height-SDS, chronological age at start of therapy, height-SDS, BMI-SDS, height velocity and GH dose between the different subgroups according to the genotype. After the first treatment year, height (H)-SDS (P < 0·05), height velocity (HV) (P < 0·01), HV-SDS (P < 0·001) and delta-H-SDS (P < 0·05) were significantly higher in patients with d3-GHR than in those with fl-GHR. The mean IOR was above 0 in children with at least one d3 allele, and highest, with 0·54, in those with the d3-GHR isoform. After the second year on GH, no differences between the different GHR-isoforms were found. CONCLUSIONS: According to our results, the exon 3-deleted GHR explains the better growth response to GH only for the first and not for the second year.

Deficient knowledge in adult Turner syndrome care as an incentive to found Turner centers in Germany.

OBJECTIVE: Turner syndrome (TS) is characterized by the complete or partial loss of the second sex chromosome and associated with a wide range of clinical manifestations. We aimed to assess the medical care of adult patients with TS in Germany. DESIGN: Retrospective multicenter observational study. METHODS: Data were collected from medical records of 258 women with TS treated between 2001 and 2017 in five non-university endocrinologic centers in Germany. RESULTS: Mean age was 29.8 ± 11.6 years, mean height 152 ± 7.7 cm, and mean BMI 26.6 ± 6.3 kg/m2. The karyotype was known in 50% of patients. Information on cholesterol state, liver enzymes, and thyroid status was available in 81-98% of women with TS; autoimmune thyroiditis was diagnosed in 37%. Echocardiography was performed in 42% and cardiac MRI in 8.5%, resulting in a diagnosis of cardiovascular disorder in 28%. Data on growth hormone therapy were available for 40 patients (15%) and data concerning menarche in 157 patients (61%). CONCLUSION: In 258 women with TS, retrospective analysis of healthcare data indicated that medical management was focused on endocrine manifestations. Further significant clinical features including cardiovascular disease, renal malformation, liver involvement, autoimmune diseases, hearing loss, and osteoporosis were only marginally if at all considered. Based on this evaluation and in accordance with recent guidelines, we compiled a documentation form facilitating the transition from pediatric to adult care and further medical management of TS patients. The foundation of Turner Centers in March 2019 will improve the treatment of TS women in Germany.

Prevalence of autoantibodies associated with thyroid and celiac disease in Ullrich-Turner syndrome in relation to adult height after growth hormone treatment.

A prospective, multicenter study of patients with Ullrich-Turner syndrome (UTS) was conducted to estimate the prevalence of autoantibodies to tissue transglutaminase (tTg), thyroid stimulating hormone receptor (TSH-R), thyroglobulin (TG) and thyroid peroxidase (TPO) in relation to adult height after long-term growth hormone (GH) treatment. Out of 347 near-adult (> 16 years) patients with UTS from 96 German centers, whose longitudinal growth was documented within the Pharmacia International Growth Study (KIGS), 188 returned for a standardized follow-up visit at a median chronological age of 18.7 (16.0-23.6) years (bone age > 15 years). Serum samples of 120 patients were obtained for central measurements of TSH, thyroxine (T4) and free T4 and autoantibodies by standard immunoassays. Information regarding thyroid disease, karyotype and anthropometric data was extracted from the KIGS database. Thirty-six percent of the patients with UTS had positive TG and/or TPO autoantibodies and 4% had positive tTg autoantibodies, whereas 2% had positive TG and/or TPO autoantibodies as well as positive tTg autoantibodies. TSH-R autoantibodies were undetectable in all patients. The detection of autoantibodies was unrelated to a specific karyotype. Median height standard deviation scores (SDS, UTS) at start of GH treatment (0.43; -1.07, 1.85) and at follow-up (1.36; -0.11, 2.57) were comparable in all patients independent of their antibody status. The total deltaheight SDS, however, was higher in patients with negative autoantibody titers (1.08; -0.03, 2.25) compared to those with positive antibody titers (0.68; -0.44, 1.82; p < 0.01). Our study confirms the high prevalence of autoantibodies in patients with UTS predisposing them to autoimmune thyroid disease and celiac disease, and indicates for the first time that autoimmune pathologies may interfere with GH therapy and thus compromise final height. Therefore, medical care for patients with UTS should routinely include screening for these autoimmune disorders in order to assure early detection and appropriate treatment.

Central reassessment of GH concentrations measured at local treatment centers in children with impaired growth: consequences for patient management.

OBJECTIVE: GH deficiency is diagnosed in children if serum GH fails to rise above a predefined cutoff value in response to at least two stimuli. Diagnostic decisions based on this testing are highly variable between centers and depend on the GH assays used. Considering the large spectrum of commercially available GH assays, we wanted to evaluate the agreement between assays, and to test whether assay-related variability of diagnostic decisions could be reduced by reassessment of peak GH concentrations in a reference center. DESIGN: We reanalysed 699 peak GH serum samples obtained after GH testing of 382 children and adolescents from 19 centers using three reference assays and compared these results with those obtained with the local assays. A subgroup of 132 patients tested with the combination of insulin hypoglycemia test and arginine test was evaluated for changes in the assignment to the diagnostic group of GH deficiency. RESULTS: The mean difference between methods ranged from 5.4 to 10.3 mU/l, slopes of the regression lines from 1.28 to 1.65. Significant non-linearity was detected in five of six assay comparisons, indicating that most assay results cannot be interconverted by the use of a factor. Overall agreement between reference and local assays was only moderate. Significant changes in diagnostic assignment occurred when different assays were used on the same patient (P<0.0001-P<0.0023). Based on GH remeasurement by one reference assay, 36 of 132 patients were categorized differently, with 35 patients changing into the GH-deficient group. Similar findings were obtained with the other reference assays. CONCLUSIONS: To decrease variability in GH testing related to assays and cutoff values, we recommend nationwide reassessment of GH peak sera in reference centers. Decisions to treat GH deficiency should incorporate the reference center results.

Central laboratory reassessment of IGF-I, IGF-binding protein-3, and GH serum concentrations measured at local treatment centers in growth-impaired children: implications for the agreement between outpatient screening and the results of somatotropic axis functional testing.

BACKGROUND: Childhood GH deficiency, suspected in the presence of decreased height velocity and short stature, is usually characterized by low IGF-I and IGF-binding protein-3 (IGFBP-3) serum concentrations and is conventionally confirmed by diminished GH peak responses to pharmacological stimuli. OBJECTIVE: We evaluated the agreement between different IGF-I (IGFBP-3) assays in predicting GH deficiency and tested whether variability between growth factor screening and pharmacological testing could be diminished by reassessment of growth factor and GH peak concentrations in a single laboratory. DESIGN: Using the Tuebingen IGF-I (IGFBP-3) RIA, 317 (321) sera from children evaluated for growth disorders in 19 centers were reanalyzed. In 103 children with insulin hypoglycemia and arginine tests, we evaluated how the association between the outcome of growth factor screening and functional testing would change if different assays were employed. RESULTS: Locally measured IGF-I correlated better than IGFBP-3 with the results of the central laboratory (Tuebingen) assay (slope of the regression curve 1.05; 95% confidence interval (95% CI) 1.01-1.1 versus 1.18; 95% CI 1.09-1.3). Agreement between local and central laboratory assays in predicting GH deficiency was better for IGF-I than for IGFBP-3 assays (kappa =0.59 versus kappa =0.47). The poor agreement between growth factor screening and GH pharmacological testing was not improved when hormone concentrations were remeasured in the central laboratory (kappa local=-0.0031, central=0.12). CONCLUSIONS: In children with impaired growth, growth factor screening reflects different aspects of GH insufficiency than does functional testing. Agreement between these approaches is poor and could not be improved by reduction of assay-related variability.

Uterine size in women with Turner syndrome after induction of puberty with estrogens and long-term growth hormone therapy: results of the German IGLU Follow-up Study 2001.

BACKGROUND: To evaluate the factors influencing uterine size in young adult women with Turner syndrome (TS) after long-term growth hormone (GH) treatment. METHODS: Cross-sectional study. Out of 188 women with TS from 96 German centres, whose longitudinal growth was documented within KIGS (Pfizer International Growth Database), data on uterine size were collected voluntarily at a standardized follow-up visit: 75 TS women (ages: 15.8-30.8 years) with complete data were included. Classification according to karyotype: 45,X (78.6%), 45,X/46,XX (5.4%), 45,X/46,iXq (8%), 45,X/46,XY (8%). Puberty was induced with estrogens in all women. At follow-up, 66 were on cyclic estrogens and progestins. RESULTS: 13/66 (19.6%) TS women who received estrogens had a reduced uterine length <5 cm. Calculating the data in standard deviation scores (SDS), only women with 45,X/46,XX karyotype had normal median uterine length and volume of 0.6 and 1.59 SDS respectively. An incomplete breast development (Tanner stage B 3) was found in women with 45,X karyotype (n = 11; 18.6%) and with 45,X/46,XY (n = 2). CONCLUSIONS: Only TS women with karyotype 45,X/46,XX had normal uterine sizes, whereas 26% of the TS women with karyotype 45,X had a uterine length <-2 SDS, and 18% a volume <-2 SDS.