Diagnosing eosinophilic asthma using a multivariate prediction model based on blood granulocyte responsiveness.

BACKGROUND: The identification of inflammatory asthma phenotypes, using sputum analysis, has proven its value in diagnosis and disease monitoring. However due to technical limitations of sputum analysis, there is a strong need for fast and noninvasive diagnostics. This study included the activation state of eosinophils and neutrophils in peripheral blood to phenotype and monitor asthma. OBJECTIVES: To (i) construct a multivariable model using the activation state of blood granulocytes, (ii) compare its diagnostic value with sputum eosinophilia as gold standard and (iii) validate the model in an independent patient cohort. METHODS: Clinical parameters, activation of blood granulocytes and sputum characteristics were assessed in 115 adult patients with asthma (training cohort/Utrecht) and 34 patients (validation cohort/Oxford). RESULTS: The combination of blood eosinophil count, fractional exhaled nitric oxide, Asthma Control Questionnaire, medication use, nasal polyposis, aspirin sensitivity and neutrophil/eosinophil responsiveness upon stimulation with formyl-methionyl-leucyl phenylalanine was found to identify sputum eosinophilia with 90.5% sensitivity and 91.5% specificity in the training cohort and with 77% sensitivity and 71% specificity in the validation cohort (relatively high percentage on oral corticosteroids [OCS]). CONCLUSIONS: The proposed prediction model identifies eosinophilic asthma without the need for sputum induction. The model forms a noninvasive and externally validated test to assess eosinophilic asthma in patients not on OCS.

Extending the limits of reconstructive microsurgery in elderly patients.

BACKGROUND: Population aging strongly affects the demographic development of industrialized countries. While microsurgical procedures were initially believed to be only feasible in patients of younger age because of the duration of the surgical procedure and the higher risk of vascular insufficiency due to age-related comorbidities, it has become evident that these procedures are beneficial even for patients at an advanced age. METHODS: We retrospectively investigated microsurgical procedures in a patient cohort (n = 25 with 27 free flaps) with a minimum age of 78 years with regard to patients' characteristics, flap survival, and postoperative surgical and medical complications. RESULTS: Median age was 81 years (IQR 6). Most defects were located in the head and neck region. The mean operation time was 384 min (standard deviation (SD) 131). Flap failure was observed in three cases (11%). The median length of hospital stay was 17 days (interquartile range (IQR) 8). The mean ASA score was 2.48. Patients' age and ASA group did not correlate. The mortality rate was 4%. Postoperative surgical complications were observed in 11 cases (41%), while 19 patients (70%) showed one or more medical complications. Higher ASA classes tended to show more postoperative complications. However, neither age nor operating time nor ASA status showed significant influence on the occurrence of postoperative medical or surgical complications. CONCLUSION: There is growing demand for structural and functional restoration using free tissue transfer in an aging population. If there are no alternative treatment options available promising similar structural and functional preservation, free tissue transfer is justifiably in very old patients despite a potentially increased flap failure. As such, free tissue transfer is used as a curative treatment concept aiming at a maximum of patients' independence and early ambulation. Occurrence of complications can be diminished by adequate patient selection and thorough perioperative care.

Complete mitochondrial genomes of ancient canids suggest a European origin of domestic dogs.

The geographic and temporal origins of the domestic dog remain controversial, as genetic data suggest a domestication process in East Asia beginning 15,000 years ago, whereas the oldest doglike fossils are found in Europe and Siberia and date to >30,000 years ago. We analyzed the mitochondrial genomes of 18 prehistoric canids from Eurasia and the New World, along with a comprehensive panel of modern dogs and wolves. The mitochondrial genomes of all modern dogs are phylogenetically most closely related to either ancient or modern canids of Europe. Molecular dating suggests an onset of domestication there 18,800 to 32,100 years ago. These findings imply that domestic dogs are the culmination of a process that initiated with European hunter-gatherers and the canids with whom they interacted.

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.

[Ageing and change of values]. / Altern und Wertewandel.

The process of ageing and the relevant scientific disciplines are influenced by societal values und priorities. Values are the object of scientific and public reflection mainly in times of strong changes and obvious conflicts. The article discusses fundamental social and cultural changes from collective integration to personal freedom and autonomy. The focus of this paper is directed towards the impact of the consequences and contradictions of such cultural changes on the process of ageing and of ageing research.

Variants of the FTO gene in obese children and their impact on body composition and metabolism before and after lifestyle intervention.

OBJECTIVE: To investigate the impact of variants of the FTO gene (rs1421085, rs17817449, rs9939609) in obese children before and after lifestyle intervention. DESIGN: Longitudinal, clinical intervention study with an increase in physical activity, and nutritional recommendations based on the 'Optimized Mixed Diet for German Children and Adolescents' (Research Institute of Child Nutrition, Germany). STUDY POPULATION: 75 overweight children (40 male, mean BMI 30.4±5.5 kg/m², mean age 12.6±2.6 years). MEASUREMENTS: Genotyping by means of a TaqMan SNP genotyping assay. Lean and fat mass were determined by means of DXA. RESULTS: For the whole study population, the 6-month lifestyle intervention resulted in a significant improvement (before intervention minus time point 6 months; mean±SD) in BMI-SDS (0.10±0.17, p<0.001), HOMA (1.41±3.19, p<0.001) and relative fat-mass-SDS (0.09±0.23, p=0.005). Before and after lifestyle intervention, there was no significant difference between heterozygote (n=52) and homozygote (n=21) carriers of the FTO gene in terms of BMI, body composition, and the metabolic profile (Insulin, HOMA, lipids, liver function tests). CONCLUSION: Variants in the FTO gene are common in obese children but have no impact on body composition and metabolism before and after lifestyle intervention.

Morphology and hemodynamics during vascular regeneration in critically ischemic murine skin studied by intravital microscopy techniques.

BACKGROUND: With the understanding of angiogenesis and arteriogenesis, new theories about the orchestration of these processes have emerged. The aim of this study was to develop an in vivo model that enables visualization of vascular regenerating mechanisms by intravital microscopy techniques in collateral arteriolar flap vascularity. METHODS: A dorsal skin flap (15 × 30 mm) was created in mice and fixed into a skinfold chamber to allow for assessment of morphology and microhemodynamics by intravital fluorescence microscopy (IVFM). Laser scanning confocal microscopy (LSCM) was utilized for three-dimensional reconstruction of the microvascular architecture. RESULTS: Flap tpO(2) was 5.3 ± 0.9 versus 30.5 ± 1.2 mm Hg in controls (p < 0.01). The collateral arterioles in the flap tissue were dilated (29.4 ± 5.3 µm; p < 0.01 vs. controls) and lengthened in a tortuous manner (tortuosity index 1.00 on day 1 vs. 1.35± 0.05 on day 12; p < 0.01). Functional capillary density was increased from 121.00 ± 25 to 170 ± 30 cm/cm(2) (day 12; p < 0.01) as a result of angiogenesis. Morphological evidence of angiogenesis on capillary level and vascular remodeling on arteriolar level could be demonstrated by IVFM and LSCM. CONCLUSIONS: Present intravital microscopy techniques offer unique opportunities to study structural changes and hemodynamic effects of vascular regeneration in this extended axial pattern flap model.

Analysis of the GH content within archived dried blood spots of newborn screening cards from children diagnosed with growth hormone deficiency after the neonatal period.

OBJECTIVE: It is unknown whether GH secretion of children with growth hormone deficiency (GHD) is already diminished at birth. We aimed to determine the GH content within archived dried blood spots of newborn screening cards from children diagnosed with GHD at childhood. DESIGN: At our hospital, all children with the diagnosis of GHD and an actual age <10years were identified. For 16 patients (mean age, 7.4years; range, 1.0-9.7), screening cards were available. The archived dried blood from the first 48 to 96h of life was eluated in buffer of a highly sensitive hGH-ELISA to measure the GH content. Reference values were calculated based on 600 anonymous newborn screening cards of different ages. RESULTS: Median GH content within the archived dried blood spots of the reference had declined by 30% during the first year and by further 35% during the next 8.5years of storage. After correction for time of storage, four out of the 16 archived dried blood spots of the GHD children contained low amounts of GH (≤5th percentile). Diminished GH secretion at birth was absent in isolated GHD, but associated with multiple pituitary hormone deficiency (MPHD) (P=0.0013), ectopic neurohypophysis (P=0.0013), lower GH test peak values (P=0.02) and higher weight at diagnosis (P=0.015). CONCLUSIONS: Children with isolated GHD have normal GH secretory capacity during the first week of life while the majority of children with MPHD and pituitary malformation were GH deficient immediately after birth.

Short children with low birth weight born either small for gestational age or average for gestational age show similar growth response and changes in insulin-like growth factor-1 to growth hormone treatment during the first prepubertal year.

BACKGROUND/AIMS: Growth hormone (GH) is an accepted treatment for short children born small for gestational age (SGA). The aim of this analysis was to compare the growth response to GH in children with low birth weight born SGA or appropriate for gestational age (AGA). METHODS: This retrospective observational study is from one center. Of all the children with a birth weight <2,500 g treated, 50 were primarily diagnosed as having growth hormone deficiency ([A] SGA, n = 26; [B] AGA, n = 24) and 138 were originally diagnosed SGA or AGA (reclassified: [C] SGA, n = 102; [D] AGA, n = 36). RESULTS: [Median; A, B, C, D]: at an age of 4.9, 5.2, 5.8, 5.8 years, a height of -2.9, -2.4, -2.8, -2.9 SDS and a GH dose of 27, 28, 41, 39 µg/kg/day, the children grew 0.9, 0.9, 0.8, 0.9 SDS in height, respectively. Insulin-like growth factor-1 (IGF-1) at GH start was, respectively, -2.1, -2.2, -0.4, -0.9 SDS and rose to (delta IGF-1) 1.8, 2.0, 1.7, 1.5 SDS during the first year on GH. All differences were not significant. CONCLUSIONS: We show for the first time that short stature children with low birth weight born AGA experience the same increase in height and IGFs to GH treatment as those born SGA irrespective of actual GH secretory status.

Auxology-based cut-off values for biochemical testing of GH secretion in childhood.

OBJECTIVE: The diagnosis of GH deficiency (GHD) in childhood requires GH tests with arbitrary cut-offs. We aimed to define GH cut-offs based on auxology. DESIGN: From a total of 349 children diagnosed with GHD between 1985 and 2005 at our hospital, we excluded all children who had additional characteristics likely to interfere with growth velocity. Age at start of therapy was defined as 4 to 8/9 years (girls/boys). Auxological inclusion criteria were pathological growth velocity, height at start of therapy >1.5 SD below the target, and efficient catch-up growth during GH therapy. Basal IGF-I/IGFBP-3, GH response to arginine and spontaneous GH secretion at night had been measured by the same polyclonal RIA. The reference was a group of 108 normally growing age-matched children with Turner syndrome or born small for gestational age tested during the same time period. RESULTS: We identified 52 children with GHD who fulfilled the inclusion criteria. ROC analysis showed the best diagnostic accuracy at a peak GH cut-off for arginine of 6.6 µg/L (sensitivity, 84.3%; specificity, 75.5%; AUC=0.83) and at a peak GH cut-off during spontaneous secretion at night of 7.3 µg/L (sensitivity, 96.8%; specificity, 82.4%; AUC=0.93). Our arbitrarily defined GH cut-offs had been higher. Children diagnosed with GHD in the past with GH test values above the new cut-offs were less responsive to GH therapy (P=0.007). CONCLUSIONS: Here we provide a new rational approach which allows the substitution of arbitrarily defined GH cut-offs by those based on auxology.

The functional muscle-bone unit in obese children - altered bone structure leads to normal strength strain index.

UNLABELLED: Obese children have a twofold increased risk of fracture of the forearm compared to non-obese children. OBJECTIVE: To investigate bone strength and bone structure of the forearm, and the relationship between muscle and bone in obese children. METHODS: The study-group consisted of 84 (40 female) overweight children (mean (SD)) age 11.8 (3.2) years, BMI 29.0 (5.1) kg/m(2)). Bone geometry and strength were measured at the proximal radius of the non-dominant forearm (65% measurement site) by means of pQCT (XCT 2000). Bone mineral density and lean mass of the total body was determined by means of DXA (Lunar, DPXL/PED). Results were compared to reference values by calculating age (SDS(CA)) and height-age (SDS(HA)) dependent standard deviation scores (SDS). RESULTS: Cortical density, -1.11 (1.74) SDS(HA), -0.45 (1.52) SDS(CA); cortical thickness, -1.46 (1.33) SDS(HA), -1.01 (1.46) SDS(CA); cortical area, -0.42 (1.31) SDS(HA), 0.26 (1.58) SDS(CA); total bone area +2.21 (1.47) SDS(HA), 2.91 (1.80) SDS(CA), marrow area +3.12 (2.29) SDS(HA), 3.37 (2.38) SDS(CA); strength strain index +0.10 (1.10) SDS(HA), 0.95 (1.57) SDS(CA). These changes in bone structure were independent from pubertal stage. Measurements revealed correlations between muscle area and SSI (R(2)=0.67, p<0.001), and muscle mass and bone mineral content (DXA; R (2)=0.81, p<0.001). CONCLUSION: Low cortical density, normal cortical area and increased total bone area led to a normal strength strain index adjusted both for height and for age. We assume that this normal bone strength is not appropriate for the higher kinetic energy of impact in case of a fall in overweight children.

Investigation of myostatin serum levels before and after a 6-month lifestyle intervention program in obese children.

OBJECTIVE: To investigate the relationship between myostatin serum levels and muscle mass, fat mass and HOMA before and after a 6-month lifestyle intervention program in obese children and adolescents. DESIGN: A total of 57 overweight children and adolescents (female, n=27; age range, 6.0-16.1 years) were examined between 2007 and 2009. Mean BMI (±SD) was 31.1 (5.7) kg/m(2) corresponding to a mean BMI-SDS LMS of 2.2 (0.4). Muscle and fat mass were determined by means of DXA. Serum myostatin was measured by using a competitive ELISA. RESULTS [MEAN±SD]: After the 6-month intervention program, muscle mass (+2.1±2.7 kg, p<0.0001), and percentage myostatin serum levels (+23.7±26.7%, p<0.0001) were higher than before, whereas decreases in BMI (-0.4 kg/m(2)±1.5, p<0.0001), fat mass (-1.2±3.9 kg, p<0.0001), and HOMA insulin sensitivity index (-0.78±3.28 SD, p=0.0004) were observed. In 86% (n=49, p<0.0001) of all cases, the intervention program resulted in a higher level of myostatin. After lifestyle intervention, patients with the greatest increase of myostatin had a significantly lower increase of muscle mass (p=0.048) but did not differ for fat mass. There was no significant correlation between Myostatin and HOMA insulin sensitivity index before and after lifestyle intervention. CONCLUSION: Both muscle mass and serum myostatin increased concordantly. Patients with the greatest rise of myostatin had a significantly lower increase of muscle mass suggesting a negative feedback loop between myostatin and muscle tissue. In our study, the change of myostatin serum levels was not associated with the amount of fat mass or HOMA insulin sensitivity index.

Steroids induce a disequilibrium of secreted interleukin-1 receptor antagonist and interleukin-1ß synthesis by human neutrophils.

Chronic obstructive pulmonary disease (COPD) is characterised by neutrophilic inflammation in the airways and these neutrophils contribute to the production of inflammatory mediators. Dampening the production of proinflammatory mediators might be an important strategy to treat COPD and glucocorticosteroids are known to do so via inhibition of nuclear factor-κB. However, this pathway is important for the control of pro- and anti-inflammatory genes. We studied the effects of dexamethasone on production and secretion of pro-inflammatory interleukin (IL)-1ß and anti-inflammatory secreted IL-1 receptor antagonist (sIL-1Ra) by human neutrophils activated with tumor necrosis factor (TNF)-α. In vitro, TNF-α-stimulated neutrophils produced significant amounts of IL-1ß and sIL-1Ra; this production was inhibited by dexamethasone. However, synthesis and secretion of sIL-1Ra was inhibited at lower concentrations dexamethasone compared to IL-1ß, which changed the IL-1ß:sIL-1Ra ratio significantly. This altered ratio resulted in a more pro-inflammatory condition, as visualised by increased intercellular adhesion molecule-1 expression on human endothelial cells. In vivo, moderate-to-severe COPD patients using inhaled glucocorticosteroids have decreased plasma sIL-Ra levels compared with mild-to-moderate patients not on glucocorticosteroid treatment. In conclusion, dexamethasone induces a pro-inflammatory shift in the IL-1ß:sIL-1Ra cytokine balance in neutrophils in vitro, which might contribute to a lack of endogenous anti-inflammatory signals to dampen inflammation in vivo.

[Waiting time for and length of physicianc's consultation define the patient-physician interaction: results of a prospective study in 478 patients with chronic viral hepatitis]. / Wartezeiten und Länge des Arztgesprächs bestimmen aus Patientensicht die Qualität der Arzt-Patienten-Beziehung bei chronischer Hepatitis B und C: Ergebnisse einer prospektiven Studie bei 478 Patienten mit chronischer Virushepatitis.

BACKGROUND: Little is known about the physician-patient interaction in hepatitis B and C. METHODS: This study by the federal competence network hepatitis analysed the physician-patient interaction using the validated FAPI questionnaire. The questionnaire also contained questions concerning demography and disease characteristics. Of the total 1500 questionnaires sent out, 478 were returned (32 %) (20 % HBV vs. 80 % HCV). RESULTS: The FAPI index of patients with HBV/HCV infection (3.10 +/- 0,99) was lower than that in patients with other internal medicine diseases (3.61 +/- 0.92; n = 148). Women had lower values than men (2.98 vs. 3.25; p = 0.005). Patients with active HBV infection showed higher values than those with HCV infection (3.27 vs. 2.97; p < 0.05). Patients with successfully treated hepatitis B/C had higher values than those with active disease (3.36 vs. 3.02; p = 0.004). The index was lower in patients who waited > 2 weeks for the consultation when compared to those with a shorter wait (2.92 vs. 3.31; p < 0.001) and was also lower in patients who waited > 30 min at the consultation day when compared to those with a shorter wait (2.81 vs. 3.39; p < 0.001). The index gradually increased with the consultation length (2.47 < 10 min vs. 2.79 10 - 15 min vs. 3.21 15 - 30 min vs. 3.82 > 30 min; p < 0.001). The index was higher in patients seen by gastroenterologists (3.43) when compared with general practioners (3.10), internists (3.02) and clinical settings (3.13) (p < 0.05). A good information status was associated with higher FAPI values when compared with a bad information status (3.43 vs. 2.76; p < 0.001). Fibrosis, health insurance and age were not associated with FAPI index (p > 0.2). By multivariate analysis a long consultation, a good information status, patients' patience, short waiting times, and providing contact to a patient support group were independently associated with a high index. CONCLUSIONS: The physician-patient interaction in chronic viral hepatitis is worse than in other internal medicine diseases with problems being more pronounced in HCV infection and women when compared to men and HBV infection. Short waiting times and patients' patience ameliorated the interaction as well as the consultation length, the information status of the patient and providing contact to a patient support group. Type of health insurance did not affect either waiting times or physician-patient interaction; thus there is no hint for a two-class medicine in this part of hepatology.

Follow-up of adolescents with diabetes after transition from paediatric to adult care: results of a 10-year prospective study.

OBJECTIVE: Our main objective in this study was to identify the type of clinical care received by young type 1 diabetic patients who have made the transition from paediatric to adult care, and to assess the metabolic status of long-term treatment after the transition. METHODS: A standardized questionnaire was used prospectively to follow 99 patients with type 1 diabetes mellitus after their transition to adult care. This survey was done once a year, from 1998 to 2008. RESULTS: Directly after transition from paediatric care 38.4% of patients were found at specialised outpatient units; whereas 41.1% received care at a diabetes centre and 20.5% were monitored by general practitioners or specialists in internal medicine. Five-year results showed that 25.0% had continued to visit an outpatient unit; 41.7% were still visiting a diabetes centre; and 33.3% had remained in the care of general practitioners or internal specialists. We observed a trend showing slight improvements in the HbA1c values over time, however no major changes in metabolic control were observed after transition. CONCLUSIONS: Transition marks a critical phase for young, diabetic patients as they may frequently switch from one physician or centre to another. The individual optimization of therapy, established during paediatric care, provides the decisive groundwork for disease control in young adults.

Prevalence and incidence of endocrine disorders in children: results of a survey in Baden-Wuerttemberg and Bavaria (EndoPrIn BB) 2000-2001.

BACKGROUND: Sparse data is available on the incidence of endocrine disorders among children in Germany. AIM: A pioneer study was established to analyse, in the German states of Baden-Wuerttemberg (BW) and Bavaria (BY), the incidence and prevalence of congenital adrenal hyperplasia (AGS; CAH), precocious puberty (PP), primary congenital hypothyreosis (PCH), Graves disease (MB), and growth disorders related to the Ullrich-Turner syndrome (UTS) and growth hormone deficiency (GHD). METHODS: Participation in the study involved each paediatric hospital in BW and BY (n = 63),and all regional paediatricians belonging to the Association of Statutory Health Insurance Physicians (SHI) practising in these states (n = 1 443). Data collection was done from January 1, 2000, to December 31, 2001, and included all patients in the 0- < 18 age range. RESULTS: Completeness of data was 81 % for CAH and 55 % for UTS (capture-mark-recapture method).The incidence rate (IR, per 100 000 / year)versus prevalence rate (per 100 000 at the time point December 31, 2001) was: CAH 0.64 vs.9.60; PP 2.42 vs. 10,85; PCH 1.88 vs. 14.97; MB 0.89 vs. 3.25; UTS 2.15 vs. 29.07; and GHD 3.47(IR). Among neonates, the incidence of CAH was 1 / 7 794; PCH 1 / 2 629 and UTS 1 / 2 300. CONCLUSIONS: A pioneer study has been established in Germany for investigating the frequency of AGS (CAH), PP, PCH, MB, UTS, and GHD among children and adolescents. Our data shows that these disorders occur in approx. 2,700 children per year in total Germany, and about 12 000 of these children need to be treated in specialized paediatric endocrinological centres.

Musculoskeletal abnormalities in juvenile idiopathic arthritis--a 4-year longitudinal study.

OBJECTIVES: Bone density in juvenile idiopathic arthritis (JIA) is largely normal whereas geometric parameters of bone are abnormal. The most prominent changes are a reduction in muscle cross sectional area (CSA) and muscle force. The aim of this study was to assess the evolution of these changes throughout the course of the disease. METHODS: Twenty-five JIA patients were assessed by peripheral quantitative computed tomography longitudinally with a median of 48 months between measurements. At the non-dominant forearm, parameters of bone density and geometry as well as muscle CSA were recorded. The strength-strain index (SSI) as an indicator of bone strength was determined. RESULTS: Muscle CSA improved from a median Z-score of -1.94 to -1.10 at follow-up. Cortical thickness increased from -1.55 to -0.97 whereas marrow area remained enlarged at 0.96 vs 1.05. Cortical density remained normal at 0.34 vs 0.69 and trabecular density improved from -0.75 to -0.36. The SSI increased from -0.79 to -0.13. CONCLUSIONS: JIA patients show some improvement in muscle CSA and an increase in cortical thickness. The marrow area remains enlarged but by increasing the cortical thickness, area and diameter, bone strength increases. These geometric adaptations, for the first time shown in this study, nevertheless represent a disturbance in skeletal development. In addition to efficient disease control, training modalities to improve muscle strength and subsequent bone development have to be included in therapeutic approaches.

The d3-growth hormone (GH) receptor polymorphism is associated with increased responsiveness to GH in Turner syndrome and short small-for-gestational-age children.

CONTEXT: A protein polymorphism of the GH receptor (GHR) based on the genomic deletion of exon 3 (d3-GHR) has recently been linked to the magnitude of growth response to high-dose recombinant human GH (rhGH) therapy of short children without GH deficiency. OBJECTIVE: This study tests the novel association in two distinct groups of rhGH-treated patients, short girls with Turner syndrome and short children born small for gestational age (SGA). DESIGN: The retrospective study included all children who were treated with rhGH during the last 18 yr at our hospital. PATIENTS: Patients with Turner syndrome were defined by the specific karyotype (n = 53), short children born SGA were determined by birth length and/or weight less than -2.0 sd score and a height at start of rhGH therapy less than -2.0 sd score (n = 60). Exclusion criteria were puberty, an age less than 3.5 or more than 14 yr, and GH deficiency. MATERIALS AND METHODS: Growth prediction for the first year of therapy was calculated on the basis of rhGH dose, age, weight, height, and gender-adjusted midparental height according to the prediction models by Ranke et al. The GHR-exon 3 locus was genotyped using a PCR multiplex assay. GH, IGF-I, and IGF binding protein 3 (IGFBP-3) were measured by RIA. INTERVENTION: For growth promotion, a mean rhGH dose of 38 mug/kg.d (sd, +/-8) was administered in Turner syndrome patients and 56 mug/kg.d (sd, +/-11) in short children born SGA. RESULTS: No significant difference in height, spontaneous height velocity, IGF-I, and IGFBP-3 levels was found at the start of rhGH therapy in the three GHR genotype groups studied. At the first year of treatment, girls with Turner syndrome carrying one or two d3-GHR alleles showed a significantly higher increment in height velocity (P = 0.019) and exceeded their growth prediction significantly (P = 0.007), whereas their increments of IGF-I and IGFBP-3, weight, and height were not significantly different. Carriers of d3-GHR in the group of short children born SGA grew significantly faster than predicted (P = 0.023). However, in comparison to the carriers of full-length GHR, gain of height velocity was not significantly higher (P = 0.067). The mean gain of height associated with d3-GHR accounted for approximately 0.75 cm in SGA and 1.5 cm in Turner syndrome during the first year of rhGH therapy. CONCLUSIONS: Our data support the theory that there is increased responsiveness to high-dose rhGH in association with the d3-GHR genotype. The magnitude of this effect may depend on the primary origin of the short stature.

Dominant transmission of prepubertal gynecomastia due to serum estrone excess: hormonal, biochemical, and genetic analysis in a large kindred.

Increased extraglandular aromatization has been reported to cause the rare entity of familial gynecomastia. Recently heterozygous inversions at the p450 aromatase gene promotor locus were detected in two different families with this syndrome. We studied a family in which seven affected males over three generations had inherited prepubertal gynecomastia in an autosomal dominant manner. The proband developed gynecomastia at 11.5 yr, entered puberty at 12.5 yr, but was incompletely virilized at 19 yr. A similar development was observed in his affected stepbrother and one first-degree cousin. All three boys had acceleration of prepubertal growth and bone age. The older two had a diminished pubertal growth spurt and precocious growth arrest, but their final heights were within the range of their target height. In addition, the maternal grandfather and three maternal uncles were affected, who all had been mastectomized. The mother of the proband had normal age at menarche and no macromastia. Estrone levels of the proband and the other affected boys were elevated, 17beta-estradiol levels were high-normal, and testosterone levels were low. Hormonal analyses of the affected adults, who had all fathered children, revealed pathologically low serum testosterone levels but normal to high-normal levels of estradiol and estrone. The mother of the proband had elevated estrone levels. Treatment of the proband was more effective with anastrozole than with testolactone and increased the initially reduced testes volume to normal size, promoted virilization, and normalized serum estrone and testosterone levels. Neither preadipocytes from breast fat tissue of the affected stepbrother nor peripheral lymphocytes of the affected boys exhibited increased aromatase activity in culture. Therefore, these cells can be excluded from being the source of estrone excess. In addition, serum of the proband and his stepbrother did not contain factors promoting aromatase activity as assayed using preadipocytes from control individuals.A repeat polymorphism of the p450 aromatase gene cosegregated with the disease phenotype in the family, making a mutation of the p450 aromatase gene likely. Single-strand conformational polymorphism analysis of the known alternative untranslated exons and all coding exons of the p450 aromatase gene did not indicate any mutation. In addition, fluorescent in situ hybridization analysis using four probes covering the promotor region did not reveal the presence of any major inversion at this locus. In conclusion, preadipocytes and blood cells were excluded as the cell source of increased aromatization. Fluorescent in situ hybridization and single-strand conformational polymorphism analyses did not reveal any mutation of the p450 aromatase gene, but an intragenic polymorphic marker cosegregated with the disease phenotype. Excess of serum estrone in the presence of normal 17beta-estradiol levels may be the only indicative serum parameter of this mild manifestation of aromatase excess syndrome, which includes prepubertal gynecomastia and moderate hypogonadism in men but not necessarily short stature. In women, this mode of aromatase excess may remain clinically inapparent.

Cortical bone density is normal in prepubertal children with growth hormone (GH) deficiency, but initially decreases during GH replacement due to early bone remodeling.

Dual energy x-ray absorptiometry (DEXA) has revealed that GH- deficient adults gain in bone mineral density during GH therapy. Measurements of volumetric bone density (grams per cubic centimeter vs. grams per square centimeter) and structure, however, are achieved through peripheral quantitative computed tomography (pQCT). In 45 prepubertal GH-deficient children, we studied pQCT measurements before the start and for 12 months of GH treatment. Serum alkaline phosphatase (AP), procollagen I carboxyl-terminal propeptide (PICP), and deoxypyridinoline reflected bone metabolism status. Findings at the start of GH treatment were (mean SD score): bone area, -0.44; cortical density, -0.03; cortical area, -1.32; cortical thickness, -1.41; and marrow area, +0.66. At 12 months, cortical density had fallen to -0.73 (P < 0.001), whereas cortical area and thickness, and marrow area did not change. AP, PICP, and deoxypyridinoline increased significantly within the first 3 months (increase: AP, 66.5 U/liter; PICP, 72 microg/liter; DPD, 11.4 nmol/mmol creatinine). The pQCT showed that cortical density is not reduced in GH-deficient patients. Higher bone metabolism explains the lower cortical density after GH therapy commenced. Thus, the manifestation of GH deficiency is evidently similar in children and adults, and pQCT provides important information in addition to DEXA measurements, as DEXA does not take bone structure into account.