Stefan Riedl - Academia.edu (original) (raw)

Papers by Stefan Riedl

Research paper thumbnail of Pituitary Hyperplasia in a Girl with Gonadal Dysgenesis and Primary Hypothyroidism

Hormone research, 1997

A 16-year-old Brazilian girl presented with severe growth retardation (-6.3 SDS), obesity, delaye... more A 16-year-old Brazilian girl presented with severe growth retardation (-6.3 SDS), obesity, delayed pubertal development, facial dysmorphia, dry skin, and borderline low intelligence (IQ 89). Endocrinological evaluation showed primary hypothyroidism (no uptake of iodine-131 of the right thyroid lobe). Basal and stimulated gonadotropins were increased and ultrasonography revealed hypoplastic ovaries. The karyotype of peripheral lymphocytes was 46,X,i(Xq). The GH response in euthyroid condition after stimulation with GHRH and insulin was diminished. MRI of the pituitary region showed a suprasellar mass (12 x 15 mm) which was removed by transsphenoidal surgery because of extension to the optic chiasm. Histological examinations revealed regular pituitary tissue with hyperplasia of TSH- and FSH-producing cells. Thyroxine treatment was adjusted and GH was given. We conclude that the suprasellar mass was the consequence of long-lasting hypothalamic overstimulation with TRH and LHRH, due to gonadal and thyroid insufficiency.

Research paper thumbnail of How effective and safe is growth hormone therapy in children born small for gestational age?

Research paper thumbnail of Childhood growth hormone deficiency (GHD) and idiopathic short stature (ISS): how far can a consensus go?

Research paper thumbnail of Transition from paediatric to adult endocrine care in patients with childhood onset growth hormone deficiency

Research paper thumbnail of Lymphocyte subsets in renal transplant recipients during growth hormone therapy

PubMed, Mar 1, 1999

Objective: To evaluate the effect of growth hormone treatment on growth, levels of insulin-like g... more Objective: To evaluate the effect of growth hormone treatment on growth, levels of insulin-like growth factor I (IGF-I) and lymphocyte subsets in immunosuppressed renal allograft recipients. Methods: 18 children (aged 8.0-16.6 years) received growth hormone 1 IU/Kg/week daily for two years. Height, IGF-I levels and in 11/18 patients, lymphocyte subsets were evaluated serially. Results: Standardized growth velocity increased from -1.0+1.5 to +1.2+2.2 and standardized IGF-I levels from +0.8+1.5 to +3.1+1.1 (1 year) and to +1.4+1.7 (2 years). The total lymphocyte count and the number of T lymphocytes (CD3+) decreased. The decrease was more marked in CD8+ (from 1.5+0.3 x10(9)/L to 0.9+0.3 x10(9)/L, 1 year and to 0.8+0.1 x10(9)/L, 2 years) compared to CD4+ (from 1.5+0.3 x10(9)/L to 1.0+0.2 x10(9)/L, 1 year and to 1.3+0.2 x10(9)/L, 2 years), resulting in an increment of the CD4+/CD8+ index. Conclusions: The differential effect of growth hormone treatment on CD4+ and CD8+ lymphocytes might be explained by different expression of the IGF-I receptor in these distinct subsets.

Research paper thumbnail of Diagnosis of Growth Hormone Excess and Hyperprolactinemia

Research paper thumbnail of Posterior Pituitary Ectopy in Children with Idiopathic Growth Hormone Deficiency

Journal of Pediatric Endocrinology and Metabolism, 2000

Aims: To evaluate the underlying pathogenesis in children with pituitary hormone deficiency by me... more Aims: To evaluate the underlying pathogenesis in children with pituitary hormone deficiency by means of high resolution MRI of the brain. Patients/Methods: Thirty-seven children with short stature and isolated GH deficiency (IGHD, η = 17) or multiple pituitary hormone deficiency (MPHD, n=20) were subjected to an MRI of the brain at the age of 1.0-17.3 years. The anatomic condition of the hypothalamo-pituitary area was analyzed and the height of the pituitary gland was measured and compared to the data of agematched healthy subjects. Results: Seventy percent of the patients had a characteristic anomaly: the adenohypophysis was hypoplastic, the infundibulum was absent and the posterior pituitary lobe was ectopic at the bottom of the median eminence. The height of the anterior pituitary was significantly reduced in these patients (1.9 ± 0.1 mm; mean ± SD) when compared to age-matched healthy controls (4.1 ± 0.8 mm, p<0.001) or hypopituitary patients with a normal MRI (4.3 ± 0.8 mm). MPHD was found in 62% of patients with the pituitary anomaly whereas only 27% of children with a normal MRI had MPHD (p<0.05). Conclusions: The pathogenesis of the pituitary anomaly is unknown; a disorder during embryonal development or perinatal events have been discussed as causal factors. MRI should have a prominent position in the work-up of hypopituitary children. When an anatomical malform

Research paper thumbnail of Effects of Growth Hormone (GH) and Insulin-like Growth Factor-I Therapy in patients with Gene Defects in the GH Axis

Journal of Pediatric Endocrinology and Metabolism, 2006

We report on four patients (3 F) who were diagnosed as having either a 6.7 kb GH1 gene deletion, ... more We report on four patients (3 F) who were diagnosed as having either a 6.7 kb GH1 gene deletion, a GH1 signalling peptide mutation, or a GH receptor mutation, with particular regard to treatment modalities (GH, rhIGF-I) and final height. Patients with GH1 gene defects developed anti-GH antibodies (GH-Ab) following GH treatment. Surprisingly, growth response to GH was unrestricted in one girl, who reached a final height within her target height range, whereas her cousin with the identical genetic defect responded far less favourably. Variability in the growth inhibiting potency of GH-Ab may therefore depend on genetic disposition, specific epitopes, or induction of immunological tolerance. Growth response during rhIGF-I treatment carried out in three of the patients was moderate, but pubertal development and bone age acceleration occurred in the two patients treated at pubertal age. GH resistance, either caused by GH-Ab or GH receptor mutations, is still difficult to treat and results in a heterogeneous outcome.

Research paper thumbnail of LHRH-Agonist-Behandlung von kleinw�chsigen Jugendlichen

Monatsschrift Kinderheilkunde, Aug 1, 2003

Die Therapie mit einem LHRH-Agonisten (LHRHa) zur Unterdrückung der pulsatilen LH-Ausschüttung wi... more Die Therapie mit einem LHRH-Agonisten (LHRHa) zur Unterdrückung der pulsatilen LH-Ausschüttung wird seit nunmehr über 20 Jahren bei Kindern mit zentraler Pubertas praecox angewendet. Nicht allzu ferneliegend war die etwas später erprobte Idee, durch Unterdrückung der zum normalen Zeitpunkt eintretenden Pubertät bei kleinwüchsigen Adoleszenten die präpubertäre Wachstumsphase zu verlängern und einen Nettoendlängengewinn zu erzielen. Man sah jedoch, dass eine kurzzeitige (1–2 Jahre) isolierte pubertätshemmende Behandlung statistisch keinen Zuwachs brachte, wobei die kombinierte Therapie mit Wachstumshormon (WH) bei einzelnen Patienten eine Wirkung zeigte. Die Evaluation des Effekts wurde jeweils durch Vergleich der prospektiven Endlänge anhand der Knochenalterbestimmung vor Therapie mit der Prognose nach Therapie bzw.der tatsächlich erreichten Endlänge ermittelt.

Research paper thumbnail of Growth Hormone Suppression: Diagnosis of Growth Hormone Excess and Hyperprolactinemia

Research paper thumbnail of LHRH-Agonist-Behandlung von kleinw�chsigen Jugendlichen

Monatsschrift Kinderheilkunde, 2003

Die Therapie mit einem LHRH-Agonisten (LHRHa) zur Unterdrückung der pulsatilen LH-Ausschüttung wi... more Die Therapie mit einem LHRH-Agonisten (LHRHa) zur Unterdrückung der pulsatilen LH-Ausschüttung wird seit nunmehr über 20 Jahren bei Kindern mit zentraler Pubertas praecox angewendet. Nicht allzu ferneliegend war die etwas später erprobte Idee, durch Unterdrückung der zum normalen Zeitpunkt eintretenden Pubertät bei kleinwüchsigen Adoleszenten die präpubertäre Wachstumsphase zu verlängern und einen Nettoendlängengewinn zu erzielen. Man sah jedoch, dass eine kurzzeitige (1–2 Jahre) isolierte pubertätshemmende Behandlung statistisch keinen Zuwachs brachte, wobei die kombinierte Therapie mit Wachstumshormon (WH) bei einzelnen Patienten eine Wirkung zeigte. Die Evaluation des Effekts wurde jeweils durch Vergleich der prospektiven Endlänge anhand der Knochenalterbestimmung vor Therapie mit der Prognose nach Therapie bzw.der tatsächlich erreichten Endlänge ermittelt.

Research paper thumbnail of Diagnosis of Growth Hormone Excess and Hyperprolactinemia

Diagnostics of Endocrine Function in Children and Adolescents, 2011

Research paper thumbnail of Lymphocyte subsets in renal transplant recipients treated with mycophenolate mofetil

Transplantation Proceedings, 2000

Introduction: The incidence of genitourinary tumors (GUT) in renal transplant recipients (RTR) is... more Introduction: The incidence of genitourinary tumors (GUT) in renal transplant recipients (RTR) is higher than in the general population. We previously reported that CD4 lymphocytopenia is associated with a high incidence of skin cancer in RTR. Here, we investigate whether persistent CD4 T cell lymphopenia is associated with GUT occurrence. Patients and Methods: A total of 433 patients were included in this study. All patients underwent annually systematic lymphocyte subset (CD3, CD4, CD8, CD19) determination by flow cytometry. Results and Conclusion: During the follow-up period, 13 patients developed GUT: 6 patients a prostate adenocarcinoma (incidence 0.06%/year) and 7 patients a renal cell carcinoma (incidence 0.07%/year). The patients with GUT were older than those without. Both groups did not differ in posttransplant duration, dialysis mode and duration, induction regimen, or acute rejection history. No persistent CD4 lymphopenia was observed in the patients with GUT. Although CD4 T cell lymphopenia is associated with skin cancer in long-term RTR, it did not appear to be a risk factor

Research paper thumbnail of Effects of Growth Hormone (GH) and Insulin-like Growth Factor-I Therapy in patients with Gene Defects in the GH Axis

Journal of Pediatric Endocrinology and Metabolism, 2006

We report on four patients (3 F) who were diagnosed as having either a 6.7 kb GH1 gene deletion, ... more We report on four patients (3 F) who were diagnosed as having either a 6.7 kb GH1 gene deletion, a GH1 signalling peptide mutation, or a GH receptor mutation, with particular regard to treatment modalities (GH, rhIGF-I) and final height. Patients with GH1 gene defects developed anti-GH antibodies (GH-Ab) following GH treatment. Surprisingly, growth response to GH was unrestricted in one girl, who reached a final height within her target height range, whereas her cousin with the identical genetic defect responded far less favourably. Variability in the growth inhibiting potency of GH-Ab may therefore depend on genetic disposition, specific epitopes, or induction of immunological tolerance. Growth response during rhIGF-I treatment carried out in three of the patients was moderate, but pubertal development and bone age acceleration occurred in the two patients treated at pubertal age. GH resistance, either caused by GH-Ab or GH receptor mutations, is still difficult to treat and results in a heterogeneous outcome.

Research paper thumbnail of Posterior Pituitary Ectopy in Children with Idiopathic Growth Hormone Deficiency

Journal of Pediatric Endocrinology and Metabolism, 2000

Aims: To evaluate the underlying pathogenesis in children with pituitary hormone deficiency by me... more Aims: To evaluate the underlying pathogenesis in children with pituitary hormone deficiency by means of high resolution MRI of the brain. Patients/Methods: Thirty-seven children with short stature and isolated GH deficiency (IGHD, η = 17) or multiple pituitary hormone deficiency (MPHD, n=20) were subjected to an MRI of the brain at the age of 1.0-17.3 years. The anatomic condition of the hypothalamo-pituitary area was analyzed and the height of the pituitary gland was measured and compared to the data of agematched healthy subjects. Results: Seventy percent of the patients had a characteristic anomaly: the adenohypophysis was hypoplastic, the infundibulum was absent and the posterior pituitary lobe was ectopic at the bottom of the median eminence. The height of the anterior pituitary was significantly reduced in these patients (1.9 ± 0.1 mm; mean ± SD) when compared to age-matched healthy controls (4.1 ± 0.8 mm, p<0.001) or hypopituitary patients with a normal MRI (4.3 ± 0.8 mm). MPHD was found in 62% of patients with the pituitary anomaly whereas only 27% of children with a normal MRI had MPHD (p<0.05). Conclusions: The pathogenesis of the pituitary anomaly is unknown; a disorder during embryonal development or perinatal events have been discussed as causal factors. MRI should have a prominent position in the work-up of hypopituitary children. When an anatomical malform

Research paper thumbnail of Treatment of Peripubertal Children after Renal Transplantation (RTX) with Recombinant Human Growth Hormone: Auxological Data and Effects on Insulin-like Growth Factor-I (IGF-Γ) and IGF-Binding Protein-3 (IGFBP-3) during 24 Months

Journal of Pediatric Endocrinology and Metabolism, 1998

To evaluate growth and endocrine parameters in RTX children with GH treatment during 24 months. 1... more To evaluate growth and endocrine parameters in RTX children with GH treatment during 24 months. 18 children (13 boys), age 13.1 yr (8.0-16.6), bone age 10.1 yr (5.4-15.3). Patients were 2.8 yr (0.5-7.5) after RTX and had immunosuppressive therapy, prednisone 0.16 mg/kg/d (0.08-0.68). GH (4 IU/m2/day s.c.) was given and patients were seen every 3 months for evaluation of height, height velocity, bone age, and hormone parameters. Serum IGF-I was determined by RIA, IGFBP-3 by RIA and Western ligand blotting (WLB). Renal function and adverse effects (GFR, glucose tolerance, rejection episodes) were monitored. Height (+1 SDS) and height velocity (+2.2 SDS) increased significantly during 24 months GH treatment, but delta BA/delta CA was 1.7 and 1.5 during the first and second treatment year, respectively, and all patients entered puberty during the treatment period. GFR decreased slightly during 2 yr (p = 0.048), two patients had chronic rejection and GH therapy was terminated in one patient because of glucose intolerance. The ratio IGF-I/IGFBP-3 rose during the first year (p = 0.002) indicating more bioavailable IGF-I. IGFBP-3 determined by WLB was decreased, but IGFBP-1, -2 and -4 were elevated as compared to a standard. GH treatment increased height and growth rate in children after RTX. This may be due to significant changes in IGF-I and IGFBP-3 relationship. However, bone maturation was also accelerated thus diminishing height potential. From month 12 to 24 a continuous decrease of IGF-I was observed. There was a slight but significant deterioration of graft function. Adverse events that led to termination of GH therapy were observed in 3 of 18 patients.

Research paper thumbnail of SHOXHaploinsufficiency and Leri-Weill Dyschondrosteosis: Prevalence and Growth Failure in Relation to Mutation, Sex, and Degree of Wrist Deformity

The Journal of Clinical Endocrinology & Metabolism, 2004

SHOX mutations causing haploinsufficiency were reported in Leri-Weill dyschondrosteosis (LWD), wh... more SHOX mutations causing haploinsufficiency were reported in Leri-Weill dyschondrosteosis (LWD), which is characterized by mesomelic short stature and Madelung deformity of the wrists. The aim of this study was to determine the prevalence of SHOX mutations in LWD and to investigate the degree of growth failure in relation to mutation, sex, age of menarche, and wrist deformity. We studied 20 families with 24 affected children (18 females) and nine affected parents (seven females). All patients presented with bilateral Madelung deformity and shortening of the limbs. Height, sitting height, parental height, birth length, age of menarche, and presence of minor abnormalities were recorded. The degree of Madelung deformity was estimated by analysis of left hand radiographs. Microsatellite typing of the SHOX locus was used for detection of SHOX deletions and PCR direct sequencing for the detection of SHOX point mutations. In 14 of 20 families (70%), SHOX mutations were detected, with seven deletions (four de novo) and seven point mutations (one de novo). The latter included five missense mutations of the SHOX homeodomain, one nonsense mutation (E102X) truncating the whole homeodomain, and one point mutation (X293R) causing a C-terminal elongation of SHOX. Median age of the affected children was 13.4 yr (range, 6.1-18.3), mean height SD score (SDS) (SD in parentheses) was-2.85 (1.04), and mean sitting height/height ratio SDS was ؉3.06 (1.09). Mean birth length SDS was-0.59 (1.26). Growth failure occurred before school age. Height change during a median follow-up of 7.4 yr (range, 2.3-11.3) was insignificant with a mean change in height SDS of-0.10 (0.52). Abbreviations: LWD, Leri-Weill dyschondrosteosis; SDS, sd score. JCEM is published monthly by The Endocrine Society (http://www. endo-society.org), the foremost professional society serving the endocrine community.

Research paper thumbnail of Primary Growth Hormone (GH) Insensitivity and Insulin-Like Growth Factor Deficiency Caused by Novel Compound Heterozygous Mutations of the GH Receptor Gene: Genetic and Functional Studies of Simple and Compound Heterozygous States

The Journal of Clinical Endocrinology & Metabolism, 2007

Context: Primary GH insensitivity (GHI) or Laron syndrome, caused by mutations of the GH receptor... more Context: Primary GH insensitivity (GHI) or Laron syndrome, caused by mutations of the GH receptor (GHR) gene, has a clinical phenotype of postnatal growth failure associated with normal elevated serum concentrations of GH and low serum levels of IGF-I. Objective: We investigated the clinical and biochemical implications of molecular defects in the GHR gene in an Austrian family with two daughters who were GHI. Patients: Patient 1 [height, Ϫ4.8 SD score (SDS)] and patient 2 (height, Ϫ5.0 SDS) had elevated circulating levels of GH, low-normal levels of GH-binding protein, and abnormally low IGF-I (Ϫ5.0 SDS and Ϫ2.6 SDS, respectively) and IGF-binding protein-3 (Ϫ2.6 SDS and Ϫ2.0 SDS, respectively). Results: Both patients carry novel compound, missense, heterozygous GHR mutations, C94S and H150Q. In vitro reconstitution experiments demonstrated that whereas each of the mutants could be stably expressed, GHR(C94S) lost its affinity for GH and could neither activate signal transducer and activator of transcription (STAT)-5b nor drive STAT5b-dependent gene transcription in response to GH (1-100 ng/ml). GHR(H150Q) showed normal affinity for GH but impaired capacity for signal transduction. The compound heterozygote and C94S heterozygote, but not the H150Q heterozygote, showed significant deficiency in activating GH-induced gene expression, corroborating diminished GH-induced STAT5b activation in fibroblasts carrying GHR(C94S) as either a compound heterozygote (in the patients) or a simple heterozygote (in one parent). Conclusions: Each of the compound heterozygous mutations contributed additively to the pathological condition seen in the patients, and the more detrimental of the two mutations, C94S, may cause (partial) primary GHI, even in a heterozygous state.

Research paper thumbnail of Auxological, Ophthalmological, Neurological and MRI Findings in 25 Austrian Patients with Septo-Optic Dysplasia (SOD)

Hormone Research in Paediatrics, 2002

Septo-optic dysplasia (SOD) comprises ophthalmological, endocrinological and neurological disorde... more Septo-optic dysplasia (SOD) comprises ophthalmological, endocrinological and neurological disorders resulting from varying degrees of midline malformation of the forebrain like visual impairment by optic nerve hypoplasia, endocrine deficits due to hypothalamic and/or pituitary anomalies, and psychomental retardation by associated cortical malformation. MRI shows aplasia/hypoplasia of the septum pellucidum and corpus callosum as a radiological hallmark. For etiology, genetic defects (Hesx1/HESX1 gene) as well as vascular disruption during embryonic brain development are discussed. Aim: To perform detailed analysis of morphological findings and clinical symptoms and to improve care of SOD patients by interdisciplinary management. Patients: We investigated 25 patients with a mean age of 5.1 years at diagnosis. Results: Pituitary insufficiency was present in 11/25 patients, multiple deficits in 6 of them. Bilateral optic nerve hypoplasia was found in 70% of patients, unilateral in 20%. ...

Research paper thumbnail of Validation of a Mathematical Model Predicting the Response to Growth Hormone Treatment in Prepubertal Children with Idiopathic Growth Hormone Deficiency

Hormone Research in Paediatrics, 2004

Objective: To validate a mathematical model developed by Ranke et al. (J Clin Endocrinol Metab 19... more Objective: To validate a mathematical model developed by Ranke et al. (J Clin Endocrinol Metab 1999;84:1174–7783) to predict the GH response during the first years of GH replacement therapy. Patients and Methods: 38 children with idiopathic GH deficiency (GHD) met all inclusion criteria for the prediction model, but the group differed in some characteristics from the cohort from which the model was derived. Results: Using the model for the 1st year including maximum GH after stimulation and the equation for the 6th year, the predicted value corresponded well with actual height gain. Differences were found when the growth response of the 1st year excluding maximum GH and that of the 2nd–5th year were calculated, resulting in a significant underestimation of actual height gain (–0.63 to –1.07 cm/year). Conclusion: The mathematical prediction model tended to underpredict the growth response to GH treatment in our patients with pronounced GHD. The severity of GHD seems to be an importan...

Research paper thumbnail of Pituitary Hyperplasia in a Girl with Gonadal Dysgenesis and Primary Hypothyroidism

Hormone research, 1997

A 16-year-old Brazilian girl presented with severe growth retardation (-6.3 SDS), obesity, delaye... more A 16-year-old Brazilian girl presented with severe growth retardation (-6.3 SDS), obesity, delayed pubertal development, facial dysmorphia, dry skin, and borderline low intelligence (IQ 89). Endocrinological evaluation showed primary hypothyroidism (no uptake of iodine-131 of the right thyroid lobe). Basal and stimulated gonadotropins were increased and ultrasonography revealed hypoplastic ovaries. The karyotype of peripheral lymphocytes was 46,X,i(Xq). The GH response in euthyroid condition after stimulation with GHRH and insulin was diminished. MRI of the pituitary region showed a suprasellar mass (12 x 15 mm) which was removed by transsphenoidal surgery because of extension to the optic chiasm. Histological examinations revealed regular pituitary tissue with hyperplasia of TSH- and FSH-producing cells. Thyroxine treatment was adjusted and GH was given. We conclude that the suprasellar mass was the consequence of long-lasting hypothalamic overstimulation with TRH and LHRH, due to gonadal and thyroid insufficiency.

Research paper thumbnail of How effective and safe is growth hormone therapy in children born small for gestational age?

Research paper thumbnail of Childhood growth hormone deficiency (GHD) and idiopathic short stature (ISS): how far can a consensus go?

Research paper thumbnail of Transition from paediatric to adult endocrine care in patients with childhood onset growth hormone deficiency

Research paper thumbnail of Lymphocyte subsets in renal transplant recipients during growth hormone therapy

PubMed, Mar 1, 1999

Objective: To evaluate the effect of growth hormone treatment on growth, levels of insulin-like g... more Objective: To evaluate the effect of growth hormone treatment on growth, levels of insulin-like growth factor I (IGF-I) and lymphocyte subsets in immunosuppressed renal allograft recipients. Methods: 18 children (aged 8.0-16.6 years) received growth hormone 1 IU/Kg/week daily for two years. Height, IGF-I levels and in 11/18 patients, lymphocyte subsets were evaluated serially. Results: Standardized growth velocity increased from -1.0+1.5 to +1.2+2.2 and standardized IGF-I levels from +0.8+1.5 to +3.1+1.1 (1 year) and to +1.4+1.7 (2 years). The total lymphocyte count and the number of T lymphocytes (CD3+) decreased. The decrease was more marked in CD8+ (from 1.5+0.3 x10(9)/L to 0.9+0.3 x10(9)/L, 1 year and to 0.8+0.1 x10(9)/L, 2 years) compared to CD4+ (from 1.5+0.3 x10(9)/L to 1.0+0.2 x10(9)/L, 1 year and to 1.3+0.2 x10(9)/L, 2 years), resulting in an increment of the CD4+/CD8+ index. Conclusions: The differential effect of growth hormone treatment on CD4+ and CD8+ lymphocytes might be explained by different expression of the IGF-I receptor in these distinct subsets.

Research paper thumbnail of Diagnosis of Growth Hormone Excess and Hyperprolactinemia

Research paper thumbnail of Posterior Pituitary Ectopy in Children with Idiopathic Growth Hormone Deficiency

Journal of Pediatric Endocrinology and Metabolism, 2000

Aims: To evaluate the underlying pathogenesis in children with pituitary hormone deficiency by me... more Aims: To evaluate the underlying pathogenesis in children with pituitary hormone deficiency by means of high resolution MRI of the brain. Patients/Methods: Thirty-seven children with short stature and isolated GH deficiency (IGHD, η = 17) or multiple pituitary hormone deficiency (MPHD, n=20) were subjected to an MRI of the brain at the age of 1.0-17.3 years. The anatomic condition of the hypothalamo-pituitary area was analyzed and the height of the pituitary gland was measured and compared to the data of agematched healthy subjects. Results: Seventy percent of the patients had a characteristic anomaly: the adenohypophysis was hypoplastic, the infundibulum was absent and the posterior pituitary lobe was ectopic at the bottom of the median eminence. The height of the anterior pituitary was significantly reduced in these patients (1.9 ± 0.1 mm; mean ± SD) when compared to age-matched healthy controls (4.1 ± 0.8 mm, p<0.001) or hypopituitary patients with a normal MRI (4.3 ± 0.8 mm). MPHD was found in 62% of patients with the pituitary anomaly whereas only 27% of children with a normal MRI had MPHD (p<0.05). Conclusions: The pathogenesis of the pituitary anomaly is unknown; a disorder during embryonal development or perinatal events have been discussed as causal factors. MRI should have a prominent position in the work-up of hypopituitary children. When an anatomical malform

Research paper thumbnail of Effects of Growth Hormone (GH) and Insulin-like Growth Factor-I Therapy in patients with Gene Defects in the GH Axis

Journal of Pediatric Endocrinology and Metabolism, 2006

We report on four patients (3 F) who were diagnosed as having either a 6.7 kb GH1 gene deletion, ... more We report on four patients (3 F) who were diagnosed as having either a 6.7 kb GH1 gene deletion, a GH1 signalling peptide mutation, or a GH receptor mutation, with particular regard to treatment modalities (GH, rhIGF-I) and final height. Patients with GH1 gene defects developed anti-GH antibodies (GH-Ab) following GH treatment. Surprisingly, growth response to GH was unrestricted in one girl, who reached a final height within her target height range, whereas her cousin with the identical genetic defect responded far less favourably. Variability in the growth inhibiting potency of GH-Ab may therefore depend on genetic disposition, specific epitopes, or induction of immunological tolerance. Growth response during rhIGF-I treatment carried out in three of the patients was moderate, but pubertal development and bone age acceleration occurred in the two patients treated at pubertal age. GH resistance, either caused by GH-Ab or GH receptor mutations, is still difficult to treat and results in a heterogeneous outcome.

Research paper thumbnail of LHRH-Agonist-Behandlung von kleinw�chsigen Jugendlichen

Monatsschrift Kinderheilkunde, Aug 1, 2003

Die Therapie mit einem LHRH-Agonisten (LHRHa) zur Unterdrückung der pulsatilen LH-Ausschüttung wi... more Die Therapie mit einem LHRH-Agonisten (LHRHa) zur Unterdrückung der pulsatilen LH-Ausschüttung wird seit nunmehr über 20 Jahren bei Kindern mit zentraler Pubertas praecox angewendet. Nicht allzu ferneliegend war die etwas später erprobte Idee, durch Unterdrückung der zum normalen Zeitpunkt eintretenden Pubertät bei kleinwüchsigen Adoleszenten die präpubertäre Wachstumsphase zu verlängern und einen Nettoendlängengewinn zu erzielen. Man sah jedoch, dass eine kurzzeitige (1–2 Jahre) isolierte pubertätshemmende Behandlung statistisch keinen Zuwachs brachte, wobei die kombinierte Therapie mit Wachstumshormon (WH) bei einzelnen Patienten eine Wirkung zeigte. Die Evaluation des Effekts wurde jeweils durch Vergleich der prospektiven Endlänge anhand der Knochenalterbestimmung vor Therapie mit der Prognose nach Therapie bzw.der tatsächlich erreichten Endlänge ermittelt.

Research paper thumbnail of Growth Hormone Suppression: Diagnosis of Growth Hormone Excess and Hyperprolactinemia

Research paper thumbnail of LHRH-Agonist-Behandlung von kleinw�chsigen Jugendlichen

Monatsschrift Kinderheilkunde, 2003

Die Therapie mit einem LHRH-Agonisten (LHRHa) zur Unterdrückung der pulsatilen LH-Ausschüttung wi... more Die Therapie mit einem LHRH-Agonisten (LHRHa) zur Unterdrückung der pulsatilen LH-Ausschüttung wird seit nunmehr über 20 Jahren bei Kindern mit zentraler Pubertas praecox angewendet. Nicht allzu ferneliegend war die etwas später erprobte Idee, durch Unterdrückung der zum normalen Zeitpunkt eintretenden Pubertät bei kleinwüchsigen Adoleszenten die präpubertäre Wachstumsphase zu verlängern und einen Nettoendlängengewinn zu erzielen. Man sah jedoch, dass eine kurzzeitige (1–2 Jahre) isolierte pubertätshemmende Behandlung statistisch keinen Zuwachs brachte, wobei die kombinierte Therapie mit Wachstumshormon (WH) bei einzelnen Patienten eine Wirkung zeigte. Die Evaluation des Effekts wurde jeweils durch Vergleich der prospektiven Endlänge anhand der Knochenalterbestimmung vor Therapie mit der Prognose nach Therapie bzw.der tatsächlich erreichten Endlänge ermittelt.

Research paper thumbnail of Diagnosis of Growth Hormone Excess and Hyperprolactinemia

Diagnostics of Endocrine Function in Children and Adolescents, 2011

Research paper thumbnail of Lymphocyte subsets in renal transplant recipients treated with mycophenolate mofetil

Transplantation Proceedings, 2000

Introduction: The incidence of genitourinary tumors (GUT) in renal transplant recipients (RTR) is... more Introduction: The incidence of genitourinary tumors (GUT) in renal transplant recipients (RTR) is higher than in the general population. We previously reported that CD4 lymphocytopenia is associated with a high incidence of skin cancer in RTR. Here, we investigate whether persistent CD4 T cell lymphopenia is associated with GUT occurrence. Patients and Methods: A total of 433 patients were included in this study. All patients underwent annually systematic lymphocyte subset (CD3, CD4, CD8, CD19) determination by flow cytometry. Results and Conclusion: During the follow-up period, 13 patients developed GUT: 6 patients a prostate adenocarcinoma (incidence 0.06%/year) and 7 patients a renal cell carcinoma (incidence 0.07%/year). The patients with GUT were older than those without. Both groups did not differ in posttransplant duration, dialysis mode and duration, induction regimen, or acute rejection history. No persistent CD4 lymphopenia was observed in the patients with GUT. Although CD4 T cell lymphopenia is associated with skin cancer in long-term RTR, it did not appear to be a risk factor

Research paper thumbnail of Effects of Growth Hormone (GH) and Insulin-like Growth Factor-I Therapy in patients with Gene Defects in the GH Axis

Journal of Pediatric Endocrinology and Metabolism, 2006

We report on four patients (3 F) who were diagnosed as having either a 6.7 kb GH1 gene deletion, ... more We report on four patients (3 F) who were diagnosed as having either a 6.7 kb GH1 gene deletion, a GH1 signalling peptide mutation, or a GH receptor mutation, with particular regard to treatment modalities (GH, rhIGF-I) and final height. Patients with GH1 gene defects developed anti-GH antibodies (GH-Ab) following GH treatment. Surprisingly, growth response to GH was unrestricted in one girl, who reached a final height within her target height range, whereas her cousin with the identical genetic defect responded far less favourably. Variability in the growth inhibiting potency of GH-Ab may therefore depend on genetic disposition, specific epitopes, or induction of immunological tolerance. Growth response during rhIGF-I treatment carried out in three of the patients was moderate, but pubertal development and bone age acceleration occurred in the two patients treated at pubertal age. GH resistance, either caused by GH-Ab or GH receptor mutations, is still difficult to treat and results in a heterogeneous outcome.

Research paper thumbnail of Posterior Pituitary Ectopy in Children with Idiopathic Growth Hormone Deficiency

Journal of Pediatric Endocrinology and Metabolism, 2000

Aims: To evaluate the underlying pathogenesis in children with pituitary hormone deficiency by me... more Aims: To evaluate the underlying pathogenesis in children with pituitary hormone deficiency by means of high resolution MRI of the brain. Patients/Methods: Thirty-seven children with short stature and isolated GH deficiency (IGHD, η = 17) or multiple pituitary hormone deficiency (MPHD, n=20) were subjected to an MRI of the brain at the age of 1.0-17.3 years. The anatomic condition of the hypothalamo-pituitary area was analyzed and the height of the pituitary gland was measured and compared to the data of agematched healthy subjects. Results: Seventy percent of the patients had a characteristic anomaly: the adenohypophysis was hypoplastic, the infundibulum was absent and the posterior pituitary lobe was ectopic at the bottom of the median eminence. The height of the anterior pituitary was significantly reduced in these patients (1.9 ± 0.1 mm; mean ± SD) when compared to age-matched healthy controls (4.1 ± 0.8 mm, p<0.001) or hypopituitary patients with a normal MRI (4.3 ± 0.8 mm). MPHD was found in 62% of patients with the pituitary anomaly whereas only 27% of children with a normal MRI had MPHD (p<0.05). Conclusions: The pathogenesis of the pituitary anomaly is unknown; a disorder during embryonal development or perinatal events have been discussed as causal factors. MRI should have a prominent position in the work-up of hypopituitary children. When an anatomical malform

Research paper thumbnail of Treatment of Peripubertal Children after Renal Transplantation (RTX) with Recombinant Human Growth Hormone: Auxological Data and Effects on Insulin-like Growth Factor-I (IGF-Γ) and IGF-Binding Protein-3 (IGFBP-3) during 24 Months

Journal of Pediatric Endocrinology and Metabolism, 1998

To evaluate growth and endocrine parameters in RTX children with GH treatment during 24 months. 1... more To evaluate growth and endocrine parameters in RTX children with GH treatment during 24 months. 18 children (13 boys), age 13.1 yr (8.0-16.6), bone age 10.1 yr (5.4-15.3). Patients were 2.8 yr (0.5-7.5) after RTX and had immunosuppressive therapy, prednisone 0.16 mg/kg/d (0.08-0.68). GH (4 IU/m2/day s.c.) was given and patients were seen every 3 months for evaluation of height, height velocity, bone age, and hormone parameters. Serum IGF-I was determined by RIA, IGFBP-3 by RIA and Western ligand blotting (WLB). Renal function and adverse effects (GFR, glucose tolerance, rejection episodes) were monitored. Height (+1 SDS) and height velocity (+2.2 SDS) increased significantly during 24 months GH treatment, but delta BA/delta CA was 1.7 and 1.5 during the first and second treatment year, respectively, and all patients entered puberty during the treatment period. GFR decreased slightly during 2 yr (p = 0.048), two patients had chronic rejection and GH therapy was terminated in one patient because of glucose intolerance. The ratio IGF-I/IGFBP-3 rose during the first year (p = 0.002) indicating more bioavailable IGF-I. IGFBP-3 determined by WLB was decreased, but IGFBP-1, -2 and -4 were elevated as compared to a standard. GH treatment increased height and growth rate in children after RTX. This may be due to significant changes in IGF-I and IGFBP-3 relationship. However, bone maturation was also accelerated thus diminishing height potential. From month 12 to 24 a continuous decrease of IGF-I was observed. There was a slight but significant deterioration of graft function. Adverse events that led to termination of GH therapy were observed in 3 of 18 patients.

Research paper thumbnail of SHOXHaploinsufficiency and Leri-Weill Dyschondrosteosis: Prevalence and Growth Failure in Relation to Mutation, Sex, and Degree of Wrist Deformity

The Journal of Clinical Endocrinology & Metabolism, 2004

SHOX mutations causing haploinsufficiency were reported in Leri-Weill dyschondrosteosis (LWD), wh... more SHOX mutations causing haploinsufficiency were reported in Leri-Weill dyschondrosteosis (LWD), which is characterized by mesomelic short stature and Madelung deformity of the wrists. The aim of this study was to determine the prevalence of SHOX mutations in LWD and to investigate the degree of growth failure in relation to mutation, sex, age of menarche, and wrist deformity. We studied 20 families with 24 affected children (18 females) and nine affected parents (seven females). All patients presented with bilateral Madelung deformity and shortening of the limbs. Height, sitting height, parental height, birth length, age of menarche, and presence of minor abnormalities were recorded. The degree of Madelung deformity was estimated by analysis of left hand radiographs. Microsatellite typing of the SHOX locus was used for detection of SHOX deletions and PCR direct sequencing for the detection of SHOX point mutations. In 14 of 20 families (70%), SHOX mutations were detected, with seven deletions (four de novo) and seven point mutations (one de novo). The latter included five missense mutations of the SHOX homeodomain, one nonsense mutation (E102X) truncating the whole homeodomain, and one point mutation (X293R) causing a C-terminal elongation of SHOX. Median age of the affected children was 13.4 yr (range, 6.1-18.3), mean height SD score (SDS) (SD in parentheses) was-2.85 (1.04), and mean sitting height/height ratio SDS was ؉3.06 (1.09). Mean birth length SDS was-0.59 (1.26). Growth failure occurred before school age. Height change during a median follow-up of 7.4 yr (range, 2.3-11.3) was insignificant with a mean change in height SDS of-0.10 (0.52). Abbreviations: LWD, Leri-Weill dyschondrosteosis; SDS, sd score. JCEM is published monthly by The Endocrine Society (http://www. endo-society.org), the foremost professional society serving the endocrine community.

Research paper thumbnail of Primary Growth Hormone (GH) Insensitivity and Insulin-Like Growth Factor Deficiency Caused by Novel Compound Heterozygous Mutations of the GH Receptor Gene: Genetic and Functional Studies of Simple and Compound Heterozygous States

The Journal of Clinical Endocrinology & Metabolism, 2007

Context: Primary GH insensitivity (GHI) or Laron syndrome, caused by mutations of the GH receptor... more Context: Primary GH insensitivity (GHI) or Laron syndrome, caused by mutations of the GH receptor (GHR) gene, has a clinical phenotype of postnatal growth failure associated with normal elevated serum concentrations of GH and low serum levels of IGF-I. Objective: We investigated the clinical and biochemical implications of molecular defects in the GHR gene in an Austrian family with two daughters who were GHI. Patients: Patient 1 [height, Ϫ4.8 SD score (SDS)] and patient 2 (height, Ϫ5.0 SDS) had elevated circulating levels of GH, low-normal levels of GH-binding protein, and abnormally low IGF-I (Ϫ5.0 SDS and Ϫ2.6 SDS, respectively) and IGF-binding protein-3 (Ϫ2.6 SDS and Ϫ2.0 SDS, respectively). Results: Both patients carry novel compound, missense, heterozygous GHR mutations, C94S and H150Q. In vitro reconstitution experiments demonstrated that whereas each of the mutants could be stably expressed, GHR(C94S) lost its affinity for GH and could neither activate signal transducer and activator of transcription (STAT)-5b nor drive STAT5b-dependent gene transcription in response to GH (1-100 ng/ml). GHR(H150Q) showed normal affinity for GH but impaired capacity for signal transduction. The compound heterozygote and C94S heterozygote, but not the H150Q heterozygote, showed significant deficiency in activating GH-induced gene expression, corroborating diminished GH-induced STAT5b activation in fibroblasts carrying GHR(C94S) as either a compound heterozygote (in the patients) or a simple heterozygote (in one parent). Conclusions: Each of the compound heterozygous mutations contributed additively to the pathological condition seen in the patients, and the more detrimental of the two mutations, C94S, may cause (partial) primary GHI, even in a heterozygous state.

Research paper thumbnail of Auxological, Ophthalmological, Neurological and MRI Findings in 25 Austrian Patients with Septo-Optic Dysplasia (SOD)

Hormone Research in Paediatrics, 2002

Septo-optic dysplasia (SOD) comprises ophthalmological, endocrinological and neurological disorde... more Septo-optic dysplasia (SOD) comprises ophthalmological, endocrinological and neurological disorders resulting from varying degrees of midline malformation of the forebrain like visual impairment by optic nerve hypoplasia, endocrine deficits due to hypothalamic and/or pituitary anomalies, and psychomental retardation by associated cortical malformation. MRI shows aplasia/hypoplasia of the septum pellucidum and corpus callosum as a radiological hallmark. For etiology, genetic defects (Hesx1/HESX1 gene) as well as vascular disruption during embryonic brain development are discussed. Aim: To perform detailed analysis of morphological findings and clinical symptoms and to improve care of SOD patients by interdisciplinary management. Patients: We investigated 25 patients with a mean age of 5.1 years at diagnosis. Results: Pituitary insufficiency was present in 11/25 patients, multiple deficits in 6 of them. Bilateral optic nerve hypoplasia was found in 70% of patients, unilateral in 20%. ...

Research paper thumbnail of Validation of a Mathematical Model Predicting the Response to Growth Hormone Treatment in Prepubertal Children with Idiopathic Growth Hormone Deficiency

Hormone Research in Paediatrics, 2004

Objective: To validate a mathematical model developed by Ranke et al. (J Clin Endocrinol Metab 19... more Objective: To validate a mathematical model developed by Ranke et al. (J Clin Endocrinol Metab 1999;84:1174–7783) to predict the GH response during the first years of GH replacement therapy. Patients and Methods: 38 children with idiopathic GH deficiency (GHD) met all inclusion criteria for the prediction model, but the group differed in some characteristics from the cohort from which the model was derived. Results: Using the model for the 1st year including maximum GH after stimulation and the equation for the 6th year, the predicted value corresponded well with actual height gain. Differences were found when the growth response of the 1st year excluding maximum GH and that of the 2nd–5th year were calculated, resulting in a significant underestimation of actual height gain (–0.63 to –1.07 cm/year). Conclusion: The mathematical prediction model tended to underpredict the growth response to GH treatment in our patients with pronounced GHD. The severity of GHD seems to be an importan...