Height Gain in Ullrich-Turner Syndrome after Early and Late Growth Hormone Treatment Start: Results from a Large Retrospective German Study and Potential Basis for an Individualized Treatment Approach

Background: Ullrich-Turner syndrome (UTS) girls often present with short stature in adolescence to the endocrinologist when the efficacy of growth hormone (GH) to improve growth remains unknown and parameters to estimate individual GH responsiveness have yet to be determined. Objective: Retrospective evaluation of adult height (AH) and predicted adult height at GH start (descriptive model of Ranke, Model PredAH) in early and late GH-treated German UTS patients. Subjects/Methods: 313 patients treated with GH, early [chronological age (CA) at GH start <12 years, n = 259] or late (CA at GH start ≥12 years, n = 54) who reached AH were selected from KIGS (Pfizer International Growth Database). Results: AH (152.5 ± 5.9 vs. 151.1 ± 5.4 cm, p = n.s.) after GH treatment for 7.5 ± 2.12 years (GH start early) and for 5.2 ± 1.2 years (GH start late) were similar (p = n.s.) as Model PredAH (155.7 ± 4.8 vs. 154.7 ± 4.8 cm; p = n.s.) but higher (p < 0.001) than projected adult height (Ranke, ProjAH; 148.2 ± 5.5 vs. 145.2 ± 6.7 cm; p = 0.001). Total height gain over ProjAH was 4.3 ± 4.6 cm (GH start early) and 5.8 ± 4.7 cm (GH start late, p = 0.021), respectively. Conclusions: GH may improve AH in UTS patients even when started late. The individual growth response could be estimated by the descriptive Model PredAH independent of age at treatment start

Testosterone production during puberty in two 46,XY patients with disorders of sex development and novel NR5A1 (SF-1) mutations

BACKGROUND: Steroidogenic factor 1 (SF-1, NR5A1) is a key transcriptional regulator of many genes involved in the hypothalamic–pituitary–gonadal axis and mutations in NR5A1 can result in 46,XY disorders of sex development (DSD). Patients with this condition typically present with ambiguous genitalia, partial gonadal dysgenesis, and absent/rudimentary Müllerian structures. In these cases, testosterone is usually low in early infancy, indicating significantly impaired androgen synthesis. Further, Sertoli cell dysfunction is seen (low inhibin B, anti-Müllerian hormone). However, gonadal function at puberty in patients with NR5A1 mutations is unknown. SUBJECTS AND METHODS: Clinical assessment, endocrine evaluation, and genetic analysis were performed in one female and one male with 46,XY DSD who showed spontaneous virilization during puberty. The female patient presented at adolescence with clitoral hypertrophy, whereas the male patient presented at birth with severe hypospadias and entered puberty spontaneously. Molecular analysis of NR5A1 was performed followed by in vitro functional analysis of the two novel mutations detected. RESULTS: Testosterone levels were normal during puberty in both patients. Analysis of NR5A1 revealed two novel heterozygous missense mutations in the ligand-binding domain of SF-1 (patient 1: p.L376F; patient 2: p.G328V). The mutant proteins showed reduced transactivation of the CYP11A promoter in vitro. CONCLUSION: Patients with 46,XY DSD and NR5A1 mutations can produce sufficient testosterone for spontaneous virilization during puberty. Phenotypic females (46,XY) with NR5A1 mutations can present with clitoromegaly at puberty, a phenotype similar to other partial defects of androgen synthesis or action. Testosterone production in 46,XY males with NR5A1 mutations can be sufficient for virilization at puberty. As progressive gonadal dysgenesis is likely, gonadal function should be monitored in adolescence and adulthood, and early sperm cryopreservation considered in male patients if possible

Effectiveness and Safety of rhIGF-1 Therapy in Children: The European Increlex® Growth Forum Database Experience.

BACKGROUND/AIMS: We report data from the EU Increlex® Growth Forum Database (IGFD) Registry, an ongoing, open-label, observational study monitoring clinical practice use of recombinant human insulin-like growth factor-1 (rhIGF-1) therapy in children. METHODS: Safety and effectiveness data on rhIGF-1 treatment of 195 enrolled children with growth failure were collected from December 2008 to September 2013. RESULTS: Mean ± SD (95% CI) height velocity during first year of rhIGF-1 treatment was 6.9 ± 2.2 cm/year (6.5; 7.2) (n = 144); in prepubertal patients naïve to treatment, this was 7.3 ± 2.0 cm/year (6.8; 7.7) (n = 81). Female sex, younger age at start of rhIGF-1 therapy, and lower baseline height SDS predicted first-year change in height SDS. The most frequent targeted treatment-emergent adverse events (% patients) were hypoglycemia (17.6%, predictors: young age, diagnosis of Laron syndrome, but not rhIGF-1 dose), lipohypertrophy (10.6%), tonsillar hypertrophy (7.4%), injection site reactions (6.4%), and headache (5.9%). Sixty-one serious adverse events (37 related to rhIGF-1 therapy) were reported in 31 patients (16.5%). CONCLUSION: Safety and effectiveness data on use of rhIGF-1 in a 'real-world' setting were similar to those from controlled randomized trials. Severe growth phenotype and early start of rhIGF-1 improved height response and predicted risk of hypoglycemia

Hypothyroidism mimicking chronic renal failure in reflux nephropathy

An adolescent with a history of pyelonephritis and renal scarring had antireflux surgery at the age of 2.5 years. His serum creatinine was high at the age of 14 years (133 µmol/l; glomerular filtration rate (GFR) 56 ml/min × 1.73 m(2)), and reflux nephropathy with chronic renal failure was diagnosed. Because of a fall in height velocity, endocrinological investigations were performed six months later which showed hypothyroidism caused by autoimmune thyroiditis. Substitution with thyroxine was started; renal function improved to normal six months later (GFR 108 ml/min× 1.73 m(2)). Metabolic changes of hypothyroidism led to a reduction of GFR in this patient and mimicked chronic renal failure.


Spontaneous growth in German children and adolescents with genetically confirmed Prader-Willi syndrome

Height and weight in children with Prader-Willi syndrome, diagnosed by standard clinical criteria, follow a specific developmental pattern resulting in early childhood obesity, absent pubertal growth spurt and adolescent short stature. New molecular techniques (methylation analysis, fluorescence in situ hybridization) now allow the unequivocal diagnosis of Prader-Willi syndrome (PWS). We investigated the possibility of a bias in syndrome-specific growth standards based on clinically diagnosed patients by comparing these standards with new standards derived from 100 German patients with molecularly confirmed PWS, none of whom had received a growth-promoting therapy. Height centile curves of the German patients fall in the tall range of standards derived from American patients. This is mainly due to an elevation of the lower centile ranges in both sexes. When the height standards derived from German patients are compared to those of a large multinational cohort of patients, 78% of whom were not confirmed by genetic testing, only minor differences in the height centiles become apparent. The population background therefore does not appear to play a major role for the observed differences. In a marked proportion of patients a decreased sitting height/height ratio is found. This was usually associated with scoliosis. Weight standards from our study group show that after 14 y of age German girls with PWS are heavier than their American counterparts. Standards for the body mass index of German patients of both sexes are increased over normal reference standards (p < 0.0001) and do increase with age (boys: p = 0.0038; girls: p = 0.0004). PWS genotypes or sex had no apparent influence on SDS for height, weight and body mass index. CONCLUSIONS Because of the observed differences to other growth standards, use of the newly constructed centile curves is advocated in German patients with molecularly confirmed PWS to avoid delay in the diagnosis of additional growth-compromising conditions