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

Effects of a late start to growth hormone therapy. Results of an expert workshop

Short statured children usually reach optimal final height within individual target height range if human growth hormone (HGH) therapy is started early. However, what happens if an early diagnosis is missed and the child is relatively old at start of HGH therapy? The consequences of this have been evaluated on an indication-specific basis by an expert panel of German pediatric endocrinologists using evidence from clinical studies. A late start of HGH therapy is assumed in children with growth hormone deficiency (GHD) beyond the age of 12 years and/or after the onset of puberty. The published information shows markedly reduced efficiency, especially in children with idiopathic GHD. Evidence is insufficient to recommend an increased HGH dose in children with GHD during puberty. Small for gestational age (SGA) children - children of postnatal short stature, who are presented after the onset of puberty - should only receive HGH therapy in well-founded, exceptional cases. Comparable final heights were achieved in girls with Ullrich-Turner syndrome when HGH treatment was started at chronological ages before and after 12 years. Children with Prader-Willi syndrome (PWS) can meet the definition for late start of HGH therapy already beyond four years of age. Early therapy is suggested to optimize psychomotoric development and body composition. There is no data on final height in patients with SHOX syndrome. In patients with chronic renal insufficiency, the effect of HGH therapy started in early puberty is comparable with that started before the onset of puberty. However, the availability of data is limited in this case. In summary, the option of a late start to HGH therapy needs to be analyzed on an individual basis using the data available for the relevant indication. Further examinations and analyses are necessary because the availability of data on questions concerning a late start to HGH therapy is still unsatisfactory