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Introduction: Omnitrope® was approved as a biosimilar recombinant human growth hormone (rhGH) in 2006. Objective: The purpose of this work was to evaluate the long-term safety and effectiveness of Omnitrope® in PATRO Children – an ongoing, international, longitudinal, non-interventional study in children who require rhGH treatment. Methods: The study population includes infants, children, and adolescents receiving Omnitrope®. Adverse events (AEs) are monitored for safety and rhGH effectiveness is evaluated by calculation of the height standard deviation score (HSDS), height velocity (HV), and HVSDS using height measurements and country-specific references. Results: As of November 2017, 6,009 patients from 298 centers across 14 countries were enrolled in PATRO Children. Overall, 57.7% of patients had growth hormone deficiency (GHD), 25.8% were born small for gestational age (SGA), and 4.8% had Turner syndrome (TS). In total, 84.1% were rhGH treatment naïve at study entry. The mean duration of Omnitrope® treatment in the study was 36.1 months (range 0–133.7). Overall, 10,360 AEs were reported in 2,750 patients (45.8%). Treatment-related AEs were reported in 396 patients (6.6%; 550 events), and serious AEs (SAE) in 636 patients (10.6%; 1,191 events); 50 SAEs in 37 patients (0.6%) were considered treatment related. Following 5 years of therapy in patients who were rhGH treatment naïve at study entry, improvement from baseline in mean HSDS was +1.85 in GHD, +1.76 in SGA, and +1.0 in TS patients. In total, 912 (17.9%) patients reached adult height (n = 577 GHD, n = 236 SGA, n = 62 TS). Conclusions: This analysis of PATRO Children indicates that biosimilar rhGH is well tolerated and effective in real-world clinical practice.

Background: The development of gonadotropin-independent (peripheral) precocious puberty in male children with primary adrenal insufficiency (PAI) is consistent with a defect in the genes encoding for the enzymes involved in steroid hormone biosynthesis. Methods: Two young boys presented with peripheral precocious puberty followed by PAI. In both patients, the analysis of CYP21A2 gene encoding 21-hydroxylase was normal. As a second step, a targeted next-generation sequencing (NGS) was performed in both patients using a customized panel of congenital endocrine disor ders. Results: Case 1 had a new homozygous variant in the CYP11B1 gene (c.1121+5G>A). Mutations of this gene cause congenital adrenal hyperplasia due to 11β-hydroxylase deficiency, an essential enzyme in the cortisol biosynthesis pathway. Case 2 showed a new hemizygous mutation in the NR0B1 gene (c.1091T>G), which encodes for DAX1 (dosage-sensitive sex reversal, adrenal hypoplasia congenita [AHC] and critical region on the X chromosome gene 1). NR0B1 mutations cause X-linked AHC and hypogonadotropic hypogonadism. Pathogenicity prediction software defined both mutations as probably damaging. Conclusions: Peripheral precocious puberty was the atypical presentation of 2 rare genetic diseases. The use of NGS made the characterization of these 2 cases with similar clinical phenotypes caused by 2 different genetic defects possible.

Background: 3β-Hydroxysteroid dehydrogenase (3β-HSD) deficiency is a rare cause of congenital adrenal hyperplasia (CAH) caused by inactivating mutations in the HSD3B2 gene. Patient and Methods: We report the molecular and structural analysis of the HSD3B2 gene in a 46,XY child born to apparently nonconsanguineous parents and presenting ambiguous genitalia and salt wasting. The steroid profile showed elevated concentrations of 17-hydroxyprogesterone, androstenedione, ACTH and plasma renin, but normal values of cortisol and dehydroepiandrosterone sulfate. Unexpectedly, plasma aldosterone was high. For structural and functional analyses, the three-dimensional structure of 3β-HSD2 was modeled using the crystal structure of the short-chain dehydrogenase Gox2253 from Gluconobacter oxydans as a template. Results: The direct DNA sequence of the child revealed a new homozygous frameshift mutation in exon 4 of the HSD3B2 gene, a single nucleotide deletion at codon 319 [GTC(Val)→GC], yielding premature stop codon in position 367. Molecular homology modeling and secondary structure predictions suggested that the variant sequence might both alter the substrate-binding cleft and compromise the overall stability of the enzyme. Conclusion: We have described the first HSD3B2 gene mutation in the Italian population and analyzed its effect in the context of the 3β-HSD2 structure and function.

Growth hormone (GH) is essential not only for normal growth during childhood, but also for the acquisition of bone mass and muscle strength in both sexes. This process is completed after the achievement of adult height in the phase of transition from adolescence to adulthood. Adolescents with childhood onset GH deficiency (GHD) show reduction of bone mineral density, decrease in lean body mass, increase in fat mass, and deterioration of the lipid profile. For this reason, continuation of GH replacement therapy in the transition age is recommended in all patients with a confirmed diagnosis of GHD. To confirm the diagnosis of GHD, GH treatment should be discontinued for at least 1 month after the attainment of adult height, and the patient should be re-evaluated for GH secretion. Current guidelines indicate that retesting is not required for those with a transcription factor mutation, more than 3 pituitary hormone deficits, or isolated GHD associated with an identified mutation. The key predictors of persistent GHD are its severity, the presence of additional pituitary hormone deficits, low insulin-like growth factor I (IGF-I) concentration, and the presence of structural hypothalamic-pituitary abnormalities Treatment should be initiated with a low dose (0.2-0.5 mg/day s.c.) and then adjusted according to IGF-I concentrations.

Background: Chronic autoimmune thyroiditis (CAT) displays a strong female predominance with female-to-male (F:M) ratios of 4–20:1 in adults and 2–9:1 in children and adolescents. Both genetic and hormonal factors are involved in this phenomenon. The relation between puberty and F:M ratio in CAT has never been evaluated. Methods: The F:M ratio of 133 children with CAT (group A, age at diagnosis 2.4–17.7 years) was compared with that of 113 adult CAT patients (group B, age at diagnosis 21–79 years). Group A included 64 prepubertal (aged 2.4–13.2 years, group A1) and 69 pubertal (aged 9.2–17.4, group A2) children. Results: The F:M ratio in group A was 3.0, which is significantly (p < 0.001) lower than that (10.3) found in group B patients. The F:M ratio of group A1 prepubertal children was lower (1.6) and significantly different from that of pubertal (6.7, p < 0.01) and adult patients (10.3, p < 0.0001). This phenomenon was more evident in hypothyroid as compared to euthyroid CAT. Conclusions: This study provides the first evidence that female predominance of CAT strongly increases during puberty, suggesting a major role for sex hormones in this phenomenon. Further studies are needed to clarify this point.

Children with idiopathic short stature (ISS) may not reach an adult height within their genetic target. In 2003, the United States Food and Drug Administration approved biosynthetic growth hormone (GH) for the treatment of children with ISS whose heights exceeded 2.25 standard deviation scores below the mean and who were considered unlikely to reach a normal adult height. Results of controlled studies have shown that, although GH treatment leads to a substantial increase in adult height, the individual response to therapy is difficult to predict. A number of auxological variables (i.e., age and height at start of treatment, bone age delay, mean predicted height, height velocity and first-year responsiveness) are used in multivariate analyses to predict outcomes. Estimation of target height, predicted adult height and pattern of growth should guide the decision to treat a child with ISS.

Growth hormone (GH) secretion from the pituitary is regulated by a complex network of CNS and peripheral inputs. Circulating GH binds to its receptor and initiates a cascade of signaling events which involve the JAK2-STAT pathway, the PI3K/Akt pathway and the RAS/MAPK pathway, leading to the transcription of several genes, including insulin-like growth factor 1 (IGF-1), IGFBP3, ALS, and others. Recent findings indicate that nutrition plays an important role in GH secretion and action. Furthermore, data are emerging which suggest that the RAS-MAPK pathway as well as epigenetic regulation of transcription may be important in determining both circulating and locally produced IGF-1.

Prolactinomas are the most common pituitary adenomas in children and adolescents followed by adrenocorticotropic hormone-secreting and growth hormone-secreting adenomas. Females are slightly more affected than males (who have macroadenomas more frequently). Compared with the adult setting, in children macroadenomas are more frequent than microadenomas. Diagnosis is generally based on clinical symptoms of primary or secondary gonadal failure, growth delay and/or tumor compressive symptoms. Treatment is based on medical therapy with dopamine agonists, to control prolactin levels and reduce tumor size. Surgery is indicated in patients with tumors resistant to dopamine agonists as well as in those showing severe neurological symptoms at diagnosis. Radiotherapy should be limited to the cases with aggressive tumors, nonresponsive to dopamine agonists, because of the risk of neurological damage and hypopituitarism later in the lives of these patients.