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Background: With the use of non-objective measurement, adherence to growth hormone (GH) therapy has been reported suboptimal in a large proportion of patients, and poor adherence has been shown to affect short-term growth response in patients receiving GH treatment. Objective: The Easypod™ electronic device allows objective measurement of adherence. In this study, we report 3-year prospective adherence data of the Italian cohort of naïve GH deficient (GHD) children extrapolated from the Easypod Connect Observational Study (ECOS) database. Patients and methods: Seventy-three GHD children naïve to GH treatment were included in the analysis. 22 Italian centers participated in the study. Results: Mean adherence rate was consistently above 85% across the 3-year observation period. Particularly, mean adherence was 88.5%, 86.6%, and 85.7% after 1, 2 and 3years, respectively. Mean (± SD) height-SDS increase after the first year was 0.41 (± 0.38). Conclusions: The majority of naïve GHD children starting GH treatment with Easypod maintained an adherence rate > 85% up to 3years. Easypod is a useful tool to follow-up patients’ adherence allowing timely intervention to improve optimal treatment for these patients.

Objective To study growth and puberty in a multinational longitudinal prospective cohort of children with juvenile dermatomyositis (DM). Methods Children from 31 countries who were ages DM in active phase were studied, and analyses of height, weight, and pubertal development were conducted in those who had follow-up visits during a 2-year period and for whom anthropometric data was available. Results A total of 196 of 275 children (71%) were included. We found a significant reduction in parent-adjusted height Z score over time in female patients (P < 0.0001) and male patients (P = 0.001), but with catch-up growth at the final study visit. Median body mass index Z score peaked at 6 months (P < 0.0001) and was still significantly above baseline at the final study visit, which was at a median of 26 months after baseline (P = 0.007), with no difference between sexes. Female patients with a disease duration >= 12 months after onset had significantly lower parent-adjusted height Z score (P = 0.002) and no 2-year catch-up growth. At the final study visit, growth failure was seen in 20 of 97 female patients (21%) and in 11 of 73 male patients (15%). Height deflection ( increment height Z score less than -0.25/year) was observed in 29 of 116 female patients (25%) and 25 of 80 male patients (31.3%). Delayed puberty was seen in 20 of 55 female patients (36.4%) and in 11 of 31 male patients (35.5%). Children in early pubertal stage at baseline had the highest risk of growth failure. Conclusion Juvenile DM in the active phase and/or its treatment has a significant impact on growth and puberty in affected children. Children with recent onset of puberty or previous growth failure have the highest risk of delayed pubertal development and further growth retardation.

Cardio-facio-cutaneous (CFC) syndrome is a very rare and sporadic disease whose characteristics include dysmorphic facial appearance, ectodermal abnormalities, cardiac abnormalities, growth retardation and neurodevelopmental delay. This syndrome is classified as one of the RAS syndromes which are caused by altered signal transduction of the RAS/MAPK (mitogen activated protein kinase) pathway due to the mutation of genes including BRAF, MEK1/2, HRAS and KRAS. Other RAS syndromes, such as Costello syndrome and Noonan syndrome, share clinical features with CFC. Moreover, patients with the same clinical phenotype may have different molecular diagnoses. Clinical diagnosis is the starting pointfor correct classification. We describe the clinical data of one case of CFC syndrome, genetically determined by KRAS mutation, that involved chylothorax, lymphedema, sinus pericranii, craniosynostosis, and seizures. This is the second case report of the literature.

CONTEXT: Serum IGF-I levels are often low in patients with short stature (SS) without defined etiology. Hence, genetic investigations have focused on the GH-IGF-I axis.OBJECTIVE: Our objectives were to characterize IGF-I axis status and search for a broader range of genetic associations in children with SS and normal GH.DESIGN AND SETTING: We conducted a prospective, cross-sectional, epidemiogenetic case-control study in 9 European countries (2008-2010).PARTICIPANTS: Children (n = 275) aged ≥2 years with SS without defined etiology (≤-2.5 height SD score [SDS]) and ≥1 peak GH ≥7 μg/L) were recruited.METHODS: Serum IGF-I, IGF-binding protein-3 (IGFBP-3), and acid-labile subunit (ALS) levels were measured in a central laboratory. Candidate gene exome sequencing was performed in this cohort and ethnicity-matched controls.RESULTS: Serum IGF-I, IGFBP-3, and ALS levels were highly correlated, but there was a discrepancy between prevalence of IGF-I, IGFBP-3, and ALS deficiencies (53%, 30%, and 0.8%, respectively). An insertion-deletion (Indel) on the IGF1 gene (P = 1.2 × 10(-5), Bonferroni-corrected; case vs control frequency: 0.04 vs 0.112), an Indel on NFKB1 (P = 1.36 × 10(-10); case vs control frequency: 0.464 vs 0.272), and 2 single-nucleotide polymorphisms on ZBTB38 (P < 2.3 × 10(-6)) were associated with SS. At P < 10(-4), single-nucleotide polymorphisms on genes related to protein kinase regulation, MAPK, and Fanconi pathways were also associated with SS.CONCLUSIONS: IGF-I deficiency is a common feature in SS without defined etiology; an Indel in the IGF1 gene was associated with SS. However, genes involved in transcriptional regulation (NFKB1 and ZBTB38) and growth factor signaling were also associated, providing further candidates for genetic investigations on individual patients.

Context: The diagnostic value of tests for detecting hypothalamic-pituitary adrenal insufficiency (HPAI) is controversial. Objective: Our objective was to compare standard-dose and low-dose corticotropin tests for diagnosing HPAI. Data Sources: We searched the PubMed database from 1966-2006 for studies reporting diagnostic value of standard-dose or low-dose corticotropin tests, with patient-level data obtained from original investigators. Study Selection: Eligible studies had more than 10 patients. All subjects were evaluated because of suspicion for chronic HPAI, and patient-level data were available. We excluded studies with no accepted reference standard for HPAI (insulin hypoglycemia or metyrapone test) if test subjects were in the intensive care unit or if only normal healthy subjects were used as controls. Data Extraction: We constructed receiver operator characteristic (ROC) curves using patient-level data from each study and then merged results to create summary ROC curves, adjusting for study size and cortisol assay method. Diagnostic value of tests was measured by calculating area under the ROC curve (AUC) and likelihood ratios. Data Synthesis: Patient-level data from 13 of 23 studies (57%; 679 subjects) were included in the metaanalysis. The AUC were as follows: low-dose corticotropin test, 0.92 (95% confidence interval 0.89-0.94), and standard-dose corticotropin test, 0.79 (95% confidence interval 0.74-0.84). Among patients with paired data (seven studies, 254 subjects), diagnostic value of low-dose corticotropin test was superior to standard-dose test (AUC 0.94 and 0.85, respectively; P < 0.001). Conclusions: Low-dose corticotropin test was superior to standard-dose test for diagnosing chronic HPAI, although it has technical limitations. (J Clin Endocrinol Metab 93: 4245-4253, 2008)

OBJECTIVE: To investigate which pretreatment variables most significantly affect long-term growth response to GH therapy in children with apparently idiopathic GH deficiency (GHD) treated from a similar and very young age (less than 2 years), for the same period (7 years) and with the same therapeutic protocol. DESIGN AND METHODS: Twelve children with either isolated GHD or multiple pituitary hormone deficiency were treated with biosynthetic human GH (0.7IU/kg per week) and were examined every 6 months. Height measurements were performed by Harpenden stadiometers. Bone age was evaluated every 12 months. RESULTS: The onset of therapy was followed in all patients by an important height gain, which attained its zenith during the first year of treatment and became progressively less evident during the next 4 years. Cumulative height gain was 3.0+/-1.7SDS. Thanks to the therapy, at the end of the 7-year treatment period, average height in the entire series was not significantly far from mean target height (TH) (-0.7+/-1.3 vs -0. 3+/-0.4SDS) and average predicted height (PH) (-0.2+/-1.4SDS) was very close to TH. A stepwise regression analysis showed that both catch-up growth under therapy and PH at the end of the 7-year treatment period were positively influenced by birth weight (BW). CONCLUSIONS: a) Our 7-year prospective study on GHD infants treated with GH from less than 2 years of age confirmed the importance of early diagnosis and treatment of GHD in childhood. b) The influence of BW on growth response to GH therapy in GHD children persists over time, at least when treatment is begun from less than 2 years of age.

We describe three cases of central diabetes insipidus, each with a different pathogenesis, in which unexpected hyperintensity of the posterior pituitary gland was seen on T1-weighted MR images obtained at the time of presentation. In the first case (idiopathic), the posterior pituitary signal persisted more than 10 years; in the second case (Langerhans cell histiocytosis), the signal disappeared within 3 months, despite early specific chemotherapy with etoposide; and in the third case (transient), the posterior signal disappeared within 1 year, but it was documented at the time of spontaneous reversal of polyuria and polydipsia.

PURPOSE: To describe the MR findings in the hypothalamic pituitary area in children with Langerhans cell histiocytosis and to define those MR alterations especially associated with the risk of developing diabetes insipidus. METHODS: The hypothalamic-neurohypophyseal axis was studied by sagittal and coronal 1.5 T1-weighted MR imaging in 14 children with Langerhans cell histiocytosis (five with diabetes insipidus) and in 28 low-stature controls, ages 6-14 years. RESULTS: The pituitary stalk was thicker in seven/14 patients (three with diabetes insipidus) than in controls (P less than .05). Bright posterior pituitary signal was undetectable in children with diabetes insipidus and in one/9 without diabetes insipidus. CONCLUSIONS: Thickening of the hypothalamus and/or the pituitary stalk in the absence of the posterior pituitary bright signal is seen in children with Langerhans cell histiocytosis with overt diabetes insipidus. Those Langerhans cell histiocytosis patients without diabetes insipidus but showing thickened stalk with or without posterior pituitary bright signal could be at high risk to develop diabetes insipidus.

Although there are guidelines for treatment of short stature, open questions regarding optimal management of growth hormone therapy still exist. Experts attending six international meetings agree that successful therapy results in the patient attaining mid-parental height, and relies on correct diagnosis and early intervention. Experts advocate patient followup every 3-6 months, and that growth and adherence should be monitored at each visit. Growth response is variable, and an accepted definition of good/poor response is lacking. Combined with patient education and regular patient follow-up, a definition of treatment response could lead to improved treatment outcomes. Few experts use prediction models in clinical practice, but all agree that pharmacogenetics might improve prediction, enable early therapy modulation, and promote growth. Poor growth is often due to low adherence. Guidance on optimal management of growth hormone therapy is required, with focus on early diagnosis, dosing, treatment monitoring, adherence, and motivation.

Low birth weight and length for gestational age are associated with a high risk of short stature and metabolic syndrome in adulthood. The mechanisms that link prenatal growth to adult stature and metabolic syndrome have not yet been entirely clarified. The aim of our study was to evaluate the relationship between standardized anthropometric measures at birth and insulin-like growth factor (IGF)-I, IGF-II, insulin, adiponectin, and non-esterified fatty acid (NEFA) cord blood levels in the general population. One hundred fifty-eight random newborn subjects (77F, 81M) from Genoa, Italy, were analyzed. Anthropometric parameters were measured and standardized according to standard Italian tables. Insulin values were treated as categorical, since in several cases the results fell below detection cut-off. Mean birth weight was 3,214.23#x2213;488.99 gr and mean length was 49.82#x2213;2.17 cm. Females had higher mean IGF-I (p=0.04), and were more likely to have insulin values either2#956;U/ml or4.5#956;U/ml (p= 0.04) compared to males. Weight and length SD scores (SDS) were higher in subjects with elevated insulin levels (p=0.002). A moderate correlation was found between weight and IGF-II (r=0.354). Multivariable analysis demonstrated that standardized birth weight was associated with IGFII and insulin values. Our data highlight the importance of IGF-II in fetal growth and suggest that gender differences should be taken into consideration when evaluating prenatal growth.

Purpose: We aimed to investigate a cohort of female and male patients with idiopathic central precocious puberty (CPP), negative for Makorin Ring Finger Protein 3 (MKRN3) defect, by molecular screening for Delta-like 1 homolog (DLK1) defects. DLK1 is an imprinted gene, whose mutations have been described as a rare cause of CPP in girls and adult women with precocious menarche, obesity and metabolic derangement. Methods: We enrolled 14 girls with familial CPP and 13 boys with familial or sporadic CPP from multiple academic hospital centers. Gene sequencing of DLK1 gene was performed. Circulating levels of DLK1 were measured and clinical and biochemical characteristics were described in those with DLK1 defects. Results: A novel heterozygous mutation in DLK1, c.288_289insC (p.Cys97Leufs*16), was identified in a male proband, his sister and their father. Age at onset of puberty was in line with previous reports in the girl and 8years in the boy. The father with untreated CPP showed short stature. No metabolic derangement was present in the father except hypercholesterolemia. Undetectable Dlk1 serum levels indicated the complete lack of protein production in the three affected patients. Conclusion: A DLK1 defect has been identified for the first time in a boy, underscoring the importance of genetic testing in males with idiopathic or sporadic CPP. The short stature reported by his untreated father suggests the need for timely diagnosis and treatment of subjects with DLK1 defects.

Background Autosomal dominant neurohypophyseal diabetes insipidus (adNDI) is caused by arginine vasopressin (AVP) deficiency resulting from mutations in the AVP-NPII gene encoding the AVP preprohormone. Aim To describe the clinical and molecular features of Italian unrelated families with central diabetes insipidus. Patients and methods We analyzed AVP-NPII gene in 13 families in whom diabetes insipidus appeared to be segregating. Results Twenty-two patients were found to carry a pathogenic AVP-NPII gene mutation. Two novel c.173 G>C (p.Cys58Ser) and c.215 C>A (p.Ala72Glu) missense mutations and additional eight different mutations previously described were identified; nine were missense and one non-sense mutation. Most mutations (eight out of ten) occurred in the region encoding for the NPII moiety; two mutations were detected in exon 1. No mutations were found in exon 3. Median age of onset was 32.5 months with a variability within the same mutation (3 to 360 months). No clear genotype–phenotype correlation has been observed, except for the c.55 G>A (p.Ala19Thr) mutation, which led to a later onset of disease (median age 120 months). Brain magnetic resonance imaging (MRI) revealed the absence of posterior pituitary hyperintensity in 8 out of 15 subjects, hypointense signal in 4 and normal signal in 2. Follow-up MRI showed the disappearance of the posterior pituitary hyperintensity after 6 years in one case. Conclusion adNDI is a progressive disease with a variable age of onset. Molecular diagnosis and counseling should be provided to avoid unnecessary investigations and to ensure an early and adequate treatment.

Background Prader–Willi syndrome (PWS) is a rare and complex genetic disease, with numerous implications on metabolic, endocrine, neuropsychomotor systems, and with behavioural and intellectual disorders. Rare disease patient registries are important scientific tools (1) to collect clinical and epidemiologic data, (2) to assess the clinical management including the diagnostic delay, (3) to improve patients’ care and (4) to foster research to identify new therapeutic solutions. The European Union has recommended the implementation and use of registries and databases. The main aims of this paper are to describe the process of setting up the Italian PWS register, and to illustrate our preliminary results. Materials and methods The Italian PWS registry was established in 2019 with the aims (1) to describe the natural history of the disease, (2) to determine clinical effectiveness of health care services, (3) to measure and monitor quality of care of patients. Information from six different variables are included and collected into this registry: demographics, diagnosis and genetics, patient status, therapy, quality of life and mortality. Results A total of 165 patients (50.3% female vs 49.7% male) were included into Italian PWS registry in 2019–2020 period. Average age at genetic diagnosis was 4.6 years; 45.4% of patients was less than 17 years old aged, while the 54.6% was in adult age (> 18 years old). Sixty-one percent of subjects had interstitial deletion of the proximal long arm of paternal chromosome 15, while 36.4% had uniparental maternal disomy for chromosome 15. Three patients presented an imprinting centre defect and one had a de novo translocation involving chromosome 15. A positive methylation test was demonstrated in the remaining 11 individuals but the underlying genetic defect was not identified. Compulsive food-seeking and hyperphagia was present in 63.6% of patients (prevalently in adults); 54.5% of patients developed morbid obesity. Altered glucose metabolism was present in 33.3% of patients. Central hypothyroidism was reported in 20% of patients; 94.7% of children and adolescents and 13.3% of adult patients is undergoing GH treatment. Conclusions The analyses of these six variables allowed to highlight important clinical aspects and natural history of PWS useful to inform future actions to be taken by national health care services and health professionals.

INTRODUCTION: Defects of prokineticin pathway affect the neuroendocrine control of reproduction, but their role in the pathogenesis of central hypogonadism remains undefined, and the functional impact of the missense PROKR2 variants has been incompletely characterized. MATERIAL AND METHODS: In a series of 246 idiopathic central hypogonadism patients, we found three novel (p.V158I, p.V334M, and p.N15TfsX30) and six already known (p.L173R, p.T260M, p.R268C, p.V274D, p.V331M, and p.H20MfsX23) germline variants in the PROKR2 gene. We evaluated the effects of seven missense alterations on two different prokineticin receptor 2 (PROKR2)-dependent pathways: inositol phosphate-Ca(2+) (Gq coupling) and cAMP (Gs coupling). RESULTS: PROKR2 variants were found in 16 patients (6.5%). Expression levels of variants p.V158I and p.V331M were moderately reduced, whereas they were markedly impaired in the remaining cases, except p.V334M, which was significantly overexpressed. The variants p.T260M, p.R268C, and p.V331M showed no remarkable changes in cAMP response (EC50) whereas the IP signaling appeared more profoundly affected. In contrast, cAMP accumulation cannot be stimulated through the p.L173R and p.V274D, but IP EC50 was similar to wt inp.L173R and increased by 10-fold in p.V274D. The variant p.V334M led to a 3-fold increase of EC50 for both cAMP and IP. CONCLUSION: Our study shows that single PROKR2 missense allelic variants can either affect both signaling pathways differently or selectively. Thus, the integrity of both PROKR2-dependent cAMP and IP signals should be evaluated for a complete functional testing of novel identified allelic variants.

Purpose: To detect the presence of antipituitary (APA) and antihypothalamus antibodies (AHA) in subjects treated for brain cancers, and to evaluate their potential association with pituitary dysfunction. Methods: We evaluated 63 patients with craniopharyngioma, glioma, and germinoma treated with surgery and/or radiotherapy and/or chemotherapy at a median age of 13 years. Forty-one had multiple pituitary hormone deficiencies (MPHD), six had a single pituitary defect. GH was the most common defect (65.1%), followed by AVP (61.9%), TSH (57.1%), ACTH (49.2%), and gonadotropin (38.1%). APA and AHA were evaluated by simple indirect immunofluorescence method indirect immunofluorescence in patients and in 50 healthy controls. Results: Circulating APA and/or AHA were found in 31 subjects (49.2%) and in none of the healthy controls. In particular, 25 subjects out of 31 were APA (80.6%), 26 were AHA (83.90%), and 20 were both APA and AHA (64.5%). Nine patients APA and/or AHA have craniopharyngioma (29%), seven (22.6%) have glioma, and 15 (48.4%) have germinoma. Patients with craniopharyngioma were positive for at least one antibody in 39.1% compared to 33.3% of patients with glioma and to 78.9% of those with germinoma with an analogous distribution for APA and AHA between the three tumors. The presence of APA or AHA and of both APA and AHA was significantly increased in patients with germinoma. The presence of APA (P = 0.001) and their titers (P = 0.001) was significantly associated with the type of tumor in the following order: germinomas, craniopharyngiomas, and gliomas; an analogous distribution was observed for the presence of AHA (P = 0.002) and their titers (P = 0.012). In addition, we found a significant association between radiotherapy and APA (P = 0.03). Conclusions: Brain tumors especially germinoma are associated with the development of hypothalamic–pituitary antibodies and pituitary defects. The correct interpretation of APA/AHA antibodies is essential to avoid a misdiagnosis of an autoimmune infundibulo-neurohypophysitis or pituitary hypophysitis in patients with germinoma.

OBJECTIVE: The diagnosis of growth hormone deficiency (GHD) is currently based on clinical, auxological, biochemical and neuro-radiological investigation. Provocative tests of GH secretion using physiological/pharmacological stimuli are required to confirm GHD. The clonidine test (CT) is widely used to assess GH secretory status. In this retrospective study, we analyzed the reliability of CT and the effect of puberty in a large number of children with short stature who had been evaluated for suspected GHD. DESIGN AND PATIENTS: Data were collected retrospectively from 327 children and adolescents with short stature (204 boys and 123 girls, median age 10.5 years (IQR 7.90-12.40) followed in four Italian Paediatric Endocrine Units (Cagliari, Genova, Napoli and Roma) between 2005 and 2013. MEASUREMENTS: All children underwent CT as the first GH stimulation test after exclusion of other known cause of their short stature. RESULTS: In 73 prepubertal children and 25 pubertal children, the GH peak after CT was

ObjectiveIdiopathic early-onset central diabetes insipidus (CDI) might be due to mutations of arginine vasopressin–neurophysin II (AVP–NPII (AVP)) or wolframin (WFS1) genes.Design and methodsSequencing of AVP and WFS1 genes was performed in nine children with CDI, aged between 9 and 68 months, and negative family history for polyuria and polydipsia.ResultsTwo patients carried a mutation in the AVP gene: a heterozygous G-to-T transition at nucleotide position 322 of exon 2 (c.322G>T) resulting in a stop codon at position 108 (p.Glu108X), and a novel deletion from nucleotide 52 to 54 (c.52_54delTCC) producing a deletion of a serine at position 18 (p.Ser18del) of the AVP pre-prohormone signal peptide. A third patient carried two heterozygous mutations in the WFS1 gene localized on different alleles. The first change was A-to-G transition at nucleotide 997 in exon 8 (c.997A>G), resulting in a valine residue at position 333 in place of isoleucine (p.Ile333Val). The second novel mutation was a 3 bp insertion in exon 8, c.2392_2393insACG causing the addition of an aspartate residue at position 797 and the maintenance of the correct open reading frame (p. Asp797_Val798insAsp). While similar WFS1 protein levels were detected in fibroblasts from healthy subjects and from the patient and his parents, a major sensitivity to staurosporine-induced apoptosis was observed in the patient fibroblasts as well as in patients with Wolfram syndrome.ConclusionsEarly-onset CDI is associated with de novo mutations of the AVP gene and with hereditary WFS1 gene changes. These findings have valuable implications for management and genetic counseling.

PURPOSE: Poor adherence to recombinant human growth hormone (r-hGH) therapy is associated with reduced growth velocity in children with growth hormone deficiency (GHD). This twelve-month observational study was to assess adherence in r-hGH patients treated with the easypod™, an electronic, fully automated injection device designed to track the time, date and dose administered. METHODS: Ninety-seven prepubertal patients receiving r-hGH therapy were included in the study from ten Italian clinical sites and 88 completed the study. To avoid possible confounding effects, only GHD patients (79/88; 89.7 % of the overall study population) were considered in the final analysis. The primary endpoint-adherence to treatment-was calculated as the proportion of injections correctly administered during the observational period out of the expected total number of injections. The relevant information, tracked by the easypod™, was collected at months 6 (V1) and 12 (V2) after baseline (V0). At study termination, adherence data were partially available from 16 patients and fully available from 53 patients. As secondary endpoints, serum IGF-1 levels, fasting serum glucose and insulin levels and key anthropometric characteristics (height, waist circumference and BMI) were also determined. RESULTS: The easypod™ data showed that 56.7 % of the patients were considered to be fully (≥92 %) adherent to their treatment throughout the period V0-V2. Treatment improved stature, significantly increased IGF-1 and produced a non-significant increase in blood glucose and insulin levels. CONCLUSIONS: The injection-recording system and other characteristics of easypod™ could enhance the ability of physicians to monitor adherence to r-hGH treatment.

ObjectiveTo define the appropriate diagnostic cut-off limits for the GH response to GHRH+arginine (ARG) test and IGF-I levels, using receiver operating characteristics (ROC) curve analysis, in late adolescents and young adults.Design and methodsWe studied 152 patients with childhood-onset organic hypothalamic–pituitary disease (85 males, age (mean±s.e.m.): 19.2±0.2 years) and 201 normal adolescents as controls (96 males, age: 20.7±0.2 years). Patients were divided into three subgroups on the basis of the number of the other pituitary hormone deficits, excluding GH deficiency (GHD): subgroup A consisted of 35 panhypopituitary patients (17 males, age: 21.2±0.4 years), subgroup B consisted of 18 patients with only one or with no more than two pituitary hormone deficits (7 males, age: 20.2±0.9 years); and subgroup C consisted of 99 patients without any known hormonal pituitary deficits (60 males, age: 18.2±0.2 years). Both patients and controls were lean (body mass index, BMI2). Patients in subgroup A were assumed to be GHD, whereas in patients belonging to subgroups B and C the presence of GHD had to be verified.ResultsFor the GHRH+ARG test, the best pair of highest sensitivity (Se; 100%) and specificity (Sp; 97%) was found choosing a peak GH of 19.0 μg/l. For IGF-I levels, the best pair of highest Se (96.6%) and Sp (74.6%) was found using a cut-off point of 160 μg/l (SDS: −1.3). Assuming 19.0 μg/l to be the cut-off point established for GHRH+ARG test, 72.2% of patients in subgroup B and 39.4% in subgroup C were defined as GHD. In patients belonging to group B and C and with a peak GH response ConclusionsIn late adolescent and early adulthood patients, a GH cut-off limit using the GHRH+ARG test lower than 19.0 μg/l is able to discriminate patients with a suspicion of GHD and does not vary from infancy to early adulthood.

By retrospectively collecting data from nine Italian centres of pediatric endocrinology, we assessed the different management and final outcome of children with short stature and idiopathic delayed puberty. Data were obtained in 77 patients (54 males, 23 females) diagnosed and followed-up in the various centres during the last 15 years. Inclusion criteria were short stature at initial observation and idiopathic delayed puberty diagnosed during follow-up. At first observation, age was 13.8 +/- 1.0 years and height standard deviation score (SDS) was -2.6 +/- 0.6 in males. In females age was 13.1 +/- 0.9 years and height SDS -2.6 +/- 0.4. Local diagnostic and therapeutic protocols included testing for growth-hormone deficiency (six centres) and treatment in case of deficiency or, in the remaining centres, testosterone or no treatment in males, and no treatment in females. At diagnosis, both in males and in females, the auxological features (height SDS, target height SDS and bone age delay) were similar in the patients treated with growth hormone, testosterone or not treated. Overall 32 patients received growth hormone (25 males, 7 females), 33 no treatment (17 males, 16 females) and 12 testosterone. There was no difference in the adult height of males and females in the different treatment groups. In males there were no differences between adult and target height SDSs (growth hormone-treated 0.31 +/- 0.79, untreated 0.10 +/- 0.82, testosterone-treated 0.05 +/- 0.95), between adult and initial height SDSs (growth hormone-treated 1.70 +/- 0.93, untreated 1.55 +/- 0.92, testosterone-treated 1.53 +/- 1.43) and percentage of subjects with adult height above target height. In females, there were no differences between adult and target height SDSs (growth hormone-treated -0.49 +/- 1.13; untreated 0.10 +/- 0.97) and between adult and initial height SDSs (growth hormone-treated 1.76 +/- 0.92; untreated 1.77 +/- 0.98), whereas a significantly higher percentage of patients remained below target height in the growth hormone-treated group (6/7, 85.7% vs 5/11, 31.3%) (P = 0.02). In conclusion, the diagnostic and therapeutic management of the patients with short stature and delayed puberty is different among Italian pediatric endocrinologists. Our data do not support the usefulness of growth-hormone therapy in improving adult height in subjects with short stature and delayed puberty, particularly in the female sex.

Hypochondroplasia is an autosomal dominant skeletal dysplasia characterized by disproportionate short stature. A mutation (N540K) in the fibroblast growth factor receptor 3 (FGFR3) gene was described in some patients with this condition. The aims of the study were to identify the frequency of the FGFR3 gene mutation, to define the salient clinical and radiological abnormalities of the affected subjects, and to verify the contribution of molecular findings to the clinical and radiological definition of hypochondroplasia. Based on the most common radiological criteria, we selected 18 patients with a phenotype compatible with hypochondroplasia. Height, sitting height, and cranial circumference were measured in all patients. Radiographs of the lumbar spine, left leg, pelvis, and left hand were also obtained. The presence of the N540K mutation was verified by restriction enzyme digestions. Half of our patients carried the N540K mutation. Although similar in phenotype to the patients without the mutation, they showed in addition relative macrocephaly. The association of the unchanged/narrow interpedicular distance with the fibula longer than the tibia was more common in patients with gene mutation. Although we did not find a firm correlation between genotype and phenotype, in our study the N540K mutation was most often associated with disproportionate short stature, macrocephaly, and with radiological findings of unchanged/narrow interpedicular distance and fibula longer than tibia.

Developmental syndromes are characterized by numerous phenotypical signs and malformations. In most of them such as Turner, Noonan, Prader-Willi, Silver-Russel, Williams, Kabuki, Leri-Weill syndrome and skeletal dysplasias, short stature is a common feature. Growth defect is very often related to a defect in cellular growth, but some unknown abnormality in GH action is possible. Recently, the greater availability of recombinant GH has expanded the interest towards GH secretion and therapy also in developmental syndromes. We recognize syndromes associated with GH deficiency (GHD), showing a developmental midline defect such as Pallister-Hall syndrome, septo-optic dysplasia, but many of these conditions do not have a convincing link with GHD. Moreover, some conditions, in particular the well-studied Turner syndrome, that do not have a real GHD, have proven to benefit from GH therapy at supra-physiological doses obtaining a higher final height than the expected one according to the natural history. This has expanded the indications for GH therapy. The aim of our paper is to review the literature on GH secretion, on the effects and costs-benefits of GH therapy in many dysmorphic syndromes, presenting some results of GH secretion and therapy obtained in our experience.

The nuclear receptor transcription factors DAX-1 (NROB1) and SF-1 (NR5A1) regulate many aspects of adrenal and reproductive development and function. Disruption of the genes encoding these factors can be associated with pediatric adrenal disease. DAX-1 mutations are classically associated with X-linked adrenal hypoplasia congenita, hypogonadotropic hypogonadism and impaired spermatogenesis. However, other phenotypes are also being reported, such as isolated mineralocorticoid insufficiency, premature sexual development, primary adrenal insufficiency in a 46,XX patient and late-onset X-linked adrenal hypoplasia congenita and/or hypogonadotropic hypogonadism. SF-1 mutations have also been associated with primary adrenal insufficiency, together with 46,XY disorders of sex development. However it is emerging that SF-1 changes are a relatively rare cause of primary adrenal failure in humans, and most individuals with SF-1 mutations have a spectrum of 46,XY disorders of sex development phenotypes. These conditions range from 46,XY females with streak gonads and miillerian structures, through children with ambiguous genitalia and inguinal testes, to severe penoscrotal hypospadias with undescended testes. Therefore, the human gonad appears to be more sensitive than the adrenal gland to loss of SF-1 function. This review will focus on the expanding range of phenotypes associated with DAX-1 and SF-1 mutations.