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Alessandro Cicognani, Emanuele Cacciari, Moreno Tacconi, Maria G. Pascucci, Susanna Tonioli, Piero Pirazzoli, and Antonio Balsamo


IGF-I, testosterone and estradiol levels were evaluated in 8 girls with androgen insensitivity immediately before and from 1 to 3 months after bilateral gonadectomy. In 6 patients GH secretion was evaluated before and after gonadectomy by means of an arginine test and in 3 a sleep test was also performed. Mean IGF-I level before surgery was significantly higher than that of normal controls (2850 ± 1230 vs 1680 ± 1040 U/l, p < 0.025). After gonadectomy a significant decrease was evident for testosterone, estradiol and IGF-I levels. A positive correlation between IGF-I and estradiol levels was present before surgery (p < 0.005). The presence of a correlation with estradiol, but not with testosterone, and the knowledge that this syndrome is due to an insensitivity to androgens, but not to estradiol, support the hypothesis that the estradiol level is the major determinant for the control of IGF-I values in these patients. After gonadectomy, a substantial decrease of the 12-h nocturnal GH secretion was evident. Comparison of the nocturnal GH levels before surgery of the 3 patients with those of normal subjects of the same age showed hormonal values higher than 1 sd over the mean values of control subjects. Even if the number of patients studied is too small to draw any definitive conclusion, these data may suggest that sex hormones play a role in the control of IGF-I levels, a function which seems to be mediated through GH secretion.

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Antonio Balsamo, Alessandro Cicognani, Monia Gennari, Wolfgang G Sippell, Soara Menabò, Federico Baronio, and Felix G Riepe

Objective: The renal form of pseudohypoaldosteronism type 1 (PHA1) is a rare disease caused by mutations in the human mineralocorticoid receptor gene (NR3C2).

Design: Aim of the study was to analyze the NR3C2 gene in three Italian patients with clinical signs of renal PHA1 and to evaluate the distribution of the -2G > C, c.538A > G, and c.722C > T single nucleotide polymorphism (SNP) pattern in the PHA1 patients and in 90 controls of the same ethnic origin.

Methods: Analysis of the NR3C2 gene sequence and of the polymorphic SNP markers. Functional characterization of the detected novel NR3C2 mutations utilizing aldosterone-binding assays and reporter gene transactivation assays.

Results: One novel nonsense (Y134X) and one novel frameshift (2125delA) mutation were detected. They exhibited no aldosterone binding and no transactivation abilities. No mutation was detected in the third patient. Haploinsufficiency of NR3C2 was ruled out by microsatellite analysis in this patient. The c.722T SNP was detected in 97% of alleles in the Italian population which is significantly different from the general German or US population.

Conclusions: Molecular analysis of the NR3C2 gene in PHA1 patients is warranted to detect novel mutations in order to clarify the underlying genetic cause, which may extend the insight into relevant functional regions of the hMR protein. The effect the different distribution of the c.722T SNP is not clear to date. Further studies are necessary to provide evidence as to a possible advantage of a less sensitive hMR in southern countries.

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Alessandra Antelli, Lilia Baldazzi, Antonio Balsamo, Piero Pirazzoli, Annalisa Nicoletti, Monia Gennari, and Alessandro Cicognani

Objective: Mutations in the gonadotropin-releasing hormone receptor (GnRHR) gene are the cause of isolated hypogonadotropic hypogonadism (HH). We describe the molecular investigations of the GnRHR gene in two siblings affected by HH and their clinical course.

Design: The female was referred at age 14 for pubertal delay with no secondary sexual signs, whereas the male had been followed since prepuberty. Hormonal evaluation showed very low levels of gonadotropins, luteinizing hormone-releasing hormone test (LHRH test) and sexual steroids in both patients, suggesting a possible defect in the mechanism of action of the GnRH gene on its receptor.

Methods: The GnRHR gene of the two siblings and their parents were analyzed by PCR followed by direct sequencing.

Results: Two new single nucleotide substitutions resulting in the T104I and the Y108C substitutions in the first extracellular loop (ECL1) were identified in both siblings. The molecular analysis confirmed the carrier status of the parents.

Conclusions: We identified two new missense mutations in the GnRHR gene in two siblings with HH. The nature of the substitutions lying in the ECL1 involved in the ligand–receptor interaction, as well as the high conservation of the two residues in all mammalian GnRHR, are suggestive of some implications in the phenotype observed.

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Alessandra Cassio, Emanuele Cacciari, Antonia D'Errico, Antonio Balsamo, Franco W. Grigioni, Maria G. Pascucci, Francesco Bacci, Moreno Tacconi, and Antonio M. Mancini


Gonadal histology was investigated by means of conventional microscopy in 6 patients with complete androgen insensitivity syndrome, in 11 with incomplete androgen insensitivity syndrome, and in 3 with 5α-reductase syndrome. Twelve subjects were prepubertal and 8 pubertal. In all patients gonadal tissue was removed as a prophylactic measure and no patients gave rise to any clinical suspicion of a tumour. Eight patients with incomplete androgen insensitivity syndrome, 5 of whom (62.5%) were prepubertal, showed intratubular germ cell neoplasia and in 6 of them it was bilateral. Histochemical and immunohistochemical analysis showed considerable agreement between atypical morphological aspects and positive response to Schiff's periodic acid and to staining with the anti-placenta alkaline phosphatase antibody. Our patients were characterized by one of the highest reported incidences of intratubular germ cell neoplasia, particularly at prepubertal age. These findings would seem to indicate that a rethink is needed concerning the general opinion that patients with androgen intensivity syndrome have practically no risk of developing malignancy, and that orchidectomy is not advisable before puberty is completed.

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Giuseppa Patti, Saverio Scianguetta, Domenico Roberti, Alberto Di Mascio, Antonio Balsamo, Milena Brugnara, Marco Cappa, Maddalena Casale, Paolo Cavarzere, Sarah Cipriani, Sabrina Corbetta, Rossella Gaudino, Lorenzo Iughetti, Lucia Martini, Flavia Napoli, Alessandro Peri, Maria Carolina Salerno, Roberto Salerno, Elena Passeri, Mohamad Maghnie, Silverio Perrotta, and Natascia Di Iorgi


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.


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.


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.


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.

Open access

Irina Bacila, Nicole Freeman, Eleni Daniel, Marija Sandrk, Jillian Bryce, Salma Rashid Ali, Zehra Yavas Abalı, Navoda Atapattu, Tania A Bachega, Antonio Balsamo, Niels Birkebæk, Oliver Blankenstein, Walter Bonfig, Martine Cools, Eduardo Correa Costa, Feyza Darendeliler, Silvia Einaudi, Heba Hassan Elsedfy, Martijn Finken, Evelien Gevers, Hedi L Claahsen-van der Grinten, Tulay Guran, Ayla Güven, Sabine E. Hannema, Claire E Higham, Violeta Iotova, Hetty J. van der Kamp, Marta Korbonits, Ruth E Krone, Corina Lichiardopol, Andrea Luczay, Berenice Bilharinho Mendonca, Tatjana Milenkovic, Mirela C Miranda, Klaus Mohnike, Uta Neumann, Rita Ortolano, Sukran Poyrazoglu, Ajay Thankamony, Jeremy W Tomlinson, Ana Vieites, Liat de Vries, S Faisal Ahmed, Richard J Ross, and Nils P Krone

Objective: Despite published guidelines no unified approach to hormone replacement in congenital adrenal hyperplasia (CAH) exists. We aimed to explore geographical and temporal variations in the treatment with glucocorticoids and mineralocorticoids in CAH.

Design: This retrospective multi-center study, including 31 centers (16 countries), analyzed data from the International-CAH Registry.

Methods: Data was collected from 461 patients aged 0-18 years with classic 21-hydroxylase deficiency (54.9% females) under follow-up between 1982 – 2018. Type, dose and timing of glucocorticoid and mineralocorticoid replacement was analyzed from 4174 patient visits.

Results: The most frequently used glucocorticoid was hydrocortisone (87.6%). Overall, there were significant differences between age groups with regards to daily hydrocortisone-equivalent dose for body surface, with the lowest dose (median with interquartile range) of 12.0 (10.0 – 14.5) mg/ m2/ day at age 1 - 8 years and the highest dose of 14.0 (11.6 - 17.4) mg/ m2/ day at age 12-18 years. Glucocorticoid doses decreased after 2010 in patients 0-8 years (p<0.001) and remained unchanged in patients aged 8-18 years. Fludrocortisone was used in 92% of patients, with relative doses decreasing with age. A wide variation was observed among countries with regards to all aspects of steroid hormone replacement.

Conclusions: Data from the I-CAH Registry suggests international variations in hormone replacement therapy, with a tendency to treatment with high doses in children.

Free access

Marco Bonomi, Valeria Vezzoli, Csilla Krausz, Fabiana Guizzardi, Silvia Vezzani, Manuela Simoni, Ivan Bassi, Paolo Duminuco, Natascia Di Iorgi, Claudia Giavoli, Alessandro Pizzocaro, Gianni Russo, Mirella Moro, Letizia Fatti, Alberto Ferlin, Laura Mazzanti, Maria Chiara Zatelli, Salvo Cannavò, Andrea M Isidori, Angela Ida Pincelli, Flavia Prodam, Antonio Mancini, Paolo Limone, Maria Laura Tanda, Rossella Gaudino, Mariacarolina Salerno, Pregnolato Francesca, Mohamad Maghnie, Mario Maggi, Luca Persani, and Italian Network on Central Hypogonadism


Isolated hypogonadotropic hypogonadism (IHH) is a rare disorder with pubertal delay, normal (normoosmic-IHH, nIHH) or defective sense of smell (Kallmann syndrome, KS). Other reproductive and non-reproductive anomalies might be present although information on their frequency are scanty, particularly according to the age of presentation.


Observational cohort study carried out between January 2008 and June 2016 within a national network of academic or general hospitals.


We performed a detailed phenotyping of 503 IHH patients with: (1) manifestations of hypogonadism with low sex steroid hormone and low/normal gonadotropins; (2) absence of expansive hypothalamic/pituitary lesions or multiple pituitary hormone defects. Cohort was divided on IHH onset (PPO, pre-pubertal onset or AO, adult onset) and olfactory function: PPO-nIHH (n = 275), KS (n = 184), AO-nIHH (n = 36) and AO-doIHH (AO-IHH with defective olfaction, n = 8).


90% of patients were classified as PPO and 10% as AO. Typical midline and olfactory defects, bimanual synkinesis and familiarity for pubertal delay were also found among the AO-IHH. Mean age at diagnosis was significantly earlier and more frequently associated with congenital hypogonadism stigmata in patients with Kallmann’s syndrome (KS). Synkinesis, renal and male genital tract anomalies were enriched in KS. Overweight/obesity are significantly associated with AO-IHH rather than PPO-IHH.


Patients with KS are more prone to develop a severe and complex phenotype than nIHH. The presence of typical extra-gonadal defects and familiarity for PPO-IHH among the AO-IHH patients indicates a common predisposition with variable clinical expression. Overall, these findings improve the understanding of IHH and may have a positive impact on the management of patients and their families.