Andrea Secco, Anna Elsa Maria Allegri, Natascia di Iorgi, Flavia Napoli, AnnaLisa Calcagno, Enrica Bertelli, Irene Olivieri, Giovanna Pala, Stefano Parodi, Roberto Gastaldi, Andrea Rossi and Mohamad Maghnie
Controversies exist about posterior pituitary (PP) function in subjects with ectopic PP (EPP) and with cerebral midline defects and/or their co-occurrence. We investigate water and electrolyte disturbances in patients at risk for PP dysfunction.
The study was conducted in a single Pediatric Endocrinology Research Unit.
Forty-two subjects with childhood-onset GH deficiency were subdivided into five groups: normal magnetic resonance imaging (n=8, group 1); EPP (n=15, group 2); septo-optic dysplasia (SOD) with normal PP (n=4, group 3); EPP and SOD without (n=7, group 4), and with additional midline brain abnormalities (n=8, group 5). At a mean age of 16.0±1.1 years, they underwent a 120 min i.v. infusion with hypertonic 5% saline and evaluation of plasma osmolality (Posm), arginine vasopressin (AVP), thirst score (in groups 1 and 2), and urinary osmolality were performed.
Mean Posm and AVP significantly increased from baseline scores (284.7±4.9 mosm/kg and 0.6±0.2 pmol/l) to 120 min after saline infusion (300.5±8.0 mosm/kg and 10.3±3.3 pmol/l, P<0.0001). Group 5 showed higher mean Posm and lower mean AVP at all time points (P<0.0001). Mean thirst score did not show a significantly different trend between the groups 1 and 2. Urine osmolality was above 750 mosm/kg in all but seven patients after osmotic challenge.
Patients with midline brain abnormalities and EPP have defective osmoregulated AVP. Patients with EPP and congenital hypopituitarism have normal PP function.
Silverio Perrotta, Natascia Di Iorgi, Fulvio Della Ragione, Saverio Scianguetta, Adriana Borriello, Anna Elsa Maria Allegri, Marcella Ferraro, Claudia Santoro, Flavia Napoli, Annalisa Calcagno, Marta Giaccardi, Marco Cappa, Maria Carolina Salerno, Domenico Cozzolino and Mohamad Maghnie
Idiopathic 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 methods
Sequencing 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.
Two 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.
Early-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.
Lucia Ghizzoni, Marco Cappa, Alessandra Vottero, Graziamaria Ubertini, Daniela Carta, Natascia Di Iorgi, Valentina Gasco, Maddalena Marchesi, Vera Raggi, Anastasia Ibba, Flavia Napoli, Arianna Massimi, Mohamad Maghnie, Sandro Loche and Ottavia Porzio
Premature pubarche (PP) is the most frequent sign of nonclassic congenital adrenal hyperplasia (NCCAH) due to 21-hydroxylase deficiency in childhood. The aim of this study was to assess the relationship between the CYP21A2 genotype and baseline and ACTH-stimulated 17-hydroxyprogesterone (17-OHP) and cortisol serum levels in patients presenting with PP.
Patients and methods
A total of 152 Italian children with PP were studied. Baseline and ACTH-stimulated 17-OHP and cortisol serum levels were measured and CYP21A2 gene was genotyped in all subjects.
Baseline and ACTH-stimulated serum 17-OHP levels were significantly higher in NCCAH patients than in both heterozygotes and children with idiopathic PP (IPP). Of the patient population, four NCCAH patients (7.3%) exhibited baseline 17-OHP values <2 ng/ml (6 nmol/l). An ACTH-stimulated 17-OHP cutoff level of 14 ng/ml (42 nmol/l) identified by the receiver-operating characteristics curves showed the best sensitivity (90.9%) and specificity (100%) in distinguishing NCCAH patients. This value, while correctly identifying all unaffected children, missed 9% of affected individuals. Cortisol response to ACTH stimulation was <18.2 μg/dl (500 nmol/l) in 14 NCCAH patients (28%) and none of the heterozygotes or IPP children. Among the 55 NCCAH patients, 54.5% were homozygous for mild CYP21A2 mutations, 41.8% were compound heterozygotes for one mild and one severe CYP21A2 gene mutations, and 3.6% had two severe CYP21A2 gene mutations.
In children with PP, baseline 17-OHP levels are not useful to rule out the diagnosis of NCCAH, which is accomplished by means of ACTH testing only. The different percentages of severe and mild CYP21A2 gene mutations found in PP children compared with adult NCCAH patients is an indirect evidence that the enzyme defect is under-diagnosed in childhood, and it might not lead to the development of hyperandrogenic symptoms in adulthood. Stress-dose glucocorticoids should be considered in patients with suboptimal cortisol response to ACTH stimulation.
Elisabetta Godano, Giovanni Morana, Natascia Di Iorgi, Angela Pistorio, Anna Elsa Maria Allegri, Flavia Napoli, Roberto Gastaldi, Annalisa Calcagno, Giuseppa Patti, Annalisa Gallizia, Sara Notarnicola, Marta Giaccardi, Serena Noli, Mariasavina Severino, Domenico Tortora, Andrea Rossi and Mohamad Maghnie
To investigate the role of T2-DRIVE MRI sequence in the accurate measurement of pituitary stalk (PS) size and the identification of PS abnormalities in patients with hypothalamic–pituitary disorders without the use of gadolinium.
This was a retrospective study conducted on 242 patients who underwent MRI due to pituitary dysfunction between 2006 and 2015. Among 135 eligible patients, 102 showed eutopic posterior pituitary (PP) gland and 33 showed ‘ectopic’ PP (EPP).
Two readers independently measured the size of PS in patients with eutopic PP at the proximal, midpoint and distal levels on pre- and post-contrast T1-weighted as well as T2-DRIVE images; PS visibility was assessed on pre-contrast T1 and T2-DRIVE sequences in those with EPP. The length, height, width and volume of the anterior pituitary (AP), PP height and length and PP area were analyzed.
Significant agreement between the two readers was obtained for T2-DRIVE PS measurements in patients with ‘eutopic’ PP; a significant difference was demonstrated between the intraclass correlation coefficient calculated on the T2-DRIVE and the T1-pre- and post-contrast sequences. The percentage of PS identified by T2-DRIVE in EPP patients was 72.7% compared to 30.3% of T1 pre-contrast sequences. A significant association was found between the visibility of PS on T2-DRIVE and the height of AP.
T2-DRIVE sequence is extremely precise and reliable for the evaluation of PS size and the recognition of PS abnormalities; the use of gadolinium-based contrast media does not add significant information and may thus be avoided.
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.