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Familial Neurohypophyseal Diabetes Insipidus in 13 Kindreds and 2

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Familial Neurohypophyseal Diabetes Insipidus in 13 Kindreds and 2 3 181 G Patti, S Scianguetta and Familial centralQ1 diabetes 181:3 233–244 Clinical Study others insipidus Familial neurohypophyseal diabetes insipidus in 13 kindreds and 2 novel mutations in the vasopressin gene Giuseppa Patti1,*, Saverio Scianguetta2,*, Domenico Roberti2, Alberto Di Mascio3, Antonio Balsamo4, Milena Brugnara5, Marco Cappa6, Maddalena Casale2, Paolo Cavarzere5, Sarah Cipriani7, Sabrina Corbetta8, Rossella Gaudino5, Lorenzo Iughetti9, Lucia Martini5, Flavia Napoli1, Alessandro Peri7, Maria Carolina Salerno10, Roberto Salerno11, Elena Passeri8, Mohamad Maghnie1, Silverio Perrotta2 and Natascia Di Iorgi1 1Department of Pediatrics, IRCCS Istituto Giannina Gaslini Institute, University of Genova, Genova, Italy, 2Department of Women, Child and General and Specialized Surgery, University of Campania ‘Luigi Vanvitelli’, Naples, Italy, 3University of Trieste, Trieste, Italy, 4Pediatrics Unit, Policlinico S. Orsola-Malpighi, Bologna, Italy, 5Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of Verona, Verona, Italy, 6Unit of Endocrinology, Bambino Gesù Children’s Hospital, IRCCS, Roma, Italy, 7Endocrine Unit, Department of Experimental and Clinical Biomedical Sciences ‘Mario Serio’, University of Firenze, Correspondence Ospedale Careggi Firenze, Firenze, Italy, 8Endocrinology and Diabetology Service, IRCCS Istituto Ortopedico Galeazzi, should be addressed University of Milan, Milan, Italy, 9Policlinico Universitario Modena, Modena, Italy, 10Department of Translational to M Maghnie or S Perrotta Medical Sciences-Pediatric Section, University of Naples Federico II, Naples, Italy, and 11SOD Endocrinologia, DAI Email Medico-Geriatrico, AOU Careggi Florence, Florence, Italy mohamadmaghnie@gaslini. *(G Patti and S Scianguetta contributed equally to this work) org or silverio.perrotta@ unicampania.it Abstract 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 European Journal of Endocrinology 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. European Journal of Endocrinology (2019) 181, 233–244 https://eje.bioscientifica.com © 2019 European Society of Endocrinology Published by Bioscientifica Ltd. https://doi.org/10.1530/EJE-19-0299 Printed in Great Britain Downloaded from Bioscientifica.com at 09/29/2021 01:17:47AM via free access -19-0299 Clinical Study G Patti, S Scianguetta and Familial central diabetes 181:3 234 others insipidus Introduction typically ranges from the first to the sixth year of life, but various cases of early or delayed onset have also been Central diabetes insipidus (CDI) is a heterogeneous reported (31). Symptoms usually worsen with time in condition characterized by polyuria and polydipsia due patients with early onset of mild polyuria and polydipsia, to a deficiency of arginine vasopressin (AVP). In many especially before 10 years of age, but it is also possible that patients, especially children and adolescents, it is caused complete CDI is expressed from the neonatal period in by the destruction or degeneration of the neurons patients with brain malformations (32). that originate in the supraoptic and paraventricular The wide variability in the age of onset and the nuclei of the hypothalamus. Germinoma (1, 2, 3, severity of the AVP deficiency among patients with the 4) craniopharyngioma (1, 2, 3, 4), Langerhans’-cell same mutation may be ascribed to individual differences histiocytosis (1, 2, 3, 4, 5), inflammatory, autoimmune (1, among such patients, like the rate of production of the 2, 3, 4, 5, 6)/vascular diseases (6), brain malformations (7), mutant precursor, the intensity of neurohypophyseal trauma resulting from surgery or an accident (1, 2, 3, 4, 5) stimulation, individual susceptibility to the toxic effect and in rare cases autosomal dominant neurohypophyseal of the mutant precursor, the ability to degrade mutant DI (adNDI) (8, 9, 10, 11, 12) or X-linked recessive traits (13, precursors and variations in secretory reserve capacity or 14, 15) can cause permanent damage to supraoptic and in the development of the gland itself (8, 9, 10, 11, 12, 13, paraventricular nuclei. The differential diagnosis of the 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, above reported conditions, all presenting with hypotonic 30). Recent data demonstrated that although autophagy polyuria and polydipsia, is challenging and requires a should primarily be a protective mechanism, continuous long-term follow-up, including endocrine and imaging autophagy leads to gradual loss of organelles including evaluations (2, 3) suggesting that early diagnosis of genetic endoplasmic reticulum (ER), resulting in autophagy- conditions could avoid unnecessary investigations. associated cell death of AVP neurons in mice with familial The frequency of adNDI due to AVP-neurophysin II NDI (33). (AVP-NPII) gene mutation is currently unknown, although Aim of this study was to investigate the presence autosomal dominant forms account for between 3.5 and of mutations in the AVP-NPII gene in 13 families with 8% among reported series of patients with CDI (1, 3, 9), clinical diagnosis of CDI. Establishing the genetic etiology but these data are skewed by differing inclusion criteria of CDI enables early appropriate management and family and the availability of genetic testing. Among 79 children counseling and could be useful to avoid unnecessary with CDI of different etiologies, five of 41 patients (6%) neuroimaging follow-up. European Journal of Endocrinology with isolated AVP deficiency and without other evolving pituitary dysfunctions over time, with a normal pituitary stalk size and normal central nervous system appearances Patients and methods were diagnosed with autosomal dominant CDI in one study (1), while three patients with autosomal dominant We studied 22 members of 13 Italian families, in whom CDI (3.5%) were identified among 85 CDI patients in a CDI appeared to be segregating. The family history was more recent one (3). described by a pedigree covering the indicated number of More than 70 disease-causing mutations resulting in generations (Fig. 1). Patients were referred by eight Italian a defective pro-hormone and a deficiency of AVP have Pediatric Endocrine Units (Istituto Giannina Gaslini been described in adNDI (8, 9, 10, 11, 12, 13, 14, 15, Genova, Federico II University Napoli, Ospedale Bambino 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30). Gesù Roma, Policlinico San Donato Milan, Policlinico The AVP-NPII gene consists of three exons where exon 1 Verona, Policlinico S. Orsola-Malpighi Bologna, Policlinico encodes the signal peptide, the AVP peptide and the first Modena, Ospedale Careggi Firenze) between January 2003 nine amino acids of NPII; exon 2 encodes the majority of and April 2016. NPII and exon 3 encodes the carboxyl-terminal 17 amino The diagnosis of CDI was based on a standard acids of NPII and copeptin. The pathophysiology could be protocol as reported previously (3); the criteria for the explained by a progressive postnatal degeneration of the enrolment of patients were (1) isolated AVP deficiency magnocellular neurons producing AVP (8, 10, 11, 12, 16). and (2) family history of CDI. Brain MRI studies in The severity of polyuria may vary considerably between T1-weighted sequences were performed in 15 subjects. different families and even among siblings carrying the MRI was performed at the time of diagnosis and same mutation. In fact, in adNDI, clinical disease onset was repeated during follow-up in one patient. https://eje.bioscientifica.com Downloaded from Bioscientifica.com at 09/29/2021 01:17:47AM via free access Clinical Study G Patti, S Scianguetta and Familial central diabetes 181:3 235 others insipidus Family 1A Family 2 B Family 3 C I I I II II II III III IV Family 4D Family 5E Family 6 F I I I II II II III III III IV IV Family 7G Family 8H Family 9 I I I I European Journal of Endocrinology II II II III III Family 10 J Family 11 K Family 12 L Family 13 M I I I I II II II II I II III III III Figure 1 Pedigrees of the
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