sive sive decline of arginine- (AVP) secretion. among other causes. Autosomal dominant central DI presents the clinical feature of a progres post-traumatic,autoimmune, genetic, including etiologiesdifferent has urine, concentrate to region of the of region gene in four patients, which represents an alternative gene assembly. No the mutation of in InsG) the +28code (IVS2 2 intron the in insertion guanine homozygous a revealed sis ved. withidiopathic central DIinanattempt todetermine whether genetica cause would beinvol the sequenced and features clinical the gene. Nenhuma mutação da região codificadora do gene do codificadora região da mutação Nenhuma gene. no íntron 2 (IVS2 +28 InsG) em quatro pacientes, correspondendo a um arranjo alternativo do do sequenciamento do gene AVP-NPII revelou uma inserção em homozigose de uma guanina pela reação em cadeia da polimerase e, posteriormente, sequenciado. posteriormente, e, polimerase da cadeia em reação pela gene o e extraído foi molecular,genômico análise DNA da o lização foi estabelecido por meio do teste de jejum hídrico e infusão de salina hipertônica. Para a rea­ Arq Bras Metab. Endocrinol 2010;54/3 Introduction: ABSTRACT L. Batista Sergio seguimento longo com idiopático central insípido diabetes com pacientes de II neurofisina arginina-vasopressina da gene do molecular análise e clínica Apresentação central follow-up patientswithidiopathic neurophysin IIgeneinlong-term analysis ofarginine-vasopressin Clinical features andmolecular Introdução: RESUMO Central Keywords Margaret de Castro de Margaret mento, necessitandodecontínua vigilânciadaetiologia. idiopático em crianças pode não se tornar evidente mesmo após um longo período de - segui não contribui na modulação do gene terística clínica de falência progressiva da secreção da arginina-vasopressina (AVP). carac- a apresenta dominante autossômico central DI O outras. entre pós-traumática, mune, autoi- genética, causas incluindo etiologias, diferentes apresenta urina, a concentrar em de sões: Diabetes insípido central; gene gene central; insípido Diabetes Descritores follow-up, and requires continuous etiological surveillance. tion, the etiology of idiopathic central DI in children may not be apparent even after long-term intron 2 (IVS2 +28 InsG) is unlikely to contribute to the se uma causa genética estava envolvida na etiologia. na envolvida estava genética causa uma se de sete pacientes com DI central idiopático seguidos de longa data na tentativa de determinar gene AVP-NPIIo sequenciou-se e clínica apresentação a caracterizou-se estudo, presente No gene was amplified by polymerase chain reactionthe and sequenced. and extracted was DNA genomic analysis, molecular For infusion. saline tonic Methods: A inserção em homozigose de uma guanina no íntron 2 (IVS2 +28 InsG) provavelmente diabetes insipidus diabetes O diabetes insípido (DI) central, caracterizado por poliúria, polidipsia e inabilida- e polidipsia poliúria, por caracterizado central, (DI) insípido diabetes O AVP-NPII Central The diagnosis of central DI was established by fluid deprivation test and hyper 1 ,C. Moreira Ayrton ; ; AVP-NPII diabetes insipidus gene was found. was gene 2 AVP-NPII , Lucila L. ,K. Elias Lucila gene; PCR; sequencing; mutation sequencing; PCR; gene; ; PCR; sequenciamento; mutação sequenciamento; PCR; ; AVP-NPII no DI. Adicionalmente, a etiologia do DI central (DI) characterized by polyuria, polydipsia and inability AVP-NPII Conclusions: 2 , Antunes-Rodrigues Jose 1 , Paula C., L. Paula Elias gene of seven long-term follow-up patientsfollow-up long-term seven of gene Objective: AVP-NPII The homozygous guanine insertion in insertion guanine homozygous The Métodos: Arq Bras Endocrinol Metab. 2010;54(3): Arq Bras Endocrinol Metab. 2010;54(3):269-73 foi encontrada. AVP-NPIIfoi gene modulation in DI. In addi In this study, we characterized 2 O diagnóstico do DI central DI do diagnóstico O Results: AVP-NPIIamplificado foi Resultados: 1 ,

Sequencing analy Objetivo: AVP-NPII AVP-NPII A análise A Conclu 269-73 ------

1 Accepted onNov/5/2009 Received onOct/15/2009 [email protected] 14049-900 − Ribeirão Preto, SP,Av. Bandeirantes, 3.900 Brasil Preto, USP Faculdade de Medicina de Ribeirão Departamento de Clínica Médica, Divisão de Endocrinologia, Paula C. L. Elias Correspondence to: 2 Ribeirão Preto, SP, Brasil de SãoPaulo (FMRP-USP), Ribeirão Preto, Universidade Faculdade deMedicina FMRP-USP, RibeirãoPreto, SP, Brasil Departamento deFisiologia, Departamento Departamento deClínicaMédica, Departamento original article original

269

Copyright© ABE&M todos os direitos reservados. Copyright© ABE&M todos os direitos reservados. pressin-producing magnocellular neurons in the in neurons magnocellular pressin-producing vaso- of degeneration progressive a with associated is and life, of decade first the during apparent gradually becomes usually (adFNDI) DI neurohypophyseal tral cen- familial dominant autosomal in deficiency pressin the endoplasmic reticulum (3,9,10). The onset of vaso- in accumulates which neurophysin-II of dimerization and folding improper an to leading (2,7,8), physin-II - neuro encoding portion gene the in described been have DI central dominant autosomal causing tations mu- the of Most (6). glycoprotein a co-peptin, and II 3 encodes the carboxy-terminal region of neurophysin- encodes the central region of neurophysin-II; and exon 2 exon neurophysin-II; of region amino-terminal the and peptide AVP peptide, signal the encodes 1 exon exons: three contains and 20 chromosome on located The (5). forms recessive and (2) dominant autosomal include and (AVP-NPIIgene) II AVP and its intracellular binding , neurophysin- encode that mutations gene to due usually are DI tral cen- of causes Genetic (2-4). DI central of cases some (AVP) (1). bytheneurohypophysis arginine-vasopressin of secretion deficient a by caused is It urine. dilute of volumes large of excretion quent to failure and genesis patho- the to contribute may that mechanism negative dominant a to leading occur, may precursors mutant AVP-NPII geneanalysisinidiopathiccentral DI 270 C Introduction with idiopathic central DI in order to rule out associ- out rule to order in DI central idiopathic with of follow-up the during required are (MRI) imaging resonance magnetic by evaluations imaging and laboratorial clinical, periodic Therefore, (17). ing thicken- stalk pituitary and deficiencies pituitary rior ante - other with patients those in especially pursued, be should etiology its and (14-16) patients of 50% to 15% in idiopathic considered still is DI central theless, Never (1). disease vascular and inflammatory trauma, disease, granulomatous tumors, etiolo- intrasellar as such acquired gies different to due be can neurons gic in te dimerization the tion, addi- In (3,9,12). neurons magnocellular the in sin-II a cytotoxic effect of the retained - vasopressin-neurophy to due probably is degeneration neuron The (2,8,11). the of nuclei paraventricular and optic Although rare, familial inherited forms account for account forms inherited familial rare, Although h dsrcin r eeeain f vasopressiner of degeneration or destruction The ies caatrzd y oyra n polydipsia and polyuria by characterized disease entral

of adFNDI(13). (DI) is a heterogeneous heterogeneous a is (DI) insipidus diabetes ocnrt uie edn t a conse- a to leading urine concentrate

ewe te id ye n the and type wild the between ee is gene AVP-NPII patients

supra- - - toms duringchildhood. patients withidiopathiccentralDIonsetofsymp- the of analysis molecular presentation the clinical and the evaluate to aimed we study present the In (19). patients many in established not remains DI central idiopathic so-called the of etiology the However,follow-up, (17,18). long-term after even diseases cerebral or deficiencies pituitary anterior ated fore thetechniquewasavailableathospital. fore but one patient who was lost to follow-up in 1995, be- published immunoassays(22). previously ing standard line or measurements us- stimulated pituitary function was evaluated at base- (21). Anterior pituitary infusion saline hypertonic on or (20) test deprivation fluid the on based was DI central of diagnosis The tee. the approval of the University Hospital Ethics Commit- pathic central DI after obtaining consent informed and We studied seven patients (5 male, 2 female) with idio- P presented in table 1. None of the patients had family had patients the of None 1. table in presented are patients studied of findings laboratory and Clinical Resul and cols. (23) (GenBank access number X62890). sequencing was compared to data described by DNA Bahnsen Biosystems). Applied 377; (ABI sequencing ed visualizedwere agarosefollowed1%gelin automat by productsPCR 72°C). at minute 1 and 60°C atminute 1 95°C, atminute 1 3: and 2 exons72°C; atminute 1 cation (exon 1: 1 minute at 95°C, 1 minute at 66°C and the hot start method followed by forty cycles of amplifi using DMSO, 10% with out carried was reaction PCR The used. were primers, GAG CCA CCG TTC CTC TCC CCT TCC CTC CCT antisense and CTC CGA the sense TCG CTG CGT TCC CCT CCA ACC CCT intronictheirregion,and 3 and 2exons forused; were primers,GTGACACCCTGG AGA CTG GCC GCT ATG GCT antisense and ACA GGA ACG TCC GCC ers.For exon 1,the sense TGG CGG CCG CGT CTC prim specific using (PCR) reaction chain polymerase Valencia, Inc.,the and USA), (Qiagen CA, kit QIAmp a using samples blood peripheral from extracted was DNA Genomic Molecular analysis atients adMethods Central nervous system MRI was performed in all in performed was MRI system nervous Central ts AVP-NPII Arq Bras Metab. Endocrinol 2010;54/3 gene was amplified by amplified was gene ee in gene AVP-NPII - - - M: male; F: female; pOsm: plasma osmolality; uOsm: urinary osmolality;MRI:magneticresonanceimage. M: male;F:female;pOsm:plasmaosmolality;uOsm:urinary Arq Bras Metab. Endocrinol 2010;54/3 in neurohypophysis the of spot bright the lost which also; patients three in presence its and patients three in signal hyperintense pituitary posterior the of absence the in resulted patients six in studies MRI turcica sella media a and thickness infundibulum mild showed who 6 patient except patient, any in study imaging by were followed for 22 years at our out-patient clinic. bertal development were normal in all patients. Patients pu and functions thyroid and Adrenal 7. and 1 tients pa in observed were delay age bone and retardation Growth 6). (Patient response DI central partial withcompatible a had that patient one but all in DI central log responses were consistent with the diagnosis of total kg/day). The fluid deprivation test and vasopressin ana mL/ 320 to (143 L/24h 13.3 to 3 from ranged nosis symptoms in all patients, whose volumeurinary at diag and 5 years. Polyuria and polydipsia were the presenting tion of symptoms at dura diagnosis varied and between 2 months age, of years 7 to 1 from varied polydipsia and polyuria of onset at Age patients. nine the of any in identified was disease autoimmune no Also, fected. were third-degree cousins but had no other relatives af history of Table 1. dataforpatientswithcentraldiabetesinsipidus Clinical,radiologicalandlaboratory Patient 7 6 5 4 3 2 1 o xasv sla ucc lsos ee visualized were lesions turcica sella expansive No cyst, which disappeared during follow-up. Initial diagnosis (years)/ Age at Genre 7.5/M 5.8/M 3.6/M 3.7/F 7/M 6/M 1/F diabetes insipidus Follow-up (years) 10 16 28 34 30 28 7 Familial history Present Present Absent Absent Absent Absent Absent except patients 1 and 3 who (mL/kg/d) Diuresis 206 200 150 143 320 250 – sodium serum Basal 127 144 150 143 147 135 143 pars inter- pars pOsm Basal 293 291 286 289 300 296 296 uOsm Basal 298 64 70 46 51 64 72 ------dehydrata- Maximum . outofninecontrols was foundinthree 2 intron in insertion same sequenced the and controls from gene also we finding, latter the to Due patients. 4 in found was InsG) +28 (IVS2 2 tron in- in guanine additional an of insertion homozygous a However, patients. any in 3 and 2 1, exons in tions showed a reduced anteriorpituitary.showed areduced patient one Only follow-up. during MRI subsequent ature usually describes a more dilated latency between latency dilated more a describes usually ature within 6 months after the onset of symptoms. The liter diagnosed were one but patients all cohort, our In DI. central with patients pediatric of study multi-centric a in (16) cols. and Maghnie by reported years 6.4 of age median the to similar very years, 5.8 of median age, of years 7 and 1 between was polydipsia and polyuria of ofthisgene. region AVP-NPII of analysis Molecular follow-up. long-term after ology eti- apparent no with infancy the during diagnosed DI central with patients seven presented we study this In Discussion pOsm post- tion 294 318 294 307 – – – Sequencing of Sequencing In the present series the age of onset for symptoms for onset of age the series present the In dehydrata- Maximum uOsm post- tion 591 291 52 50 84 – – ee hwd o uain i te coding the in mutations no showed gene Dehydra- duration (hours) tation time gene revealed no muta- no revealed gene AVP-NPII AVP-NPII geneanalysisinidiopathiccentral DI – – 8 6 3 2 6 Minimum desmo- pressin pOsm post- 290 280 281 300 295 – – Maximum desmo- pressin uOsm post- 717 502 180 600 466 – – Bright spot not present Bright spot not present Bright spot not present Reduced hypophysis Normal hypophysis Normal hypophysis Normal hypophysis Normal hypophysis Normal hypophysis mild infundibulum Progressive bright Progressive bright Progressive bright Image (MRI) AVP-NPII thickness spot loss spot loss spot loss volume volume volume volume volume volume N/A 271 -

Copyright© ABE&M todos os direitos reservados. Copyright© ABE&M todos os direitos reservados. AVP-NPII geneanalysisinidiopathiccentral DI 272 present the In (29). DI centralautoimmune of marker reliable a be not may antibodies these of presence the including Langerhans (19,27-29), cell histiocytosis and DI germinoma; therefore, central of causes different autoantibodies have also beenin reported patients with cell vasopressin-secreting hypothalamus human lating circu However, (27). DI central idiopathic apparent suggests autoimmunity in almost 100% of patients with thickening stalk pituitary with association in tibodies to contributetheAVP-NPII genemodulation(26). unlikely is that assembly gene alternative an represent might variation this that indicated controls 9 of out 3 ed PCR experiments. Indeed, finding the G insertion in both, sense and antisense sequences as well as in - repeat in found was result the since findings our for account to likely less is problems technique PCR/sequencing not to due error an Moreover, issue. do particular this discuss authors the and individuals, non-affected or patients other their in present also was insertion G the whether know not do we members, affected 6 of dred direct gene sequencing in only one member of the kin- performed authors the As (Gly57Ser). region the coding in mutation concomitant a with X62891) access (GenBank (23) cols. and Bahnsen by described been 2 (IVS2 +28 InsG) in 4 patients. This insertion has also we identified a homozygous guanine insertion in intron develop idiopathicDIduringchildhood. who patients in useful be may testing genetic that ing early onset of central DI and no family history, suggest- a patients, Rutishauser and cols. (10) previously reported the in mutation analysis of the molecular out carried we patients, these in disease the of etiology the uncover to attempt an In years. 34 to 3 of follow-up the deficiency, despite vasopressin the for described(16,24,25). previously stature and short DI central idiopathic with patients of 35% to 20% the in served patients 1 and 7, which are in accordance with polydipsia inchildren. and polyuria of symptoms the investigate to need the of aware be not may clinicians that suggests patients pediatric in insipidus diabetes of diagnosis the of The delay (24). years 4 of interval an showing reports ous - previ with diagnosis, the and symptoms of onset the de novo de h peec o vspesnsceig el autoan cell vasopressin-secreting of presence The While no mutation in the coding was region found, All seven patients in this series had no clear etiology ob- were delay age bone and retardation Growth AVP-NPII AVP-NPII gene. Although we found no AVP-NPII gene mutation in a patient with patient a in mutation gene ee n hs eis f DI of series this in gene - - pituitary arterial abnormal since patients, of of series present the cause in deficiency plausible vasopressin a as considered be also should ity AVP (8). secretion development of MRI features, similar to the decrease in progressive indicating follow-up, during later appeared presented a normal posterior pituitary signal, which dis- DI. In fact, three out of six patients in the current study of the posterior signal pituitary in this inherited form of loss progressive a suggesting one, but patients adult all but fected an children, absent visible or signal barely in af- all in signal hypertensive pituitary posterior the of presence the showed and imaging resonance magnetic ney and cols. (34) studied the kindred with adFNDI by Maho- (31). secretion vasopressin normal indicate not (31-33). On the other hand, presence of the signal may bright tuitary signal has been associated with central DI was absent in five patients. The absence of posterior pi- images T1-weighted resonance magnetic on lobe rior stalkthickening(18,30). DI withpituitary central isolated with associated been has histiocytosis, cell Langerhans and germinoma as such DI, central of cause organic since follow-up, long-term for need the thickening in patients with central DI strongly indicates by De Buyst and cols. (24), the finding of pituitary stalk reported as transient, and reversible be can DI central in patient stalk 6, whothickness. showed pituitary an out rule secreting cells was not available, therefore, we could not vasopressin to autoantibodies of determination study, patients with idiopathic central DI and normal and DI central idiopathic with patients was reported. Disclosure: no potential conflict of interestrelevant to this article number 07/58365-3). (grant Fapesp by supported was work Acknowledgements:This requires continuous etiological surveillance. may not be apparent even after long-term follow-up, and firm that the etiology of idiopathic central DI in children to the contributeto unlikely is thatassembly genealternative genepatientsDIin wellascontrols,inas suggesting an the in InsG) +28 (IVS2 2 intron in sertion rior poste- of absence with size stalk pituitary and pituitary - to point out that vascular abnormal It is important poste- study,the present of the signal In brightness Although, pituitary Although, pituitary In conclusion,homozygousInfounda guaninewe in

pituitary brightsignalintheMRI(35). pituitary AVP-NPII

been previously described in described previously been has supply blood autoimmune cause of central DI, especiallyDI, central of causeautoimmune gene modulation. In addition, we con stalk thickening in patients with blood flow affecting posterior affecting flow blood Arq Bras Metab. Endocrinol 2010;54/3 AVP-NPII

anterior - - Arq Bras Metab. Endocrinol 2010;54/3 14. 13. 12. 11. 10. 9. 8. 7. 6. 5. 4. 3. 2. 1. References 17. 16. 15. 18.

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