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Arquivos Brasileiros de Endocrinologia & Metabologia

On-line version ISSN 1677-9487

Arq Bras Endocrinol Metab vol.54 no.3 São Paulo Apr./Mar. 2010 



Idiopathic central diabetes insipidus: the challenge remains



Madson Q. Almeida

Doutor em Endocrinologia, Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM/42, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo (HCFMUSP), São Paulo, SP, Brasil e Post-doctoral Fellow, Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Estados Unidos

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Central diabetes insipidus (CDI) is a heterogeneous hypothalamus-pituitary disease due to the deficiency of arginine vasopressin (AVP), and is characterized by polyuria and polydipsia. CDI is caused by the destruction or degeneration of the AVP-secreting magnocellular neurons in the hypothalamic supraoptic and paraventricular nuclei. The etiology of CDI can be familial or secondary to malformations, autoimmune, infiltrative (e.g. neoplastic or histiocytsis) or traumatic processes (1). Genetic defects in the synthesis of vasopressin are typically inherited as an autosomal dominant trait and caused by mutations in the AVP-NPII gene, but autosomal recessive defects have also been described (2-4). Autosomal dominant familial neurohypophyseal diabetes insipidus accounts for ∼1% of all cases of CDI and its clinical features usually begin between 1 and 6 years of age (2). Familial CDI is often accompanied by the loss of the posterior pituitary bright spot on T1 magnetic resonance imaging (MRI) (1).

The AVP-NPII gene, which is located on chromosome 20p13, consists of 3 exons and encodes the preproAVP. Exon 1 encodes the signal peptide, AVP, and the aminoterminal region of neurophysin II (NPII). Exon 2 gives rise to the central region of NPII, and exon 3 contains the carboxyterminal region of NPII and glycoprotein. PreproAVP is converted to proAVP by removal of its signal peptide and the addition of carbohydrate side chains. Additional posttranslational processing occurs within neurosecretory vesicles during transport to axon terminals in the posterior pituitary, yielding AVP, NPII and glycoprotein (5). To date, more than 50 mutations in the AVP-NPII gene have been reported (5). Most AVP-NPII mutations are located in the coding sequence of NPII and promote conformational changes in protein structure which disrupt the normal cellular folding and processing of the preproAVP and lead to neuronal damage. In consequence, the mutant precursor cannot be folded and dimerized and is retained in the endoplasmic reticulum, where it accumulates and promotes cell toxicity (2,3).

The etiology of CDI remains unknown in 15%-50% of the patients, classified as idiopathic CDI (1). In this issue of ABE&M, Batista and cols. (6) describe the clinical features and investigated AVP-NPII sequencing variants in 7 patients with idiopathic CDI and a long-term follow-up. The diagnosis of CDI was confirmed by fluid deprivation test and vasopressin analog response in all cases. No history of autoimmunity was identified in any patients. A mild infundibulum thickness was identified in only one patient and disappeared during follow-up. The sequencing analysis of the AVP-NPII gene revealed no mutation in the coding region. A homozygous guanine insertion in intron 2 (IVS2 +28 InsG) was identified in 4 of 7 patients, but also in the controls.

Considering the early onset of the clinical features and the absence of autoimmune disease and stalk thickening in the patients described by Batista and cols. (6), it was reasonable and clinically relevant to investigate the association between AVP-NPII gene mutations and idiopathic CDI in this cohort. A de novo AVP-NPII gene mutation was previously described in a patient with early onset of CDI and no family history (7). Since CDI can be associated with growth retardation and bone delay in children, the diagnosis of de novo mutations has important implications for genetic counseling and a subsequent precocious diagnosis.

Circulating vasopressin-cell autoantibodies (AVPc-Abs) have been detected in 23%-75% of young patients with CDI, indicating that autoimmune CDI might account for a significant number of the idiopathic cases (8,9). The history of autoimmune disease and the presence of stalk thickening strongly support the hypothesis of autoimmune CDI. However, circulating AVPc-Abs were also frequently measured in patients with non-idiopathic CDI, demonstrating that AVPc-Abs are not reliable markers of an autoimmune etiology (8,9). Thus, the diagnosis of autoimmune CDI may be suspected by examining clinical characteristics and past history of the patients and by MRI evaluation.

Abnormal blood supply to the posterior pituitary gland was also evidenced in patients with idiopathic CDI, suggesting that selective vascular damage affecting the inferior hypophyseal arteries can be associated with the pathogenesis of CDI (10). However, the etiology of a significant subset of young patients with CDI remains to be characterized and explored. Therefore, continuing clinical and genetic studies are necessary to further investigate the etiological variability of what, until now, has been considered idiopathic CDI.

Disclosure: no potential conflict of interest relevant to this article was reported.



1. Maghnie M, Cosi G, Genovese E, Manca-Bitti ML, Cohen A, Zecca S, et al. Central diabetes insipidus in children and young adults. N Engl J Med. 2000;343(14):998-1007.         [ Links ]

2. Ito M, Jameson JL. Molecular basis of autosomal dominant neurohypophyseal diabetes insipidus. Cellular toxicity caused by the accumulation of mutant vasopressin precursors within the endoplasmic reticulum. J Clin Invest. 1997;99(8):1897-905.         [ Links ]

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4. Melo ME, Marui S, Brito VN, Mancini MC, Mendonca BB, Knoepfelmacher M. Autosomal dominant familial neurohypophyseal diabetes insipidus caused by a novel mutation in arginine-vasopressin gene in a Brazilian family. Arq Bras Endocrinol Metabol. 2008;52(8):1272-6.         [ Links ]

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6. Batista SL, Moreira AC, Antunes-Rodrigues J, De Castro M, Elias LLK, Elias PCL. Clinical features and molecular analysis of arginine-vasopressin neurophysin II gene in long-term follow-up patients with idiopathic central diabetes insipidus. Arq Bras Endocrinol Metabol. 2010;54(3):269-73.         [ Links ]

7. Rutishauser J, Kopp P, Gaskill MB, Kotlar TJ, Robertson GL. Clinical and molecular analysis of three families with autosomal dominant neurohypophyseal diabetes insipidus associated with a novel and recurrent mutations in the vasopressin-neurophysin II gene. Eur J Endocrinol. 2002;146(5):649-56.         [ Links ]

8. Pivonello R, De Bellis A, Faggiano A, Di Salle F, Petretta M, Di Somma C, et al. Central diabetes insipidus and autoimmunity: relationship between the occurrence of antibodies to arginine vasopressin-secreting cells and clinical, immunological, and radiological features in a large cohort of patients with central diabetes insipidus of known and unknown etiology. J Clin Endocrinol Metab. 2003;88(4):1629-36.         [ Links ]

9. Maghnie M, Ghirardello S, De Bellis A, di Iorgi N, Ambrosini L, Secco A, et al. Idiopathic central diabetes insipidus in children and young adults is commonly associated with vasopressin-cell antibodies and markers of autoimmunity. Clin Endocrinol (Oxf) 2006;65(4):470-8.         [ Links ]

10. Maghnie M, Altobelli M, Di Iorgi N, Genovese E, Meloni G, Manca-Bitti ML, et al. Idiopathic central diabetes insipidus is associated with abnormal blood supply to the posterior pituitary gland caused by vascular impairment of the inferior hypophyseal artery system. J Clin Endocrinol Metab. 2004;89(4):1891-6.         [ Links ]



Correspondence to:
Madson Q. Almeida
Av. Dr. Enéas de Carvalho Aguiar, 155, 20º andar, Bloco 6
05403-900 - São Paulo, SP, Brasil,

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