Clinical manifestations and causes of central

diabetes insipidus
Author:
Daniel G Bichet, MD
Section Editor:
Richard H Sterns, MD
Deputy Editor:
John P Forman, MD, MSc
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Mar 2021. | This topic last updated: Nov 11, 2020.

INTRODUCTION Central diabetes insipidus (CDI) is characterized by

decreased release of antidiuretic hormone (ADH; also called arginine vasopressin or

AVP), resulting in a variable degree of polyuria. Lack of ADH can be caused by
disorders that act at one or more of the sites involved in ADH secretion: the
hypothalamic osmoreceptors; the supraoptic or paraventricular nuclei; or the superior
portion of the supraopticohypophyseal tract [1]. By contrast, damage to the tract below
the median eminence or to the posterior pituitary generally causes only transient
polyuria, because ADH produced in the hypothalamus can still be secreted into the
systemic circulation via the portal capillaries in the median eminence [1].
(See "Hypothalamic-pituitary axis".)

The clinical manifestations and causes of CDI will be reviewed here. The treatment of
CDI, the clinical manifestations and causes of nephrogenic diabetes insipidus (DI), and
the diagnostic approach to the polyuric patient are discussed separately:

●(See "Treatment of central diabetes insipidus".)

●(See "Clinical manifestations and causes of nephrogenic diabetes insipidus".)
●(See "Evaluation of patients with polyuria".)

CLINICAL MANIFESTATIONS Patients with untreated central diabetes

insipidus (CDI) typically present with polyuria, nocturia, and, due to the initial elevation
in serum sodium and osmolality, polydipsia. They may also have neurologic symptoms
related to the underlying neurologic disease.
The serum sodium concentration in untreated CDI is often in the high normal range,
which is required to provide the ongoing stimulation of thirst to replace the urinary water
losses. Moderate to severe hypernatremia can develop when thirst is impaired or
cannot be expressed. This can occur in patients with central nervous system lesions
who also have hypodipsia or adipsia, in adipsic young patients who have autoantibodies
to the subfornical organ [2], in infants and young children who cannot independently
access free water, and in the postoperative period in patients with unrecognized
diabetes insipidus (DI). (See "Etiology and evaluation of hypernatremia in adults",
section on 'Adipsic diabetes insipidus'.)
Patients with CDI may develop decreased bone mineral density at the lumbar spine and
femoral neck, even in those treated with desmopressin (dDAVP) [3]. It is unclear how
the deficiency of ADH results in bone loss, particularly since treatment fails to prevent
bone disease. However, since ADH acts upon both V1 and V2 receptors and
desmopressin principally upon V2 receptors, one possible mechanism is that activation
of V1 receptors stimulates bone formation.

CAUSES The most common causes of central diabetes insipidus (CDI),

accounting for the vast majority of cases, are idiopathic diabetes insipidus (DI) [1,4,5],
primary or secondary tumors or infiltrative diseases (such as Langerhans cell
histiocytosis) [6], neurosurgery, and trauma. In a report of 79 children and young adults,
for example, CDI was idiopathic in 52 percent and resulted from a tumor or infiltrative
disease in 38 percent [5]. In another cohort of 147 children followed from 2000 to 2013
in a single North American center, the most common single diagnosis was
craniopharyngioma (25.2 percent) [7].
Cranial magnetic resonance imaging (MRI) to identify hyperintensities in the posterior
pituitary or thickening of the pituitary stalk can help determine the cause of CDI [8-10].
Any form of CDI can be exacerbated or first become apparent during pregnancy, since
catabolism of antidiuretic hormone (ADH; also called arginine vasopressin or AVP) is
increased by vasopressinases released from the placenta [11,12]. (See "Maternal
adaptations to pregnancy: Renal and urinary tract physiology".)
Idiopathic CDI — Approximately 30 to 50 percent of cases of CDI are idiopathic, being
associated with destruction of the hormone-secreting cells in the hypothalamic nuclei. It
has been suggested that an autoimmune process is involved in many, if not most,
patients [13-16]. Insight into the mechanism of autoimmunity in some individuals was
provided by a longitudinal study evaluating the presence of cytoplasmic antibodies
directed against vasopressin cells (Ab-positive) in patients with endocrine autoimmune
diseases but initially without CDI [14]. Among almost 900 such patients, 9 found to be
Ab-positive and 139 Ab-negative controls were prospectively followed. At four years,
none of the controls developed CDI. By comparison, four of the nine Ab-positive
patients had partial CDI at study entry and, among the remaining five patients, three
developed partial DI and one developed complete CDI.

This autoimmune process is characterized by lymphocytic inflammation of the pituitary

stalk and posterior pituitary that resolves after destruction of the target neurons. MRI
early in the course often reveals thickening or enlargement of these structures.

The incidence of such antibodies in those with CDI, their association with other
autoimmune diseases, and their correlation with radiologic features was evaluated in a
study of 150 patients with CDI that was performed by the same Italian group [15]. The
disease was idiopathic in 43 percent, familial in 4 percent, granulomatous in 8 percent,
and secondary to cranial trauma, tumor, or surgery in 45 percent. Antibodies to
vasopressin cells were found in approximately one-third of the patients with idiopathic
disease and approximately one-quarter of patients with non-idiopathic disease. Antibody
positivity was independently associated with age less than 30 years at disease onset in
those with idiopathic disease, a history of autoimmune disease, or pituitary stalk
thickening. Autoimmune CDI was highly probable in young patients with a history of
autoimmune disease and pituitary stalk thickening.
The autoantigens involved in idiopathic CDI are not fully elucidated. However,
autoantibodies to rabphilin-3A, a regulator of secretory vesicle trafficking, may be found
in a large majority of patients with lymphocytic infundibuloneurohypophysitis (LINH) [17].
LINH accounts for a substantial subset of autoimmune CDI and is characterized by
lymphocytic inflammation of the posterior pituitary and infundibular stalk (damage to the
stalk is what produces CDI) [18].
Other autoimmune mechanisms for CDI include immunoglobulin (Ig) G4-related
systemic syndrome, which may be successfully treated with glucocorticoids [19-21], and
granulomatosis with polyangiitis (GPA), a systemic disease characterized by pauci-
immune, necrotizing, small-vessel vasculitis, often associated with positive
antineutrophil cytoplasmic antibodies (ANCA) [22]. (See "Pathogenesis and clinical
manifestations of IgG4-related disease" and "Granulomatosis with polyangiitis and
microscopic polyangiitis: Clinical manifestations and diagnosis".)
Thickening of the pituitary stalk is a nonspecific finding, since some patients with this
finding later develop a germinoma or histiocytosis [23]. In children, progressive
thickening of the stalk as determined by serial MRIs is strongly suggestive of a
germinoma [5].
Anterior pituitary hormone deficiency, with decreased release of growth hormone,
thyroid stimulating hormone, and adrenocorticotropic hormone, also may be present or
develop in patients with idiopathic CDI [5,24]. However, some patients who develop an
anterior pituitary endocrinopathy years after the diagnosis of CDI may have a pituitary or
suprasellar tumor, suggesting that the initial abnormality was due to an occult pathologic
process. As an example, in one study of 16 patients first diagnosed with idiopathic CDI,
the detection of evolving gonadotropin deficiency in three individuals resulted in the
diagnosis of pituitary or suprasellar germinomas 20, 6, and 3 years after the initial
presentation [25]. These data, if confirmed, suggest that such patients should undergo
regular endocrine follow-up. (See "Diagnostic testing for hypopituitarism".)
Familial and congenital disease — A number of familial and congenital diseases have
been associated with CDI. These include familial CDI, Wolfram syndrome, and
congenital diseases such as congenital hypopituitarism and septo-optic dysplasia.
Familial CDI — Familial CDI, also called familial neurohypophyseal DI, or FNDI (MIM
125700), is usually an autosomal dominant disease caused by mutations in the gene
encoding antidiuretic hormone (ADH; also called arginine vasopressin or AVP) [26].
ADH and its corresponding carrier, neurophysin II, are synthesized as a composite
precursor by the magnocellular neurons of the supraoptic and paraventricular nuclei of
the hypothalamus [27].
The mechanism underlying the "dominant-negative" effect of autosomal familial CDI
mutations involves the retention of the mutant ADH prohormone in the endoplasmic
reticulum (ER) of magnocellular neurons [28]. Mutant ADH, and functional ADH protein
produced from the non-affected allele, form high-molecular-weight complexes that are
destined for ubiquitylation and proteasomal degradation by the ER quality-control
pathway ER-associated degradation (ERAD) [29]. This model helps explain results
obtained in some mouse models of DI with human proAVP mutations, in which ADH-
producing neuronal cell death was not observed at disease onset and was therefore not
thought to have a role in disease initiation [30].
This autosomal dominant form of CDI contrasts with congenital ADH deficiency that has
been described in three families with autosomal recessive CDI. Two families bear a
missense variation affecting the seventh amino acid of the ADH nonapeptide
(p.Pro26Leu) [31,32], and four members of one family with two loops of inbreeding bear
a large deletion involving the majority of the AVP gene as well as the intergenic region
between the AVP and OXT gene [33]. Affected members have early polyuria and
hypernatremia, in contrast to the autosomal dominant disease mentioned above. The
existence of this autosomal recessive, early onset CDI is important because it must be
considered, along with congenital nephrogenic DI, in the differential diagnosis of
congenital polyuria and dehydration, and therapy for these disorders differ.
Wolfram syndrome — The Wolfram or DIDMOAD (diabetes insipidus, diabetes
mellitus, optic atrophy, and deafness) syndrome is characterized by CDI, diabetes
mellitus, optic atrophy, and deafness, with cognitive and psychiatric issues that may
appear later in life [34]; it is inherited as an autosomal recessive trait with incomplete
penetrance. The Wolfram syndrome is caused by at least two different
genes: WFS1 and CISD2 [35]. Both encode ER proteins and seem to affect calcium
homeostasis. Wolframin, the product of WFS1, is expressed in a number of tissues,
including the pancreas [36] and brain supraoptic paraventricular nuclei [37]. DI in this
disorder is due to loss of vasopressin-secreting neurons in the supraoptic nucleus and
impaired processing of vasopressin precursors [38].
Variations in WFS1 also predispose to type 2 diabetes mellitus [39]. WFS1 negatively
regulates a key transcription factor involved in ER stress signaling, resulting in
pancreatic beta cell death and possibly in magnocellular cell death, which could explain
the vasopressin deficiency [40]. (See "Classification of diabetes mellitus and genetic
diabetic syndromes", section on 'Wolfram syndrome'.)
Proprotein convertase subtilisin/kexin-type 1 (PCSK1) gene
deficiency — The PCSK1 gene encodes a 753-amino acid precursor, preproPC1/3,
which is processed in the ER into its proenzyme form, proPC1/3. ProPC1/3 is then
modified by cleavage of its prodomain into active PC1/3 [41]. PC1/3 is involved in the
processing of numerous digestive and hypothalamic prohormones, including ADH. More
than 25 cases of PC1/3 deficiency have been reported in the literature; 30 percent were
of Turkish origin [42,43]. All individuals had early and severe malabsorptive diarrhea,
and approximately 80 percent had polyuria-polydipsia syndrome (before 5 years of
age). Most had early-onset obesity. Various endocrine disorders were present, including
growth hormone deficiency (44 percent), mild central hypothyroidism (56 percent),
central hypogonadism (44 percent), central hypocortisolism (57 percent), and
postprandial hypoglycemia (52 percent). A history of consanguinity was present in 83
percent [42].
Congenital hypopituitarism — CDI has been described in patients with congenital
hypopituitarism with or without ectopia of the posterior pituitary lobe [44-46]. The defects
in posterior pituitary function in these disorders include symptomatic CDI, nocturia,
reduced ADH release after osmotic challenge, and hypodipsia or polydipsia. These
findings may be associated with isolated growth hormone deficiency or multiple anterior
pituitary hormone deficiencies.
Septo-optic dysplasia — CDI can be seen in a number of congenital cerebral midline
abnormalities. As an example, septo-optic dysplasia (SOD) has been associated with
defects in both anterior and posterior pituitary function [47,48]. SOD is a highly
heterogeneous condition with phenotypes that include midline and forebrain
abnormalities as well as optic nerve and pituitary hypoplasia. Most cases of SOD are
sporadic, but familial cases have been described in association with mutations in genes
for developmental transcription factors (such as HESX1) that are essential for normal
forebrain/pituitary development [49]. Affected patients may have abnormal thirst as well
as a defect in ADH release [48,50]. As a result, we recommend monitoring of the serum
sodium in these patients once per week for one month, and then if stable, once every
six months.
Neurosurgery or trauma — CDI can be induced by neurosurgery (usually
transsphenoidal) or trauma to the hypothalamus and posterior pituitary [51-55]. The
incidence of CDI in these patients varies with the extent of injury, ranging from 10 to 20
percent after transsphenoidal removal of an adenoma limited to the sella to as high as
60 to 80 percent after removal of very large tumors.
A much lower rate of postoperative CDI has been reported with minimally invasive
endoscopic pituitary surgery (2.7 percent permanent and 13.6 percent transient) [56]. A
serum sodium higher than 145 mEq/L within the first five postoperative days had a high
predictive value for permanent DI development. By contrast, patients with a serum
sodium less than 145 mEq/L in the first five postoperative days will rarely, if ever,
develop permanent DI, thereby validating short postoperative inpatient stays with
minimal risk of readmission for DI management.
Craniopharyngioma has been associated with CDI both before surgery and particularly
after surgery [53,57]. A somewhat different response has been detected after
transfrontal surgery for a craniopharyngioma. In this setting, the polyuria appears to
result in at least some patients from the release of an ADH precursor from the
hypothalamus that competes for but does not activate ADH V2 receptors [55]. These
patients initially have high serum immunoreactive ADH concentrations, but their ADH
has little or no biological activity and they have diminished response to exogenous
hormone replacement. Thus, they behave as if they have nephrogenic DI (NDI),
although the polyuria is typically transient.
Severe damage to the hypothalamus or tract by neurosurgery or trauma often results in
a typical triphasic response [1,53]. There is an initial polyuric phase, beginning within
24 hours and lasting 4 to 5 days; this phase reflects inhibition of ADH release due to
hypothalamic dysfunction [51]. This is followed, on days 6 to 11, by an antidiuretic
phase in which stored hormone is slowly released from the degenerating posterior
pituitary. During this stage, excessive water intake can lead to hyponatremia because of
a transient syndrome of inappropriate ADH secretion [58]. Permanent DI may then
ensue after the posterior pituitary stores are depleted.
Most cases are not permanent [59]. As an example, patients with less severe
hypothalamic or tract injury often have transient CDI that begins 24 to 48 hours after
surgery and may then resolve over the first week. Furthermore, not all patients progress
through all three phases. Some patients develop transient hyponatremia, with or without
preceding polyuria, and then recover. (See "Pathophysiology and etiology of the
syndrome of inappropriate antidiuretic hormone secretion (SIADH)".)
A study of 1571 patients with pituitary adenomas of all types who underwent
transsphenoidal surgery at the same center provides insight into the relative frequency
of these different responses [60]. Among these patients, 30 percent had
microadenomas and 70 percent macroadenomas. The key findings were:
●31 percent had immediate postoperative polyuria, 17 percent had polyuria on day
three, and 6 percent on day seven. Of these patients, 24 percent received one or
more doses of ADH. After three months, only 0.9 percent were still receiving ADH
or had polyuria.
●3.4 percent of patients had transient polyuria and then transient hyponatremia.
●1.1 percent had the triphasic pattern of polyuria, hyponatremia, and then polyuria.
●5.2 percent had only transient hyponatremia, either within one to three days or five
to ten days after surgery.
Despite the relatively high frequency of CDI in patients undergoing neurosurgery, most
cases of polyuria in this setting are not due to CDI [51]. More common causes are
excretion of excess fluid administered during surgery [61] and/or an osmotic diuresis
induced by mannitol or glucocorticoids (which cause hyperglycemia and glucosuria)
given in an attempt to reduce cerebral edema. These conditions can be differentiated
from CDI by measuring the urine osmolality and the response to water restriction and
the administration of ADH. (See "Evaluation of patients with polyuria".)
CDI after neurosurgery rarely occurs in combination with cerebral salt-wasting.
Depending upon the balance of the ensuing water and solute (NaCl) diuresis,
hyponatremia, normonatremia, or hypernatremia may be present [62].
(See "Pathophysiology and etiology of the syndrome of inappropriate antidiuretic
hormone secretion (SIADH)", section on 'Cerebral salt wasting'.)
Cancer — Primary or secondary (most often due to lung cancer, leukemia, or
lymphoma) tumors in the brain can involve the hypothalamic-pituitary region and lead to
CDI [4]. CDI may also be observed in myelodysplastic syndrome [63]. In some patients
with metastatic disease, polyuria is the presenting symptom [4].
Hypoxic encephalopathy — Hypoxic encephalopathy or severe ischemia (as with
cardiopulmonary arrest or shock) can lead to diminished ADH release [1,64]. The
severity of this defect varies, ranging from mild and asymptomatic to marked polyuria.
As an example, overt CDI is unusual in patients with Sheehan's syndrome (postpartum
hypopituitarism) even though ADH secretion is often subnormal [65]. The appearance of
DI in these patients is consistent with the occasional pathologic findings of scarring and
atrophy in the supraoptic nuclei and posterior pituitary gland [66]. (See "Causes of
hypopituitarism".)
Infiltrative disorders — Patients with Langerhans cell histiocytosis (also called
histiocytosis X and eosinophilic granuloma) are at particularly high risk for CDI due to
hypothalamic-pituitary disease [6,67]. Up to 40 percent of patients become polyuric
within the first four years, particularly if there is multisystem involvement and proptosis.
(See "Clinical manifestations, pathologic features, and diagnosis of Langerhans cell
histiocytosis".)
A similar infiltrative disease can occur with sarcoidosis, which can also cause polyuria
due to NDI (induced by hypercalcemia) or primary polydipsia [68]. Additional infiltrative
disorders that rarely cause CDI include granulomatosis with polyangiitis [69,70] and
autoimmune lymphocytic hypophysitis [13,71-73]; the latter disorder may spontaneously
improve. (See "Causes of hypopituitarism", section on 'Hypophysitis'.)
Post-supraventricular tachycardia — Transient polyuria is occasionally seen after
correction of a supraventricular tachycardia [74,75]. Both a water diuresis and a
natriuresis may be seen, due respectively due to decreased secretion of ADH and to
increased release of atrial natriuretic peptide. These humoral changes may be mediated
by increases in left atrial and systemic pressure, thereby activating local volume
receptors.
Anorexia nervosa — ADH release is often subnormal or erratic in patients with
anorexia nervosa, presumably due to the cerebral dysfunction [76]. This defect is
relatively mild in most cases and polyuria, when present, is often due mostly to a
primary increase in thirst.

SOCIETY GUIDELINE LINKS Links to society and government-sponsored

guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Fluid and electrolyte disorders in adults".)

INFORMATION FOR PATIENTS UpToDate offers two types of patient

education materials, "The Basics" and "Beyond the Basics." The Basics patient
education pieces are written in plain language, at the 5th to 6th grade reading level, and
they answer the four or five key questions a patient might have about a given condition.
These articles are best for patients who want a general overview and who prefer short,
easy-to-read materials. Beyond the Basics patient education pieces are longer, more
sophisticated, and more detailed. These articles are written at the 10th to 12th grade
reading level and are best for patients who want in-depth information and are
comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you
to print or e-mail these topics to your patients. (You can also locate patient education
articles on a variety of subjects by searching on "patient info" and the keyword(s) of
interest.)

●Basics topics (see "Patient education: Diabetes insipidus (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Central diabetes insipidus (CDI) is characterized by decreased release of

antidiuretic hormone (ADH), resulting in a variable degree of polyuria. Lack of ADH
can be caused by disorders that act at one or more of the sites involved in ADH
secretion: the hypothalamic osmoreceptors; the supraoptic or paraventricular
 nuclei; or the superior portion of the supraopticohypophyseal tract.
(See 'Introduction' above.)
●Patients with untreated CDI typically present with polyuria, nocturia, and, due to
the initial elevation in serum sodium and osmolality, polydipsia. They may also
have neurologic symptoms related to the underlying neurologic disease.
(See 'Clinical manifestations' above.)
●The causes of CDI include idiopathic disease, familial and congenital disorders,
neurosurgery or trauma, primary or secondary cancers, hypoxic encephalopathy,
infiltrative disorders, post-supraventricular tachycardia, and anorexia nervosa. The
vast majority of cases are due to idiopathic CDI or result from primary or secondary
tumors, or infiltrative diseases (such as Langerhans cell histiocytosis).
(See 'Causes' above.)

REFERENCES

1. Rose BD, Post TW. Clinical Physiology of Acid-Base and Electrolyte Disorders,
5th ed, McGraw-Hill, New York 2001. p.751.
2. Hiyama TY, Utsunomiya AN, Matsumoto M, et al. Adipsic hypernatremia without
hypothalamic lesions accompanied by autoantibodies to subfornical organ. Brain
Pathol 2017; 27:323.
3. Pivonello R, Colao A, Di Somma C, et al. Impairment of bone status in patients
with central diabetes insipidus. J Clin Endocrinol Metab 1998; 83:2275.
4. Kimmel DW, O'Neill BP. Systemic cancer presenting as diabetes insipidus.
Clinical and radiographic features of 11 patients with a review of metastatic-
induced diabetes insipidus. Cancer 1983; 52:2355.
5. Maghnie M, Cosi G, Genovese E, et al. Central diabetes insipidus in children and
young adults. N Engl J Med 2000; 343:998.
6. Grois N, Fahrner B, Arceci RJ, et al. Central nervous system disease in
Langerhans cell histiocytosis. J Pediatr 2010; 156:873.
7. Werny D, Elfers C, Perez FA, et al. Pediatric Central Diabetes Insipidus: Brain
Malformations Are Common and Few Patients Have Idiopathic Disease. J Clin
Endocrinol Metab 2015; 100:3074.
8. Ranadive SA, Ersoy B, Favre H, et al. Identification, characterization and rescue
of a novel vasopressin-2 receptor mutation causing nephrogenic diabetes
insipidus. Clin Endocrinol (Oxf) 2009; 71:388.
9. Di Iorgi N, Napoli F, Allegri AE, et al. Diabetes insipidus--diagnosis and
management. Horm Res Paediatr 2012; 77:69.
10. Turcu AF, Erickson BJ, Lin E, et al. Pituitary stalk lesions: the Mayo Clinic
experience. J Clin Endocrinol Metab 2013; 98:1812.
11. Brewster UC, Hayslett JP. Diabetes insipidus in the third trimester of pregnancy.
Obstet Gynecol 2005; 105:1173.
12. Lindheimer MD. Polyuria and pregnancy: its cause, its danger. Obstet Gynecol
2005; 105:1171.
13. Imura H, Nakao K, Shimatsu A, et al. Lymphocytic infundibuloneurohypophysitis
as a cause of central diabetes insipidus. N Engl J Med 1993; 329:683.
14. De Bellis A, Colao A, Di Salle F, et al. A longitudinal study of vasopressin cell
antibodies, posterior pituitary function, and magnetic resonance imaging
evaluations in subclinical autoimmune central diabetes insipidus. J Clin
Endocrinol Metab 1999; 84:3047.
15. Pivonello R, De Bellis A, Faggiano A, 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; 88:1629.
16. De Bellis A, Colao A, Bizzarro A, et al. Longitudinal study of vasopressin-cell
antibodies and of hypothalamic-pituitary region on magnetic resonance imaging
in patients with autoimmune and idiopathic complete central diabetes insipidus. J
Clin Endocrinol Metab 2002; 87:3825.
17. Iwama S, Sugimura Y, Kiyota A, et al. Rabphilin-3A as a Targeted Autoantigen in
Lymphocytic Infundibulo-neurohypophysitis. J Clin Endocrinol Metab 2015;
100:E946.
18. Johnston PC, Chew LS, Hamrahian AH, Kennedy L. Lymphocytic infundibulo-
neurohypophysitis: a clinical overview. Endocrine 2015; 50:531.
19. Harano Y, Honda K, Akiyama Y, et al. A Case of IgG4-Related Hypophysitis
Presented with Hypopituitarism and Diabetes Insipidus. Clin Med Insights Case
Rep 2015; 8:23.
20. Caturegli P, Iwama S. From Japan with love: another tessera in the hypophysitis
mosaic. J Clin Endocrinol Metab 2013; 98:1865.
21. Shikuma J, Kan K, Ito R, et al. Critical review of IgG4-related hypophysitis.
Pituitary 2017; 20:282.
22. Kapoor E, Cartin-Ceba R, Specks U, et al. Pituitary dysfunction in
granulomatosis with polyangiitis: the Mayo Clinic experience. J Clin Endocrinol
Metab 2014; 99:3988.
23. Leger J, Velasquez A, Garel C, et al. Thickened pituitary stalk on magnetic
resonance imaging in children with central diabetes insipidus. J Clin Endocrinol
Metab 1999; 84:1954.
24. Czernichow P, Pomarede R, Basmaciogullari A, et al. Diabetes insipidus in
children. III. Anterior pituitary dysfunction in idiopathic types. J Pediatr 1985;
106:41.
25. Charmandari E, Brook CG. 20 years of experience in idiopathic central diabetes
insipidus. Lancet 1999; 353:2212.
26. Christensen JH, Rittig S. Familial neurohypophyseal diabetes insipidus--an
update. Semin Nephrol 2006; 26:209.
27. Burbach JP, Luckman SM, Murphy D, Gainer H. Gene regulation in the
magnocellular hypothalamo-neurohypophysial system. Physiol Rev 2001;
81:1197.
28. Bichet DG, Lussier Y. Mice deficient for ERAD machinery component Sel1L
develop central diabetes insipidus. J Clin Invest 2017; 127:3591.
29. Shi G, Somlo DRM, Kim GH, et al. ER-associated degradation is required for
vasopressin prohormone processing and systemic water homeostasis. J Clin
Invest 2017; 127:3897.
30. Russell TA, Ito M, Ito M, et al. A murine model of autosomal dominant
neurohypophyseal diabetes insipidus reveals progressive loss of vasopressin-
producing neurons. J Clin Invest 2003; 112:1697.
31. Willcutts MD, Felner E, White PC. Autosomal recessive familial
neurohypophyseal diabetes insipidus with continued secretion of mutant weakly
active vasopressin. Hum Mol Genet 1999; 8:1303.
32. Abu Libdeh A, Levy-Khademi F, Abdulhadi-Atwan M, et al. Autosomal recessive
familial neurohypophyseal diabetes insipidus: onset in early infancy. Eur J
Endocrinol 2010; 162:221.
33. Christensen JH, Kvistgaard H, Knudsen J, et al. A novel deletion partly removing
the AVP gene causes autosomal recessive inheritance of early-onset
neurohypophyseal diabetes insipidus. Clin Genet 2013; 83:44.
34. Bischoff AN, Reiersen AM, Buttlaire A, et al. Selective cognitive and psychiatric
manifestations in Wolfram Syndrome. Orphanet J Rare Dis 2015; 10:66.
35. Amr S, Heisey C, Zhang M, et al. A homozygous mutation in a novel zinc-finger
protein, ERIS, is responsible for Wolfram syndrome 2. Am J Hum Genet 2007;
81:673.
36. Ishihara H, Takeda S, Tamura A, et al. Disruption of the WFS1 gene in mice
causes progressive beta-cell loss and impaired stimulus-secretion coupling in
insulin secretion. Hum Mol Genet 2004; 13:1159.
37. Takeda K, Inoue H, Tanizawa Y, et al. WFS1 (Wolfram syndrome 1) gene
product: predominant subcellular localization to endoplasmic reticulum in cultured
cells and neuronal expression in rat brain. Hum Mol Genet 2001; 10:477.
38. Gabreëls BA, Swaab DF, de Kleijn DP, et al. The vasopressin precursor is not
processed in the hypothalamus of Wolfram syndrome patients with diabetes
insipidus: evidence for the involvement of PC2 and 7B2. J Clin Endocrinol Metab
1998; 83:4026.
39. Sandhu MS, Weedon MN, Fawcett KA, et al. Common variants in WFS1 confer
risk of type 2 diabetes. Nat Genet 2007; 39:951.
40. Fonseca SG, Ishigaki S, Oslowski CM, et al. Wolfram syndrome 1 gene
negatively regulates ER stress signaling in rodent and human cells. J Clin Invest
2010; 120:744.
41. Seidah NG, Prat A. The biology and therapeutic targeting of the proprotein
convertases. Nat Rev Drug Discov 2012; 11:367.
42. Pépin L, Colin E, Tessarech M, et al. A New Case of PCSK1 Pathogenic Variant
With Congenital Proprotein Convertase 1/3 Deficiency and Literature Review. J
Clin Endocrinol Metab 2019; 104:985.
43. Christ-Crain M, Bichet DG, Fenske WK, et al. Diabetes insipidus. Nat Rev Dis
Primers 2019; 5:54.
44. Yagi H, Nagashima K, Miyake H, et al. Familial congenital hypopituitarism with
central diabetes insipidus. J Clin Endocrinol Metab 1994; 78:884.
45. Lukezic M, Righini V, Di Natale B, et al. Vasopressin and thirst in patients with
posterior pituitary ectopia and hypopituitarism. Clin Endocrinol (Oxf) 2000; 53:77.
46. Yamanaka C, Momoi T, Fujisawa I, et al. Neurohypophyseal function of an
ectopic posterior lobe in patients with growth hormone deficiency. Acta
Endocrinol (Copenh) 1990; 122:664.
47. Hoyt WF, Kaplan SL, Grumbach MM, Glaser JS. Septo-optic dysplasia and
pituitary dwarfism. Lancet 1970; 1:893.
48. Masera N, Grant DB, Stanhope R, Preece MA. Diabetes insipidus with impaired
osmotic regulation in septo-optic dysplasia and agenesis of the corpus callosum.
Arch Dis Child 1994; 70:51.
49. McCabe MJ, Alatzoglou KS, Dattani MT. Septo-optic dysplasia and other midline
defects: the role of transcription factors: HESX1 and beyond. Best Pract Res Clin
Endocrinol Metab 2011; 25:115.
50. Secco A, Allegri AE, di Iorgi N, et al. Posterior pituitary (PP) evaluation in patients
with anterior pituitary defect associated with ectopic PP and septo-optic
dysplasia. Eur J Endocrinol 2011; 165:411.
51. Seckl J, Dunger D. Postoperative diabetes insipidus. BMJ 1989; 298:2.
52. Nemergut EC, Zuo Z, Jane JA Jr, Laws ER Jr. Predictors of diabetes insipidus
after transsphenoidal surgery: a review of 881 patients. J Neurosurg 2005;
103:448.
53. Ghirardello S, Hopper N, Albanese A, Maghnie M. Diabetes insipidus in
craniopharyngioma: postoperative management of water and electrolyte
disorders. J Pediatr Endocrinol Metab 2006; 19 Suppl 1:413.
54. Hadjizacharia P, Beale EO, Inaba K, et al. Acute diabetes insipidus in severe
head injury: a prospective study. J Am Coll Surg 2008; 207:477.
55. Seckl JR, Dunger DB, Bevan JS, et al. Vasopressin antagonist in early
postoperative diabetes insipidus. Lancet 1990; 335:1353.
56. Sigounas DG, Sharpless JL, Cheng DM, et al. Predictors and incidence of central
diabetes insipidus after endoscopic pituitary surgery. Neurosurgery 2008; 62:71.
57. Crowley RK, Hamnvik OP, O'Sullivan EP, et al. Morbidity and mortality in patients
with craniopharyngioma after surgery. Clin Endocrinol (Oxf) 2010; 73:516.
58. Hoorn EJ, Zietse R. Water balance disorders after neurosurgery: the triphasic
response revisited. NDT Plus 2010; 3:42.
59. Olson BR, Gumowski J, Rubino D, Oldfield EH. Pathophysiology of hyponatremia
after transsphenoidal pituitary surgery. J Neurosurg 1997; 87:499.
60. Hensen J, Henig A, Fahlbusch R, et al. Prevalence, predictors and patterns of
postoperative polyuria and hyponatraemia in the immediate course after
transsphenoidal surgery for pituitary adenomas. Clin Endocrinol (Oxf) 1999;
50:431.
61. Bohn D, Davids MR, Friedman O, Halperin ML. Acute and fatal hyponatraemia
after resection of a craniopharyngioma: a preventable tragedy. QJM 2005;
98:691.
62. Laredo S, Yuen K, Sonnenberg B, Halperin ML. Coexistence of central diabetes
insipidus and salt wasting: the difficulties in diagnosis, changes in natremia, and
treatment. J Am Soc Nephrol 1996; 7:2527.
63. Sun R, Wang C, Zhong X, Wu Y. Diabetes Insipidus as an Initial Presentation of
Myelodysplastic Syndrome: Diagnosis with Single-Nucleotide Polymorphism
Array-Based Karyotyping. Tohoku J Exp Med 2016; 238:305.
64. Wickramasinghe LS, Chazan BI, Mandal AR, et al. Cranial diabetes insipidus
after upper gastrointestinal hemorrhage. Br Med J (Clin Res Ed) 1988; 296:969.
 65. Bakiri F, Benmiloud M, Vallotton MB. Arginine-vasopressin in postpartum
panhypopituitarism: urinary excretion and kidney response to osmolar load. J
Clin Endocrinol Metab 1984; 58:511.
66. Jialal I, Desai RK, Rajput MC. An assessment of posterior pituitary function in
patients with Sheehan's syndrome. Clin Endocrinol (Oxf) 1987; 27:91.
67. Dunger DB, Broadbent V, Yeoman E, et al. The frequency and natural history of
diabetes insipidus in children with Langerhans-cell histiocytosis. N Engl J Med
1989; 321:1157.
68. Stuart CA, Neelon FA, Lebovitz HE. Disordered control of thirst in hypothalamic-
pituitary sarcoidosis. N Engl J Med 1980; 303:1078.
69. Garovic VD, Clarke BL, Chilson TS, Specks U. Diabetes insipidus and anterior
pituitary insufficiency as presenting features of Wegener's granulomatosis. Am J
Kidney Dis 2001; 37:E5.
70. Czarnecki EJ, Spickler EM. MR demonstration of Wegener granulomatosis of the
infundibulum, a cause of diabetes insipidus. AJNR Am J Neuroradiol 1995;
16:968.
71. Thodou E, Asa SL, Kontogeorgos G, et al. Clinical case seminar: lymphocytic
hypophysitis: clinicopathological findings. J Clin Endocrinol Metab 1995; 80:2302.
72. Sato N, Sze G, Endo K. Hypophysitis: endocrinologic and dynamic MR findings.
AJNR Am J Neuroradiol 1998; 19:439.
73. Nishioka H, Ito H, Fukushima C. Recurrent lymphocytic hypophysitis: case
report. Neurosurgery 1997; 41:684.
74. Canepa-Anson R, Williams M, Marshall J, et al. Mechanism of polyuria and
natriuresis in atrioventricular nodal tachycardia. Br Med J (Clin Res Ed) 1984;
289:866.
75. Fujii T, Kojima S, Imanishi M, et al. Different mechanisms of polyuria and
natriuresis associated with paroxysmal supraventricular tachycardia. Am J
Cardiol 1991; 68:343.
76. Gold PW, Kaye W, Robertson GL, Ebert M. Abnormalities in plasma and
cerebrospinal-fluid arginine vasopressin in patients with anorexia nervosa. N
Engl J Med 1983; 308:1117.
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