C H A P T E R
5
Diabetes Insipidus
Jane Hvarregaard Christensen*, Søren Rittig**
*Department of Biomedicine, Aarhus University, Aarhus, Denmark
**Department of Pediatrics, Aarhus University Hospital, Aarhus, Denmark
INTRODUCTION
Disorders of water balance are common, and prac-
ticing physicians are often met with complaints of in-
creased urination and thirst. Only a minority of such
patients, however, suffers from diabetes insipidus and
in even fewer the symptoms are caused by genetic
defects in any one of the genes being essential in en-
suring proper water homeostasis of the human body.
Nevertheless, such patients should be identified and
subjected to proper clinical and genetic testing in or-
der to secure correct diagnosis and optimal treatment.
The clinical differential diagnosis of diabetes insipidus
can be challenging, and there are multiple examples of
misdiagnosis, especially when the disease presents in
a partial form. Although familial forms of diabetes in-
sipidus were recognized more than 150 years ago, the
genetic causes have only been revealed in recent de-
cades. At present, genetic testing represents not only an
important tool in the differential diagnosis of diabetes
insipidus, but also a major advance in clinical care, as it
has to some extent eliminated the problem of trying to
identify at birth which offspring are likely to develop
the disease.
The term “diabetes insipidus” is derived from the
Greek “diabainein,” meaning to pass through, and from
Latin “insipidus,” meaning tasteless. A distinction be-
tween diabetes associated with sweet tasting urine (di-
abetes mellitus) and diabetes associated with insipid
(tasteless) urine (diabetes insipidus) seems to have been
firmly established in 1831,1,2 but as early as in 1790, a case
of diabetes in which “the urine was perfectly insipid”
was recorded in the literature and noted to be “very rare;
and that the other (read: diabetes mellitus) is by much
the more common.”2,3
The prevalence of diabetes insipidus is yet not clearly
established but has been estimated to be approximately
Genetic Diagnosis of Endocrine Disorders. http://dx.doi.org/10.1016/B978-0-12-800892-8.00005-1
Copyright © 2016 Elsevier Inc. All rights reserved.
93
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1:25,000 and with an annual incidence of approximate-
ly 0.01%.4 Of these, less than 10% are inherited.5
Diabetes insipidus is characterized by the excretion
of abnormally large volumes of dilute urine under con-
ditions of ad libitum fluid intake.6–10 Diabetes insipidus is
defined clinically by the following two criteria:
1. 24-h urine volume exceeding 50 mL/kg body weight
(in children 75–100 mL/kg body weight, due to
higher water content in their food)
2. Urinary osmolality < 300 mosmol/kg
The polyuria is distinguishable from the osmotic di-
uresis of uncontrolled diabetes mellitus or other forms of
solute diuresis by the absence of glucosuria and a normal
rate of solute excretion (10–20 mosmol/kg per day).
This chapter aims to provide a brief overview of clini-
cal and genetic aspects of different types of diabetes in-
sipidus and the differential diagnosis and information
about the indications and practicalities of genetic testing
in diabetes insipidus available today.
TYPES OF DIABETES INSIPIDUS
Diabetes insipidus can be divided into four different
types that are caused by any one of four fundamentally
different defects (Fig. 5.1): 1. pituitary, central, neurogenic,
or neurohypophyseal diabetes insipidus, the most com-
mon type, results from a deficiency in the production
of the antidiuretic hormone arginine vasopressin (AVP);
2. renal or nephrogenic diabetes insipidus is caused by
renal insensitivity to the antidiuretic effects of AVP, for
example, due to impairment of the renal vasopressin
V2 receptor or aquaporin-2 water channel; 3. primary
polydipsia is due to suppression of AVP secretion as a
result of excessive fluid intake. Depending on whether
the excessive fluid intake is due to abnormal thirst or
 94 5. 
Diabetes Insipidus

but may also involve renal resistance and/or subclinical

deficiency in AVP production.
Complete diabetes insipidus is defined by persis-
tently low urine osmolality (<300 mosmol/kg) during
a fluid deprivation test providing plasma osmolality
rises above 295 mosmol/kg. Partial diabetes insipidus
is defined by a subnormal increase in urine osmolality
(300–600 mosmol/­kg) during a fluid deprivation test
with the same rise in plasma osmolality.4

FAMILIAL TYPES OF DIABETES

INSIPIDUS

Neurohypophyseal and nephrogenic diabetes insipi-

FIGURE 5.1  Four different types of diabetes insipidus. The neu-
rohypophyseal form is caused by a deficiency in the production of the
antidiuretic hormone, arginine vasopressin (AVP) and the nephrogenic
form by insensitivity to the antidiuretic action of AVP. A third type is
due to suppression of AVP secretion as a result of excessive fluid in-
take (primary polydipsia) and a fourth is caused by increased AVP
metabolism in pregnant women (gestational diabetes insipidus). The
pituitary/neurohypophyseal and renal/nephrogenic types of diabetes
insipidus exist in both acquired and genetic (familial) forms.
due to a psychological disorder, primary polydipsia is
subdivided into, respectively, dipsogenic diabetes insipi-
dus11,12 psychogenic diabetes insipidus,13,14 and 4. gesta-
tional diabetes insipidus,15–18which is primarily due to
increased metabolism of AVP by circulating vassopres-
sinase produced by the placenta in the pregnant woman
dus are in rare cases inherited and thus referred to as
familial neurohypophyseal diabetes insipidus (FNDI) and con-
genital nephrogenic diabetes insipidus (CNDI or NDI). Based
upon further clinical characteristics and inheritance pat-
terns, FNDI can be subdivided into six different forms
and NDI into three (Table 5.1). The underlying genetic
defects have been identified in the majority of these dif-
ferent forms, and in FNDI they include mutations in ei-
ther the AVP gene (Entrez Gene: 551) encoding the AVP
prohormone (vasopressin-neurophysin 2-copeptin),6 the
WFS1 gene (Entrez Gene: 7466) encoding wolframin19 or
in the PCSK1 gene (Entrez Gene: 5122) encoding propro-
tein convertase 1/3 (neuroendocrine convertase 1).20–22
In NDI, they include mutation in either the AVPR2 gene
(Entrez Gene: 554) encoding the vasopressin V2 receptor8
or the AQP2 gene (Entrez Gene: 359) encoding aquaporin-
­2.8 In the following sections, we will summarize the main
clinical characteristics and genetic aspects of the four
most common forms of inherited diabetes insipidus:
1. ­autosomal dominant FNDI, 2. autosomal recessive FNDI,

TABLE 5.1 Overview of the Familial Types of Diabetes Insipidus

Chromosomal Number of
Disease Inheritance pattern location Affected gene OMIM kindreds

FNDI Autosomal dominant 20p13 AVP 125700 >100

Autosomal recessive, type a 20p13 AVP 125700 2

Autosomal recessive, type b 20p13 AVP NR 1

Autosomal recessive, type c 4p16.1 WFS1 222300 >175*

Autosomal recessive, type d 5q15 PCSK1 NR 8**

X-linked recessive Xq28 Unknown NR 1

NDI X-linked recessive Xq28 AVPR2 304800 >300

Autosomal dominant 12q13.12 AQP2 125800 NR

Autosomal recessive 12q13.12 AQP2 125800 NR

NR, not reported; OMIM, Online Mendelian Inheritance in Man (http://www.ncbi.nlm.nih.gov/omim/)
* As reviewed by Rigoli et al.19. According to Yu et al.,23 diabetes insipidus occurs in 52.8% of the patients.
** According to Martin et al.21 and Yourshaw et al.,22 diabetes insipidus occurs in at least 8/14 patients.

III.  Pituitary

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 Familial types of diabetes insipidus 95
type c (in Wolfram syndrome), 3. X-linked recessive NDI, and
4. autosomal dominant/recessive NDI (Table 5.1).
Autosomal Dominant FNDI
The familial occurrence of severe polyuria and poly-
dipsia (up to 28 L/24 h), segregating in an autosomal
dominant pattern, and responding readily to exogenous
dDAVP (autosomal dominant FNDI) (OMIM: 125700)
shows several intriguing features that separate it from
other familial forms of diabetes insipidus (Table 5.2).
Usually, affected family members show no signs of dis-
turbed water balance at birth and during early infancy
but develop progressive symptoms of excessive drinking
and polyuria at some point during infancy or early child-
hood.7 Even at this stage, the deficiency of AVP, although
marked, is often incomplete, and can be stimulated by
hypertonic dehydration, leading to concentration of the
urine. This may lead to delayed recognition of the con-
dition and even misdiagnosis. In the few cases in which
it has been studied by repetitive fluid-deprivation tests,
AVP production is normal before the onset of FNDI but
diminishes progressively during early childhood.7,24–26
Once fully developed, the diabetes insipidus with severe
thirst, polydipsia, and polyuria (8–20 L/day) is similar
to the diabetes insipidus in other complete forms. In a
few patients, yet, the AVP deficiency remains partial for
decades, even though it is complete in other affected
members of the same family with the same disease caus-
ing mutation, implying that other factors, genetic and/
or environmental, are in play to modulate the penetrance
of the mutations.27 That could, for example, be differ-
ences between families (and individuals) in their ability/
awareness to ensure early fluid replacement in affected
children, which would be expected to delay the time
of onset and slow down disease progression.27 In some
middle-­aged male patients, diabetes insipidus symptoms
decrease markedly without treatment and with preserved
AVP deficiency and normal glomerular filtration.28 The
mechanism of these remissions is currently unexplained.
Consistent with potential loss of AVP-producing magno-
cellular neurons,9 the hyperintense MRI (magnetic reso-
nance imaging) signal normally emitted by the posterior
pituitary is absent or very small in patients with autoso-
mal dominant FNDI, at least by the time AVP deficiency
becomes clinically recognizable. Since the same lack of
signal is characteristic in patients with NDI,29 the useful-
ness of this investigation in the differential diagnosis is
questionable.
The clinical characteristics of the rare autosomal re-
cessive forms of FNDI (type a and type b) and autosomal
recessive FNDI in congenital malabsorptive diarrhea
(type d) (Table 5.1) differ in many aspects from those
of autosomal dominant FNDI, for example, regarding
age of onset, plasma levels of AVP during fluid depri-
vation, inter-/intrafamily variation, and cooccurrence
with a complex picture of other symptoms.21,22,30–32 For a
thorough discussion of some of these rare conditions we
refer to Refs [9,21].
Nonsyndromic FNDI has been reported in more
than 100 kindreds worldwide, and in the majority of
these, the disease is caused by mutations in the AVP
gene (Table 5.1). With only a few well-documented ex-
ceptions, FNDI is transmitted by autosomal dominant
inheritance and appears to be largely, if not completely,
penetrant with age.33 Based upon the initial report in
1945 by Forssman34,35 it has been listed in databases
(OMIM: 304900) that an X-linked recessive form of
FNDI exists. However, a reinvestigation, including
genetic and clinical examinations on descendants of

TABLE 5.2 Comparison of Clinical Features in Nonsyndromic Forms of Familial Diabetes Insipidus

FNDI NDI NDI
Clinical features Autosomal dominant X-linked recessive Autosomal dominant/recessive

Affected gene AVP AVPR2 AQP2

Male:female ratio 1:1 Males only* 1:1

Debut of symptoms 6 months to 6 years From birth** From birth†

Plasma AVP during thirst Low/undetectable High High

Decrease of symptoms at middle age Yes, in some cases NR NR

Antidiuretic response to dDAVP >50% increase in U-osm <50% increase in U-osm <50% increase in U-osm

Extrarenal response to dDAVP (e.g., factor VIII) Normal Reduced Normal

Posterior pituitary bright signal on MRI Lacking Lacking NR

FNDI, familial neurohypophyseal diabetes insipidus; NDI, nephrogenic diabetes insipidus; AVP, arginine vasopressin; NR, not reported; dDAVP, desmopressin;
U-osm, urine osmolality; MRI, magnetic resonance imaging.
* Females may have mild symptoms of diabetes insipidus due to skewed X-chromosome inactivation.
** In some patients with partial (mild) diabetes insipidus debut has been reported later in life.
†
Debut is usually reported from the second half of the first year or later.

III. Pituitary

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 96 5. 
Diabetes Insipidus
the original patients, has revealed that the original pa-
tients more likely had a partial NDI phenotype, and
consistent with this the reinvestigated patients actu-
ally carried a mutation in the AVPR2 gene (g.310C > T,
p.Arg104Cys). On the other hand, in another report of
X-linked recessive inheritance of FNDI (Table 5.1), the
clinical phenotype in one family is clearly consistent
with that of neurohypophyseal diabetes insipidus, and
although the disease seems to be linked to the same
chromosomal location as the AVPR2 gene (Xq28), mu-
tations have been found neither in this gene nor in the
AVP gene.7,36 For a more thorough discussion of this
rare condition, we refer to Ref. [9].
Until now, FNDI has been associated with >70 dif-
ferent mutations in the AVP gene.9 All but one of these
mutations (g.1919 + 1delG) disturbs the coding region
of the gene. The type and location of the mutations dif-
fer widely and affect amino acid residues ranging from
the N-terminal residue of the signal peptide (the start co-
don), through the AVP moiety and into the C-terminal
part of the neurophysin 2 domain of the AVP preprohor-
mone. Of note, however, FNDI has not been attributed
to any mutation affecting solely copeptin, the glycosyl-
ated peptide encoded by exon 3. A copeptin mutation
(p.Ala159Thr) has been identified in one family in which
autosomal dominant FNDI was segregating. It did not,
however, segregate with the disease and all affected fam-
ily members were heterozygous for another mutation
(p.Gly96Asp) previously reported to cause FNDI. This
strongly suggests that the p.Ala159Thr mutation had no
pathological effect.37
There is no real prevalent mutation in the AVP gene in
autosomal dominant FNDI but one mutation is nonethe-
less more frequent than all others, namely, the g.279G > A
substitution (predicting an p.Ala19Thr amino acid sub-
stitution), which has been identified in 11 kindreds with
no known relationship to each other.38
The genetic basis of autosomal dominant FNDI re-
mains unknown in one reported kindred.39 In this ­Chinese
family, the disease showed linkage to a 7-cM interval on
chromosome 20p13 containing the AVP gene; however,
unexpectedly, no mutations could be found in the cod-
ing regions, the promoter, or the introns of the AVP gene.
In addition, the coding regions of the nearby UBCE7IP5
gene and the AQP2 gene on chromosome 12 were ana-
lyzed, but no mutations were detected. Thus, the cause of
FNDI in this specific family remains unexplained.
The diversity of the mutations identified in the AVP
gene in autosomal dominant FNDI could indicate diverse
pathogenic mechanisms. However, the fact that different
disease alleles result in rather uniform clinical presenta-
tions calls for a single unifying explanation. One such ex-
planation suggests that mutations in the AVP gene exert
a dominant-negative effect by leading to the production
of a mutant AVP prohormone that fails to fold and/or
III.  Pituitary
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dimerize properly in the endoplasmatic reticulum (ER)
and, as a consequence, is retained by the ER protein qual-
ity control resulting in cytotoxic accumulation of protein
in the magnocellular neurons that produce AVP (i.e., a
misfolding-neurotoxicity hypothesis).6
Autosomal Recessive FNDI, Type C
Autosomal recessive inheritance of FNDI has been de-
scribed and is by far most common in conjunction with
Wolfram syndrome (OMIM: 222300) (Table 5.1). The
syndrome is a rare, multifaceted, and progressive neu-
rodegenerative disease also referred to as DIDMOAD,
abbreviating its symptom spectrum, including diabetes
insipidus, early-onset, insulin-dependent diabetes mel-
litus, progressive optic atrophy, and sensorineural deaf-
ness, combined with many other neurological abnor-
malities.19 It has been estimated that approximately 75%
of patients with Wolfram syndrome present with par-
tial neurohypophyseal diabetes insipidus at an average
age of 14 years (range: three months to 40 years of age).
This is about the same time as they lose their hearing,
but after onset of diabetes mellitus and loss of vision.
The polyuria in Wolfram syndrome is due to a partial
or severe deficiency in AVP production,40 and seems to
be associated with posterior pituitary degeneration and
impaired processing of the AVP prohormone.41 In gen-
eral, the patients respond well to dDAVP administration.
Accordingly, the diabetes insipidus observed in Wolfram
syndrome seems to be clinically distinguishable from
autosomal dominant FNDI only by its mode of inheri-
tance, a tendency toward higher age of onset, and most
obvious by its cooccurrence with a complex picture of
other symptoms. Besides, in clear contrast to the rather
mild course of autosomal dominant FNDI, patients with
Wolfram syndrome usually die from central respiratory
failure as a result of brainstem atrophy in the third or
fourth decade of life.
Patients with the Wolfram syndrome are often offspring
from consanguineous marriages between unaffected par-
ents, and they have affected siblings, strongly support-
ing a recessive pattern of inheritance. Most commonly,
patients are homozygous or compound heterozygous for
mutations in the WFS1 gene located on chromosome 4
(4p16.1). Infrequently, mutations in the CISD2 gene can
also result in Wolfram syndrome; however in these cases
diabetes insipidus seems to be absent.42
The protein product Wolframin, encoded by WFS1,
has been shown to play a crucial role in the negative
regulation of a feedback loop of the ER stress–signaling
network, induced by the accumulation of misfolded and
unfolded proteins in the organelle. More specifically,
it seems to prevent secretory cells, such as pancreatic
b-cells, from death caused by dysregulation of this signal-
ing pathway.43 It could be that Wolframin plays a similar
 Familial types of diabetes insipidus 97
role in the AVP producing magnocellular neurons. These
cells may experience ER stress as an effect of the large bio-
synthetic load placed on the ER by the exceptional high
demands for AVP prohormone production under physi-
ological conditions that stimulate the neurons (elevated
osmotic pressure), exactly as pancreatic b-cells during
postprandial stimulation of proinsulin biosynthesis. Loss
of Wolframin function under such conditions would lead
to unregulated ER stress signaling and probably neuro-
nal cell death, exactly as has been shown in pancreatic
b-cells.44 This mechanism links directly to the ER stress,
possibly elicited by the accumulation of misfolded mu-
tant AVP prohormone in the magnocellular neurons of
patients with autosomal dominant FNDI.
X-Linked Recessive NDI
NDI is characterized by the same symptoms of diabe-
tes insipidus as seen in FNDI but shows renal insensitivity
to the antidiuretic effect of endogenously produced AVP
as well as to dDAVP treatment (Table 5.2). As mentioned
earlier, it is inherited either in an X-linked recessive pat-
tern (in approximately 90% of NDI cases) (OMIM: 304800)
and caused by mutations in the AVPR2 gene or in an au-
tosomal dominant or recessive pattern (in approximately
10% of NDI cases) (OMIM: 125800) and caused by muta-
tions in the AQP2 gene (Table 5.2). Inherited NDI addi-
tionally exists in complex forms characterized by loss of
water and ions, for example, Bartter syndrome (OMIM:
601678, 241200, 607364, and 602522). These rare variant
forms of NDI are caused by mutation in genes (KCNJ1,
SLC12A1, CLCNKB, CLCNKB, and CLCNKA in combina-
tion, or BSND) encoding other renal tubular transporters,
resulting in a disturbance of the inner medullary concen-
tration mechanism and thereby polyuria and polydipsia
together with characteristic electrolyte disturbances.45
The electrolyte disturbances, however, clearly distinguish
these conditions from genuine diabetes insipidus.
The clinical characteristics of NDI attributable to mu-
tations in the AVPR2 or AQP2 gene, regardless of the
mode of inheritance or specific mutation involved, in-
clude hypernatremia, hyperthermia, mental retardation,
and repeated episodes of dehydration if patients cannot
obtain enough water. In contrast to autosomal domi-
nant FNDI, the urinary concentration defect is present at
birth, and newborns and infants are especially prone to
dehydration (Table 5.2). Furthermore, the clinical picture
of dehydration is often difficult to interpret at this age
(usually manifested as failure to thrive), and therefore
severe cases of prolonged dehydration are seen. Mental
retardation was prevalent in 70–90% of the patients re-
ported in the original studies of NDI and was thought
to be part of the disease.46 However, early recognition of
NDI based on genetic screening of at-risk children and
early treatment of the disease permit such children to
III. Pituitary
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have normal physical and mental development47 and
suggest that the mental retardation reported in the origi-
nal studies probably resulted from repeated episodes of
severe dehydration rather than from pathologies direct-
ly caused by the genetic defect.
The X-linked recessive and most frequent form of fa-
milial NDI is caused by loss-of-function mutations in the
AVPR2 gene, encoding the renal vasopressin V2 recep-
tor. Currently, at least 214 putative disease-causing mu-
tations in the AVPR2 gene have been identified in more
than 300 families.7,10,48 Usually, heterozygous females
are asymptomatic but may in some cases have variable
degrees of polyuria and polydipsia because of skewed
X-chromosome inactivation.47 Recent reports of patients
having mutations in the AVPR2 gene and initially sus-
pected of having FNDI due to in some cases an impres-
sive antidiuretic response to exogenous AVP49 have
emphasized the importance of genetic testing and have
added to the complexity of clinical differential diagnosis
in diabetes insipidus.
The molecular mechanism underlying the renal
AVP insensitivity in NDI differs among disease alleles.
Hence, AVPR2 mutations have been divided into five
different classes according to their pathogenic effect at
the cellular levels,50 exactly as the system used for classi-
fication of mutant low-density lipoprotein (LDL) recep-
tors. Most mutations in the AVPR2 gene (>50%) result in
vasopressin V2 receptors that are trapped inside the cell
due to impaired intracellular trafficking, and they are
consequently unable to reach the plasma membrane and
bind the ligand (AVP) (Type 2 mutations). Other muta-
tions lead to an unstable mRNA, and thereby no pro-
tein product (Type 3 mutations) or mutant vasopressin
V2 receptors that reach the cell surface, but either cannot
bind AVP (the ligand) efficiently (Type 1 mutations) or
properly trigger an increase in intracellular cyclic AMP
(cAMP) production (Type 4 mutations).
Treatment of patients with NDI with dDAVP is usually
not effective, although females having symptoms due to
skewed X-chromosome inactivation and patients with
partial NDI can be alleviated from their diabetes insipi-
dus by using high doses, possibly because such patients
retain some functional vasopressin V2 receptors. Low
sodium diets to reduce the solute load to the kidneys
and treatment with diuretic thiazide eventually in com-
bination with cyclooxygenase inhibitor (indomethacin)
or hydrochlorothiazide in combination with amiloride
represents treatment regimens that to some extent can
relieve symptoms of NDI.8 Novel strategies suggested
for the treatment of NDI are: vasopressin V2 receptor
antagonists and agonists, pharmacological chaperones,
nonpeptide agonists, cyclic guanosine monophosphate
pathway activation, cAMP pathway activation, statins,
prostaglandins, and molecular chaperones. For a detailed
discussion of these approaches, we refer to Ref. [8].
 98 5. 
Diabetes Insipidus
Autosomal Dominant/Recessive NDI
As mentioned earlier, the clinical characteristics of
NDI attributable to mutations in the AVPR2 or AQP2
gene, regardless of the mode of inheritance or specific
mutation involved, are similar (Table 5.2). Autosomal
dominant or autosomal recessive modes of inheritance oc-
cur in approximately 10% of the families with inherited
NDI, with the autosomal recessive form being the most
common among the two (90% vs. 10%). Typically, these
families have mutations in the AQP2 gene, encoding the
aquaporin-2 water channel. Currently, at least 51 puta-
tive disease-causing mutations in the AQP2 gene have
been identified, mostly in children of consanguineous
parents.8
In vitro studies show that different mutations in the
AQP2 gene have different pathological effects at the cel-
lular level. Misfolding of mutant aquaporin-2 proteins
and subsequent degradation in the ER is likely the major
mechanism underlying autosomal recessive NDI,51 where-
as mutations causing autosomal dominant NDI gener-
ally affect the carboxy-terminus of aquaporin-2, causing
misrouting of both mutant and wild-type a­quaporin-2
proteins.8 Thus, these mutations probably act by a domi-
nant negative mechanism by preventing the normal
­aquaporin-2 protein from reaching the apical surface of
the collecting duct epithelial cells. Some of these muta-
tions result in a partial NDI phenotype, which has also
been observed in patients with mutations in the AVPR2
gene. For a detailed discussion of partial NDI in patients
with AVPR2 or AQP2 mutations, we refer to Ref. [7].
CLINICAL DIAGNOSIS
Differentiating between the types of diabetes insipi-
dus is relatively easy if the patient has a severe deficiency
in either the production or renal action of AVP. In either
condition, dehydration induced by fluid deprivation fails
to result in concentration of the urine. Because this result
excludes primary polydipsia, measuring the urinary re-
sponse to a subsequent injection of AVP or dDAVP will
differentiate nephrogenic diabetes insipidus from the
neurohypophyseal and gestational forms. Neurohypoph-
yseal and gestational diabetes insipidus can usually be
distinguished on clinical grounds. If fluid deprivation re-
sults in concentration of the urine, other tests are necessary
to determine whether the patient has primary polydipsia
or a less severe (“partial”) deficiency in the secretion or
action of AVP.4 The most reliable way to make this distinc-
tion is to measure plasma AVP and to relate the results to
the concurrent plasma and urine osmolality during a fluid
deprivation and/or hypertonic saline infusion test. A sat-
isfactory alternative is to closely monitor changes in fluid
balance during a therapeutic trial of dDAVP.
III.  Pituitary
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In addition to the renal vasopressin V2 receptor,
which mediates the antidiuretic effect of AVP and
dDAVP, there is evidence for an extrarenal vasopressin
V2 receptor, which mediates extrarenal effects such as an
increase in factor VIII, von Willebrand factor, and tissue-
type plasminogen activator.52 Although rarely neces-
sary, a dDAVP infusion test can be used to distinguish
NDI caused by mutations in the AVPR2 gene from other
causes (Table 5.2).
GENETIC TESTING
The four genes associated with the most common
forms of diabetes insipidus as described above are the
AVP gene (autosomal dominant FNDI), the WFS1 gene
(autosomal recessive FNDI, type c in Wolfram syn-
drome), the AVPR2 gene (X-linked recessive NDI), and
the AQP2 gene (autosomal dominant or recessive NDI).
The AVP gene has three exons covering a 2.2 kb genomic
region at chromosome 20p13, the WFS1 gene spans ap-
proximately 33.4 kb of genomic DNA at chromosome
4p16.1 and consists of eight exons, the AVPR2 gene has
three exons and two small introns covering a 4.6 kb
genomic region at chromosome Xq28, and the AQP2
gene has four exons covering a 8.1 kb genomic region
at chromosome 12q13.12. Thus, all genes involved in
the common forms of diabetes insipidus are relatively
small genes with few exons. This makes genetic testing
by direct sequence analysis of the entire coding region
feasible in most cases, and clinical molecular genetics
tests based upon this approach are available for all fours
genes (Table 5.3). The same goes for deletion/duplication
analysis (Table 5.3) whereas sequence analysis of select
exons and targeted variant analysis is only available as
clinical tests in the case of the WFS1 gene (Table 5.3).
TABLE 5.3 Molecular Genetics Tests Available for the Four Genes
Most Commonly Being Affected in Diabetes Insipidus
Molecular genetics AVP WFS1 AVPR2 AQP2
tests* gene** gene gene** gene**
Sequence analysis of NA + NA NA
select exons
Sequence analysis of + + + +
entire coding region
Deletion/duplication + + + +
analysis
Targeted variant NA + NA NA
analysis
NA, not available as clinical tests; +, available as clinical tests.
* According to GTR: Genetic Testing Registry (https://www.ncbi.nlm.nih.gov/gtr/).
** All molecular genetics test approaches are available at a research basis (see contact
information in the last section of this chapter).
 Genetic testing 99
All molecular genetics test approaches in the relation to
the AVP, AVPR2, and AQP2 genes are, however, avail-
able at a research basis.
Which Gene to Test?
Genetic testing of patients with clinical characteris-
tics in accordance with nonsyndromic FNDI usually in-
volves sequence analysis of the entire coding region of
the AVP gene, as the large majority of cases have muta-
tions in this gene. If no mutations are found, it should be
considered whether the clinical characteristics and the
eventual inheritance of the disease in the family is in ac-
cordance with partial NDI49 indicating sequence analy-
sis of either the AVPR2 or the AQP2 genes. Since most
NDI cases are caused by mutations in the AVPR2 gene,
molecular genetics testing of a symptomatic individual,
male or female, usually starts with sequencing of the en-
tire coding region of the AVPR2 gene. If no mutations
are found, sequencing of the coding region of the AQP2
gene should be performed. In children with NDI (male
or female) from consanguineous parents, sequencing of
the AQP2 gene should be performed first, followed by
sequencing of the AVPR2 gene if no mutations in the
AQP2 gene are identified. Genetic testing in syndromic
forms of inherited diabetes insipidus involves analysis
of the WFS1 gene in patients with Wolfram syndrome,
and in the rare cases of autosomal recessive FNDI in
congenital malabsorptive diarrhea (type d), it should
include analysis of the PCSK1 gene. Locus heterogene-
ity (KCNJ1, SLC12A1, CLCNKB, CLCNKB, and CLCNKA
in combination or BSND) in the complex form of NDI,
Bartter syndrome, calls for careful clinical evaluation
and alternative approaches in genetic testing (reviewed
in Ref. [53]).
Diagnostic Genetic Testing
There are several reasons why all patients with familial
occurrence of diabetes insipidus should be properly di-
agnosed using molecular genetics testing. As mentioned
earlier, there are now multiple examples where genetic
testing resolved the differential diagnosis and changed
treatment options. Furthermore, confirming the presence
of a mutation in the AVP gene in patients with neuro-
hypophyseal diabetes insipidus relieves the physician
from further exploration of the cause of diabetes insipi-
dus, for example, searching for a hypothalamic lesion/
tumor, testing anterior pituitary function, and so forth.
In NDI, early diagnosis in newborns is essential to en-
sure prompt treatment in order to reduce morbidity from
hypernatremia, dehydration, and dilation of the urinary
tract. Therefore, in all patients with familial occurrence
of diabetes insipidus regardless of age and the results of
clinical tests, genetic testing should be performed.
III. Pituitary
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Genetic testing should also be considered in all pa-
tients with NDI without an identifiable clinical cause re-
gardless of family history as de novo mutations are not
uncommon. It has not been clear whether patients with
idiopathic neurohypophyseal diabetes insipidus should
be tested genetically for de novo mutations in the AVP
gene. These patients constitute a relatively large pro-
portion of neurohypophyseal diabetes insipidus cases
(20–50%), and some occur during childhood.54 In our ex-
perience approximately 5% of these have abnormalities
in the AVP gene33 and therefore we suggest that patients
with neurohypophyseal diabetes insipidus occurring
during childhood, without a family history, and with-
out an identifiable cause (e.g., thickening of the pituitary
stalk), should be tested genetically.
Presymptomatic Genetic Diagnosis in FNDI
Once the molecular diagnosis is established in fami-
lies with FNDI, it is feasible to screen other family
members for the specific mutation in question. This is
particularly relevant in infants at risk of inheriting the
mutation because presymptomatic diagnosis thereby
is possible, relieving years of parental concern about
the carrier status of their offspring, as well as repeated
clinical diagnostic examinations. Usually, the parents
request a genetic test already when the children are
newborn.
Genetic Testing in Individuals at Risk
of Being Carriers
In all recessive forms of diabetes insipidus (autoso-
mal recessive FNDI, types a–d, X-linked recessive NDI,
and autosomal recessive NDI) testing of relatives at risk
of being carriers would be possible if the mutation has
been identified in the proband. This is particularly useful
in X-linked recessive NDI both to explain possible mild
symptoms in female carriers and for genetic counseling.
Carrier testing in autosomal dominant FNDI is relevant
due to the age-dependent penetrance whereby presymp-
tomatic genetic testing is both possible and useful for the
reasons mentioned earlier.
Prenatal Genetic Diagnosis
Prenatal genetic diagnosis seems not to be indicated
in most forms of FNDI, first of all because it rarely pres-
ents at birth whereby the risk of severe central nervous
system complications are low compared with congeni-
tal NDI, and second because the disease, when fully
developed, is associated with few symptoms that are
compatible with an almost normal quality of life at least
when treated appropriately. However, it could be indi-
cated in autosomal recessive FNDI, types c and d, due
 100 5. 
Diabetes Insipidus
to the severe cause of Wolfram syndrome and congeni-
tal malabsorptive diarrhea.
In conditions such as NDI that do not affect intellect
and have available treatment options, requests for pre-
natal genetic testing are not common. Prenatal testing is
available for pregnancies at increased risk if the AVPR2
mutation has been identified in an affected family mem-
ber. The usual procedure is to determine fetal sex by
performing chromosome analysis on fetal cells obtained
either by chorionic villus sampling or by amniocentesis.
If the karyotype is 46,XY, DNA from fetal cells can be
analyzed for known mutations.
Prenatal diagnosis is available for pregnancies at in-
creased risk for autosomal recessive NDI by the methods
described above. Both disease-causing alleles within the
family must have been identified to allow efficient pre-
natal testing.
Differences in perspective may exist among medical
professionals and in families regarding the use of prena-
tal genetic testing, particularly if the testing is being con-
sidered for the purpose of pregnancy termination rather
than timely diagnosis. Although most centers would con-
sider decisions about prenatal genetic testing to be the
choice of the parents, careful discussion of these issues is
appropriate.
Preimplantation genetic diagnosis may be available
for families in which the disease-causing allele(s) has
been identified.
Available Laboratories and Resources
Below listed is a few contact addresses to laboratories
that have been actively involved in research-based mo-
lecular genetics testing in diabetes insipidus for many
years and where different approaches for the analysis
of the AVP, AVPR2, and AQP2 genes can be performed.
Additional contacts and more details can be found at
GTR: Genetic Testing Registry (https://www.ncbi.nlm.
nih.gov/gtr/).
Søren Rittig, MD, DMSc, Pediatric Research Labora-
tory, Department of Pediatrics, Aarhus University Hos-
pital, Skejby Palle Juul-Jensens Boulevard 99, DK-8200
Aarhus N, Denmark; Email: soren.rittig@skejby.rm.dk
Daniel G. Bichet, MD, Centre de Recherche, Hopital
du Sacre-Coeur de Montreal, 5400 Blvd. Gouin Ouest,
Montreal, Quebec, Canada, H4J 1C5; Email: daniel.
bichet@umontreal.ca
Peter M.T. Deen, PhD, Department of Physiology, Rad-
boud University Medical Center (RUMC), Geert Groot-
eplein Zuid 30, 6525 GA Nijmegen, The Netherlands;
Email: peter.deen@Radboudumc.nl
An important diabetes insipidus information resource
is the NDI Foundation that has been formed to support
education, research, treatment, and cure for diabetes in-
sipidus. Their contact details are:
III.  Pituitary
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NDI Foundation, Main Street, PO Box 1390, Eastsound,
WA 98245, USA; Phone: 1-888-376-6343, Fax: 1-888-376-
6356, E-mail: info@ndif.org; www.ndif.org.
References
1. Eberle J. Treatise on the practice of medicine. 2nd ed. Grigg J.,
Philadelphia; 1831. p. 381–396.
2. Robertson GL. History. In: Robertson, GL, ed. Translational En-
docrinology & Metabolism: Posterior Pituitary Update. Chevy
Chase: The Endocrine Society; 2012. p. 15–26.
3. Cullen W. First lines of the practice of physic. Isaiah Thomas,
Worcester, Massachusetts; 1790. vol. 3, p. 153–155.
4. Robertson GL. Diabetes insipidus. Endocrinol Metab Clin North Am
1995;24(3):549–5472.
5. Fujiwara TM, Bichet DG. Molecular biology of hereditary diabetes
insipidus. J Am Soc Nephrol 2005;16(10):2836–46.
6. Christensen JH, Rittig S. Familial neurohypophyseal diabetes in-
sipidus – an update. Semin Nephrol 2006;26(3):209–23.
7. Babey M, Kopp P, Robertson GL. Familial forms of diabetes in-
sipidus: clinical and molecular characteristics. Nat Rev Endocrinol
2011;7(12):701–14.
8. Moeller HB, Rittig S, Fenton RA. Nephrogenic diabetes insipidus:
essential insights into the molecular background and potential
therapies for treatment. Endocr Rev 2013;34(2):278–301.
9. Christensen JH., Robertson GL. Deficiencies of vasopressin and
thirst. In: Robertson GL, ed. Translational Endocrinology & Me-
tabolism: Posterior Pituitary Update. Chevy Chase: The Endocrine
Society; 2012. p. 57–94.
10. Bichet DG. Renal actions of vasopressin. In: Robertson GL, ed.
Translational Endocrinology & Metabolism: Posterior Pituitary
Update. Chevy Chase: The Endocrine Society; 2012. p. 95–122.
11. Stuart CA, Neelon FA, Lebovitz HE. Disordered control of thirst
in hypothalamic-pituitary sarcoidosis. N Engl J Med 1980;303(19):
1078–82.
12. Robertson GL. Dipsogenic diabetes insipidus: a newly recognized
syndrome caused by a selective defect in the osmoregulation of
thirst. Trans Assoc Am Physicians 1987;100:241–9.
13. Barlow ED, De Wardener HE. Compulsive water drinking. Q J
Med 1959;28(110):235–58.
14. Sleepert FH, Jellinek EM. A comparative physiologic, psychologic
and psychiatric study of polyuric and non-polyuric schizophrenic
patients. J Nerv Ment Dis 1936;83:557–63.
15. Durr JA, Hoggard JG, Hunt JM, Schrier RW. Diabetes insipidus in
pregnancy associated with abnormally high circulating vasopres-
sinase activity. N Engl J Med 1987;316(17):1070–4.
16. Barron WM, Cohen LH, Ulland LA, Lassiter WE, Fulghum EM,
Emmanouel D, et al. Transient vasopressin-resistant diabetes in-
sipidus of pregnancy. N Engl J Med 1984;310(7):442–4.
17. Ford Jr SM, Lumpkin III HL. Transient vasopressin-resistant dia-
betes insipidus of pregnancy. Obstet Gynecol 1986;68(5):726–8.
18. Iwasaki Y, Oiso Y, Kondo K, Takagi S, Takatsuki K, Hasegawa H,
et al. Aggravation of subclinical diabetes insipidus during preg-
nancy. N Engl J Med 1991;324(8):522–6.
19. Rigoli L, Lombardo F, Di BC. Wolfram syndrome and WFS1 gene.
Clin Genet 2011;79(2):103–17.
20. Farooqi IS, Volders K, Stanhope R, Heuschkel R, White A, Lank E,
et al. Hyperphagia and early-onset obesity due to a novel homo-
zygous missense mutation in prohormone convertase 1/3. J Clin
Endocrinol Metab 2007;92(9):3369–73.
21. Martin MG, Lindberg I, Solorzano-Vargas RS, Wang J, Avitzur Y,
Bandsma R, et al. Congenital proprotein convertase 1/3 deficiency
causes malabsorptive diarrhea and other endocrinopathies in a
pediatric cohort. Gastroenterology 2013;145(1):138–48.
 REFERENCES 101
22. Yourshaw M, Solorzano-Vargas RS, Pickett LA, Lindberg I, Wang
J, Cortina G, et al. Exome sequencing finds a novel PCSK1 muta-
tion in a child with generalized malabsorptive diarrhea and diabe-
tes insipidus. J Pediatr Gastroenterol Nutr 2013;57(6):759–67.
23. Yu G, Yu ML, Wang JF, Gao CR, Chen ZJ. WS1 gene mutation anal-
ysis of Wolfram syndrome in a Chinese patient and a systematic
review of literatures. Endocrine 2010;38(2):147–52.
24. Elias PC, Elias LL, Torres N, Moreira AC, Antunes-Rodrigues J,
Castro M. Progressive decline of vasopressin secretion in familial
autosomal dominant neurohypophyseal diabetes insipidus pre-
senting a novel mutation in the vasopressin-neurophysin II gene.
Clin Endocrinol (Oxf) 2003;59(4):511–8.
25. Mahoney CP, Weinberger E, Bryant C, et al. Effects of aging on
vasopressin production in a kindred with autosomal dominant
neurohypophyseal diabetes insipidus due to the DeltaE47 neuro-
physin mutation. J Clin Endocrinol Metab 2002;87(2):870–6.
26. McLeod JF, Kovacs L, Gaskill MB, Rittig S, Bradley GS, Robert-
son GL. Familial neurohypophyseal diabetes insipidus associated
with a signal peptide mutation [see comments]. J Clin Endocrinol
Metab 1993;77(3):599A–1599A.
27. Jendle J, Christensen JH, Kvistgaard H, Gregersen N, Rittig S. Late-
onset familial neurohypophyseal diabetes insipidus due to a novel
mutation in the AVP gene. Clin Endocrinol (Oxf) 2012;77(4):586–92.
28. Robertson GL. The use of vasopressin assays in physiology and
pathophysiology. Semin Nephrol 1994;14(4):368–83.
29. Sato N, Ishizaka H, Yagi H, Matsumoto M, Endo K. Posterior lobe
of the pituitary in diabetes insipidus: dynamic MR imaging. Radi-
ology 1993;186(2):357–60.
30. 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(7):
1303–7.
31. Abu LA, Levy-Khademi F, Abdulhadi-Atwan M, Bosin E, Korner
M, White PC, et al. Autosomal recessive familial neurohypoph-
yseal diabetes insipidus: onset in early infancy. Eur J Endocrinol
2010;162(2):221–6.
32. Christensen JH, Kvistgaard H, Knudsen J, Shaikh G, Tolmie J,
Cooke S, et al. A novel deletion partly removing the AVP gene
causes autosomal recessive inheritance of early-onset neurohy-
pophyseal diabetes insipidus. Clin Genet 2013;83(1):44–52.
33. Christensen JH, Siggaard C, Corydon TJ, deSanctis L, Kovacs L,
Robertson GL, et al. Six novel mutations in the arginine vasopres-
sin gene in 15 kindreds with autosomal dominant familial neu-
rohypophyseal diabetes insipidus give further insight into the
pathogenesis. Eur J Hum Genet 2004;12(1):44–51.
34. Forssman H. On hereditary diabetes insipidus with special regard
to a sex-linked form. Acta Med Scand 1945;159(Suppl):1–196.
35. Hansen LK, Rittig S, Robertson GL. Genetic basis of familial neuro-
hypophyseal diabetes insipidus. Trends Endocrinol Metab 1997;8(9):
363–72.
36. Habiby RL, Robertson GL, Kaplowitz PB, Morris M, Siggaard C,
Rittig S. A novel X-linked form of familial neurohypophyseal dia-
betes insipidus. J Invest Med 1996;44:388A.
37. Hedrich CM, Zachurzok-Buczynska A, Gawlik A, Russ S, Hahn G,
Koehler K, et al. Autosomal dominant neurohypophyseal diabetes
insipidus in two families. Molecular analysis of the vasopressin-
neurophysin II gene and functional studies of three missense mu-
tations. Horm Res 2009;71(2):111–9.
III. Pituitary
Descargado para Ariana Valentina Andrade Cabrera (ariana.andrade@uninavarra.edu.co) en Fundacion Universitaria Navarra - Uninavarra de ClinicalKey.es por Elsevier en marzo 20, 2019.
Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2019. Elsevier Inc. Todos los derechos reservados.
38. Cizmarova M, Nagyova G, Janko V, Pribilincova Z, Virgova D,
Ilencikova D, et al. Late onset of familial neurogenic diabetes in-
sipidus in monozygotic twins. Endocr Regul 2013;47(4):211–6.
39. Ye L, Li X, Chen Y, Sun H, Wang W, Su T, et al. Autosomal domi-
nant neurohypophyseal diabetes insipidus with linkage to chro-
mosome 20p13 but without mutations in the AVP-NPII gene. J Clin
Endocrinol Metab 2005;90:4388–93.
40. Thompson CJ, Charlton J, Walford S, Baird J, Hearnshaw J,
McCulloch A, et al. Vasopressin secretion in the DIDMOAD
­
(Wolfram) syndrome. Q J Med 1989;71(264):333–45.
41. Gabreels BA, Swaab DF, de KD, Dean A, Seidah NG, Van de Loo
JW, et al. The vasopressin precursor is not processed in the hypo-
thalamus of Wolfram syndrome patients with diabetes insipidus:
evidence for the involvement of PC2 and 7B2. J Clin Endocrinol
Metab 1998;83(11):4026–33.
42. Amr S, Heisey C, Zhang M, Xia XJ, Shows KH, Ajlouni K, et al.
A homozygous mutation in a novel zinc-finger protein, ERIS, is
responsible for Wolfram syndrome 2. Am J Hum Genet 2007;81(4):
673–83.
43. Fonseca SG, Ishigaki S, Oslowski CM, Lu S, Lipson KL, Ghosh
R, et al. Wolfram syndrome 1 gene negatively regulates ER stress
signaling in rodent and human cells. J Clin Invest 2010;120(3):
744–55.
44. Cnop M, Ladriere L, Hekerman P, Ortis F, Cardozo AK, Dogusan
Z, et al. Selective inhibition of eukaryotic translation initiation
factor 2 alpha dephosphorylation potentiates fatty acid-induced
endoplasmic reticulum stress and causes pancreatic beta-cell dys-
function and apoptosis. J Biol Chem 2007;282(6):3989–97.
45. Kleta R, Bockenhauer D. Bartter syndromes and other salt-losing
tubulopathies. Nephron Physiol 2006;104(2):73–80.
46. van Lieburg AF, Knoers NV, Monnens LA. Clinical presentation
and follow-up of 30 patients with congenital nephrogenic diabetes
insipidus. J Am Soc Nephrol 1999;10(9):1958–64.
47. Morello JP, Bichet DG. Nephrogenic diabetes insipidus. Annu Rev
Physiol 2001;63:607–30.
48. Spanakis E, Milord E, Gragnoli C. AVPR2 variants and mutations
in nephrogenic diabetes insipidus: review and missense mutation
significance. J Cell Physiol 2008;217(3):605–17.
49. Faerch M, Christensen JH, Corydon TJ, Kamperis K, de ZF,
­Gregersen N, et al. Partial nephrogenic diabetes insipidus caused
by a novel mutation in the AVPR2 gene. Clin Endocrinol (Oxf)
2008;68(3):395–403.
50. Robben JH, Knoers NV, Deen PM. Cell biological aspects of the va-
sopressin type-2 receptor and aquaporin 2 water channel in neph-
rogenic diabetes insipidus. Am J Physiol Renal Physiol 2006;291(2):
F257–70.
51. Loonen AJ, Knoers NV, van Os CH, Deen PM. Aquaporin 2 muta-
tions in nephrogenic diabetes insipidus. Semin Nephrol 2008;28(3):
252–65.
52. Kaufmann JE, Oksche A, Wollheim CB, Gunther G, Rosenthal W,
Vischer UM. Vasopressin-induced von Willebrand factor secretion
from endothelial cells involves V2 receptors and cAMP. J Clin Invest
2000;106(1):107–16.
53. Jain G, Ong S, Warnock DG. Genetic disorders of potassium ho-
meostasis. Semin Nephrol 2013;33(3):300–9.
54. Ghirardello S, Malattia C, Scagnelli P, Maghnie M. Current per-
spective on the pathogenesis of central diabetes insipidus. J Pediatr
Endocrinol Metab 2005;18(7):631–45.