C hap ter
6
Diabetes Insipidus
Soren Rittig1 AND Jane H. Christensen1,2
1
Pediatric Research Center, Department of Pediatrics, Aarhus University Hospital, Skejby, Denmark
2
Department of Human Genetics, Aarhus University, Aarhus, Denmark
Introduction
Disorders of water balance are common and practicing
physicians are often met with complaints of increased uri-
nation and thirst. Only a minority of such patients, how-
ever, have the disease “diabetes insipidus” (DI), and in
even fewer patients are the symptoms caused by genetic
defects in one of the genes involved in maintaining water
homeostasis. Nevertheless, such patients should be identi-
fied and subjected to proper clinical and genetic testing
in order to secure correct diagnosis and treatment. The
clinical differential diagnosis of diabetes insipidus can
be challenging and there are multiple examples of mis-
diagnosis, especially when the disease presents in a par-
tial form. Although familial forms of DI were recognized
more than 150 years ago the genetic background has only
been revealed in detail during the last decade and genetic
testing now represents an important tool in the differential
diagnosis of DI.
This chapter aims to provide a brief overview of the defi-
nition, clinical and genetic types, and differential diagnosis
of DI and to provide information about the indications and
practicalities of genetic DI tests available today.
Definition
The term diabetes insipidus is derived from the Greek “dia-
bainein” meaning to pass through and from Latin “insip-
idus” meaning tasteless. The disease was first described in
the literature as early as 1664 where the disease was dis-
tinguished from diabetes mellitus by the famous taste test
of Willis [38]. The prevalence is not clearly established but
has been estimated to be approximately 1:25,000, with an
annual incidence of approximately 0.01%. Of these, less
than 10% is hereditary [14].
Genetic Diagnosis of Endocrine Disorders
DI is characterized by extreme thirst and excretion
of abnormally large volumes of dilute urine (for recent
reviews, see [1–3, 8, 36]). DI is defined clinically by the
following two criteria:
1. 24-hour urine production on ad-libitum fluid intake
exceeding 3.5 L or 50  ml/kg b.w. (in children 75–
100  ml/kg b.w. due to higher water content in their
food).
2. Low urinary osmolality (300  mosmol/kg).
Clinical types of diabetes insipidus
DI can be divided into four different types (Fig. 6.1): (1)
pituitary, central, neurogenic or neurohypophyseal DI
is the most common type which results from inadequate
secretion of the antidiuretic hormone, arginine vasopressin
(AVP); (2) nephrogenic DI, is caused by renal insensitiv-
ity to the antidiuretic effects of AVP, most commonly due
to impairment of the renal vasopressin V2 receptor or the
aquaporin-2 protein; (3) primary polydipsia is due to exces-
sive fluid intake. It can be subdivided into two categories:
dipsogenic DI, caused by an abnormal thirst mechanism
[22, 31], and psychogenic DI, which appears to be due to
a psychological impairment [7, 16]; and (4) gestational DI,
due to increased metabolism of AVP by placental enzymes
during pregnancy.
Complete DI is defined by persistently low urine osmo-
lality (300  mosmol/kg) during a fluid deprivation test
providing plasma osmolality rises above 295 mosmol/kg.
Partial DI is defined by a subnormal increase in urine
osmolality (300–600  mosmol/kg) during a fluid depriva-
tion test with the same rise in plasma osmolality. No clini-
cal definitions of complete and partial DI exist based upon
measurements of plasma AVP although the normal response
to an osmotic stimulus has been reported [23, 32].
Copyright © 2010 Elsevier Inc.
67 All rights of reproduction in any form reserved.
68 Genetic Diagnosis of Endocrine Disorders

Familial types of diabetes insipidus
Familial DI exists in two hereditary forms, familial neuro-
hypophyseal DI (FNDI) and congenital nephrogenic DI
(NDI or CNDI) caused by mutations in one of the three
genes encoding proteins involved in antidiuresis, i.e. the pre-
­prohormone of AVP (causing FNDI), the renal vasopressin V2
receptor (causing NDI), and the renal water channel protein
aquaporin-2 (causing NDI) (Fig. 6.1 and Tables 6.1 and 6.2).
FNDI
FNDI – Genetic Aspects
Until now, FNDI has been reported in at least 97 kindreds
worldwide and in 95 of these (98%), the disease has been
Central/
neurohypophyseal
AVP
AVPR2 AQP2
Nephrogenic
Other DI types:
Primary polydipsia
Gestational
FIGURE 6.1 Clinical types of DI. The pituitary form is caused
by a deficiency of the antidiuretic hormone (AVP) and the nephro-
genic form by renal insensitivity to the antidiuretic action of AVP.
A third type is caused by high fluid intake (primary polydipsia)
and a fourth is caused by placental degradation of AVP in pregnant
women. The pituitary and nephrogenic type of DI exist in familial
forms. AVPR2, renal vasopressin V2 receptor; AQP2, aquaporin-2
(renal water channel). See plate section.
linked to mutations in the gene encoding the AVP pre-
­prohormone (the AVP gene; Entrez GeneID 551). With only
a few well-documented exceptions, FNDI is transmitted by
autosomal-dominant inheritance (adFNDI) and appears to be
largely, if not completely, penetrant [9]. In one ­kindred, the
transmission of DI is consistent with autosomal-­recessive
inheritance (arFNDI) [37]. Since the report in 1945 by
Forssman [12, 18] it has been registered in most genetic
databases (e.g. OMIM [Online Mendelian Inheritance in
Man], entry number 304900) that an X-linked recessive form
of FNDI existed (xrFNDI). However, a recent reinvestiga-
tion including genetic and clinical studies on descendants of
the original patients revealed a partial NDI phenotype, and
consistent with the clinical phenotype, the patient carried
a mutation in the AVPR2 gene (g.310C  T, p.R104C). On
the other hand, in another rare report of xrFNDI, the clinical
phenotype in one kindred clearly is consistent with that of
neurohypophyseal DI and although the disease seems to be
linked to the same chromosomal location as the AVPR2 gene
associated with NDI, namely Xq28, mutations were neither
found in this gene nor in the AVP gene [17, 18].
Until now, FNDI has been associated with 63 different
mutations in the AVP gene [8]. All but one of these mutations
(g.19191delG) are located in the coding region of the AVP
gene. In concordance with the inheritance pattern of the dis-
ease, they affect only one allele in the autosomal-dominant
form and two alleles in the recessive [37]. Almost all the
mutations identified are single base substitutions (55 of 63)
and except for two dinucleotide substitutions the remaining
mutations are deletions of either one or three nucleotides.
There is no real prevalent adFNDI mutation in the AVP gene
but one mutation is nonetheless more frequent than all others,
namely the g.279G  A substitution (predicting an A19T
amino acid substitution), which has been identified in nine
kindreds with no known relationship to each other.
It has been suggested that adFNDI mutations exert a
dominant-negative effect by the production of a mutant hor-
mone precursor that fails to fold and/or dimerize properly in
the endoplasmatic reticulum (ER) and, as a consequence, is
retained by the ER protein quality control resulting in cyto-
toxic accumulation of protein in the neurons that produce
AVP (i.e., a misfolding-neurotoxicity hypothesis) [8].

Table 6.1  Hereditary forms of DI

Disease Inheritance Chromosome Gene Mutations Kindreds References

FNDI Autosomal dominant (98%) or recessive1 20p13 AVP 63 95 [8]

Autosomal dominant 20p132 Unknown2 –2 1 [39]
X-linked recessive Xq283 Unknown3 –3 1 [17]
NDI X-linked recessive (90%) Xq28 AVPR2 193 307 [5]
Autosomal dominant or recessive 12q12-q13 AQP2 39 – [24]
1
The clinical characteristics of the autosomal recessive form differ significantly from those of classic FNDI.
2
Linkage to a 7-cM interval on chromosome 20p13. Mutations searched in the coding region, the promoter, the introns and enhancer regions of the AVP
gene, in the coding region of the nearby UBCE7IP5 gene, as well as in the AQP2 gene.
3
Linkage to the same chromosomal location as the AVPR2 gene (Xq28). Mutations searched in the coding region of the AVP and AVPR2 genes.

The genetic basis of FNDI remains unknown in two
reported kindreds (Table 6.1) [17, 18, 39]. In the first one
reported, FNDI appears to be transmitted in an xrFNDI
mode and preliminary linkage analysis suggests that the
disease gene is located at the end of the long arm of the
X-chromosome (Xq28) [17, 18]. In the second one, a
Chinese family with adFNDI, it has been reported that the
disease showed linkage to a 7-cM interval on chromosome
20p13 containing the AVP gene; however, unexpectedly no
mutations could be detected in the coding region, the pro-
moter, or the introns of the AVP gene [39].
adFNDI – Clinical Aspects
The familial occurrence of severe polyuria and polydipsia
in adFNDI (up to 28 L/24 h), which segregates in an auto-
somal-dominant pattern and responds readily to exogenous
dDAVP, shows several intriguing features that separate it
from other familial forms of DI (Table 6.2): the affected
family members show a completely normal water bal-
ance at birth and during early infancy but develop progres-
sive symptoms of excessive drinking at some point during
childhood (several months–6 years) [18]. In the few cases
in which it has been studied by repetitive fluid-deprivation
tests, AVP secretion is normal before the onset of FNDI but
diminishes progressively during early childhood [10, 25,
27]. Once fully developed, the DI phenotype with severe
thirst, polydipsia and polyuria (8–20  L/day) are similar to
other forms of complete DI, with the exception that in some
middle aged patients, symptoms decrease markedly with-
out treatment and with preserved glomerular filtration. The
mechanism of these remissions is currently unexplained.
Although not fully clarified, consistently with the loss of
AVP producing hypothalamic neurons, the bright signal
in the posterior pituitary disappears on T1 weighted MRI
images of adFNDI patients. However, the same lack of sig-
nal can be found in patients with NDI [34], questioning the
usefulness of this investigation in the differential diagnosis.
The clinical characteristics of the rare arFNDI vari-
ant differ significantly from those of adFNDI because, for
Table 6.2  Different clinical features of familial DI forms
Clinical feature adFNDI
Affected gene AVP
Gender differences Male:female 1:1
Debut of symptoms 6 months to 6 years
Plasma AVP during thirst Low/undetectable
Decrease of symptoms at middle age Yes, in some
Antidiuretic response to dDAVP 50% increase in U-osm
Extrarenal response to dDAVP (e.g. factor VIII) Normal
Posterior pituitary bright signal on MRI Lacking
*
In xrNDI with partial (mild) DI phenotype debut has been reported later in life.
**
In adNDI, debut usually occurring from the second half of the first year or later.
C h a p t e r 6 Diabetes Insipidus
l
69
this reason among others, affected individuals do not have
abnormally low levels of plasma AVP during fluid depriva-
tion tests [37].
NDI
NDI – Genetic Aspects
NDI, which apart from the DI phenotype is characterized by
renal insensitivity to the antidiuretic effect of AVP, is either
X-linked recessive (app. 90% of NDI cases) and caused by
mutations in the gene encoding the vasopressin V2 recep-
tor (the AVPR2 gene; Entrez GeneID 554) or autosomal-
dominant or recessive (app. 10% of NDI) and caused by
mutations in the gene encoding the renal aquaporin-2 water
channel (the AQP2 gene; Entrez GeneID 359) (Fig. 6.1 and
Tables 6.1 and 6.2). Furthermore, some genetic defects in
other renal tubular transporter genes are associated with a
disturbance of the inner medullary concentration mecha-
nism and result in polyuria and polydipsia together with
characteristic electrolyte disturbances, e.g. Bartter syn-
drome [21].
xrNDI – Genetic Aspects
The X-linked and most prominent form of congenital NDI
is caused by loss-of-function mutations in the AVPR2 gene,
encoding the renal vasopressin V2 receptor, which is a mem-
ber of the family of G-protein-coupled receptors. Currently,
193 putative disease-causing mutations in the AVPR2 gene
have been identified in 307 families with a history of NDI
[5]. The molecular mechanism underlying the renal AVP
insensitivity, however, differs among mutants. Thus, AVPR2
mutations have been divided into five different classes
according to the cellular fate of the encoded protein [30]. In
vitro studies show that most mutations in the AVPR2 gene
(50%) result in vasopressin V2 receptors that are trapped
intracellularly and are unable to reach the plasma membrane
(class II mutations) [29]. In contrast, a few mutated vaso-
pressin V2 receptors reach the cell surface, but cannot bind
vasopressin or properly trigger an increase in intracellular
cyclic AMP (class IV mutations) [28].
xrNDI ar/adNDI
AVPR2 AQP2
Only males (females may Male:female 1:1
have mild DI symptoms)
From birth* From birth**
High High
No No
50% increase in U-osm 50% increase in U-osm
Reduced Normal
Lacking ?
70 Genetic Diagnosis of Endocrine Disorders
xrNDI – Clinical Aspects
The clinical characteristics of NDI attributable to muta-
tions in the AVPR2 or AQP2 gene, regardless of the mode
of inheritance or genetic mutation, include hypernatremia,
hyperthermia, mental retardation and repeated episodes of
dehydration if patients cannot obtain enough water. In con-
trast to adFNDI, the urinary concentration defect is present
at birth, and newborns and infants are especially prone to
dehydration. Furthermore, the clinical picture of dehydra-
tion is often difficult to interpret at this age (e.g. failure to
thrive) and therefore at this age severe cases of prolonged
dehydration are seen. Mental retardation was prevalent in
70% to 90% of the patients reported in the original stud-
ies of NDI and was thought to be part of the disease [35].
However, early recognition of NDI based on genetic screen-
ing in at-risk children and early treatment of the disease
permit these children to have normal physical and men-
tal development [28] and suggest that the mental retarda-
tion reported in the original studies probably resulted from
repeated episodes of severe dehydration rather than from
the genetic mutation.
Heterozygous females usually are asymptomatic but may
have variable degrees of polyuria and polydipsia because of
skewed X-chromosome inactivation [28]. Recent reports of
families carrying AVPR2 mutations but initially suspected
of having FNDI due to in some cases an impressive antidiu-
retic response to exogenous AVP [11] have emphasized the
importance of genetic testing and added to the complexity
of clinical differential diagnosis in DI.
Of interest, non-peptide vasopressin V2 receptor antago-
nists were recently found to increase urine osmolality and
to facilitate the folding of mutant vasopressin V2 receptors
in patients with several different mutations in the AVPR2
gene [4]. This finding is very important because it suggests
that it may be possible to find pharmacologic agents that
will enable mutant but partially functional vasopressin V2
receptors to move to the membrane and restore partial vaso-
pressin responsiveness and water reabsorption capability to
the collecting duct.
Autosomal NDI
Autosomal recessive or autosomal dominant modes of
inheritance occur in approximately 10% of the families
with congenital NDI who have been studied. These fami-
lies generally have mutations in the AQP2 gene (located
in chromosome region 12q12-q13), which codes for the
vasopressin-sensitive aquaporin-2 water channel (Fig. 6.1).
Currently, 39 putative disease-causing AQP2 mutations in
families with a history of NDI have been identified, mostly
in children of consanguineous parents [24]. In vitro studies
show that misfolding of mutant aquaporin-2 proteins and
subsequent degradation in the ER is the major mechanism
underlying autosomal recessive NDI [24]. Autosomal dom-
inant inherited mutations in the AQP2 gene primarily affect
the carboxy-terminus of aquaporin-2, causing misrouting
of both mutant and wild type aquaporin-2 proteins [19] and
some of these result in a partial DI phenotype [26].
Other genetic defects that cause
nephrogenic polyuria
An essential part of the urinary concentrating mechanism
is the medullary osmotic gradient built up by the loop of
Henle. The high interstitial osmolality is generated by
selective permeability of specific renal tubular segments to
water and by electrolyte transporters in the tubular epithe-
lium, especially in the thick ascending limb. Mutations in
genes encoding such transporter proteins (e.g. the KCNJ1,
SLC12A1, CLCNKB and BSND genes) result in a concen-
trating defect and thereby polyuria together with excessive
loss of potassium, chloride, sodium and calcium (Bartter
syndrome) [6, 21]. The electrolyte disturbances, however,
clearly distinguish these conditions from genuine DI.
Furthermore, urea transport in the inner medullary seg-
ment plays a role for maintenance of the medullary osmotic
gradient, and mutations in the gene encoding the urea
transporter B result in a mild form of partial nephrogenic
DI [33].
Clinical Diagnosis
Differentiating between the types of DI is relatively easy
if the patient has a severe deficiency in either the secre-
tion 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 poly-
dipsia, measuring the urinary response to a subsequent
injection of AVP or dDAVP will differentiate nephrogenic
DI from the neurohypophyseal and gestational forms.
Neurohypophyseal and gestational DI can be distinguished
on clinical grounds. If fluid deprivation results in concen-
tration 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 [32].
The most reliable way to make this distinction is to meas-
ure 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 satisfactory alternative
is to monitor closely changes in fluid balance during a ther-
apeutic trial of dDAVP. For a more detailed description of
the fluid deprivation test protocol, see http://www.diabetes
insipidus.org/medical.htm.
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 [20]. Although rarely necessary, a dDAVP infu-
sion test can be used to distinguish NDI caused by AVPR2
mutations from other causes (Table 6.2).
Genetic Testing
Genetic Tests Available
The three genes associated with DI are the AVP gene (auto-
somal dominant and recessive FNDI), the AVPR2 gene
(X-linked NDI) and the AQP2 gene (autosomal dominant
and recessive NDI). The AVP gene has three exons cover-
ing a 2.2 kb genomic region at chromosome 20p13, the
AVPR2 gene has three exons and two small introns cov-
ering a 2.3 kb genomic region at chromosome Xq28; and
the AQP2 gene which has four exons covering a 8.1 kb
genomic region at chromosome 12q12-q13. As all three
genes involved in DI are small genes with few exons, the
most common genetic test performed is sequence analysis
of the entire coding region of the gene in question.
Deletion/duplication analysis is commercially available
for the AVP gene (http://www.genetests.org) and deletion
analysis has been performed on a research basis also for the
AVPR2 gene (e.g. [13]). Targeted mutation analysis, prena-
tal diagnosis and carrier testing is also available for all three
genes either commercially or on a research basis.
Which Gene to Test?
Genetic testing of patients with clinical characteristics in
accordance with FNDI usually involves sequence analysis
of the entire coding region of the AVP gene as the large
majority of cases (98%) carry mutations in this gene. If no
mutations are found, it should be considered whether the
clinical characteristics and the inheritance of the disease in
the family is in accordance with partial NDI [11], indicating
sequence analysis of either the AVPR2 or the AQP2 genes.
Since most NDI is caused by AVPR2 mutations, molecular
genetic testing of a symptomatic individual, male or female,
usually starts with sequencing of the entire coding region
of the AVPR2 gene. If no mutations are found, sequenc-
ing of the coding region of the AQP2 gene is performed.
In affected children (male or female) from consanguineous
parents, AQP2 sequencing is performed first, followed by
AVPR2 sequencing if no mutation in AQP2 is identified.
Diagnostic Testing
There are several reasons why all patients with a congen-
ital form of DI should be properly diagnosed genetically.
As mentioned earlier, there are now multiple examples
where genetic testing resolved the differential diagnosis
and changed treatment options. Furthermore, confirming a
mutation in the AVP gene in patients suspected for FNDI
relieves the physician from further exploration of the cause
of DI, e.g. searching for a hypothalamic lesion/tumor, test-
ing anterior pituitary function, etc. In NDI, early diagnosis
C h a p t e r 6 Diabetes Insipidus
l
71
in newborns is essential to ensure prompt treatment in order
to reduce morbidity from hypernatremia, dehydration and
dilation of the urinary tract.
Therefore, in all patients with familial occurrence of DI
symptoms regardless of age and the results of clinical tests,
genetic testing should be performed. Also, genetic testing
should be considered in all patients with nephrogenic DI
without an identifiable clinical cause, regardless of fam-
ily history, as de novo mutations are not uncommon. It has
not been clear whether patients with idiopathic neurohypo-
physeal DI should be tested genetically for de novo muta-
tions in the AVP gene. These patients constitute a relatively
large proportion of neurohypophyseal DI cases (20%–50%)
and some occur during childhood [15]. In our experience
approximately 5% of these have abnormalities in the AVP
gene [9] and therefore we suggest that patients with neu-
rohypophyseal DI occurring during childhood, without a
family history, and without an identifiable cause (e.g. thick-
ening of the pituitary stalk) should be tested genetically.
Pre-symptomatic Diagnosis in FNDI
Once the molecular diagnosis is established in FNDI kin-
dreds, it is relatively easy to screen other family members
for the mutation. This is particularly relevant in infants at
risk of inheriting the mutation because pre-symptomatic
diagnosis is thereby possible, relieving years of parental
concern about the carrier status of their offspring. Usually,
the parents already request a genetic test when the children
are newborn.
Carrier Testing
In all recessive forms of DI (arFNDI, xrNDI and arNDI)
testing of at-risk relatives is available if the mutation has
been identified in the proband. This is particularly useful
in xrNDI both to explain possible mild DI symptoms in
female carriers and for genetic counseling. In contrast, car-
rier testing is not very relevant in adFNDI except for pre-
symptomatic screening as mentioned above as this DI form
is fully penetrant.
Prenatal Diagnosis – adFNDI
Because FNDI is associated with very few symptoms and
with a normal quality of life at least when treated appropri-
ately, and because there is little risk of severe central nerv-
ous system complications compared with NDI, prenatal
diagnosis seems not to be indicated.
Prenatal Diagnosis – xrNDI
In conditions such as NDI that do not affect intellect and
have treatment available, requests for prenatal testing are
not common. Prenatal testing is available for pregnancies
at increased risk if the AVPR2 mutation has been identi-
fied in an affected family member. The usual procedure is
72 Genetic Diagnosis of Endocrine Disorders

to determine fetal sex by performing chromosome analysis Peter M.T. Deen, PhD
on fetal cells obtained by chorionic villus sampling at about Department of Physiology
ten to 12 weeks’ gestation or by amniocentesis usually per- Nijmegen Center for Molecular Life Sciences
formed at about 15–18 weeks’ gestation. If the karyotype is Radboud University Nijmegen Medical Center
46,XY, DNA from fetal cells can be analyzed for the known PO Box 9101, Nijmegen 6500, HB
disease-causing mutation. The Netherlands
Email: p.deen@ncmls.ru.nl

Prenatal Diagnosis – arNDI Important DI resources are the NDI Foundation and the
Prenatal diagnosis is available for pregnancies at increased Diabetes Insipidus Foundation, Inc. that have been formed
risk. Analysis of DNA extracted from fetal cells obtained by to support education, research, treatment and cure for DI.
amniocentesis is usually performed at about 15–18 weeks’ Their contact details are:
gestation or chorionic villus sampling (CVS) at about 10 NDI Foundation
to 12 weeks’ gestation. Both disease-causing alleles of an Main Street PO Box 1390
affected family member must be identified before prenatal Eastsound WA 98245
testing can be performed. Phone: 888-376-6343
Differences in perspective may exist among medical Fax: 888-376-6356
professionals and in families regarding the use of prenatal Email: info@ndif.org
testing, particularly if the testing is being considered for the www.ndif.org
purpose of pregnancy termination rather than early diagno-
sis. Although most centers would consider decisions about Diabetes Insipidus Foundation, Inc
prenatal testing to be the choice of the parents, careful dis- c/o Mike Gandrud
cussion of these issues is appropriate. 1232 24th Street
Preimplantation genetic diagnosis (PGD) may be avail- Ames IA 50010
able for families in which the disease-causing mutation(s) Phone: 706-323-7576
has been identified. Email: ndi-support@diabetesinsipidus.org
http://diabetesinsipidus.org

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Available laboratories and
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AVP. Disease: Diabetes insipidus, neurohypophyseal, Hum.
Genet. 118 (2006) 783, Accession #Hm0558.
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that for a long period of time have been actively involved in Disease: Diabetes insipidus, neurohypophyseal, Hum. Genet.
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Soren Rittig, MD 4. V. Bernier, M. Lagace, M. Lonergan, et al., Functional res-
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 Central/
neurohypophyseal

AVP

AVPR2 AQP2

Nephrogenic

Other DI types:
Primary polydipsia
Gestational

FIGURE 6.1 Clinical types of DI. The pituitary form is caused by a deficiency of the antidiuretic hormone (AVP) and the nephrogenic
form by renal insensitivity to the antidiuretic action of AVP. A third type is caused by high fluid intake (primary polydipsia) and a fourth
is caused by placental degradation of AVP in pregnant women. The pituitary and nephrogenic type of DI exist in familial forms. AVPR2,
renal vasopressin V2 receptor; AQP2, aquaporin-2 (renal water channel).