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PubMed2005

Clinical features, diagnosis and molecular studies of familial central diabetes insipidus.

BACKGROUND: Familial central diabetes insipidus (DI) is rare and is characterised by polydipsia and polyuria with a variable age of onset. The evaluation of arginine vasopressin (AVP) secretion in these individuals has been reported infrequently and only in adulthood. OBJECTIVE: To describe the clinical features, diagnosis and molecular investigation of children affected by familial central DI. METHODS: Functional studies of AVP secretion were undertaken in children from two kindreds with familial central DI. The AVP-neurophysin II (AVP-NPII) gene was also sequenced in symptomatic individuals. RESULTS: In affected individuals, the result of the water deprivation test may be inconclusive. However, the hypertonic saline test identified both the severe and partial forms of AVP deficiency. A novel mutation of the AVP-NPII gene was identified by direct gene sequencing in both families. CONCLUSIONS: This report highlights the progressive decline in AVP secretion with increasing age in this disorder and the usefulness of mutational analysis in these families. In symptomatic individuals, the hypertonic saline test may be a useful second-line investigation for functional studies of AVP secretion where molecular diagnostics are unavailable.

Arginine Vasopressin↗

PubMed1999

Mechanism of endoplasmic reticulum retention of mutant vasopressin precursor caused by a signal peptide truncation associated with diabetes insipidus.

Autosomal dominant neurohypophyseal diabetes insipidus is caused by mutations in the gene encoding the vasopressin precursor protein, prepro-vasopressin-neurophysin II. We analyzed the molecular consequences of a mutation (DeltaG227) recently identified in a Swiss kindred that destroys the translation initiation codon. In COS-7 cells transfected with the mutant cDNA, translation was found to initiate at an alternative ATG, producing a truncated signal sequence that was functional for targeting and translocation but was not cleaved by signal peptidase. The mutant precursor was completely retained within the endoplasmic reticulum. The uncleaved signal did not affect folding of the neurophysin portion of the precursor, as determined by its protease resistance. However, formation of disulfide-linked aggregates indicated that it interfered with the formation of the disulfide bond in vasopressin, most likely by blocking its insertion into the hormone binding site of neurophysin. Preventing disulfide formation in the vasopressin nonapeptide by mutation of cysteine 6 to serine was shown to be sufficient to cause aggregation and retention. These results indicate that the DeltaG227 mutation induces translation of a truncated signal sequence that cannot be cleaved but prevents correct folding and oxidation of vasopressin, thereby causing precursor aggregation and retention in the endoplasmic reticulum.

Amino Acid Sequence↗

PubMed2006

Deletion of the V2 vasopressin receptor gene in two Chinese patients with nephrogenic diabetes insipidus.

BACKGROUND: Congenital nephrogenic diabetes insipidus (NDI) is a rare X-linked inherited disorder characterized by the excretion of large volumes of diluted urine and caused by mutations in arginine vasopressin receptor 2 (AVPR2) gene. To investigate the mutation of AVPR2 gene in a Chinese family with congenital NDI, we screened AVPR2 gene in two NDI patients and eight family members by PCR amplification and direct sequencing. RESULTS: Five specific fragments, covering entire coding sequence and their flanking intronic sequences of AVPR2 gene, were not observed in both patients, while those fragments were all detected in the control subjects. Several different fragments around the AVPR2 locus were amplified step by step. It was revealed that a genomic fragment of 5,995-bp, which contained the entire AVPR2 gene and the last exon (exon 22) of the C1 gene, was deleted and a 3-bp (GAG) was inserted. Examination of the other family members showed that the mothers and the grandmother were carriers for this deletion. CONCLUSION: Our findings suggest that the two patients in a Chinese family suffering from congenital NDI had a 5,995-bp deletion and 3-bp (GAG) insertion at Xq28. The deletion contained the entire AVPR2 gene and exon 22 of the C1 gene.

Adult↗

PubMed2004

A novel mutation in the preprovasopressin gene identified in a kindred with autosomal dominant neurohypophyseal diabetes insipidus.

Autosomal dominant neurohypophyseal diabetes insipidus (ADNDI) is a defect in free water conservation caused by mutations in the single gene that encodes both vasopressin (VP) and its binding protein, neurophysin II (NP II). Most of the human mutations in this gene have been in the portion encoding the NP molecule; the resultant abnormal gene products are believed to cause cellular toxicity as improperly folded precursor molecules accumulate in the endoplasmic reticulum. We identified a new American kindred with ADNDI and found a novel mutation in the VP molecule. A 78-yr-old man was noted to have hypotonic polyuria and plasma hyperosmolarity; the urinary concentration defect was reversed by administration of VP. His symptomatology dated to childhood, and his family history was consistent with autosomal transmission of the polyuric syndrome, with affected members in three generations, including several females. Affected individuals were found to be heterozygous for a 3-bp deletion in exon 1 of arginine VP (AVP)-NP II, predicting a deletion of phenylalanine 3 (known to be critical for receptor binding) in the VP nonapeptide. Neuro 2A cells stably transfected with the mutant AVP-NP construct showed increased rates of apoptosis as assessed by flow cytometric methods. These observations support the concept that cellular toxicity of abnormal AVP-NP gene products underlies the development of ADNDI, and the data further demonstrate that mutations affecting the AVP moiety can result in initiation of these pathological processes.

Aged↗

PubMedDate not supplied

A missense mutation encoding Cys73Phe in neurophysin II is associated with autosomal dominant neurohypophyseal diabetes insipidus.

Autosomal dominant neurohypophyseal diabetes insipidus (ADNDI) is an inherited disease caused by progressive deficiency of the hormone arginine vasopressin (AVP) that typically becomes clinically apparent in the first decade of life. The genetic locus of ADNDI is the arginine vasopressin-neurophysin II (AVP-NPII) gene and mutations that cause ADNDI have been found in the nucleotides encoding the signal peptide, vasopressin, and neurophysin II peptides. In this study we have analyzed the AVP-NPII gene in a 20-year-old female who was diagnosed with ADNDI at 2 years of age. A heterozygous missense mutation (1684G>T) was found in exon 2 that predicts replacement of cysteine with phenylalanine at position 73 of neurophysin II. The mutation was confirmed by subcloning exon 2 PCR products to sequence each allele independently. Two out of four clones were found to have the missense mutation and two have the normal sequence, confirming the presence of the mutation and heterozygosity. Neurophysin II is an intracellular carrier protein for AVP during axonal transport from the hypothalamus to the posterior pituitary and contains 14 cysteine residues forming 7 disulfide bonds. This mutation is predicted to disrupt the disulfide bridge between Cys73 and Cys61 within the neurophysin II moiety. This finding of a novel mutation substituting cysteine with phenylalanine in one AVP-NPII gene allele supports the hypothesis that inability to form normal disulfide bonds in neurophysin II leads to ADNDI.

Adult↗

PubMed1994

Familial congenital hypopituitarism with central diabetes insipidus.

Congenital hypopituitarism (CH) presenting with central diabetes insipidus is typically associated with midline facial deformities or ophthalmological abnormalities. We present three brothers with CH and central diabetes insipidus not associated with any of these predisposing conditions. All three subjects presented with clinical features typical for CH (neonatal hypoglycemia, short stature, protruding forehead, and microgenitalia). All had hypoplastic genitalia indicating in utero gonadotropin deficiency, and all had complete GH deficiency. One represented low levels of thyroid hormones and TSH, indicating central hypothyroidism. Water deprivation examination in two of the brothers demonstrated complete arginine vasopressin deficiency in one and partial deficiency in the other. Magnetic resonance imaging indicated absence of the pituitary stalk, severe hypoplastic anterior pituitary in all three brothers, and absence of any posterior pituitary gland in two of the three. The other sibling had an ectopic posterior pituitary. This first report of familial CH with central diabetes insipidus may represent a previously unknown midline anomaly and provide new insights into the genetic control of pituitary and hypothalamic development.

Antibodies↗

PubMed2002

V2R structure and diabetes insipidus.

For most audiences, the term "diabetes" conjures thoughts of high levels of blood glucose and of the symptoms that characterize diabetes mellitus. In the last few years, a spirited campaign spear-headed by the families of affected individuals has made progress in educating nonprofessional and medical communities about diabetes insipidus (DI), the other disease characterized by polyuria (i.e., diabetes). Much work lies ahead to find better treatments for this affliction, but the progress in molecular biology over the last years made possible the identification of the genetic defects underlying the inherited forms of the disease. Numerous cases of adult-onset DI are triggered by toxic damage to the kidneys that impairs the concentrating capacity of the nephrons by a nonspecific mechanism. In these pages I shall deal mostly with the inherited forms of the disease. Diabetes insipidus is characterized by the inability of the kidneys of affected individuals to produce concentrated urine (Morello and Bichet 2001). The elimination of large volumes of diluted urine (polyuria) and excessive thirst (polydipsia) are the chief symptoms of the disease. Although this condition and the hints that it was a hereditary disease were described at the end of the 19th century, it took almost 100 years to gain molecular knowledge about its etiology. A brief review of the important role played by vasopressin in the maintenance of body fluids will help the reader understand the severity of this disease.

Diabetes Insipidus↗

PubMed1994

Detection of vasopressin cell antibodies in some patients with autoimmune endocrine diseases without overt diabetes insipidus.

OBJECTIVE: Cytoplasmic autoantibodies to vasopressin cells (AVP) have been detected in patients with idiopathic central diabetes insipidus and only in one patient with endocrine autoimmune diseases without clinical diabetes insipidus. The aim of this study was to look for AVP cell antibodies (AVP-cell-Ab) in human sera of a large population of autoimmune endocrine disease patients without diabetes insipidus and to test whether an occurrence of these antibodies in some patients can be associated with partial impairment of posterior pituitary function. MEASUREMENT: Sera from 410 patients (310 females, 100 males, age range 10-46 years) with autoimmune endocrine disorders (260 with thyroid autoimmune disease, and 150 with insulin dependent diabetes mellitus) without clinical diabetes insipidus, and from 100 normal subjects, were investigated for hypothalamic autoantibodies by an indirect immunofluorescence method. Positive sera were subsequently tested with specific rabbit anti AVP serum. RESULTS: None of controls, but five out of 410 patients (1.2%) were AVP-cell-Ab positive. All positive and nine negative from the 410 screened patients were tested for posterior pituitary function. Two out of five AVP-cell-Ab positive patients showed partial diabetes insipidus. CONCLUSION: AVP cell antibodies can be shown in some patients with endocrine autoimmune disease without diabetes insipidus and can sometimes be associated with findings of partial posterior pituitary dysfunction. This suggests that clinical diabetes insipidus could be preceded by a long subclinical period characterized only by the occurrence of AVP-cell-Ab in the sera associated or followed by alterations in functional tests. Longitudinal studies are needed to confirm this hypothesis.

Adolescent↗

PubMedDate not supplied

Dental fluorosis as a complication of hereditary diabetes insipidus: studies of six affected patients.

Hereditary diabetes insipidus is a rare endocrine disorder caused by a deficiency of the antidiuretic hormone, vasopressin. The disease is characterized by polyuria, extreme thirst, and polydipsia. In this study of six affected members from two families with hereditary diabetes insipidus, it was found that two children who drank water fluoridated at optimum levels developed moderate to severe fluorosis. By contrast, four other affected patients who did not consume fluoridated water showed normal dentitions. This report indicates that dental fluorosis may be an important complication of diabetes insipidus, and demonstrates the possibility that excessive consumption of optimally fluoridated water can lead to severe developmental enamel defects.

Adolescent↗

PubMed1994

The renin-aldosterone axis in patients with diabetes insipidus.

OBJECTIVE: The objective of the present study was to investigate the renin-aldosterone axis in neurogenic diabetes insipidus in man, in view of the fact that profound abnormalities of this axis have been described in experimental animals with congenital neurogenic diabetes insipidus. DESIGN AND PATIENTS: Nine patients with neurogenic diabetes insipidus and 11 healthy subjects (controls) were examined under basal conditions, following the standard 8-hour water deprivation test and 1 hour after a subsequent oral rehydration. MEASUREMENTS: Plasma and urine osmolalities were determined by freezing point depression, plasma sodium and potassium by a method using an ion-selective electrode, plasma AVP, cortisol, aldosterone and plasma renin activity by radioimmunoassay. RESULTS: Plasma renin activities under basal conditions were significantly higher in patients with diabetes insipidus than in controls (mean +/- SEM 23.4 +/- 6.6 vs 7.8 +/- 1.2 ng/l min). In the diabetes insipidus group, water deprivation caused a twofold increase in plasma renin activities (48 +/- 13.8 ng/l min) while in the control group plasma renin activity levels were not significantly altered (10.2 +/- 1.2 ng/l min). Rehydration did not alter plasma renin activity levels in either group (patients 50.4 +/- 13.2, controls 9.0 +/- 2.4 ng/l min). Plasma aldosterone concentrations under basal conditions did not differ between the two groups (patients 302.4 +/- 37, controls 326.4 +/- 36.5 pmol/l) and did not change in patients with diabetes insipidus after water deprivation or rehydration (307.5 +/- 67.2 and 385.5 +/- 91 pmol/l, respectively). Conversely, controls showed a significant decrease in plasma aldosterone levels after dehydration (201 +/- 27.9 pmol/l), which was attributed to the circardian variation in aldosterone secretion, as shown by a parallel decrease in plasma cortisol levels. CONCLUSIONS: Patients with diabetes insipidus are hyper-reninaemic, probably because of chronic volume contraction. There is a dissociation between renin and aldosterone in patients with diabetes insipidus under basal conditions, which is exaggerated during water deprivation.

Adult↗

PubMed1997

Diabetes insipidus in pregnancy: a treatable cause of oligohydramnios.

BACKGROUND: Diabetes insipidus, which presents with polyuria, polydipsia, and profound electrolyte abnormalities, occurs rarely in pregnancy. We report a patient with severe oligohydramnios that resolved after treatment of diabetes insipidus. CASE: A 14-year-old girl was admitted at 33 weeks' gestation with cramping and vaginal spotting. A sonogram indicated oligohydramnios and an amniotic fluid index (AFI) of 2.6, with normal fetal kidneys and bladder. On hospital day 2, the AFI was 0.0. Recorded fluid was 8 L in and 13.6 L out. Serum sodium was 153 mEq/L. Diabetes insipidus was diagnosed and treated with intranasal desmopressin acetate. The oligohydramnios resolved rapidly, and the patient delivered a healthy 2700-g male infant at 38 weeks. CONCLUSION: Although rare, diabetes insipidus may present initially in pregnancy and should be considered in patients with oligohydramnios. Simple diagnosis with determination of 24-hour urine volume and serum electrolytes can identify this potentially reversible cause of oligohydramnios and poor obstetric outcome.

Adolescent↗

PubMed2002

[Specificity of gene di (diabetes insipidus) expression in homologous inbred rat strains].

The diabetes insipidus mutation is displayed in homozygotes in the form of diabetes insipidus with water consumption from 30 to 100% of body weight per day. We developed two inbred sublines of the di/di Brattleboro rats as well as the recombinant inbred subline by integrating genes of August rats into the di/di mutant genome. Changes in the genetic background proved to have no effect on the quantitative parameters of the diabetes insipidus. The intensity of the secondary immune response and the content of tropomyosin in the medulla of the rat kidney can serve as additional marker traits of the di/di genotype.

Animals↗

PubMed1982

Evaluation of the renin-angiotensin system in diabetes insipidus and psychogenic polydipsia.

The role of the renin-angiotensin system in polyuric patients was studied in 5 patients with pituitary diabetes insipidus, 1 patient with nephrogenic diabetes insipidus and 3 patients with psychogenic polydipsia by determining the plasma renin activity and infusing an angiotensin II analog, 1-Sar, 8-Ile angiotensin II. In all patients with diabetes insipidus, plasma renin activity was markedly increased and the blood pressure was reduced in 5 of 6 patients by the administration of the angiotensin II analog. In the other patient, the blood pressure remained unchanged. The plasma renin activity and response of blood pressure to the angiotensin II analog in a patient with nephrogenic diabetes insipidus were not significantly different from there of patients with pituitary diabetes insipidus. On the other hand, in all patients with psychogenic polydipsia, plasma renin activity was normal or low, and the blood pressure increased with the administration of the angiotensin II analog. These results suggest that evaluation of the renin-angiotensin system by determining plasma renin activity and infusing an angiotensin II analog is useful in differentiating between diabetes insipidus and psychogenic polydipsia.

1-Sarcosine-8-Isoleucine Angiotensin II↗

PubMed1991

[Diabetes mellitus, diabetes insipidus, optic atrophy and deafness].

In France, the combination of diabetes insipidus, diabetes mellitus, optic atrophy, and deafness (DIDMOAD) is designated as Wolfram syndrome. An analysis of 14 personal cases and previous reports showed that the syndrome develops gradually and specified the most common order of occurrence of the various components as well as the other abnormalities (e.g., of the urinary tract) which may be found. Wolfram syndrome is an inherited condition (recessive autosomal transmission). The lack of association with HLA antigens seems to have been established (in the few cases where HLA typing was performed). The prognosis of Wolfram syndrome is grim, with the occurrence of each additional component adding to the severity of the disease.

Adolescent↗

PubMed1998

Two novel mutations of the vasopressin gene associated with familial diabetes insipidus and identification of an asymptomatic carrier infant.

Familial diabetes insipidus (FDI) is a syndrome of central vasopressin deficiency that is inherited in an autosomal dominant manner and that typically becomes clinically apparent in the first decade of life. Two novel mutations of the vasopressin gene have been identified in two previously unstudied kindreds with FDI. In each kindred, the inheritance of the FDI phenotype was consistent with an autosomal dominant mode of inheritance. In each proband, the diagnosis of central diabetes insipidus had been confirmed previously with a water deprivation protocol. After extraction of genomic DNA from each individual, the three exons of the vasopressin gene were separately amplified by PCR and directly sequenced using an automated dye termination method. In the proband and two other carriers of one kindred, a heterozygous C to T mutation was identified at nucleotide 1857. This is predicted to produce a serine to phenylalanine substitution at residue 56 of the vasopressin-related neurophysin peptide encoded by the mutated allele. The mutation also abolished an MspI site in the vasopressin sequence, and analysis of genomic DNA from eight members of the kindred (five with FDI) confirmed segregation of the mutation with the FDI phenotype. Another member of the kindred, a 13-month-old infant, also has the heterozygous C to T mutation, but a formal water balance study showed no evidence of diabetes insipidus. In the proband of the other kindred, a heterozygous G to A mutation was identified at nucleotide 1873. This mutation would be predicted to cause a cysteine to tyrosine substitution at residue 61 of the neurophysin encoded by the mutated allele. This heterozygous mutation was confirmed by the presence of an RsaI restriction site in one vasopressin allele in two members of the kindred. Therefore, two novel heterozygous mutations of the vasopressin gene have been identified in FDI kindreds. In one kindred, an asymptomatic carrier infant was identified and will require continued observation to determine whether she will develop clinical diabetes insipidus. The presence of these two novel mutations in a region of the vasopressin gene where other FDI mutations have been reported suggests that the part of the neurophysin peptide encoded by these sequences may be critically important in the appropriate expression of vasopressin.

Diabetes Insipidus↗

PubMed1976

Diabetes insipidus caused by craniofacial trauma.

A patient is presented with diabetes insipidus secondary to craniofacial trauma. Diabetes insipidus can occur in any patient within ten days of craniofacial trauma. Even the masked disease in the unconscious patient can be diagnosed by observation of intake and output, urinary specific gravities, and appropriate chemical studies. The disease can recur following operative reduction of facial fractures. Diabetes insipidus can be successfully treated by intramuscular Pitressin and appropriate fluid intake.

Accidents, Traffic↗

PubMed1979

Clomiphene-induced pregnancy in a patient with diabetes insipidus and hypothyroidism.

A patient with diabetes insipidus and hypothyroidism developed anovular menstrual cycles. Ovulation, which was followed by pregnancy, was induced by the administration of clomiphene. In the later stages of pregnancy, an increase in the dosage of vasopressin was necessary to achieve a satisfactory control of the symptoms of diabetes insipidus. Labour was induced before the estimated date of confinement by the intravenous administration of oxytocin and an intra-partum haemorrhage necessitated delivery by the lower-segment caesarean section. The post-partum period was uneventful. Lactation was suppressed on request from the patient.

Adult↗

PubMed1998

[Diabetes insipidus revealing primary malignant non-Hodgkin's lymphoma of bone].

INTRODUCTION: Diabetes insipidus is a very rare, occasionally misleading, revealing symptom of non Hodgkin's malignant lymphoma. We report a case of this uncommon association and a review of the literature is done. EXEGESIS: Soon after a transient attack of diplopia due to a 6th cranial nerve palsy, idiopathic cerebral diabetes insipidus was diagnosed in a 32-year-old immunocompetent man. As anterior hypopituitarism was absent, the patient was discharged and treated with desmopressin acetate. Six months later, recurrence of diploplia together with raised erythrocyte sedimentation rate was observed and B cell lymphoma was observed in the iliac bone and skull, with extension into the right cavernous sinus. Both tumoral lesions led to important uptake of gallium-67. After a 26-month follow-up following intensive chemotherapy including autologous peripheral stem cell transplantation and local radiotherapy, lymphoma symptoms had disappeared, but the patient's condition had only partially improved with regard to diabetes insipidus. The association of lymphoma and diabetes insipidus which has only been reported in 14 cases is discussed. CONCLUSION: Since endocrine symptoms are often preceding hematological diagnosis, malignant lymphomas should systematically be viewed as potential etiology of diabetes insipidus. Magnetic resonance imaging which is more sensitive than computerized tomography in revealing brain lymphomas is mandatory. Gallium scan imaging might help guide the diagnosis in some instances.

Abducens Nerve↗