ABSTRACT
Disruption of water and electrolyte balance is frequently encountered in clinical medicine. Regulating water metabolism is critically important. Diabetes insipidus (DI) presented with excessive water loss from the kidney is a major disorder of water metabolism. To understanding the molecular and cellular mechanisms and pathophysiology of DI and rationales of clinical management of DI is important for both research and clinical practice. This chapter will first review various forms of DI focusing on central diabetes insipidus (CDI) and nephrogenic diabetes insipidus (NDI). This is followed by a discussion of regulatory mechanisms underlying CDI and NDI, with a focus on the regulatory axis of vasopressin, vasopressin receptor 2 (V2R) and the water channel molecule, aquaporin 2 (AQP2). The clinical manifestation, diagnosis, and management of various forms of DI will also be discussed with highlights of some of the latest therapeutic strategies that are developed from in vitro experiments and animal studies.
Subject(s)
Aquaporins , Diabetes Insipidus, Nephrogenic , Diabetes Insipidus , Diabetes Mellitus , Animals , Aquaporin 2/genetics , Aquaporin 2/metabolism , Diabetes Insipidus, Nephrogenic/genetics , Diabetes Insipidus, Nephrogenic/metabolism , Diabetes Insipidus/diagnosis , Diabetes Insipidus/genetics , Aquaporins/genetics , Aquaporins/metabolism , Kidney/metabolism , Water/metabolism , Mutation , Receptors, Vasopressin/genetics , Receptors, Vasopressin/metabolismABSTRACT
Diabetes insipidus (DI) is a disorder characterised by the excretion of large amounts of hypotonic urine, with a prevalence of 1 per 25,000 population. Central DI (CDI), better now referred to as arginine vasopressin (AVP)-deficiency, is the most common form of DI resulting from deficiency of the hormone AVP from the pituitary. The less common nephrogenic DI (NDI) or AVP-resistance develops secondary to AVP resistance in the kidneys. The majority of causes of DI are acquired, with CDI developing when more than 80% of AVP-secreting neurons are damaged. Inherited/familial CDI causes account for approximately 1% of cases. Although the pathogenesis of NDI is unclear, more than 280 disease-causing mutations affecting the AVP2 protein or AVP V2 receptor, as well as in aquaporin 2 (AQP2), have been described. Although the cAMP/protein kinase A pathway remains the major regulatory pathway of AVP/AQP2 action, in vitro data have also revealed additional cAMP independent pathways of NDI pathogenesis. Diagnosing partial forms of DI, and distinguishing them from primary polydipsia, can be challenging, previously necessitating the use of the water deprivation test. However, measurements of circulating copeptin levels, especially after stimulation, are increasingly replacing the classical tests in clinical practice because of their ease of use and high sensitivity and specificity. The treatment of CDI relies on desmopressin administration, whereas NDI requires the management of any underlying diseases, removal of offending drugs and, in some cases, administration of diuretics. A better understanding of the pathophysiology of DI has led to novel evolving therapeutic agents that are under clinical trial.
Subject(s)
Diabetes Insipidus, Nephrogenic , Diabetes Insipidus, Neurogenic , Diabetes Insipidus , Diabetes Mellitus , Humans , Aquaporin 2/genetics , Diabetes Insipidus/diagnosis , Diabetes Insipidus/drug therapy , Diabetes Insipidus/genetics , Diabetes Insipidus, Neurogenic/diagnosis , Diabetes Insipidus, Neurogenic/drug therapy , Diabetes Insipidus, Neurogenic/genetics , Diabetes Insipidus, Nephrogenic/diagnosis , Diabetes Insipidus, Nephrogenic/genetics , Diabetes Insipidus, Nephrogenic/therapy , Receptors, Vasopressin/geneticsABSTRACT
We studied the growth dynamics of Walker 256 carcinosarcoma in recombinant progeny of dihybrid crosses of Brattleboro and WAG rats. A mutation in the vasopressin gene determining hypothalamic diabetes insipidus was detected in Brattleboro rats. WAG rats are carriers of normal vasopressin gene. Another interlinear difference was linked to tyrosinase gene controlling melanin synthesis. WAG rats express mutant allele determining albino phenotype. Brattleboro rats had normal working tyrosinase gene. F2 segregation yielded phenotypic classes with two patterns of tumor growth: linear growth or regression. Tumors regression was not linked to tyrosinase activity and was observed only in rats with diabetes insipidus. Analysis of mutants in next generations F3 and F4 confirmed this regularity in the Walker 256 carcinosarcoma growth pattern.
Subject(s)
Carcinoma 256, Walker , Carcinosarcoma , Diabetes Insipidus , Diabetes Mellitus , Animals , Carcinoma 256, Walker/genetics , Diabetes Insipidus/genetics , Melanins , Monophenol Monooxygenase , Rats , Rats, Brattleboro , VasopressinsABSTRACT
CONTEXT: Familial pituitary diabetes insipidus has been described only in an autosomal dominant or recessive mode of inheritance. OBJECTIVE: This work aims to determine the cause of a novel form of familial diabetes insipidus (DI) that is controlled by desmopressin therapy but segregates in an X-linked recessive manner. METHODS: Thirteen members from 3 generations of the kindred with familial DI were studied. Water intake, urine volume, urine osmolality, plasma osmolality, and plasma vasopressin were measured under basal conditions, during fluid deprivation, 3% saline infusion, and water loading. Magnetic resonance images of the posterior pituitary also were obtained. In affected males, the effects of desmopressin therapy and linkage of the DI to markers for chromosome Xq28 were determined. In addition, the genes encoding vasopressin, aquaporin-2, the AVPR2 receptor, and its flanking regions were sequenced. RESULTS: This study showed that 4 males from 3 generations of the kindred have DI that is due to a deficiency of vasopressin, is corrected by standard doses of desmopressin, and segregates with markers for the AVPR2 gene in Xq28. However, no mutations were found in AVPR2 or its highly conserved flanking regions. Exome sequencing confirmed these findings and also revealed no deleterious variants in the provasopressin and aquaporin-2 genes. The 4 obligate female carriers osmo-regulated vasopressin in the low normal range. CONCLUSION: X-linked recessive transmission of DI can be due to a defect in either the secretion or the action of vasopressin. Other criteria are necessary to differentiate and manage the 2 disorders correctly.
Subject(s)
Diabetes Insipidus, Nephrogenic , Diabetes Insipidus , Diabetes Mellitus , Aquaporin 2/genetics , Deamino Arginine Vasopressin/therapeutic use , Diabetes Insipidus/genetics , Diabetes Insipidus, Nephrogenic/genetics , Female , Humans , Male , Receptors, Vasopressin/genetics , Vasopressins/geneticsABSTRACT
BACKGROUND: Autoimmune polyendocrine syndrome type 1 (APS-1) is a rare monogenic inherited disease caused by mutations of the autoimmune regulator gene (AIRE). The three major components of this syndrome are chronic mucocutaneous candidiasis, hypoparathyroidism and adrenocortical insufficiency. CASE PRESENTATION: We report a 20-year-old male who was clinically diagnosed with APS-1 at the age of 15. He was admitted to our department this time for suffering from polyuria and polydipsia for 6 months and was finally diagnosed with diabetes insipidus. Whole-exome sequencing (WES) revealed a novel compound heterozygous mutation of the AIRE gene -the c.239 T > G (p.Val80Gly) variant on one allele and the copy number variant (CNV) of 21q22.3(chr21:45,670,150-45,706,528)*1 on the other. CONCLUSIONS: This case suggests that diabetes insipidus is a rare component of APS-1 and expands the variety of mutations on AIRE gene.
Subject(s)
Diabetes Insipidus/pathology , Genetic Predisposition to Disease , Mutation , Polyendocrinopathies, Autoimmune/pathology , Transcription Factors/genetics , Adult , Diabetes Insipidus/complications , Diabetes Insipidus/genetics , Humans , Male , Phenotype , Polyendocrinopathies, Autoimmune/complications , Polyendocrinopathies, Autoimmune/genetics , Prognosis , Young Adult , AIRE ProteinABSTRACT
Diabetes insipidus (DI) is a syndrome characterized by the persistent excretion of abnormally large volumes of dilute urine. It can be caused by any of four fundamentally different abnormalities: deficient production of the antidiuretic hormone, arginine vasopressin (AVP) by magnocellular neurons that form the posterior pituitary (hypothalamic DI); impaired renal effects of AVP (nephrogenic DI); reduced AVP secretion due to excessive water intake (primary polydipsia); or degradation of AVP by placental vasopressinase (gestational DI). Each type of DI can be caused or potentiated by other disorders. Hypothalamic and nephrogenic DI can also be caused by mutation of the gene that encodes the AVP prohormone, the AVP-2 receptors in the kidney, or the aquaporin-2 water channels that mediate antidiuresis. Familial hypothalamic DI is usually transmitted in an autosomal dominant mode, but autosomal recessive or X-linked recessive forms also exist. Familial nephrogenic DI is usually transmitted in an X-linked recessive mode but can also be autosomal recessive or dominant. Hence the mode of inheritance does not always indicate the type of DI. Indirect methods of differential diagnosis are also unreliable and the pituitary MRI signal is diminished in both types of familial DI. Thus the determination of plasma AVP and/or the response to desmopressin therapy plus gene sequencing provides the best basis for effective management and family counseling.
Subject(s)
Diabetes Insipidus, Nephrogenic , Diabetes Insipidus , Diabetes Mellitus , Diabetes Insipidus/diagnosis , Diabetes Insipidus/genetics , Diabetes Insipidus, Nephrogenic/diagnosis , Diagnosis, Differential , Female , Humans , Placenta , Pregnancy , Receptors, Vasopressin/geneticsABSTRACT
The hormone arginine vasopressin (AVP) is a nonapeptide synthesized by hypothalamic magnocellular nuclei and secreted from the posterior pituitary into the bloodstream. It binds to AVP receptor 2 in the kidney to promote the insertion of aquaporin channels (AQP2) and antidiuretic responses. AVP secretion deficits produce central diabetes insipidus (CDI), while renal insensitivity to the antidiuretic effect of AVP causes nephrogenic diabetes insipidus (NDI). Hereditary and acquired forms of CDI and NDI generate hypotonic polyuria, polydipsia, hyperosmolality, and hypernatremia. The AVP mutant (Brattleboro) rat is the principal animal model of hereditary CDI, while neurohypophysectomy, pituitary stalk compression, hypophysectomy, and mediobasal hypothalamic lesions produce acquired CDI. In animals, hereditary NDI is mainly caused by mutations in AVP2R or AQP2 genes, while acquired NDI is most frequently induced by lithium. We report here on the determinants of the intake and excretion of water and mineral salts and on the different types of DI in humans. We then describe the hydromineral characteristics of these animal models and the responses observed after administration of hypertonic NaCl or when they are fed with low-sodium diets. Finally, we report on the effects of drugs such as AVP analogues and/or oxytocin, another neuropeptide that increases sodium excretion in animal models and humans with CDI, and sildenafil, a compound that increases the expression and function of AQP2 channels in animal models and humans with NDI.
Subject(s)
Diabetes Insipidus, Nephrogenic , Diabetes Insipidus , Diabetes Mellitus , Animals , Aquaporin 2/genetics , Diabetes Insipidus/genetics , Diabetes Insipidus, Nephrogenic/genetics , Humans , Models, Animal , Rats , Rats, BrattleboroABSTRACT
Acute myeloid leukemia (AML) is unusually associated with diabetes insipidus (DI) in patients bearing monosomy 7 or chromosome 3 aberrations. To date, 84 cases have been reported worldwide. Physiopathological mechanisms linking these chromosomal abnormalities to DI are not yet understood. We report two patients with AML/DI and review the medical literature on those conditions.
Subject(s)
Diabetes Insipidus , Diabetes Mellitus , Leukemia, Myeloid, Acute , Chromosome Deletion , Chromosomes, Human, Pair 7 , Diabetes Insipidus/genetics , Humans , Leukemia, Myeloid, Acute/geneticsABSTRACT
No disponible
Subject(s)
Humans , Female , Child , Diabetes Insipidus/diagnosis , Diabetes Insipidus/genetics , Mutation/genetics , Diuresis , Polydipsia/complications , Polyuria/complications , Overweight/complications , Diabetes Insipidus/drug therapyABSTRACT
In the majority of cases, hereditary neurohypophyseal diabetes insipidus (DI) is a monogenic disorder caused by mutations in the AVP gene. Dominant transmission is by far the most common form. In these patients, symptoms develop gradually at various ages during childhood, progressing with complete penetrance to polyuria and polydipsia that is usually severe. In autosomal dominant neurohypophyseal DI (ADNDI), the mutant prohormone is folding deficient and consequently retained in the ER, where it forms amyloid-like fibrillar aggregates. Degradation by proteasomes occurs, but their clearance capacity appears to be insufficient. Postmortem studies in affected individuals suggest a neurodegenerative process confined to vasopressinergic neurons. Other forms of genetic neurohypophyseal DI include the very rare autosomal recessive type, also caused by mutations in the AVP gene, and complex multiorgan disorders, such as Wolfram syndrome. In all individuals where a congenital form of DI is suspected, including nephrogenic types, genetic analysis should be performed.
Subject(s)
Diabetes Insipidus, Neurogenic/classification , Diabetes Insipidus, Neurogenic/diagnosis , Diabetes Insipidus, Neurogenic/genetics , Neurophysins/genetics , Protein Precursors/genetics , Vasopressins/genetics , Child , Diabetes Insipidus/classification , Diabetes Insipidus/diagnosis , Diabetes Insipidus/genetics , Diagnosis, Differential , Genetic Predisposition to Disease , Humans , MutationABSTRACT
PURPOSE: To evaluate the ophthalmic, systemic, and genetic characteristics of patients with Wolfram syndrome. METHODS: In total, 13 patients with suspected or clinically diagnosed Wolfram syndrome underwent ophthalmic and systemic examinations and genetic analyses for Wolfram syndrome between August and October 2018. RESULTS: The mean age of the subjects was 24.2 ± 7.1 years, of which 5 (38.5%) subjects were male and 8 (61.5%) were female. The mean best-corrected visual acuity ranged from counting fingers to 20/40, with a mean of 20/250 (1.10 ± 0.69 logarithm of the minimum angle of resolution). Dyschromatopsia was present in all patients (100%). There was a severe decrease in the average peripapillary retinal nerve fiber layer and macular ganglion cell-inner plexiform layer thicknesses (54.7 ± 6.5 and 51.9 ± 4.8 µm, respectively). Optical coherence tomography angiography showed significantly lower whole-image, inside disk, and peripapillary vessel densities in the patients with Wolfram syndrome than in the healthy controls (p < 0.001 for all). All patients who underwent genetic analyses had mutations in the WFS1 gene. Moreover, two novel mutations, p.Met623Trpfs*2 (c.1867delA) and p.Arg611Profs*9 (c.1832_11847del16) at exon 8, were detected. The frequency of systemic findings was as follows: optic atrophy (100%), diabetes mellitus (92.3%), central diabetes insipidus (38.5%), sensorineural hearing loss (38.5%), and presence of urological (30.8%), psychiatric (30.8%), and neurological (23.1%) diseases. CONCLUSION: Wolfram syndrome is a rare genetic disorder that can be associated with severe ophthalmic and systemic abnormalities. All patients who present with unexplained optic atrophy should be evaluated for Wolfram syndrome, even if they do not have diabetes mellitus because optic atrophy can sometimes manifest before diabetes mellitus.
Subject(s)
Diabetes Insipidus/diagnosis , Diabetes Mellitus/diagnosis , Hearing Loss, Sensorineural/diagnosis , Membrane Proteins/genetics , Vision Disorders/physiopathology , Wolfram Syndrome/diagnosis , Wolfram Syndrome/genetics , Adolescent , Adult , Child , Diabetes Insipidus/genetics , Diabetes Mellitus/genetics , Exons/genetics , Female , Fluorescein Angiography , Hearing Loss, Sensorineural/genetics , Humans , Male , Mutation , Nerve Fibers/pathology , Optic Atrophies, Hereditary , Retinal Ganglion Cells/pathology , Tomography, Optical Coherence , Visual Acuity/physiology , Visual Fields/physiology , Young AdultABSTRACT
Char syndrome is characterized by persistent patent ductus arteriosus (PDA) associated with hand-skeletal abnormalities and distinctive facial dysmorphism. Pathogenic variants in the transcription factor gene TFAP2B have been shown to cause Char syndrome; however, there is significant phenotypic variability linked to variant location. Here, we report a pediatric patient with a novel de novo variant in the fifth exon of TFAP2B, c.917C > T (p.Thr306Met), who presented with PDA, patent foramen ovale, postaxial polydactyly of the left fifth toe and clinodactyly of the left fourth toe, sensorineural hearing loss, scoliosis, dental anomalies, and central diabetes insipidus (CDI). CDI, scoliosis, and hearing loss have not previously been reported in a patient with Char syndrome, and while the association may be coincidental, this report expands the genotypes and potentially phenotypes associated with this syndrome.
Subject(s)
Abnormalities, Multiple/genetics , Diabetes Insipidus/genetics , Ductus Arteriosus, Patent/genetics , Face/abnormalities , Fingers/abnormalities , Mutation, Missense , Transcription Factor AP-2/genetics , Adolescent , Chromosome Aberrations , Chromosomes, Human, Pair 1 , Chromosomes, Human, Pair 10 , Female , Genotype , Humans , PhenotypeABSTRACT
CONTEXT: The transcription factor RAX is a paired-type homeoprotein that plays a critical role in eye and forebrain development of vertebrate species. RAX knockout mice have anophthalmia, cleft palate, and an abnormal hypothalamus and display perinatal lethality. In humans, homozygous or compound heterozygous RAX mutations have been reported to cause bilateral microphthalmia or anophthalmia without consistent associated features. Congenital hypopituitarism can be associated with various eye or craniofacial anomalies; however, the co-occurrence of congenital hypopituitarism, anophthalmia, cleft palate, and diabetes insipidus has been very rare. RESULTS: We report the case of a child with anophthalmia, congenital hypopituitarism, diabetes insipidus, and bilateral cleft lip and palate who had a homozygous frameshift truncating mutation c.266delC (p.Pro89Argfs*114) in exon 1 of the RAX gene. Rax knockout mice show loss of ventral forebrain structures, pituitary, and basosphenoid bone and palate and a misplaced anterior pituitary gland along the roof of the oral cavity. CONCLUSIONS: Our patient's phenotype was more severe than that reported in other patients. Although most of the previously reported patients with RAX mutations showed either a missense or some less severe mutation in at least one of their RAX alleles, our patient was homozygous for truncating mutations that would yield a severe, null protein phenotype. The severity of the genetic defect, the precise match between the knockout mouse and the patient's endocrine phenotypes, and the prominent roles of RAX in eye and pituitary development and diencephalic patterning suggest that the RAX null mutations could fully account for the observed phenotype.
Subject(s)
Anophthalmos/genetics , Cleft Lip/genetics , Cleft Palate/genetics , Diabetes Insipidus/genetics , Eye Proteins/genetics , Homeodomain Proteins/genetics , Hypopituitarism/genetics , Transcription Factors/genetics , Animals , Anophthalmos/diagnostic imaging , Anophthalmos/pathology , Antidiuretic Agents/therapeutic use , Cleft Lip/diagnostic imaging , Cleft Lip/pathology , Cleft Palate/diagnostic imaging , Cleft Palate/pathology , Deamino Arginine Vasopressin/therapeutic use , Diabetes Insipidus/diagnostic imaging , Diabetes Insipidus/drug therapy , Diabetes Insipidus/pathology , Frameshift Mutation , Hormone Replacement Therapy , Human Growth Hormone/therapeutic use , Humans , Hydrocortisone/therapeutic use , Hypopituitarism/diagnostic imaging , Hypopituitarism/drug therapy , Hypopituitarism/pathology , Infant, Newborn , Magnetic Resonance Imaging , Male , Melatonin , Mice, Knockout , Pituitary Gland/abnormalities , Thyroxine/therapeutic useABSTRACT
Holoprosencephaly is a rare congenital malformation resulting from an impaired midline division of the prosencephalon into distinct cerebral hemispheres. Hydrocephalus is a frequent problem among the few survivors with alobar holoprosencephaly (aHPE), its most severe form. The literature about neurosurgical management of hydrocephalus in this condition is limited and dispersed, and there are still some points that need to be resolved. We report the case of a newborn with aHPE, hydrocephalus, and central diabetes insipidus. We delineate the complexity of the management of these patients and emphasize the benefits of using an initial programmable shunt valve. Further discussion about management strategies includes reviewing previous reports and the benefits of shunting for hypothalamic osmoreceptor function.
Subject(s)
Holoprosencephaly/complications , Holoprosencephaly/diagnosis , Hydrocephalus/diagnosis , Hydrocephalus/surgery , Skull/surgery , Diabetes Insipidus/diagnosis , Diabetes Insipidus/genetics , Holoprosencephaly/genetics , Humans , Hydrocephalus/etiology , Infant, Newborn , Magnetic Resonance Imaging , Skull/abnormalities , Ventriculoperitoneal ShuntABSTRACT
Diabetes insipidus is a disease characterized by polyuria and polydipsia due to inadequate release of arginine vasopressin from the posterior pituitary gland (neurohypophyseal diabetes insipidus) or due to arginine vasopressin insensitivity by the renal distal tubule, leading to a deficiency in tubular water reabsorption (nephrogenic diabetes insipidus). This article reviews the genetics of diabetes insipidus in the context of its diagnosis, clinical presentation, and therapy.
Subject(s)
Arginine Vasopressin , Diabetes Insipidus/genetics , Pituitary Gland, Posterior/physiopathology , Diabetes Insipidus/diagnosis , Diabetes Insipidus/therapy , Diabetes Insipidus, Nephrogenic , HumansABSTRACT
Disruption of water and electrolyte balance is frequently encountered in clinical medicine. Regulating water metabolism is critically important. Diabetes insipidus (DI) presented with excessive water loss from the kidney is a major disorder of water metabolism. To understand the molecular and cellular mechanisms and pathophysiology of DI and rationales of clinical management of DI is important for both research and clinical practice. This chapter will first review various forms of DI focusing on central diabetes insipidus (CDI) and nephrogenic diabetes insipidus (NDI ) . This is followed by a discussion of regulatory mechanisms underlying CDI and NDI , with a focus on the regulatory axis of vasopressin, vasopressin receptor 2 (V2R ) and the water channel molecule, aquaporin 2 (AQP2 ). The clinical manifestation, diagnosis and management of various forms of DI will also be discussed with highlights of some of the latest therapeutic strategies that are developed from in vitro experiments and animal studies.
Subject(s)
Aquaporin 2/metabolism , Diabetes Insipidus/metabolism , Receptors, Vasopressin/metabolism , Vasopressins/metabolism , Water/metabolism , Animals , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Antidiuretic Agents/therapeutic use , Aquaporin 2/genetics , Deamino Arginine Vasopressin/therapeutic use , Diabetes Insipidus/drug therapy , Diabetes Insipidus/genetics , Diabetes Insipidus/pathology , Disease Models, Animal , Gene Expression Regulation , Humans , Kidney/drug effects , Kidney/metabolism , Kidney/pathology , Phosphodiesterase Inhibitors/therapeutic use , Protein Isoforms/genetics , Protein Isoforms/metabolism , Receptors, Vasopressin/genetics , Vasopressins/genetics , Vasopressins/therapeutic use , Water-Electrolyte BalanceABSTRACT
INTRODUCTION: Adipsic diabetes insipidus (ADI) is a very rare disorder, characterized by hypotonic polyuria due to arginine vasopressin (AVP) deficiency and failure to generate the sensation of thirst in response to hypernatraemia. As the sensation of thirst is the key homeostatic mechanism that prevents hypernatraemic dehydration in patients with untreated diabetes insipidus (DI), adipsia leads to failure to respond to aquaresis with appropriate fluid intake. This predisposes to the development of significant hypernatraemia, which is the typical biochemical manifestation of adipsic DI. METHODS: A literature search was performed to review the background, etiology, management and associated complications of this rare condition. RESULTS: ADI has been reported to occur in association with clipping of an anterior communicating artery aneurysm following subarachnoid haemorrhage, major hypothalamic surgery, traumatic brain injury and toluene exposure among other conditions. Management is very difficult and patients are prone to marked changes in plasma sodium concentration, in particular to the development of severe hypernatraemia. Associated hypothalamic disorders, such as severe obesity, sleep apnoea and thermoregulatory disorders are often observed in patients with ADI. CONCLUSION: The management of ADI is challenging and is associated with significant morbidity and mortality. Prognosis is variable; hypothalamic complications lead to early death in some patients, but recent reports highlight the possibility of recovery of thirst.
Subject(s)
Diabetes Insipidus/metabolism , Animals , Arginine Vasopressin/genetics , Arginine Vasopressin/metabolism , Complement Factor D/genetics , Complement Factor D/metabolism , Diabetes Insipidus/genetics , Humans , Hypernatremia/genetics , Hypernatremia/metabolism , Vasopressins/genetics , Vasopressins/metabolismABSTRACT
A 4-year-old boy was referred to the nephrologist with daytime urinary incontinence and suspicion of an overactive bladder. At the age of 17 months he had been referred to the pediatric endocrinologist because of polyuria and polydipsia in order to exclude diabetes insipidus. Repeated water deprivation tests and a magnetic resonance imaging scan of the brain were normal. Diabetes insipidus was excluded, and primary polydipsia was thought to be most likely since diabetes mellitus also had been excluded. At the current presentation, he drank up to 3 L a day and quite often had wet diapers. He also seemed to pass stools infrequently and with difficulty. Curiously his grandmother had similar symptoms of polyuria and polydipsia since childhood and had been diagnosed with primary polydipsia. The physical examination of our pediatric patient was normal. In the differential diagnosis we included diabetes insipidus but also contemplated other possibilities, such as nephronophthisis, tubulopathies and hypercalciuria. Laboratory results including urinalysis and an ultrasound of the kidney did not show any abnormalities, making a tubulopathy or hypercalciuria unlikely. A desmopressin test by the intravenous route came back completely normal, pointing to another cause than diabetes insipidus. Genetic testing for the nephronophthisis came back negative but was positive for a missense mutation in the AVPR2 gene (p.Arg104Cys) associated with partial nephrogenic diabetes insipidus. He was started on daily desmopressin. Within 3 days the urinary incontinence resolved as did the polyuria and faecal incontinence. His grandmother was referred to the geneticist and eventually the adult nephrologist. This case highlights the importance of being thorough when confronted with a difficult diagnosis. It also emphasizes that a test result does not necessarily equate to the presence or absence of a condition since the test with 100 % sensitivity and specificity has yet to be discovered.
Subject(s)
Urinary Incontinence/therapy , Child, Preschool , Diabetes Insipidus/diagnosis , Diabetes Insipidus/genetics , Diabetes Insipidus/therapy , Diabetes Insipidus, Nephrogenic/diagnosis , Diabetes Insipidus, Nephrogenic/genetics , Diabetes Insipidus, Nephrogenic/therapy , Diagnosis, Differential , Humans , Male , Mutation, Missense , Receptors, Vasopressin/genetics , Urinary Incontinence/diagnosis , Urinary Incontinence/geneticsABSTRACT
Myelodysplastic syndrome (MDS) is a group of clonal hematopoietic diseases characterized by cytopenia, dysplasia and increased risk of development to acute myeloid leukemia (AML). Unfavorable cytogenetic changes such as complex karyotypes or chromosome 7 anomalies are predictive of the progression to AML and poor prognosis. Central diabetes insipidus (CDI) is the result of a deficiency of arginine vasopressin, and its major causes are idiopathic, primary or secondary tumors, neurosurgery and trauma. Importantly, CDI is a rare complication of MDS. To date, only 5 cases of MDS co-occurring with CDI have been reported; 3 of 5 had cytogenetic abnormalities uncovered by metaphase cytogenetics and 3 of 5 evolved to AML. Here, we describe a 74-year-old woman who presented with CDI as her initial symptom of MDS and eventually progressed to AML. The metaphase cytogenetics, combined with the single-nucleotide polymorphism array (SNP-A)-based karyotyping, with superiority in resolution and detecting copy number variation, revealed a complex karyotype that included monosomy of chromosome 7, deletion of 20q, and absence of heterogeneity (AOH) in more than one chromosome. To the best of our knowledge, this is the first case report of MDS co-occurring with CDI with numerous cytogenetic abnormalities revealed by the SNP-A-based karyotyping. Our case supports that the cytogenetic abnormalities may be associated with the clinical features and the prognosis of MDS co-occurring with CDI. The SNP-A-based karyotyping is helpful in revealing more subtle cytogenetic abnormalities and unveiling their roles in the pathogenesis of MDS.