Contiguous gene deletion in a Chinese family with X-linked nephrogenic diabetes insipidus: challenges in early diagnosis and implications for affected families

2019 ◽  
Vol 32 (8) ◽  
pp. 915-920
Author(s):  
Mei Tik Leung ◽  
Jacqueline K.K. Sit ◽  
Hoi Ning Cheung ◽  
Yan Ping Iu ◽  
Winnie K.Y. Chan ◽  
...  
Keyword(s):  
Genetic Analysis ◽  
Diabetes Insipidus ◽  
Nephrogenic Diabetes Insipidus ◽  
Failure To Thrive ◽  
Index Patient ◽  
Chinese Family ◽  
Molecular Testing ◽  
Carrier Status ◽  
Young Infants ◽  
Collecting Tubules

Abstract Nephrogenic diabetes insipidus (NDI) is a rare disorder of the renal collecting tubules, characterized by an inability to concentrate urine due to an impaired response to arginine vasopressin (AVP), resulting in dilute urine and polyuria. Causes of NDI are heterogeneous and diagnosing congenital NDI (cNDI) in young infants is clinically challenging, as typical symptoms are often unappreciated or inconspicuous. Instead, young infants may present with non-specific signs such as vomiting, poor feeding, failure to thrive, unexplained fevers, irritability, constipation or diarrhea. We report a 37-day-old infant who presented with polyuria and severe hypernatremic dehydration that was unresponsive to vasopressin. The patient was treated with amiloride, indomethacin and hydrochlorothiazide. Genetic analysis revealed a novel contiguous deletion involving the entire AVPR2 gene and the last exon of the adjacent ARHGAP4 gene. A study of the family confirmed the carrier status in the mother. This case illustrates the importance of molecular testing in confirming the diagnosis in the index patient, as well as in identifying asymptomatic at-risk female carriers so that appropriate genetic counselling can be given for reproductive planning. All pediatric patients with suspected cNDI should undergo genetic analysis for a definitive diagnosis.

scholarly journals MON-LB65 Lithium: The Culprit of Multiple Endocrinopathies

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Alice Yau ◽  
Gul Bahtiyar ◽  
Giovanna Rodriguez ◽  
Jose R Martinez Escudero
Keyword(s):  
Bipolar Disorder ◽  
Diabetes Insipidus ◽  
Mental Status ◽  
Nephrogenic Diabetes Insipidus ◽  
Kidney Injury ◽  
Urine Osmolality ◽  
Altered Mental Status ◽  
Clinical Findings ◽  
Volume Depletion ◽  
Collecting Tubules

Abstract Background: Lithium, commonly used to treat various psychiatric disorders such as bipolar disorder, can cause acute toxicity that presents with nausea, vomiting and diarrhea. Lithium can also cause life-threatening endocrine abnormalities, including hypercalcemia, hypernatremia, and both hypo- and hyperthyroidism. Clinical Case: A 61-year old female with hypothyroidism, bipolar disorder, hyperparathyroidism with two-gland parathyroidectomy on lithium for over 30 years presented with altered mental status. Initial labs revealed elevated creatinine 1.92 mg/dL (0.8-2.00mg/dL) compared to baseline 0.82 mg/dL, sodium 154 mg/dL (135-147 mg/dL), Corrected calcium 11.7 mg/dL (8.5-10.5 mg/dL), PTH 96 pg/mL (15-65 pg/mL), and high lithium levels 1.45 mmol/L (0.60-1.20 mmol/L). Further studies showed hypotonic polyuria with no increase in urine osmolality after desmopressin, consistent with nephrogenic diabetes insipidus. Lithium was held and she was treated with aggressive intravenous hydration with dextrose 5% water. Hypercalcemia is thought to result from increased secretion of PTH due to an increased set point at which calcium suppresses PTH release; this often resolves once lithium is stopped. Lithium can also unmask previously unrecognized mild hyperparathyroidism, and/or raise serum PTH concentrations independent of calcium levels.1 The drug interferes with the kidneys’ ability to concentrate urine in the collecting tubules by desensitizing response to antidiuretic hormone, causing diabetes insipidus. The resulting volume depletion from excessive urinary water loss in turn lead to acute kidney injury and hypernatremia.2 Hypothyroidism results from lithium-inhibited synthesis and release of thyroid hormones and decreases iodine trapping. Conclusion: Although these are infrequent complications of lithium use, they remain pertinent clinical findings to consider due to their morbidity. In this case, our patient may have avoided multiple chronic electrolyte abnormalities leading to altered mental status if lithium toxicity had been recognized earlier. References:1. García-Maldonado, Gerardo, and Rubén de Jesús Castro-García. “Endocrinological Disorders Related To The Medical Use Of Lithium. A Narrative Review”. Revista Colombiana De Psiquiatría (English Ed.), vol 48, no. 1, 2019, pp. 35-43. Elsevier BV, doi:10.1016/j.rcpeng.2018.12.005. 2. Tasci, E. “Lithium-Induced Nephrogenic Diabetes Insipidus Responsive To Desmopressin”. Acta Endocrinologica (Bucharest), vol 15, no. 2, 2019, pp. 270-271. ACTA Endocrinologica Foundation, doi:10.4183/aeb.2019.270.

Dynamics of nucleotides in distal nephron of mice with nephrogenic diabetes insipidus

1986 ◽  
Vol 250 (1) ◽  
pp. F151-F158 ◽  
Author(s):  
E. Kusano ◽  
A. N. Yusufi ◽  
N. Murayama ◽  
J. Braun-Werness ◽  
T. P. Dousa
Keyword(s):  
Diabetes Insipidus ◽  
Nephrogenic Diabetes Insipidus ◽  
Fold Increase ◽  
Thick Ascending Limb ◽  
Camp Phosphodiesterase ◽  
Camp Content ◽  
Medullary Thick Ascending Limb ◽  
Atp Levels ◽  
Collecting Tubules ◽  
Camp Levels

In mice with hereditary nephrogenic diabetes insipidus (NDI), the high activity of cAMP-phosphodiesterase (cAMP-PDIE) in medullary collecting tubules (MCT) prevents the increase in cAMP content in response to vasopressin [Arg8]vasopressin (AVP). Even when the cAMP response to AVP is partly corrected by cAMP-PDIE inhibitor 1-methyl-3-isobutylxanthine (MIX), under all tested conditions the cAMP levels in MCT of NDI mice remained much lower than in controls (B. A. Jackson, R. M. Edwards, H. Valtin, and T. P. Dousa, J. Clin. Invest. 66: 110-122, 1980). In the present study, we explored which factors may account for this defect. We determined contents of ATP, nicotinamide adenine dinucleotide (NAD), and the levels of cAMP in MCT and in medullary thick ascending limb of Henle's loop (MAL) microdissected from control and NDI mice. In the presence of 1 microM AVP and 0.05 mM MIX, the cAMP levels accumulated in MCT of NDI mice were four times lower compared with controls, but the levels of ATP and NAD were not different. ATP levels in MAL of NDI mice were slightly (delta -23%) lower than in MAL from controls, and in distal convoluted tubules (DCT) of NDI mice the ATP levels were also decreased (delta -49%). Although AVP alone had little effect on cAMP levels in mouse MAL in the presence of 0.1 mM forskolin, the AVP elicited a 20-fold increase of cAMP of both the control and NDI mice. Addition of 0.1 mM forskolin further increased the cAMP accumulation in MCT incubated with AVP.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals A Novel Mutation in the AVPR2 Gene in a Palestinian Family with Nephrogenic Diabetes Insipidus

2017 ◽  
Vol 07 (01) ◽  
pp. e1-e3
Author(s):  
Abdulsalam Abu-Libdeh ◽  
Isaiah Wexler ◽  
Imad Dweikat ◽  
David Zangen ◽  
Bassam Abu-Libdeh
Keyword(s):  
Diabetes Insipidus ◽  
Nephrogenic Diabetes Insipidus ◽  
Novel Mutation ◽  
Collecting Duct ◽  
Failure To Thrive ◽  
Male Infant ◽  
Gene Encoding ◽  
Exon 2 ◽  
Recessive Form ◽  
V2 Vasopressin Receptor

AbstractNephrogenic diabetes insipidus (NDI) is a urinary concentrating defect resulting from resistance of the collecting duct to the antidiuretic action of vasopressin (AVP). The X-linked recessive form is the most frequent genetic cause of inherited NDI and can be caused by mutations in the gene encoding the V2 vasopressin receptor (AVPR2). A Palestinian male infant presented in the neonatal period with failure to thrive, vomiting, irritability, fever, and polyuria, and had biochemical findings consistent with NDI. The diagnosis of NDI was established based on the clinical picture, absent response to desmopressin, and a similarly affected elder brother. Sequencing of the AVPR2 gene for the patient and his affected brother revealed a novel missense mutation with replacement of G by A in codon 82 located in exon 2 (TGC → TAC), causing a cysteine to tyrosine substitution (C82Y). Testing of the mother showed that she was the carrier of that mutation. This is the identified AVPR2 mutation in a Palestinian family. Knowledge of these mutations will allow genetic counseling and early diagnosis of affected males.

P95 A rare cause for failure to thrive: nephrogenic diabetes insipidus

2017 ◽  
Author(s):  
Ramona Stroescu ◽  
Mihai Gafencu ◽  
Adela Chiriţ&acaron; ◽  
Raluca Isac ◽  
Gabriela Doroş
Keyword(s):  
Diabetes Insipidus ◽  
Nephrogenic Diabetes Insipidus ◽  
Failure To Thrive

scholarly journals Hypertensive urgency in nephrogenic diabetes insipidus with concomitant Hinman syndrome

2019 ◽  
Vol 12 (7) ◽  
pp. e229095
Author(s):  
Yu Guang Tan ◽  
Daniel Wei Keong Chan ◽  
Fabian Kok Peng Yap ◽  
Te-Lu Yap
Keyword(s):  
Renal Impairment ◽  
Diabetes Insipidus ◽  
Nephrogenic Diabetes Insipidus ◽  
Failure To Thrive ◽  
Age Group ◽  
Urinary System ◽  
Hypertensive Urgency ◽  
Anatomical Changes ◽  
Hinman Syndrome ◽  
Concentrate Urine

Diabetes insipidus is a syndrome characterised by the inability to conserve water or concentrate urine, leading to excessive excretion of urine. In congenital nephrogenic diabetes insipidus (CNDI), common presentations include failure to thrive, polydipsia, polyuria and dehydration. The long trajectory of the disease, coupled with psycho-behavioural changes as a child grows, can precipitate a period of non-adherence despite initial optimal control, especially in the adolescent age group. Social inconvenience of repeated voiding and nocturnal disturbances can lead to adapted urine holding behaviour, also known as non-neurogenic neurogenic bladder (Hinman syndrome). Anatomical changes in the urinary system, such as bladder trabeculation and hydroureteronephrosis, can subsequently give rise to functional renal impairment. We present a case of CNDI with concomitant Hinman syndrome, resulting in acute renal impairment and hypertensive emergency. We aim to raise awareness of the association between these two entities.

scholarly journals Clinical and Functional Characterization of a Novel Mutation in AVPR2 Causing Nephrogenic Diabetes Insipidus in a Four-Generation Chinese Family

2021 ◽  
Vol 9 ◽  
Author(s):  
Shusen Guo ◽  
Shimin Wu ◽  
Zhuxi Li ◽  
Lianjing Huang ◽  
Di Zhan ◽  
...  
Keyword(s):  
Diabetes Insipidus ◽  
Growth Retardation ◽  
Nephrogenic Diabetes Insipidus ◽  
Novel Mutation ◽  
Bioinformatic Analysis ◽  
Chinese Family ◽  
Intracellular Camp ◽  
The Novel ◽  
Wild Type ◽  
The Impact

Background: Congenital nephrogenic diabetes insipidus (CNDI) is a rare inherited disease that is caused by mutations in arginine vasopressin receptor 2 (AVPR2) or aquaporin 2 (AQP2). Functional analysis of the mutated receptor is necessary to verify the impact of the mutation on receptor function and suggest some possible therapeutic strategies for specific functional defects.Methods: Family history and clinical information were collected. Whole-exome sequencing and sanger sequencing were performed to determine the potential genetic cause of diabetes insipidus. The identified variant was classified according to the American College of Medical Genetics (ACMG) criteria. Bioinformatic analysis was performed to predict the function of the identified variation. Moreover, wild-type and mutated AVPR2 vectors were constructed and transfection to HEK-293T cells. Immunofluorescence experiments were performed to investigate the expression and localization of the mutated protein and cAMP parameter assays were used to measure its activity in response to AVP.Results: The heights of the adult members affected with polyuria and polydipsia were normal, but all affected children had growth retardation. Next-generation sequencing identified a novel mutation in AVPR2 gene (c.530T > A) in this family. Bioinformatic analysis indicated that the mutation in AVPR2 changed the hydropathic characteristic of the protein and was probably deleterious. Although immunofluorescence showed that the mutated AVPR2 was normally expressed in the cell surface, the intracellular cAMP concentration stimulated by AVP was significantly lower in cells transfected with mutated AVPR2 than cells transfected with wild-type AVPR2. Based on the ACMG criteria, the novel c.530T > A variant of the AVPR2 gene was likely pathogenic and the affected family members were diagnosed as CNDI. After the confirmation of the diagnosis, the proband was treated with compound amiloride hydrochloride and rhGH, the symptoms of polyuria, polydipsia and growth retardation were all improved.Conclusion: These findings suggested that the novel mutation in AVPR2 (c.530T > A) was a true disease-causing variant with mild effects, which could be classified as a type III mutant receptor. Moreover, investigations of the function of growth hormone axis could be important for the pediatric CNDI patients with extreme short stature, and rhGH treatment might improve the final adult heights in these patients.

scholarly journals Clinical Presentation and Follow-Up of 30 Patients with Congenital Nephrogenic Diabetes Insipidus

1999 ◽  
Vol 10 (9) ◽  
pp. 1958-1964
Author(s):  
ANGENITA F. VAN LIEBURG ◽  
NINE V. A. M. KNOERS ◽  
LEO A. H. MONNENS
Keyword(s):  
Diabetes Insipidus ◽  
Nephrogenic Diabetes Insipidus ◽  
Clinical Presentation ◽  
Case Reports ◽  
Failure To Thrive ◽  
Study Data ◽  
Minor Trauma ◽  
Urine Retention ◽  
Congenital Nephrogenic Diabetes Insipidus

Abstract. Congenital nephrogenic diabetes insipidus is characterized by insensitivity of the distal nephron to arginine vasopressin. Clinical knowledge of this disease is based largely on case reports. For this study, data were collected on clinical presentation and during long-term follow-up of 30 male patients with congenital nephrogenic diabetes insipidus. The majority of patients (87%) were diagnosed within the first 2.5 yr of life. Main symptoms at clinical presentation were vomiting and anorexia, failure to thrive, fever, and constipation. Three older patients were diagnosed as a result of events not directly related to the disease. Except for a possibly milder phenotype in patients with a G185C mutation, no clear relationship between clinical and genetic data could be found. Most patients were on hydrochlorothiazide-amiloride treatment without significant side effects. Two patients suffered from severe hydronephrosis with a small rupture of the urinary tract after a minor trauma, and two patients experienced episodes of acute urine retention. Height SD scores for age remained below the 50th percentile in the majority of patients, whereas weight for height SD scores showed a catch-up after several years of underweight.

scholarly journals Nephrogenic Diabetes Insipidus - A Rare Report of Two Affected Sibling

2018 ◽  
Vol 41 (3) ◽  
pp. 193-195
Author(s):  
Rumana Riaaz ◽  
Mahbub Mutanabbi ◽  
Kohinoor Jahan Shamaly ◽  
CA Kawser
Keyword(s):  
Child Health ◽  
Diabetes Insipidus ◽  
Antidiuretic Hormone ◽  
Nephrogenic Diabetes Insipidus ◽  
Water Deprivation ◽  
Failure To Thrive ◽  
Urine Osmolality ◽  
Affected Sibling ◽  
Before And After ◽  
Rare Report

Nephrogenic Diabetes Insipidus (NDI) is a type of Diabetes Insipidus (DI) where distal nephrons are unresponsive to antidiuretic hormone resulting in polyuria and polydipsia. NDI can be congenital or acquired. There are very few cases of congenital NDI, more in sibs. Here we report two sibs affected with congenital NDI. Both of them presented with polyuria, polydipsia and failure to thrive since early infancy. In both cases, water deprivation tests and urine osmolality were done before and after DDAVP that suggested NDI and the acquired causes has been excluded. Both of them were treated with oral Hydrochlorothiazide and improved.Bangladesh J Child Health 2017; VOL 41 (3) :193-195

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