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Dent disease 1(NPHL2)

MedGen UID:
336322
Concept ID:
C1848336
Disease or Syndrome
Synonyms: Dent DiseaseType 1; Nephrolithiasis 2; Nephrolithiasis, hypercalciuria X-linked; NEPHROLITHIASIS, HYPERCALCIURIC, X-LINKED; NPHL2; Urolithiasis, hypercalciuric X-linked
Modes of inheritance:
X-linked recessive inheritance
MedGen UID:
425042
Concept ID:
CN001297
Genetic Function
A mode of inheritance that is observed for recessive traits related to a gene encoded on the X chromosome. In the context of medical genetics, X-linked recessive disorders manifest in males (who have one copy of the X chromosome and are thus hemizygotes), but generally not in female heterozygotes who have one mutant and one normal allele.
 
Gene: CLCN5
Cytogenetic location: Xp11.23
OMIM: 300009

Disease characteristics

Excerpted from the GeneReview: Dent Disease
Dent disease, an X-linked disorder of proximal renal tubular dysfunction, is characterized by low molecular weight (LMW) proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis, and chronic kidney disease (CKD). Males younger than age ten years may manifest only low molecular weight (LMW) proteinuria and/or hypercalciuria, which are usually asymptomatic. Thirty to 80% of affected males develop end-stage renal disease (ESRD) between ages 30 and 50 years; in some instances ESRD does not develop until the sixth decade of life or later. Rickets or osteomalacia are occasionally observed, and mild short stature, although underappreciated, may be a common occurrence. Disease severity can vary within the same family. Males with Dent disease 2 (caused by mutations in OCRL) are at increased risk for intellectual disability. Due to random X-chromosome inactivation, some female carriers may manifest hypercalciuria and, rarely, renal calculi and moderate LMW proteinuria. Females rarely if ever develop CKD. [from GeneReviews]
Full text of GeneReview (by section):
Summary  |  Diagnosis  |  Clinical Description  |  Differential Diagnosis  |  Management  |  Genetic Counseling  |  Resources  |  Molecular Genetics  |  References  |  Chapter Notes
Authors:
John C Lieske  |  Dawn S Milliner  |  Lada Beara-Lasic, et. al.   view full author information

Additional descriptions

From OMIM
The term 'X-linked hypercalciuric nephrolithiasis' comprises several related forms of hereditary renal tubular disorders caused by mutations in the CLCN5 gene, including Dent disease, X-linked recessive nephrolithiasis (310468), X-linked recessive hypophosphatemic rickets (300554), and low molecular weight proteinuria (308990). Although these disorders are allelic and are all characterized by progressive proximal renal tubulopathy with hypercalciuria, low-molecular-weight proteinuria, and nephrocalcinosis, they vary in degree of severity and were originally reported as separate disorders. Some have considered these disorders as phenotypic variants of a single disease, referred to as the 'Dent disease complex' (Scheinman, 1998; Gambaro et al., 2004). Scheinman et al. (1999) provided a comprehensive review of genetic disorders of renal electrolyte transport. Genetic Heterogeneity of Dent Disease See also Dent disease-2 (300555), which is caused by mutation in the OCRL gene (300535) on chromosome Xq26.  http://www.omim.org/entry/300009
From GHR
Dent disease is a chronic kidney disorder that occurs almost exclusively in males. In affected individuals, kidney problems result from damage to structures called proximal tubules. Signs and symptoms of this condition appear in early childhood and worsen over time. The most frequent sign of Dent disease is the presence of an abnormally large amount of proteins in the urine (tubular proteinuria). Other common signs of the disorder include excess calcium in the urine (hypercalciuria), calcium deposits in the kidneys (nephrocalcinosis), and kidney stones (nephrolithiasis). Kidney stones can cause abdominal pain and blood in the urine (hematuria). In most affected males, progressive kidney problems lead to end-stage renal disease (ESRD) in early to mid-adulthood. ESRD is a life-threatening failure of kidney function that occurs when the kidneys are no longer able to filter fluids and waste products from the body effectively. Some people with Dent disease develop rickets, a bone disorder that results when the levels of vitamin D and certain minerals (including calcium) in the blood become too low. Rickets can be associated with weakening and softening of the bones, bone pain, bowed legs, and difficulty walking. Researchers have described two forms of Dent disease, which are distinguished by their genetic cause and pattern of signs and symptoms. Both forms of Dent disease (type 1 and type 2) are characterized by the features described above, but Dent disease 2 can also be associated with abnormalities unrelated to kidney function. These additional signs and symptoms include mild intellectual disability, weak muscle tone (hypotonia), and clouding of the lens of the eyes (cataract) that is described as subclinical because it does not impair vision. Some researchers consider Dent disease 2 to be a mild variant of a similar disorder called Lowe syndrome.  http://ghr.nlm.nih.gov/condition/dent-disease

Clinical features

Glycosuria
MedGen UID:
42267
Concept ID:
C0017979
Finding
The appearance of an abnormally large amount of GLUCOSE in the urine, such as more than 500 mg/day in adults. It can be due to HYPERGLYCEMIA or genetic defects in renal reabsorption (RENAL GLYCOSURIA).
Nephrocalcinosis
MedGen UID:
504348
Concept ID:
CN000117
Finding
Nephrocalcinosis is the deposition of calcium salts in renal parenchyma.
Nephrolithiasis
MedGen UID:
504597
Concept ID:
CN000736
Finding
The presence of calculi (stones) in the kidneys.
Microscopic hematuria
MedGen UID:
505401
Concept ID:
CN002629
Finding
Microscopic hematuria detected by dipstick or microscopic examination of the urine.
Hyperphosphaturia
MedGen UID:
505453
Concept ID:
CN002803
Finding
An increased excretion of phosphates in the urine.
Aminoaciduria
MedGen UID:
425142
Concept ID:
CN003029
Finding
An increased concentration of an `amino acid` (CHEBI:33709 ) in the `urine` (FMA:12274).
Chronic kidney disease
MedGen UID:
776439
Concept ID:
CN183891
Finding
Functional anomaly of the kidney persisting for at least three months.
Osteomalacia
MedGen UID:
505343
Concept ID:
CN002494
Finding
Osteomalacia is a general term for bone weakness owing to a defect in mineralization of the protein framework known as osteoid. This defective mineralization is mainly caused by lack in vitamin D. Osteomalacia in children is known as rickets.
Recurrent fractures
MedGen UID:
500939
Concept ID:
CN002502
Finding
The repeated occurence of bone fractures (implying an abnormally increased tendency for fracture).
Bowing of the legs
MedGen UID:
505427
Concept ID:
CN002695
Finding
A bending or abnormal curvature affecting a `long bone` (FMA:7474) of the leg.
Fibular bowing
MedGen UID:
430013
Concept ID:
CN009333
Finding
A bending or abnormal curvature of the `fibula` (FMA:24479).
Glycosuria
MedGen UID:
42267
Concept ID:
C0017979
Finding
The appearance of an abnormally large amount of GLUCOSE in the urine, such as more than 500 mg/day in adults. It can be due to HYPERGLYCEMIA or genetic defects in renal reabsorption (RENAL GLYCOSURIA).
Hypophosphatemia
MedGen UID:
505125
Concept ID:
CN001946
Finding
An abnormally decreased `phosphate` (CHEBI:18367) concentration in the `blood` (FMA:9670).
Microscopic hematuria
MedGen UID:
505401
Concept ID:
CN002629
Finding
Microscopic hematuria detected by dipstick or microscopic examination of the urine.
Hyperphosphaturia
MedGen UID:
505453
Concept ID:
CN002803
Finding
An increased excretion of phosphates in the urine.
Aminoaciduria
MedGen UID:
425142
Concept ID:
CN003029
Finding
An increased concentration of an `amino acid` (CHEBI:33709 ) in the `urine` (FMA:12274).

Recent clinical studies

Diagnosis

Ludwig M, Sethi SK
Int Urol Nephrol 2011 Dec;43(4):1107-15. Epub 2011 Mar 1 doi: 10.1007/s11255-011-9914-0. [Epub ahead of print] PMID: 21360162
Devuyst O, Thakker RV
Orphanet J Rare Dis 2010 Oct 14;5:28. doi: 10.1186/1750-1172-5-28. [Epub ahead of print] PMID: 20946626Free PMC Article
Cho HY, Lee BH, Choi HJ, Ha IS, Choi Y, Cheong HI
Pediatr Nephrol 2008 Feb;23(2):243-9. Epub 2007 Nov 24 doi: 10.1007/s00467-007-0686-9. [Epub ahead of print] PMID: 18038239

Therapy

Vaisbich MH, Henriques Ldos S, Igarashi T, Sekine T, Seki G, Koch VH
J Bras Nefrol 2012 Mar;34(1):78-81. PMID: 22441187

Prognosis

Devuyst O, Thakker RV
Orphanet J Rare Dis 2010 Oct 14;5:28. doi: 10.1186/1750-1172-5-28. [Epub ahead of print] PMID: 20946626Free PMC Article

Clinical prediction guides

Ludwig M, Sethi SK
Int Urol Nephrol 2011 Dec;43(4):1107-15. Epub 2011 Mar 1 doi: 10.1007/s11255-011-9914-0. [Epub ahead of print] PMID: 21360162

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