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Dent disease type 1(NPHL2; DENT1)

MedGen UID:
336322
Concept ID:
C1848336
Disease or Syndrome
Synonyms: Nephrolithiasis 2; Nephrolithiasis, hypercalciuria X-linked; Nephrolithiasis, hypercalciuric; NEPHROLITHIASIS, HYPERCALCIURIC, X-LINKED; Urolithiasis, hypercalciuric X-linked
SNOMED CT: Dent disease type 1 (717789008)
Modes of inheritance:
X-linked recessive inheritance
MedGen UID:
375779
Concept ID:
C1845977
Finding
Source: Orphanet
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 (location): CLCN5 (Xp11.23)
 
Monarch Initiative: MONDO:0010225
OMIM®: 300009
Orphanet: ORPHA93622

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, and at least one additional finding including nephrocalcinosis, nephrolithiasis, hematuria, hypophosphatemia, chronic kidney disease (CKD), and evidence of X-linked inheritance. Males younger than age ten years may manifest only 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. The disease may also be accompanied by rickets or osteomalacia, growth restriction, and short stature. Disease severity can vary within the same family. Males with Dent disease 2 (caused by pathogenic variants in OCRL) may also have mild intellectual disability, cataracts, and/or elevated muscle enzymes. Due to random X-chromosome inactivation, some female carriers may manifest hypercalciuria and, rarely, renal calculi and moderate LMW proteinuria. Females rarely develop CKD. [from GeneReviews]
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 (DENT2; 300555), caused by mutation in the OCRL gene (300535) on chromosome Xq26.  http://www.omim.org/entry/300009
From MedlinePlus Genetics
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.

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.

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.

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.  https://medlineplus.gov/genetics/condition/dent-disease

Clinical features

From HPO
Bone pain
MedGen UID:
57489
Concept ID:
C0151825
Sign or Symptom
An unpleasant sensation characterized by physical discomfort (such as pricking, throbbing, or aching) localized to bone.
Glycosuria
MedGen UID:
42267
Concept ID:
C0017979
Finding
An increased concentration of glucose in the urine.
Hypercalciuria
MedGen UID:
43775
Concept ID:
C0020438
Finding
Abnormally high level of calcium in the urine.
Nephrocalcinosis
MedGen UID:
10222
Concept ID:
C0027709
Disease or Syndrome
Nephrocalcinosis is the deposition of calcium salts in renal parenchyma.
Aminoaciduria
MedGen UID:
116067
Concept ID:
C0238621
Disease or Syndrome
An increased concentration of an amino acid in the urine.
Microscopic hematuria
MedGen UID:
65997
Concept ID:
C0239937
Finding
Microscopic hematuria detected by dipstick or microscopic examination of the urine.
Hyperphosphaturia
MedGen UID:
78638
Concept ID:
C0268079
Disease or Syndrome
An increased excretion of phosphates in the urine.
Nephrolithiasis
MedGen UID:
98227
Concept ID:
C0392525
Disease or Syndrome
The presence of calculi (stones) in the kidneys.
Chronic kidney disease
MedGen UID:
473458
Concept ID:
C1561643
Disease or Syndrome
Functional anomaly of the kidney persisting for at least three months.
Renal insufficiency
MedGen UID:
332529
Concept ID:
C1565489
Disease or Syndrome
A reduction in the level of performance of the kidneys in areas of function comprising the concentration of urine, removal of wastes, the maintenance of electrolyte balance, homeostasis of blood pressure, and calcium metabolism.
Proximal tubulopathy
MedGen UID:
326534
Concept ID:
C1839603
Disease or Syndrome
Dysfunction of the proximal tubule, which is the portion of the duct system of the nephron of the kidney which leads from Bowman's capsule to the loop of Henle.
Low-molecular-weight proteinuria
MedGen UID:
333360
Concept ID:
C1839606
Finding
Excretion in urine of proteins of a size smaller than albumin (molecular weight 69 kD).
Renal phosphate wasting
MedGen UID:
335116
Concept ID:
C1845169
Finding
High urine phosphate in the presence of hypophosphatemia.
Stage 5 chronic kidney disease
MedGen UID:
384526
Concept ID:
C2316810
Disease or Syndrome
A degree of kidney failure severe enough to require dialysis or kidney transplantation for survival characterized by a severe reduction in glomerular filtration rate (less than 15 ml/min/1.73 m2) and other manifestations including increased serum creatinine.
Tibial bowing
MedGen UID:
332360
Concept ID:
C1837081
Finding
A bending or abnormal curvature of the tibia.
Enlargement of the wrists
MedGen UID:
325479
Concept ID:
C1838663
Finding
Enlargement of the ankles
MedGen UID:
333151
Concept ID:
C1838664
Finding
Fibular bowing
MedGen UID:
869374
Concept ID:
C4023801
Anatomical Abnormality
A bending or abnormal curvature of the fibula.
Short stature
MedGen UID:
87607
Concept ID:
C0349588
Finding
A height below that which is expected according to age and gender norms. Although there is no universally accepted definition of short stature, many refer to "short stature" as height more than 2 standard deviations below the mean for age and gender (or below the 3rd percentile for age and gender dependent norms).
Recurrent fractures
MedGen UID:
42094
Concept ID:
C0016655
Injury or Poisoning
The repeated occurrence of bone fractures (implying an abnormally increased tendency for fracture).
Osteomalacia
MedGen UID:
14533
Concept ID:
C0029442
Disease or Syndrome
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.
Rickets
MedGen UID:
48470
Concept ID:
C0035579
Disease or Syndrome
Rickets is divided into two major categories including calcipenic and phosphopenic. Hypophosphatemia is described as a common manifestation of both categories. Hypophosphatemic rickets is the most common type of rickets that is characterized by low levels of serum phosphate, resistance to ultraviolet radiation or vitamin D intake. There are several issues involved in hypophosphatemic rickets such as calcium, vitamin D, phosphorus deficiencies. Moreover, other disorder can be associated with its occurrence such as absorption defects due to pancreatic, intestinal, gastric, and renal disorders and hepatobiliary disease. Symptoms are usually seen in childhood and can be varied in severity. Severe forms may be linked to bowing of the legs, poor bone growth, and short stature as well as joint and bone pain. Hypophosphatemic rickets are associated with renal excretion of phosphate, hypophosphatemia, and mineral defects in bones. The familial type of the disease is the most common type of rickets.
Sparse bone trabeculae
MedGen UID:
371538
Concept ID:
C1833324
Finding
Thin bony cortex
MedGen UID:
318844
Concept ID:
C1833325
Finding
Abnormal thinning of the cortical region of bones.
Bulging epiphyses
MedGen UID:
371540
Concept ID:
C1833329
Finding
A morphological abnormality of epiphyses whereby they are abnormally outwardly curving (protuberant).
Metaphyseal irregularity
MedGen UID:
325478
Concept ID:
C1838662
Finding
Irregularity of the normally smooth surface of the metaphyses.
Femoral bowing
MedGen UID:
347888
Concept ID:
C1859461
Finding
Bowing (abnormal curvature) of the femur.
Delayed epiphyseal ossification
MedGen UID:
351324
Concept ID:
C1865200
Finding
Bowing of the legs
MedGen UID:
1807399
Concept ID:
C5574706
Finding
A bending or abnormal curvature affecting a long bone of the leg.
Hypophosphatemia
MedGen UID:
39327
Concept ID:
C0085682
Disease or Syndrome
An abnormally decreased phosphate concentration in the blood.
High serum calcitriol
MedGen UID:
1619023
Concept ID:
C4531136
Finding
An increased concentration of calcitriol in the blood. Calcitriol is also known as 1,25-dihydroxycholecalciferol or 1,25-dihydroxyvitamin D3.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
Follow this link to review classifications for Dent disease type 1 in Orphanet.

Professional guidelines

PubMed

Thaventhiran JED, Lango Allen H, Burren OS, Rae W, Greene D, Staples E, Zhang Z, Farmery JHR, Simeoni I, Rivers E, Maimaris J, Penkett CJ, Stephens J, Deevi SVV, Sanchis-Juan A, Gleadall NS, Thomas MJ, Sargur RB, Gordins P, Baxendale HE, Brown M, Tuijnenburg P, Worth A, Hanson S, Linger RJ, Buckland MS, Rayner-Matthews PJ, Gilmour KC, Samarghitean C, Seneviratne SL, Sansom DM, Lynch AG, Megy K, Ellinghaus E, Ellinghaus D, Jorgensen SF, Karlsen TH, Stirrups KE, Cutler AJ, Kumararatne DS, Chandra A, Edgar JDM, Herwadkar A, Cooper N, Grigoriadou S, Huissoon AP, Goddard S, Jolles S, Schuetz C, Boschann F; Primary Immunodeficiency Consortium for the NIHR Bioresource, Lyons PA, Hurles ME, Savic S, Burns SO, Kuijpers TW, Turro E, Ouwehand WH, Thrasher AJ, Smith KGC
Nature 2020 Jul;583(7814):90-95. Epub 2020 May 6 doi: 10.1038/s41586-020-2265-1. PMID: 32499645Free PMC Article
Mier RW, Dhadwal S
Dent Clin North Am 2018 Oct;62(4):611-628. Epub 2018 Aug 14 doi: 10.1016/j.cden.2018.06.006. PMID: 30189986
McKenna SJ
Dent Clin North Am 2006 Oct;50(4):591-606, vii. doi: 10.1016/j.cden.2006.06.008. PMID: 17000275

Recent clinical studies

Etiology

Ye Q, Shen Q, Rao J, Zhang A, Zheng B, Liu X, Shen Y, Chen Z, Wu Y, Hou L, Jian S, Wei M, Ma M, Sun S, Li Q, Dang X, Wang Y, Xu H, Mao J; for Chinese Children Genetic Kidney Disease Database (CCGKDD), “Internet Plus” Nephrology Alliance of National Center for Children's Care
Clin Genet 2020 Mar;97(3):407-417. Epub 2020 Jan 13 doi: 10.1111/cge.13663. PMID: 31674016
Beara-Lasic L, Cogal A, Mara K, Enders F, Mehta RA, Haskic Z, Furth SL, Trachtman H, Scheinman SJ, Milliner DS, Goldfarb DS, Harris PC, Lieske JC; investigators of the Rare Kidney Stone Consortium
Pediatr Nephrol 2020 Apr;35(4):633-640. Epub 2019 Mar 10 doi: 10.1007/s00467-019-04210-0. PMID: 30852663Free PMC Article

Diagnosis

Ye Q, Shen Q, Rao J, Zhang A, Zheng B, Liu X, Shen Y, Chen Z, Wu Y, Hou L, Jian S, Wei M, Ma M, Sun S, Li Q, Dang X, Wang Y, Xu H, Mao J; for Chinese Children Genetic Kidney Disease Database (CCGKDD), “Internet Plus” Nephrology Alliance of National Center for Children's Care
Clin Genet 2020 Mar;97(3):407-417. Epub 2020 Jan 13 doi: 10.1111/cge.13663. PMID: 31674016
Beara-Lasic L, Cogal A, Mara K, Enders F, Mehta RA, Haskic Z, Furth SL, Trachtman H, Scheinman SJ, Milliner DS, Goldfarb DS, Harris PC, Lieske JC; investigators of the Rare Kidney Stone Consortium
Pediatr Nephrol 2020 Apr;35(4):633-640. Epub 2019 Mar 10 doi: 10.1007/s00467-019-04210-0. PMID: 30852663Free PMC Article

Therapy

Beara-Lasic L, Cogal A, Mara K, Enders F, Mehta RA, Haskic Z, Furth SL, Trachtman H, Scheinman SJ, Milliner DS, Goldfarb DS, Harris PC, Lieske JC; investigators of the Rare Kidney Stone Consortium
Pediatr Nephrol 2020 Apr;35(4):633-640. Epub 2019 Mar 10 doi: 10.1007/s00467-019-04210-0. PMID: 30852663Free PMC Article

Prognosis

Tang X, Brown MR, Cogal AG, Gauvin D, Harris PC, Lieske JC, Romero MF, Chang MH
Physiol Rep 2016 Apr;4(8) doi: 10.14814/phy2.12776. PMID: 27117801Free PMC Article

Clinical prediction guides

Kalmár T, Jakab D, Maróti Z, Lakatos O, Vas T, Bereczki C, Iványi B
Int J Mol Sci 2024 Jan 12;25(2) doi: 10.3390/ijms25020966. PMID: 38256038Free PMC Article
Anglani F, Gianesello L, Beara-Lasic L, Lieske J
J Cell Mol Med 2019 Nov;23(11):7132-7142. Epub 2019 Aug 31 doi: 10.1111/jcmm.14590. PMID: 31472005Free PMC Article
Tang X, Brown MR, Cogal AG, Gauvin D, Harris PC, Lieske JC, Romero MF, Chang MH
Physiol Rep 2016 Apr;4(8) doi: 10.14814/phy2.12776. PMID: 27117801Free PMC Article

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