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Hypophosphatemic rickets, X-linked recessive

MedGen UID:
335115
Concept ID:
C1845168
Disease or Syndrome
Synonym: Rickets, hypophosphataemic
 
Gene (location): CLCN5 (Xp11.23)
 
Monarch Initiative: MONDO:0010358
OMIM®: 300554

Definition

X-linked recessive hypophosphatemic rickets is a form of X-linked hypercalciuric nephrolithiasis, which comprises a group of disorders characterized by proximal renal tubular reabsorptive failure, hypercalciuria, nephrocalcinosis, and renal insufficiency. These disorders have also been referred to as the 'Dent disease complex' (Scheinman, 1998; Gambaro et al., 2004). For a general discussion of Dent disease, see 300009. [from OMIM]

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.
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.
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.
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.
Hypophosphatemic rickets
MedGen UID:
309957
Concept ID:
C1704375
Disease or Syndrome
Rickets due to low serum phosphate concentrations, the cause of which can be nutritional or genetic. This condition is characterized by normal parathyroid hormone concentrations, usually caused by renal phosphate wasting occurring in isolation or as part of a renal tubular disorder, and characterized by resistance to treatment with ultraviolet radiation or vitamin D.
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.

Professional guidelines

PubMed

Baroncelli GI, Mora S
Front Endocrinol (Lausanne) 2021;12:688309. Epub 2021 Aug 6 doi: 10.3389/fendo.2021.688309. PMID: 34421819Free PMC Article
Fukumoto S
J Mol Endocrinol 2021 Feb;66(2):R57-R65. doi: 10.1530/JME-20-0089. PMID: 33295878
Haffner D, Emma F, Eastwood DM, Duplan MB, Bacchetta J, Schnabel D, Wicart P, Bockenhauer D, Santos F, Levtchenko E, Harvengt P, Kirchhoff M, Di Rocco F, Chaussain C, Brandi ML, Savendahl L, Briot K, Kamenicky P, Rejnmark L, Linglart A
Nat Rev Nephrol 2019 Jul;15(7):435-455. doi: 10.1038/s41581-019-0152-5. PMID: 31068690Free PMC Article

Recent clinical studies

Etiology

Ito N, Hidaka N, Kato H
Best Pract Res Clin Endocrinol Metab 2024 Mar;38(2):101851. Epub 2023 Nov 30 doi: 10.1016/j.beem.2023.101851. PMID: 38087658
Trombetti A, Al-Daghri N, Brandi ML, Cannata-Andía JB, Cavalier E, Chandran M, Chaussain C, Cipullo L, Cooper C, Haffner D, Harvengt P, Harvey NC, Javaid MK, Jiwa F, Kanis JA, Laslop A, Laurent MR, Linglart A, Marques A, Mindler GT, Minisola S, Yerro MCP, Rosa MM, Seefried L, Vlaskovska M, Zanchetta MB, Rizzoli R
Nat Rev Endocrinol 2022 Jun;18(6):366-384. Epub 2022 Apr 28 doi: 10.1038/s41574-022-00662-x. PMID: 35484227
Laurent MR, De Schepper J, Trouet D, Godefroid N, Boros E, Heinrichs C, Bravenboer B, Velkeniers B, Lammens J, Harvengt P, Cavalier E, Kaux JF, Lombet J, De Waele K, Verroken C, van Hoeck K, Mortier GR, Levtchenko E, Vande Walle J
Front Endocrinol (Lausanne) 2021;12:641543. Epub 2021 Mar 19 doi: 10.3389/fendo.2021.641543. PMID: 33815294Free PMC Article
Imel EA, Glorieux FH, Whyte MP, Munns CF, Ward LM, Nilsson O, Simmons JH, Padidela R, Namba N, Cheong HI, Pitukcheewanont P, Sochett E, Högler W, Muroya K, Tanaka H, Gottesman GS, Biggin A, Perwad F, Mao M, Chen CY, Skrinar A, San Martin J, Portale AA
Lancet 2019 Jun 15;393(10189):2416-2427. Epub 2019 May 16 doi: 10.1016/S0140-6736(19)30654-3. PMID: 31104833Free PMC Article
Carpenter TO, Imel EA, Holm IA, Jan de Beur SM, Insogna KL
J Bone Miner Res 2011 Jul;26(7):1381-8. Epub 2011 May 2 doi: 10.1002/jbmr.340. PMID: 21538511Free PMC Article

Diagnosis

Ackah SA, Imel EA
J Clin Endocrinol Metab 2022 Dec 17;108(1):209-220. doi: 10.1210/clinem/dgac488. PMID: 35981346Free PMC Article
Laurent MR, De Schepper J, Trouet D, Godefroid N, Boros E, Heinrichs C, Bravenboer B, Velkeniers B, Lammens J, Harvengt P, Cavalier E, Kaux JF, Lombet J, De Waele K, Verroken C, van Hoeck K, Mortier GR, Levtchenko E, Vande Walle J
Front Endocrinol (Lausanne) 2021;12:641543. Epub 2021 Mar 19 doi: 10.3389/fendo.2021.641543. PMID: 33815294Free PMC Article
Fukumoto S
J Mol Endocrinol 2021 Feb;66(2):R57-R65. doi: 10.1530/JME-20-0089. PMID: 33295878
Haffner D, Emma F, Eastwood DM, Duplan MB, Bacchetta J, Schnabel D, Wicart P, Bockenhauer D, Santos F, Levtchenko E, Harvengt P, Kirchhoff M, Di Rocco F, Chaussain C, Brandi ML, Savendahl L, Briot K, Kamenicky P, Rejnmark L, Linglart A
Nat Rev Nephrol 2019 Jul;15(7):435-455. doi: 10.1038/s41581-019-0152-5. PMID: 31068690Free PMC Article
Carpenter TO, Imel EA, Holm IA, Jan de Beur SM, Insogna KL
J Bone Miner Res 2011 Jul;26(7):1381-8. Epub 2011 May 2 doi: 10.1002/jbmr.340. PMID: 21538511Free PMC Article

Therapy

Miller WL, Imel EA
Horm Res Paediatr 2022;95(6):579-592. Epub 2022 Nov 29 doi: 10.1159/000527011. PMID: 36446330
Baroncelli GI, Mora S
Front Endocrinol (Lausanne) 2021;12:688309. Epub 2021 Aug 6 doi: 10.3389/fendo.2021.688309. PMID: 34421819Free PMC Article
Laurent MR, De Schepper J, Trouet D, Godefroid N, Boros E, Heinrichs C, Bravenboer B, Velkeniers B, Lammens J, Harvengt P, Cavalier E, Kaux JF, Lombet J, De Waele K, Verroken C, van Hoeck K, Mortier GR, Levtchenko E, Vande Walle J
Front Endocrinol (Lausanne) 2021;12:641543. Epub 2021 Mar 19 doi: 10.3389/fendo.2021.641543. PMID: 33815294Free PMC Article
Fukumoto S
J Mol Endocrinol 2021 Feb;66(2):R57-R65. doi: 10.1530/JME-20-0089. PMID: 33295878
Haffner D, Emma F, Eastwood DM, Duplan MB, Bacchetta J, Schnabel D, Wicart P, Bockenhauer D, Santos F, Levtchenko E, Harvengt P, Kirchhoff M, Di Rocco F, Chaussain C, Brandi ML, Savendahl L, Briot K, Kamenicky P, Rejnmark L, Linglart A
Nat Rev Nephrol 2019 Jul;15(7):435-455. doi: 10.1038/s41581-019-0152-5. PMID: 31068690Free PMC Article

Prognosis

Ertl DA, Le Lorier J, Gleiss A, Trabado S, Bensignor C, Audrain C, Zhukouskaya V, Coutant R, Berkenou J, Rothenbuhler A, Haeusler G, Linglart A
Orphanet J Rare Dis 2022 Nov 12;17(1):412. doi: 10.1186/s13023-022-02562-9. PMID: 36371259Free PMC Article
Ackah SA, Imel EA
J Clin Endocrinol Metab 2022 Dec 17;108(1):209-220. doi: 10.1210/clinem/dgac488. PMID: 35981346Free PMC Article
Arenas MA, Jaimovich S, Perez Garrido N, Del Pino M, Viterbo G, Marino R, Fano V
J Pediatr Endocrinol Metab 2021 Sep 27;34(9):1105-1113. Epub 2021 Jun 21 doi: 10.1515/jpem-2021-0042. PMID: 34147045
Baroncelli GI, Toschi B, Bertelloni S
Curr Opin Endocrinol Diabetes Obes 2012 Dec;19(6):460-7. doi: 10.1097/MED.0b013e328358be97. PMID: 23108197
Beck-Nielsen SS
Dan Med J 2012 Feb;59(2):B4384. PMID: 22293055

Clinical prediction guides

Méaux MN, Alioli C, Linglart A, Lemoine S, Vignot E, Bertholet-Thomas A, Peyruchaud O, Flammier S, Machuca-Gayet I, Bacchetta J
J Clin Endocrinol Metab 2022 Nov 25;107(12):3275-3286. doi: 10.1210/clinem/dgac543. PMID: 36112422
Ward LM, Glorieux FH, Whyte MP, Munns CF, Portale AA, Högler W, Simmons JH, Gottesman GS, Padidela R, Namba N, Cheong HI, Nilsson O, Mao M, Chen A, Skrinar A, Roberts MS, Imel EA
J Clin Endocrinol Metab 2022 Jul 14;107(8):e3241-e3253. doi: 10.1210/clinem/dgac296. PMID: 35533340Free PMC Article
Linglart A, Imel EA, Whyte MP, Portale AA, Högler W, Boot AM, Padidela R, Van't Hoff W, Gottesman GS, Chen A, Skrinar A, Scott Roberts M, Carpenter TO
J Clin Endocrinol Metab 2022 Feb 17;107(3):813-824. doi: 10.1210/clinem/dgab729. PMID: 34636899Free PMC Article
Arenas MA, Jaimovich S, Perez Garrido N, Del Pino M, Viterbo G, Marino R, Fano V
J Pediatr Endocrinol Metab 2021 Sep 27;34(9):1105-1113. Epub 2021 Jun 21 doi: 10.1515/jpem-2021-0042. PMID: 34147045
Imel EA, Glorieux FH, Whyte MP, Munns CF, Ward LM, Nilsson O, Simmons JH, Padidela R, Namba N, Cheong HI, Pitukcheewanont P, Sochett E, Högler W, Muroya K, Tanaka H, Gottesman GS, Biggin A, Perwad F, Mao M, Chen CY, Skrinar A, San Martin J, Portale AA
Lancet 2019 Jun 15;393(10189):2416-2427. Epub 2019 May 16 doi: 10.1016/S0140-6736(19)30654-3. PMID: 31104833Free PMC Article

Recent systematic reviews

Wang S, Wang X, He M, Li Y, Xiao M, Ma H
J Clin Endocrinol Metab 2023 Dec 21;109(1):293-302. doi: 10.1210/clinem/dgad440. PMID: 37497620
Vilaca T, Velmurugan N, Smith C, Abrahamsen B, Eastell R
J Bone Miner Res 2022 Jun;37(6):1188-1199. Epub 2022 May 7 doi: 10.1002/jbmr.4558. PMID: 35426179Free PMC Article
Smith S, Remmington T
Cochrane Database Syst Rev 2021 Oct 7;10(10):CD004447. doi: 10.1002/14651858.CD004447.pub3. PMID: 34618915Free PMC Article
Dodamani MH, Sehemby M, Memon SS, Sarathi V, Lila AR, Chapla A, Bhandare VV, Patil VA, Shah NS, Thomas N, Kunwar A, Bandgar TR
J Pediatr Endocrinol Metab 2021 Dec 20;34(12):1505-1513. Epub 2021 Sep 8 doi: 10.1515/jpem-2021-0403. PMID: 34492747
Seefried L, Smyth M, Keen R, Harvengt P
Osteoporos Int 2021 Jan;32(1):7-22. Epub 2020 Jul 24 doi: 10.1007/s00198-020-05548-0. PMID: 32710160Free PMC Article

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