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Enlargement of the ankles

MedGen UID:
333151
Concept ID:
C1838664
Finding
HPO: HP:0003029

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVEnlargement of the ankles

Conditions with this feature

Vitamin D-dependent rickets, type 1
MedGen UID:
124344
Concept ID:
C0268689
Disease or Syndrome
Vitamin D-dependent rickets is a disorder of bone development that leads to softening and weakening of the bones (rickets). There are several forms of the condition that are distinguished primarily by their genetic causes: type 1A (VDDR1A), type 1B (VDDR1B), and type 2A (VDDR2A). There is also evidence of a very rare form of the condition, called type 2B (VDDR2B), although not much is known about this form.\n\nThe signs and symptoms of vitamin D-dependent rickets begin within months after birth, and most are the same for all types of the condition. The weak bones often cause bone pain and delayed growth and have a tendency to fracture. When affected children begin to walk, they may develop abnormally curved (bowed) legs because the bones are too weak to bear weight. Impaired bone development also results in widening of the areas near the ends of bones where new bone forms (metaphyses), especially in the knees, wrists, and ribs. Some people with vitamin D-dependent rickets have dental abnormalities such as thin tooth enamel and frequent cavities. Poor muscle tone (hypotonia) and muscle weakness are also common in this condition, and some affected individuals develop seizures.\n\nIn vitamin D-dependent rickets, there is an imbalance of certain substances in the blood. An early sign in all types of the condition is low levels of the mineral calcium (hypocalcemia), which is essential for the normal formation of bones and teeth. Affected individuals also develop high levels of a hormone involved in regulating calcium levels called parathyroid hormone (PTH), which leads to a condition called secondary hyperparathyroidism. Low levels of a mineral called phosphate (hypophosphatemia) also occur in affected individuals. Vitamin D-dependent rickets types 1 and 2 can be grouped by blood levels of a hormone called calcitriol, which is the active form of vitamin D; individuals with VDDR1A and VDDR1B have abnormally low levels of calcitriol and individuals with VDDR2A and VDDR2B have abnormally high levels.\n\nHair loss (alopecia) can occur in VDDR2A, although not everyone with this form of the condition has alopecia. Affected individuals can have sparse or patchy hair or no hair at all on their heads. Some affected individuals are missing body hair as well.
Vitamin D-dependent rickets type II with alopecia
MedGen UID:
90989
Concept ID:
C0342646
Disease or Syndrome
Vitamin D-dependent rickets type 2A (VDDR2A) is caused by a defect in the vitamin D receptor gene. This defect leads to an increase in the circulating ligand, 1,25-dihydroxyvitamin D3. Most patients have total alopecia in addition to rickets. VDDR2B (600785) is a form of vitamin D-dependent rickets with a phenotype similar to VDDR2A but a normal vitamin D receptor, in which end-organ resistance to vitamin D has been shown to be caused by a nuclear ribonucleoprotein that interferes with the vitamin D receptor-DNA interaction. For a general phenotypic description and a discussion of genetic heterogeneity of rickets due to disorders in vitamin D metabolism or action, see vitamin D-dependent rickets type 1A (VDDR1A; 264700).
Vitamin D hydroxylation-deficient rickets, type 1B
MedGen UID:
374020
Concept ID:
C1838657
Disease or Syndrome
Vitamin D hydroxylation-deficient rickets type 1B (VDDR1B) is caused by a defect in vitamin D 25-hydroxylation (Molin et al., 2017). The major function of vitamin D is to maintain calcium and phosphate levels in the normal range to support metabolic functions, neuromuscular transmission, and bone mineralization. Disorders of vitamin D metabolism or action lead to defective bone mineralization and clinical features including intestinal malabsorption of calcium, hypocalcemia, secondary hyperparathyroidism, increased renal clearance of phosphorus, and hypophosphatemia. The combination of hypocalcemia and hypophosphatemia causes impaired mineralization of bone that results in rickets and osteomalacia (summary by Liberman and Marx, 2001). Rickets can occur because of inadequate dietary intake or sun exposure or because of genetic disorders. Vitamin D3 (cholecalciferol) is taken in the diet or synthesized in the skin from 7-dehydrocholesterol by ultraviolet irradiation. For vitamin D to be active, it needs to be converted to its active form, 1,25-dihydroxyvitamin D3. Vitamin D is transported in the blood by the vitamin D binding protein (DBP; 139200) to the liver, where vitamin D 25-hydroxylase (CYP2R1; 608713) is the key enzyme for 25-hydroxylation. Vitamin D 25(OH)D3, the major circulating form of vitamin D, is then transported to the kidney, where 25(OH)D3 is hydroxylated at the position of carbon 1 of the A ring, resulting in the active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) (summary by Christakos et al., 2010).
Hypophosphatemic rickets, X-linked recessive
MedGen UID:
335115
Concept ID:
C1845168
Disease or Syndrome
X-linked recessive hypophosphatemic rickets (XLHRR) 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.
Dent disease type 1
MedGen UID:
336322
Concept ID:
C1848336
Disease or Syndrome
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.
Autosomal recessive hypophosphatemic bone disease
MedGen UID:
501133
Concept ID:
C1853271
Disease or Syndrome
Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare autosomal recessive disorder characterized by the presence of hypophosphatemia secondary to renal phosphate wasting, radiographic and/or histologic evidence of rickets, limb deformities, muscle weakness, and bone pain. HHRH is distinct from other forms of hypophosphatemic rickets in that affected individuals present with hypercalciuria due to increased serum 1,25-dihydroxyvitamin D levels and increased intestinal calcium absorption (summary by Bergwitz et al., 2006).

Professional guidelines

PubMed

Rodriguez-Merchan EC
Cardiovasc Hematol Disord Drug Targets 2021;21(3):162-166. doi: 10.2174/1871529X21666210427134232. PMID: 33906595
Al Kaissi A, Ghachem MB, Nabil NM, Kenis V, Melchenko E, Morenko E, Grill F, Ganger R, Kircher SG
Orthop Surg 2018 Aug;10(3):241-246. Epub 2018 Jul 19 doi: 10.1111/os.12382. PMID: 30027601Free PMC Article
Lim CS, Gohel MS, Shepherd AC, Davies AH
Eur J Vasc Endovasc Surg 2009 Aug;38(2):180-6. Epub 2009 May 7 doi: 10.1016/j.ejvs.2009.03.024. PMID: 19427244

Recent clinical studies

Etiology

Kassiano W, Costa B, Kunevaliki G, Soares D, Zacarias G, Manske I, Takaki Y, Ruggiero MF, Stavinski N, Francsuel J, Tricoli I, Carneiro MAS, Cyrino ES
J Strength Cond Res 2023 Sep 1;37(9):1746-1753. Epub 2023 Apr 3 doi: 10.1519/JSC.0000000000004460. PMID: 37015016
Yow BG, Tennent DJ, Dowd TC, Loenneke JP, Owens JG
J Foot Ankle Surg 2018 May-Jun;57(3):635-638. Epub 2018 Feb 21 doi: 10.1053/j.jfas.2017.11.008. PMID: 29477554
Habets B, van Cingel REH, Backx FJG, Huisstede BMA
BMC Musculoskelet Disord 2017 Jul 11;18(1):296. doi: 10.1186/s12891-017-1656-4. PMID: 28693535Free PMC Article
Hess GW
Foot Ankle Spec 2010 Feb;3(1):29-32. Epub 2009 Dec 15 doi: 10.1177/1938640009355191. PMID: 20400437
Uchiyama M, Tsuboi R, Mitsuhashi Y
J Dermatol 2009 Nov;36(11):608-11. doi: 10.1111/j.1346-8138.2009.00718.x. PMID: 19878395

Diagnosis

Singh D, Rawat R, Thakur V
Skinmed 2022;20(4):311-313. Epub 2022 Aug 31 PMID: 35976025
McAlister JE, Urooj U
Clin Podiatr Med Surg 2021 Apr;38(2):279-290. Epub 2021 Feb 13 doi: 10.1016/j.cpm.2020.12.011. PMID: 33745657
Yow BG, Tennent DJ, Dowd TC, Loenneke JP, Owens JG
J Foot Ankle Surg 2018 May-Jun;57(3):635-638. Epub 2018 Feb 21 doi: 10.1053/j.jfas.2017.11.008. PMID: 29477554
Habets B, van Cingel REH, Backx FJG, Huisstede BMA
BMC Musculoskelet Disord 2017 Jul 11;18(1):296. doi: 10.1186/s12891-017-1656-4. PMID: 28693535Free PMC Article
Uchiyama M, Tsuboi R, Mitsuhashi Y
J Dermatol 2009 Nov;36(11):608-11. doi: 10.1111/j.1346-8138.2009.00718.x. PMID: 19878395

Therapy

Matthews BG, Thomson CE, Harding MP, McKinley JC, Ware RS
Cochrane Database Syst Rev 2024 Feb 9;2(2):CD014687. doi: 10.1002/14651858.CD014687.pub2. PMID: 38334217Free PMC Article
Rodriguez-Merchan EC
Expert Rev Hematol 2023 Jul-Dec;16(7):525-534. Epub 2023 May 3 doi: 10.1080/17474086.2023.2209717. PMID: 37119182
Kassiano W, Costa B, Kunevaliki G, Soares D, Zacarias G, Manske I, Takaki Y, Ruggiero MF, Stavinski N, Francsuel J, Tricoli I, Carneiro MAS, Cyrino ES
J Strength Cond Res 2023 Sep 1;37(9):1746-1753. Epub 2023 Apr 3 doi: 10.1519/JSC.0000000000004460. PMID: 37015016
Habets B, van Cingel REH, Backx FJG, Huisstede BMA
BMC Musculoskelet Disord 2017 Jul 11;18(1):296. doi: 10.1186/s12891-017-1656-4. PMID: 28693535Free PMC Article
Bollinger A, Jäger K, Sgier F, Seglias J
Circulation 1981 Dec;64(6):1195-200. doi: 10.1161/01.cir.64.6.1195. PMID: 6170474

Prognosis

Migliorini F, Maffulli N, Eschweiler J, Götze C, Hildebrand F, Betsch M
Eur J Trauma Emerg Surg 2023 Apr;49(2):723-745. Epub 2022 Nov 7 doi: 10.1007/s00068-022-02155-y. PMID: 36344653Free PMC Article
Vasan RS, Song RJ, Xanthakis V, Beiser A, DeCarli C, Mitchell GF, Seshadri S
Hypertension 2022 Mar;79(3):505-515. Epub 2021 Dec 6 doi: 10.1161/HYPERTENSIONAHA.121.18502. PMID: 35138872Free PMC Article
Yow BG, Tennent DJ, Dowd TC, Loenneke JP, Owens JG
J Foot Ankle Surg 2018 May-Jun;57(3):635-638. Epub 2018 Feb 21 doi: 10.1053/j.jfas.2017.11.008. PMID: 29477554
Habets B, van Cingel REH, Backx FJG, Huisstede BMA
BMC Musculoskelet Disord 2017 Jul 11;18(1):296. doi: 10.1186/s12891-017-1656-4. PMID: 28693535Free PMC Article
Uchiyama M, Tsuboi R, Mitsuhashi Y
J Dermatol 2009 Nov;36(11):608-11. doi: 10.1111/j.1346-8138.2009.00718.x. PMID: 19878395

Clinical prediction guides

Matthews BG, Thomson CE, Harding MP, McKinley JC, Ware RS
Cochrane Database Syst Rev 2024 Feb 9;2(2):CD014687. doi: 10.1002/14651858.CD014687.pub2. PMID: 38334217Free PMC Article
Khan MJ, Asif N, Aziz MH, Shaikh SAH, Siddiqui FB, Moizuddin K, Nuhmani S
J Med Life 2023 Aug;16(8):1235-1239. doi: 10.25122/jml-2023-0117. PMID: 38024814Free PMC Article
Sezer M, Aydın F, Kurt T, Tekgöz N, Tekin ZE, Karagöl C, Çakar N, Acar B
Mod Rheumatol 2021 Sep;31(5):1025-1030. Epub 2020 Oct 27 doi: 10.1080/14397595.2020.1836788. PMID: 33050742
Hess GW
Foot Ankle Spec 2010 Feb;3(1):29-32. Epub 2009 Dec 15 doi: 10.1177/1938640009355191. PMID: 20400437
Bollinger A, Jäger K, Sgier F, Seglias J
Circulation 1981 Dec;64(6):1195-200. doi: 10.1161/01.cir.64.6.1195. PMID: 6170474

Recent systematic reviews

Matthews BG, Thomson CE, Harding MP, McKinley JC, Ware RS
Cochrane Database Syst Rev 2024 Feb 9;2(2):CD014687. doi: 10.1002/14651858.CD014687.pub2. PMID: 38334217Free PMC Article
Migliorini F, Maffulli N, Eschweiler J, Götze C, Hildebrand F, Betsch M
Eur J Trauma Emerg Surg 2023 Apr;49(2):723-745. Epub 2022 Nov 7 doi: 10.1007/s00068-022-02155-y. PMID: 36344653Free PMC Article
Migliorini F, Eschweiler J, Goetze C, Pastor T, Giorgino R, Hildebrand F, Maffulli N
J Orthop Surg Res 2022 Jun 11;17(1):308. doi: 10.1186/s13018-022-03203-4. PMID: 35690865Free PMC Article
Lohrer H
J Foot Ankle Surg 2019 Sep;58(5):969-973. Epub 2019 Jul 24 doi: 10.1053/j.jfas.2019.01.011. PMID: 31350138
Lins CF, Santiago MB
Eur Radiol 2015 Sep;25(9):2688-92. Epub 2015 Feb 27 doi: 10.1007/s00330-015-3670-y. PMID: 25716942

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