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Paget disease of bone 6(PDB6)

MedGen UID:
908743
Concept ID:
C4085250
Disease or Syndrome
Synonym: PDB6
 
Gene (location): ZNF687 (1q21.3)
 
Monarch Initiative: MONDO:0014792
OMIM®: 616833

Definition

Paget disease of bone-6 (PDB6) is an autosomal dominant disorder characterized by adult onset of bone pain associated with polyostotic bone lesions primarily affecting the axial skeleton. A subset of patients develop coronary artery disease and/or malignant giant cell tumor (GCT) of the bone, which arises within the Paget bone lesions (summary by Divisato et al., 2016). For a general phenotypic description and a discussion of genetic heterogeneity of Paget disease of bone, see 167250. [from OMIM]

Additional description

From MedlinePlus Genetics
Paget disease of bone is a disorder that causes bones to grow larger and weaker than normal. Affected bones may be misshapen and easily broken (fractured).

The classic form of Paget disease of bone typically appears in middle age or later. It usually occurs in one or a few bones and does not spread from one bone to another. Any bones can be affected, although the disease most commonly affects bones in the spine, pelvis, skull, or legs.

Many people with classic Paget disease of bone do not experience any symptoms associated with their bone abnormalities. The disease is often diagnosed unexpectedly by x-rays or laboratory tests done for other reasons. People who develop symptoms are most likely to experience pain. The affected bones may themselves be painful, or pain may be caused by arthritis in nearby joints. Arthritis results when the distortion of bones, particularly weight-bearing bones in the legs, causes extra wear and tear on the joints. Arthritis most frequently affects the knees and hips in people with this disease.

Other complications of Paget disease of bone depend on which bones are affected. If the disease occurs in bones of the skull, it can cause an enlarged head, hearing loss, headaches, and dizziness. If the disease affects bones in the spine, it can lead to numbness and tingling (due to pinched nerves) and abnormal spinal curvature. In the leg bones, the disease can cause bowed legs and difficulty walking.

Early-onset Paget disease of bone is a less common form of the disease that appears in a person's teens or twenties. Its features are similar to those of the classic form of the disease, although it is more likely to affect the skull, spine, and ribs (the axial skeleton) and the small bones of the hands. The early-onset form of the disorder is also associated with hearing loss early in life.

A rare type of bone cancer called osteosarcoma has been associated with Paget disease of bone. This type of cancer probably occurs in less than 1 in 1,000 people with this disease.  https://medlineplus.gov/genetics/condition/paget-disease-of-bone

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.
Nephrocalcinosis
MedGen UID:
10222
Concept ID:
C0027709
Disease or Syndrome
Nephrocalcinosis is the deposition of calcium salts in renal parenchyma.
Coronary artery atherosclerosis
MedGen UID:
3623
Concept ID:
C0010054
Disease or Syndrome
Reduction of the diameter of the coronary arteries as the result of an accumulation of atheromatous plaques within the walls of the coronary arteries, which increases the risk of myocardial ischemia.
Left ventricular hypertrophy
MedGen UID:
57442
Concept ID:
C0149721
Disease or Syndrome
Enlargement or increased size of the heart left ventricle.
Recurrent fractures
MedGen UID:
42094
Concept ID:
C0016655
Injury or Poisoning
The repeated occurrence of bone fractures (implying an abnormally increased tendency for fracture).
Osteoarthritis
MedGen UID:
45244
Concept ID:
C0029408
Disease or Syndrome
Osteoarthritis (OA) is a degenerative disease of the joints characterized by degradation of the hyaline articular cartilage and remodeling of the subchondral bone with sclerosis (Meulenbelt et al., 2006). Clinical problems include pain and joint stiffness often leading to significant disability and joint replacement. Osteoarthritis exhibits a clear predilection for specific joints; it appears most commonly in the hip and knee joints and lumbar and cervical spine, as well as in the distal interphalangeal and the first carpometacarpal (base of thumb) and proximal interphalangeal joints of the hand; however, patients with osteoarthritis may have 1, a few, or all of these sites affected (Stefansson et al., 2003). According to a conservative estimate, greater than 70% of the population of the United States at age 65 years is affected by the disease, reflecting its age dependence. Genetic Heterogeneity of Susceptibility to Osteoarthritis Susceptibility to osteoarthritis has been associated with variation in other genes: OS2 (140600) with variation in the MATN3 gene (602109) on chromosome 2p24; OS3 (607850) with variation in the ASPN gene (608135) on chromosome 9q22; and OS5 (612400) with variation in the GDF5 gene (601146) on chromosome 20q11. Other susceptibility loci for osteoarthritis have been mapped to chromosomes 2q33 (OS4; 610839) and 3p24 (OS6; 612401).
Elevated circulating alkaline phosphatase concentration
MedGen UID:
727252
Concept ID:
C1314665
Finding
Abnormally increased serum levels of alkaline phosphatase activity.

Professional guidelines

PubMed

Singer FR
Best Pract Res Clin Rheumatol 2020 Jun;34(3):101506. Epub 2020 Apr 11 doi: 10.1016/j.berh.2020.101506. PMID: 32291204
Griz L, Fontan D, Mesquita P, Lazaretti-Castro M, Borba VZ, Borges JL, Fontenele T, Maia J, Bandeira F; Brazilian Society of Endocrinology and Metabolism
Arq Bras Endocrinol Metabol 2014 Aug;58(6):587-99. doi: 10.1590/0004-2730000002941. PMID: 25211441
Nardone V, D'Asta F, Brandi ML
Clinics (Sao Paulo) 2014 Jun;69(6):438-46. doi: 10.6061/clinics/2014(06)12. PMID: 24964310Free PMC Article

Recent clinical studies

Etiology

Pianou NK, Stavrou PZ, Vlontzou E, Rondogianni P, Exarhos DN, Datseris IE
Hell J Nucl Med 2019 Jan-Apr;22(1):6-9. Epub 2019 Mar 7 doi: 10.1967/s002449910952. PMID: 30843003
Cremers S, Drake MT, Ebetino FH, Bilezikian JP, Russell RGG
Br J Clin Pharmacol 2019 Jun;85(6):1052-1062. Epub 2019 Feb 28 doi: 10.1111/bcp.13867. PMID: 30650219Free PMC Article
Corral-Gudino L, Tan AJ, Del Pino-Montes J, Ralston SH
Cochrane Database Syst Rev 2017 Dec 1;12(12):CD004956. doi: 10.1002/14651858.CD004956.pub3. PMID: 29192423Free PMC Article
Ottaviani G, Jaffe N
Cancer Treat Res 2009;152:3-13. doi: 10.1007/978-1-4419-0284-9_1. PMID: 20213383
Whitehouse RW
Semin Musculoskelet Radiol 2002 Dec;6(4):313-22. doi: 10.1055/s-2002-36730. PMID: 12541188

Diagnosis

Singer FR
Best Pract Res Clin Rheumatol 2020 Jun;34(3):101506. Epub 2020 Apr 11 doi: 10.1016/j.berh.2020.101506. PMID: 32291204
Cremers S, Drake MT, Ebetino FH, Bilezikian JP, Russell RGG
Br J Clin Pharmacol 2019 Jun;85(6):1052-1062. Epub 2019 Feb 28 doi: 10.1111/bcp.13867. PMID: 30650219Free PMC Article
Fassio A, Idolazzi L, Rossini M, Viapiana O, Gatti D
Reumatismo 2016 Dec 16;68(3):154-158. doi: 10.4081/reumatismo.2016.917. PMID: 27981818
Rousière M, Michou L, Cornélis F, Orcel P
Best Pract Res Clin Rheumatol 2003 Dec;17(6):1019-41. doi: 10.1016/j.berh.2003.09.003. PMID: 15123049
Cundy T
Semin Musculoskelet Radiol 2002 Dec;6(4):307-12. doi: 10.1055/s-2002-36729. PMID: 12541187

Therapy

Singer FR
Best Pract Res Clin Rheumatol 2020 Jun;34(3):101506. Epub 2020 Apr 11 doi: 10.1016/j.berh.2020.101506. PMID: 32291204
Cremers S, Drake MT, Ebetino FH, Bilezikian JP, Russell RGG
Br J Clin Pharmacol 2019 Jun;85(6):1052-1062. Epub 2019 Feb 28 doi: 10.1111/bcp.13867. PMID: 30650219Free PMC Article
Fassio A, Idolazzi L, Rossini M, Viapiana O, Gatti D
Reumatismo 2016 Dec 16;68(3):154-158. doi: 10.4081/reumatismo.2016.917. PMID: 27981818
Cundy T
Semin Musculoskelet Radiol 2002 Dec;6(4):307-12. doi: 10.1055/s-2002-36729. PMID: 12541187
Goa KL, Balfour JA
Drugs Aging 1998 Jul;13(1):83-91; discussion 92. doi: 10.2165/00002512-199813010-00008. PMID: 9679211

Prognosis

Pianou NK, Stavrou PZ, Vlontzou E, Rondogianni P, Exarhos DN, Datseris IE
Hell J Nucl Med 2019 Jan-Apr;22(1):6-9. Epub 2019 Mar 7 doi: 10.1967/s002449910952. PMID: 30843003
Paccou J, Michou L, Kolta S, Debiais F, Cortet B, Guggenbuhl P
Joint Bone Spine 2018 Dec;85(6):693-699. Epub 2018 Mar 2 doi: 10.1016/j.jbspin.2018.01.007. PMID: 29407041
Michou L, Orcel P
Joint Bone Spine 2016 Dec;83(6):650-655. Epub 2016 Apr 7 doi: 10.1016/j.jbspin.2016.02.011. PMID: 27068613
Numan MS, Amiable N, Brown JP, Michou L
Drug Des Devel Ther 2015;9:4695-707. Epub 2015 Aug 14 doi: 10.2147/DDDT.S88845. PMID: 26316708Free PMC Article
Ottaviani G, Jaffe N
Cancer Treat Res 2009;152:3-13. doi: 10.1007/978-1-4419-0284-9_1. PMID: 20213383

Clinical prediction guides

Pianou NK, Stavrou PZ, Vlontzou E, Rondogianni P, Exarhos DN, Datseris IE
Hell J Nucl Med 2019 Jan-Apr;22(1):6-9. Epub 2019 Mar 7 doi: 10.1967/s002449910952. PMID: 30843003
Paccou J, Michou L, Kolta S, Debiais F, Cortet B, Guggenbuhl P
Joint Bone Spine 2018 Dec;85(6):693-699. Epub 2018 Mar 2 doi: 10.1016/j.jbspin.2018.01.007. PMID: 29407041
Corral-Gudino L, Tan AJ, Del Pino-Montes J, Ralston SH
Cochrane Database Syst Rev 2017 Dec 1;12(12):CD004956. doi: 10.1002/14651858.CD004956.pub3. PMID: 29192423Free PMC Article
Numan MS, Amiable N, Brown JP, Michou L
Drug Des Devel Ther 2015;9:4695-707. Epub 2015 Aug 14 doi: 10.2147/DDDT.S88845. PMID: 26316708Free PMC Article
Haugeberg G
Best Pract Res Clin Rheumatol 2008 Dec;22(6):1127-39. doi: 10.1016/j.berh.2008.09.016. PMID: 19041081

Recent systematic reviews

Corral-Gudino L, Tan AJ, Del Pino-Montes J, Ralston SH
Cochrane Database Syst Rev 2017 Dec 1;12(12):CD004956. doi: 10.1002/14651858.CD004956.pub3. PMID: 29192423Free PMC Article
Hess LM, Jeter JM, Benham-Hutchins M, Alberts DS
Am J Med 2008 Jun;121(6):475-483.e3. doi: 10.1016/j.amjmed.2008.01.047. PMID: 18501224Free PMC Article

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