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Paget disease of bone 2, early-onset(PDB2)

MedGen UID:
899166
Concept ID:
C4085251
Disease or Syndrome
Synonyms: Paget disease of bone 2; PDB2
 
Gene (location): TNFRSF11A (18q21.33)
Related gene: SQSTM1
 
Monarch Initiative: MONDO:0011183
OMIM®: 602080

Definition

Paget disease (PDB) is a metabolic bone disease characterized by focal abnormalities of increased bone turnover affecting one or more sites throughout the skeleton, primarily the axial skeleton. Bone lesions in this disorder show evidence of increased osteoclastic bone resorption and disorganized bone structure. See reviews by Ralston et al. (2008) and Ralston and Albagha (2014). For a discussion of genetic heterogeneity of Paget disease of bone, see 167250. [from OMIM]

Additional description

From MedlinePlus Genetics
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.

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.

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.

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.

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.

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).  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.
Hydroxyprolinuria
MedGen UID:
215298
Concept ID:
C0948585
Finding
An increased concentration of 4-hydroxy-L-proline in the urine.
Short femur
MedGen UID:
87499
Concept ID:
C0345375
Congenital Abnormality
An abnormal shortening of the femur.
Osteosclerosis of the ulna
MedGen UID:
867333
Concept ID:
C4021697
Disease or Syndrome
Osteosclerosis (increased density related to increased bone mass) of the ulna.
Bilateral conductive hearing impairment
MedGen UID:
99093
Concept ID:
C0452136
Disease or Syndrome
A bilateral type of conductive hearing impairment.
Headache
MedGen UID:
9149
Concept ID:
C0018681
Sign or Symptom
Cephalgia, or pain sensed in various parts of the head, not confined to the area of distribution of any nerve.
Cranial nerve paralysis
MedGen UID:
57717
Concept ID:
C0151311
Disease or Syndrome
Injury to any of the cranial nerves or their nuclei in the brain resulting in muscle weakness.
Paraparesis
MedGen UID:
113150
Concept ID:
C0221166
Sign or Symptom
Weakness or partial paralysis in the lower limbs.
Brain stem compression
MedGen UID:
82849
Concept ID:
C0270680
Disease or Syndrome
Tetraparesis
MedGen UID:
78731
Concept ID:
C0270790
Finding
Weakness of all four limbs.
Long-tract signs
MedGen UID:
356397
Concept ID:
C1865903
Finding
Long-tract signs refer to symptoms that are attributable to the involvement of the long fiber tracts in the spinal cord, which connect the spinal cord to the brain and mediate spinal and motor functions.
Recurrent long bone fractures
MedGen UID:
66802
Concept ID:
C0240231
Finding
An increased tendency to fractures of the long bones (Mainly, the femur, tibia, fibula, humerus, radius, and ulna).
Vertebral compression fracture
MedGen UID:
75497
Concept ID:
C0262431
Finding
Increased susceptibility to fractures
MedGen UID:
234655
Concept ID:
C1390474
Finding
An abnormally increased tendency to fractures of bones caused by an abnormal reduction in bone strength that is generally associated with an increased risk of fracture.
Sandwich appearance of vertebral bodies
MedGen UID:
340470
Concept ID:
C1850134
Finding
Sclerosis of skull base
MedGen UID:
377095
Concept ID:
C1851714
Finding
Increased bone density of the skull base without significant changes in bony contour.
Bowing of the long bones
MedGen UID:
340849
Concept ID:
C1855340
Congenital Abnormality
A bending or abnormal curvature of a long bone.
Femoral bowing
MedGen UID:
347888
Concept ID:
C1859461
Finding
Bowing (abnormal curvature) of the femur.
Osteolysis
MedGen UID:
1648424
Concept ID:
C4721411
Pathologic Function
Osteolysis refers to the destruction of bone through bone resorption with removal or loss of calcium.
Hypercalcemia
MedGen UID:
5686
Concept ID:
C0020437
Disease or Syndrome
An abnormally increased calcium concentration in the blood.
Elevated circulating alkaline phosphatase concentration
MedGen UID:
727252
Concept ID:
C1314665
Finding
Abnormally increased serum levels of alkaline phosphatase activity.
Premature loss of teeth
MedGen UID:
66678
Concept ID:
C0232513
Finding
Exfoliation of a tooth more than 2 SD earlier than the normal age for the deciduous teeth and not related to traume or neglect. Exfoliation of a permanent tooth is per se abnormal.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  

Recent clinical studies

Etiology

Johnson MA, Klickstein JA, Khanna R, Gou Y; Cure VCP Disease Research Consortium, Raman M
Neurobiol Dis 2022 Jul;169:105722. Epub 2022 Apr 8 doi: 10.1016/j.nbd.2022.105722. PMID: 35405261Free PMC Article
Wang SC, Smith CD, Lombardo DM, Kimonis V
Neuromuscul Disord 2021 Aug;31(8):701-705. Epub 2021 Jun 12 doi: 10.1016/j.nmd.2021.06.005. PMID: 34244020
Qi X, Pang Q, Wang J, Zhao Z, Wang O, Xu L, Mao J, Jiang Y, Li M, Xing X, Yu W, Asan, Xia W
Calcif Tissue Int 2017 Aug;101(2):159-169. Epub 2017 Apr 7 doi: 10.1007/s00223-017-0269-0. PMID: 28389692
van der Zee J, Van Langenhove T, Kovacs GG, Dillen L, Deschamps W, Engelborghs S, Matěj R, Vandenbulcke M, Sieben A, Dermaut B, Smets K, Van Damme P, Merlin C, Laureys A, Van Den Broeck M, Mattheijssens M, Peeters K, Benussi L, Binetti G, Ghidoni R, Borroni B, Padovani A, Archetti S, Pastor P, Razquin C, Ortega-Cubero S, Hernández I, Boada M, Ruiz A, de Mendonça A, Miltenberger-Miltényi G, do Couto FS, Sorbi S, Nacmias B, Bagnoli S, Graff C, Chiang HH, Thonberg H, Perneczky R, Diehl-Schmid J, Alexopoulos P, Frisoni GB, Bonvicini C, Synofzik M, Maetzler W, vom Hagen JM, Schöls L, Haack TB, Strom TM, Prokisch H, Dols-Icardo O, Clarimón J, Lleó A, Santana I, Almeida MR, Santiago B, Heneka MT, Jessen F, Ramirez A, Sanchez-Valle R, Llado A, Gelpi E, Sarafov S, Tournev I, Jordanova A, Parobkova E, Fabrizi GM, Testi S, Salmon E, Ströbel T, Santens P, Robberecht W, De Jonghe P, Martin JJ, Cras P, Vandenberghe R, De Deyn PP, Cruts M, Sleegers K, Van Broeckhoven C
Acta Neuropathol 2014 Sep;128(3):397-410. Epub 2014 Jun 5 doi: 10.1007/s00401-014-1298-7. PMID: 24899140Free PMC Article
Daroszewska A, Ralston SH
Nat Clin Pract Rheumatol 2006 May;2(5):270-7. doi: 10.1038/ncprheum0172. PMID: 16932700

Diagnosis

Wang SC, Smith CD, Lombardo DM, Kimonis V
Neuromuscul Disord 2021 Aug;31(8):701-705. Epub 2021 Jun 12 doi: 10.1016/j.nmd.2021.06.005. PMID: 34244020
Scotto di Carlo F, Pazzaglia L, Esposito T, Gianfrancesco F
J Bone Miner Res 2020 Aug;35(8):1387-1398. Epub 2020 Feb 19 doi: 10.1002/jbmr.3964. PMID: 31991009
Shamirian S, Nalbandian A, Khare M, Castellani R, Kim R, Kimonis VE
Alzheimer Dis Assoc Disord 2015 Jan-Mar;29(1):90-3. doi: 10.1097/WAD.0b013e318298e54f. PMID: 23715207
Spina S, Van Laar AD, Murrell JR, Hamilton RL, Kofler JK, Epperson F, Farlow MR, Lopez OL, Quinlan J, DeKosky ST, Ghetti B
Eur J Neurol 2013 Feb;20(2):251-8. Epub 2012 Aug 20 doi: 10.1111/j.1468-1331.2012.03831.x. PMID: 22900631Free PMC Article
Osterberg PH, Wallace RG, Adams DA, Crone RS, Dickson GR, Kanis JA, Mollan RA, Nevin NC, Sloan J, Toner PG
J Bone Joint Surg Br 1988 Mar;70(2):255-60. doi: 10.1302/0301-620X.70B2.3346299. PMID: 3346299

Therapy

Johnson MA, Klickstein JA, Khanna R, Gou Y; Cure VCP Disease Research Consortium, Raman M
Neurobiol Dis 2022 Jul;169:105722. Epub 2022 Apr 8 doi: 10.1016/j.nbd.2022.105722. PMID: 35405261Free PMC Article
Cheng C, Weiss L, Leinonen H, Shmara A, Yin HZ, Ton T, Do A, Lee J, Ta L, Mohanty E, Vargas J, Weiss J, Palczewski K, Kimonis V
J Transl Med 2022 Jan 8;20(1):21. doi: 10.1186/s12967-021-03186-6. PMID: 34998409Free PMC Article

Prognosis

Craven M, Vajravelu ME, Shekdar KV, Levine MA, Mumm S, Whyte MP, Mancilla EE
Bone 2023 May;170:116698. Epub 2023 Feb 3 doi: 10.1016/j.bone.2023.116698. PMID: 36740137Free PMC Article
Scotto di Carlo F, Pazzaglia L, Esposito T, Gianfrancesco F
J Bone Miner Res 2020 Aug;35(8):1387-1398. Epub 2020 Feb 19 doi: 10.1002/jbmr.3964. PMID: 31991009
Guo L, Elcioglu NH, Karalar OK, Topkar MO, Wang Z, Sakamoto Y, Matsumoto N, Miyake N, Nishimura G, Ikegawa S
J Hum Genet 2018 Jun;63(6):769-774. Epub 2018 Mar 22 doi: 10.1038/s10038-018-0447-6. PMID: 29568001
Shamirian S, Nalbandian A, Khare M, Castellani R, Kim R, Kimonis VE
Alzheimer Dis Assoc Disord 2015 Jan-Mar;29(1):90-3. doi: 10.1097/WAD.0b013e318298e54f. PMID: 23715207

Clinical prediction guides

Cheng C, Weiss L, Leinonen H, Shmara A, Yin HZ, Ton T, Do A, Lee J, Ta L, Mohanty E, Vargas J, Weiss J, Palczewski K, Kimonis V
J Transl Med 2022 Jan 8;20(1):21. doi: 10.1186/s12967-021-03186-6. PMID: 34998409Free PMC Article
Wang SC, Smith CD, Lombardo DM, Kimonis V
Neuromuscul Disord 2021 Aug;31(8):701-705. Epub 2021 Jun 12 doi: 10.1016/j.nmd.2021.06.005. PMID: 34244020
Guo L, Elcioglu NH, Karalar OK, Topkar MO, Wang Z, Sakamoto Y, Matsumoto N, Miyake N, Nishimura G, Ikegawa S
J Hum Genet 2018 Jun;63(6):769-774. Epub 2018 Mar 22 doi: 10.1038/s10038-018-0447-6. PMID: 29568001
Rodriguez-Ortiz CJ, Flores JC, Valenzuela JA, Rodriguez GJ, Zumkehr J, Tran DN, Kimonis VE, Kitazawa M
Am J Pathol 2016 Jun;186(6):1623-34. Epub 2016 Apr 20 doi: 10.1016/j.ajpath.2016.02.007. PMID: 27106764Free PMC Article
Takata T, Kimura Y, Ohnuma Y, Kawawaki J, Kakiyama Y, Tanaka K, Kakizuka A
J Struct Biol 2012 Aug;179(2):93-103. Epub 2012 Jun 19 doi: 10.1016/j.jsb.2012.06.005. PMID: 22728077

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