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Autosomal recessive osteopetrosis 6(OPTB6)

MedGen UID:
409754
Concept ID:
C1969093
Disease or Syndrome
Synonyms: Osteopetrosis autosomal recessive intermediate form; PLEKHM1-Related Autosomal Recessive Osteopetrosis
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): PLEKHM1 (17q21.31)
 
Monarch Initiative: MONDO:0012679
OMIM®: 611497
Orphanet: ORPHA210110

Definition

A few individuals have been diagnosed with intermediate autosomal osteopetrosis (IAO), a form of the disorder that can have either an autosomal dominant or an autosomal recessive pattern of inheritance. The signs and symptoms of this condition become noticeable in childhood and include an increased risk of bone fracture and anemia. People with this form of the disorder typically do not have life-threatening bone marrow abnormalities. However, some affected individuals have had abnormal calcium deposits (calcifications) in the brain, intellectual disability, and a form of kidney disease called renal tubular acidosis.

Other features of autosomal recessive osteopetrosis can include slow growth and short stature, dental abnormalities, and an enlarged liver and spleen (hepatosplenomegaly). Depending on the genetic changes involved, people with severe osteopetrosis can also have brain abnormalities, intellectual disability, or recurrent seizures (epilepsy).

Autosomal recessive osteopetrosis (ARO) is a more severe form of the disorder that becomes apparent in early infancy. Affected individuals have a high risk of bone fracture resulting from seemingly minor bumps and falls. Their abnormally dense skull bones pinch nerves in the head and face (cranial nerves), often resulting in vision loss, hearing loss, and paralysis of facial muscles. Dense bones can also impair the function of bone marrow, preventing it from producing new blood cells and immune system cells. As a result, people with severe osteopetrosis are at risk of abnormal bleeding, a shortage of red blood cells (anemia), and recurrent infections. In the most severe cases, these bone marrow abnormalities can be life-threatening in infancy or early childhood.

In individuals with ADO who develop signs and symptoms, the major features of the condition include multiple bone fractures after minor injury, abnormal side-to-side curvature of the spine (scoliosis) or other spinal abnormalities, arthritis in the hips, and a bone infection called osteomyelitis. These problems usually become apparent in late childhood or adolescence.

Autosomal dominant osteopetrosis (ADO), which is also called Albers-Schönberg disease, is typically the mildest type of the disorder. Some affected individuals have no symptoms. In affected people with no symptoms, the unusually dense bones may be discovered by accident when an x-ray is done for another reason. 

Osteopetrosis is a bone disease that makes bone tissue abnormally compact and dense and also prone to breakage (fracture). Researchers have described several major types of osteopetrosis, which are usually distinguished by their pattern of inheritance: autosomal dominant or autosomal recessive. The different types of the disorder can also be distinguished by the severity of their signs and symptoms. [from MedlinePlus Genetics]

Clinical features

From HPO
Erlenmeyer flask deformity of the femurs
MedGen UID:
383796
Concept ID:
C1855895
Finding
Flaring of distal femur.
Osteopetrosis
MedGen UID:
18223
Concept ID:
C0029454
Finding
Abnormally increased formation of dense trabecular bone tissue. Despite the increased density of bone tissue, osteopetrotic bones tend to be more fracture-prone than normal.
Dense metaphyseal bands
MedGen UID:
866573
Concept ID:
C4020919
Finding
Dense radiopaque bands of bone which are thicker than the adjacent diaphyseal cortex and may form at the metaphysis of growing bones. They appear on radiographs as bone that is more radiopaque that the adjacent diaphyseal cortex.
Cortical sclerosis of the iliac wing
MedGen UID:
1779707
Concept ID:
C5539766
Pathologic Function
Increased density related to increased bone mass in the outermost layer (edge) of the iliac wing.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVAutosomal recessive osteopetrosis 6

Professional guidelines

PubMed

Even-Or E, Schiesel G, Simanovsky N, NaserEddin A, Zaidman I, Elpeleg O, Mor-Shaked H, Stepensky P
Bone 2022 Jan;154:116229. Epub 2021 Oct 8 doi: 10.1016/j.bone.2021.116229. PMID: 34624559
Kapelushnik J, Shalev C, Yaniv I, Aker M, Carmi R, Cohen Z, Mozer A, Schulman C, Stein G, Or R
Bone Marrow Transplant 2001 Jan;27(2):129-32. doi: 10.1038/sj.bmt.1702743. PMID: 11281380

Recent clinical studies

Etiology

Hofstaetter JG, Atkins GJ, Kato H, Kogawa M, Blouin S, Misof BM, Roschger P, Evdokiou A, Yang D, Solomon LB, Findlay DM, Ito N
Calcif Tissue Int 2022 Oct;111(4):430-444. Epub 2022 May 26 doi: 10.1007/s00223-022-00988-8. PMID: 35618777Free PMC Article
Even-Or E, Schiesel G, Simanovsky N, NaserEddin A, Zaidman I, Elpeleg O, Mor-Shaked H, Stepensky P
Bone 2022 Jan;154:116229. Epub 2021 Oct 8 doi: 10.1016/j.bone.2021.116229. PMID: 34624559
Li L, Lv SS, Wang C, Yue H, Zhang ZL
Mol Med Rep 2019 Jun;19(6):5030-5038. Epub 2019 Apr 3 doi: 10.3892/mmr.2019.10123. PMID: 30942407
Rees H, Ang LC, Casey R, George DH
Pediatr Neurosurg 1995;22(6):321-7. doi: 10.1159/000120923. PMID: 7577667
Gerritsen EJ, Vossen JM, van Loo IH, Hermans J, Helfrich MH, Griscelli C, Fischer A
Pediatrics 1994 Feb;93(2):247-53. PMID: 8121736

Diagnosis

Even-Or E, Schiesel G, Simanovsky N, NaserEddin A, Zaidman I, Elpeleg O, Mor-Shaked H, Stepensky P
Bone 2022 Jan;154:116229. Epub 2021 Oct 8 doi: 10.1016/j.bone.2021.116229. PMID: 34624559
Lee A, Cortez S, Yang P, Aum D, Singh P, Gooch C, Smyth M
Childs Nerv Syst 2021 Dec;37(12):3695-3703. Epub 2021 Sep 14 doi: 10.1007/s00381-021-05345-y. PMID: 34519872
Moore JB, Hoang TD, Shwayhat AF
Mil Med 2017 Mar;182(3):e1886-e1888. doi: 10.7205/MILMED-D-16-00234. PMID: 28290981
Stoker DJ
Semin Musculoskelet Radiol 2002 Dec;6(4):299-305. doi: 10.1055/s-2002-36728. PMID: 12541186
Gerritsen EJ, Vossen JM, van Loo IH, Hermans J, Helfrich MH, Griscelli C, Fischer A
Pediatrics 1994 Feb;93(2):247-53. PMID: 8121736

Therapy

De Cuyper E, De Cuyper C, Willems L, Casselman J, Dhooge I, Van Hoecke H
J Int Adv Otol 2021 Nov;17(6):551-558. doi: 10.5152/iao.2021.21266. PMID: 35177394Free PMC Article
Dunphy L, Warfield A, Williams R
BMJ Case Rep 2019 Mar 20;12(3) doi: 10.1136/bcr-2018-224452. PMID: 30898950Free PMC Article
Shadur B, Zaidman I, NaserEddin A, Lokshin E, Hussein F, Oron HC, Avni B, Grisariu S, Stepensky P
Pediatr Blood Cancer 2018 Jun;65(6):e27010. Epub 2018 Feb 22 doi: 10.1002/pbc.27010. PMID: 29469225
Otero JE, Gottesman GS, McAlister WH, Mumm S, Madson KL, Kiffer-Moreira T, Sheen C, Millán JL, Ericson KL, Whyte MP
J Bone Miner Res 2013 Feb;28(2):419-30. doi: 10.1002/jbmr.1752. PMID: 22972716
Tolar J, Bonfim C, Grewal S, Orchard P
Bone Marrow Transplant 2006 Dec;38(12):783-7. Epub 2006 Nov 6 doi: 10.1038/sj.bmt.1705533. PMID: 17086207

Prognosis

Hofstaetter JG, Atkins GJ, Kato H, Kogawa M, Blouin S, Misof BM, Roschger P, Evdokiou A, Yang D, Solomon LB, Findlay DM, Ito N
Calcif Tissue Int 2022 Oct;111(4):430-444. Epub 2022 May 26 doi: 10.1007/s00223-022-00988-8. PMID: 35618777Free PMC Article
Lee A, Cortez S, Yang P, Aum D, Singh P, Gooch C, Smyth M
Childs Nerv Syst 2021 Dec;37(12):3695-3703. Epub 2021 Sep 14 doi: 10.1007/s00381-021-05345-y. PMID: 34519872
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
Moore JB, Hoang TD, Shwayhat AF
Mil Med 2017 Mar;182(3):e1886-e1888. doi: 10.7205/MILMED-D-16-00234. PMID: 28290981
Gerritsen EJ, Vossen JM, van Loo IH, Hermans J, Helfrich MH, Griscelli C, Fischer A
Pediatrics 1994 Feb;93(2):247-53. PMID: 8121736

Clinical prediction guides

Hofstaetter JG, Atkins GJ, Kato H, Kogawa M, Blouin S, Misof BM, Roschger P, Evdokiou A, Yang D, Solomon LB, Findlay DM, Ito N
Calcif Tissue Int 2022 Oct;111(4):430-444. Epub 2022 May 26 doi: 10.1007/s00223-022-00988-8. PMID: 35618777Free PMC Article
Zirngibl RA, Wang A, Yao Y, Manolson MF, Krueger J, Dupuis L, Mendoza-Londono R, Voronov I
J Cell Biochem 2019 Oct;120(10):17180-17193. Epub 2019 May 20 doi: 10.1002/jcb.28979. PMID: 31111556
Li L, Lv SS, Wang C, Yue H, Zhang ZL
Mol Med Rep 2019 Jun;19(6):5030-5038. Epub 2019 Apr 3 doi: 10.3892/mmr.2019.10123. PMID: 30942407
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
Ajmal M, Mir A, Wahid S, Khor CC, Foo JN, Siddiqi S, Kauser M, Malik SA, Nasir M
BMC Med Genet 2017 Dec 13;18(1):148. doi: 10.1186/s12881-017-0506-4. PMID: 29237407Free PMC Article

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