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Osteopetrosis autosomal recessive 2(OPTB2)

MedGen UID:
342420
Concept ID:
C1850126
Disease or Syndrome
Synonyms: OPTB2; Osteopetrosis osteoclast-poor; OSTEOPETROSIS, MILD AUTOSOMAL RECESSIVE FORM; TNFSF11-Related Autosomal Recessive Osteopetrosis
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Sources: HPO, OMIM, 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).
Autosomal recessive inheritance (HPO, OMIM, Orphanet)
 
Gene (location): TNFSF11 (13q14.11)
OMIM®: 259710

Definition

Osteopetrosis is a bone disease that makes bones abnormally dense and prone to breakage (fracture). Researchers have described several major types of osteopetrosis, which are usually distinguished by their pattern of inheritance: autosomal dominant, autosomal recessive, or X-linked. The different types of the disorder can also be distinguished by the severity of their signs and symptoms.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 these people, the unusually dense bones may be discovered by accident when an x-ray is done for another reason. In affected individuals who develop signs and symptoms, the major features of the condition include multiple bone fractures, 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 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.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).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.Rarely, osteopetrosis can have an X-linked pattern of inheritance. In addition to abnormally dense bones, the X-linked form of the disorder is characterized by abnormal swelling caused by a buildup of fluid (lymphedema) and a condition called anhydrotic ectodermal dysplasia that affects the skin, hair, teeth, and sweat glands. Affected individuals also have a malfunctioning immune system (immunodeficiency), which allows severe, recurrent infections to develop. Researchers often refer to this condition as OL-EDA-ID, an acronym derived from each of the major features of the disorder.
[from GHR]

Clinical features

Genu valgum
MedGen UID:
154364
Concept ID:
C0576093
Anatomical Abnormality
An inward slant of the thigh in which the knees are close together and the ankles far apart. Genu valgum can develop due to skeletal and joint dysplasias (e.g., OSTEOARTHRITIS; HURLER SYNDROME); and malnutrition (e.g., RICKETS; FLUORIDE POISONING).
Hepatosplenomegaly
MedGen UID:
9225
Concept ID:
C0019214
Sign or Symptom
An abnormal enlargement of both the liver and spleen.
Facial paralysis
MedGen UID:
5101
Concept ID:
C0015469
Disease or Syndrome
Complete loss of ability to move facial muscles innervated by the facial nerve (i.e., the seventh cranial nerve).
Pancytopenia
MedGen UID:
18281
Concept ID:
C0030312
Disease or Syndrome
A finding of low numbers of red and white blood cells and platelets in the peripheral blood.
Thrombocytopenia
MedGen UID:
52737
Concept ID:
C0040034
Disease or Syndrome
A reduction in the number of circulating thrombocytes.
Anemia
MedGen UID:
56401
Concept ID:
C0162119
Finding
A laboratory test result demonstrating decreased levels of hemoglobin in a biological specimen.
Extramedullary hematopoiesis
MedGen UID:
220947
Concept ID:
C1292120
Finding
Facial paralysis
MedGen UID:
5101
Concept ID:
C0015469
Disease or Syndrome
Complete loss of ability to move facial muscles innervated by the facial nerve (i.e., the seventh cranial nerve).
Hepatosplenomegaly
MedGen UID:
9225
Concept ID:
C0019214
Sign or Symptom
An abnormal enlargement of both the liver and spleen.
Mandibular osteomyelitis
MedGen UID:
266218
Concept ID:
C1290708
Disease or Syndrome
Osteomyelitis of the lower jaw.
Diaphyseal dysplasia
MedGen UID:
4268
Concept ID:
C0011989
Finding
Camurati-Engelmann disease (CED) is characterized by hyperostosis of the long bones and the skull, proximal muscle weakness, limb pain, a wide-based, waddling gait, and joint contractures. Facial features such as macrocephaly, frontal bossing, enlargement of the mandible, proptosis, and cranial nerve impingement resulting in facial palsy are seen in severely affected individuals later in life.
Recurrent fractures
MedGen UID:
42094
Concept ID:
C0016655
Injury or Poisoning
Injuries involving the breaking of either several bones or one bone in two or more places.
Osteopetrosis
MedGen UID:
18223
Concept ID:
C0029454
Finding
A rare genetic disorder inherited in an autosomal dominant, autosomal recessive, or X-linked recessive pattern. In the majority of cases it is caused by mutations in the CLCN7, TCIRG1, or IKBKG genes. It is characterized by excessive bone formation due to the failure of osteoclasts to resorb bone. It manifests with deformities, fractures, hepatosplenomegaly, anemia, and extramedullary hematopoiesis.
Mandibular prognathia
MedGen UID:
98316
Concept ID:
C0399526
Finding
Abnormal prominence of the chin related to increased length of the mandible.
Genu valgum
MedGen UID:
154364
Concept ID:
C0576093
Anatomical Abnormality
An inward slant of the thigh in which the knees are close together and the ankles far apart. Genu valgum can develop due to skeletal and joint dysplasias (e.g., OSTEOARTHRITIS; HURLER SYNDROME); and malnutrition (e.g., RICKETS; FLUORIDE POISONING).
Mandibular osteomyelitis
MedGen UID:
266218
Concept ID:
C1290708
Disease or Syndrome
Osteomyelitis of the lower jaw.
Cranial hyperostosis
MedGen UID:
318629
Concept ID:
C1832451
Finding
Excessive growth of the bones of cranium, i.e., of the skull.
Carious teeth
MedGen UID:
8288
Concept ID:
C0011334
Disease or Syndrome
Caries is a multifactorial bacterial infection affecting the structure of the tooth. This term has been used to describe the presence of more than expected dental caries.
Facial paralysis
MedGen UID:
5101
Concept ID:
C0015469
Disease or Syndrome
Complete loss of ability to move facial muscles innervated by the facial nerve (i.e., the seventh cranial nerve).
Persistence of primary teeth
MedGen UID:
75597
Concept ID:
C0266050
Disease or Syndrome
Persistence of the primary teeth beyond the age by which they normally are shed and replaced by the permanent teeth.
Mandibular prognathia
MedGen UID:
98316
Concept ID:
C0399526
Finding
Abnormal prominence of the chin related to increased length of the mandible.
Mandibular osteomyelitis
MedGen UID:
266218
Concept ID:
C1290708
Disease or Syndrome
Osteomyelitis of the lower jaw.
Cranial hyperostosis
MedGen UID:
318629
Concept ID:
C1832451
Finding
Excessive growth of the bones of cranium, i.e., of the skull.
Chronic rhinitis due to narrow nasal airway
MedGen UID:
870858
Concept ID:
C4025318
Disease or Syndrome
Optic atrophy
MedGen UID:
18180
Concept ID:
C0029124
Disease or Syndrome
A disorder characterized by loss of optic nerve fibers. It may be inherited or acquired. Acquired causes include ischemia, optic nerve neuropathy, glaucoma, trauma, radiation, brain tumors, and multiple sclerosis. It leads to vision disturbances.
Blindness
MedGen UID:
99138
Concept ID:
C0456909
Finding
Blindness is the condition of lacking visual perception due to physiological or neurological factors.

Recent clinical studies

Etiology

Zhang H, Xu Y, Yue H, Wang C, Gu J, He J, Fu W, Hu W, Zhang Z
Int J Mol Med 2018 Jun;41(6):3662-3670. Epub 2018 Mar 7 doi: 10.3892/ijmm.2018.3542. PMID: 29512769
Teti A, Econs MJ
Bone 2017 Sep;102:50-59. Epub 2017 Feb 4 doi: 10.1016/j.bone.2017.02.002. PMID: 28167345
Pangrazio A, Cassani B, Guerrini MM, Crockett JC, Marrella V, Zammataro L, Strina D, Schulz A, Schlack C, Kornak U, Mellis DJ, Duthie A, Helfrich MH, Durandy A, Moshous D, Vellodi A, Chiesa R, Veys P, Lo Iacono N, Vezzoni P, Fischer A, Villa A, Sobacchi C
J Bone Miner Res 2012 Feb;27(2):342-51. doi: 10.1002/jbmr.559. PMID: 22271396Free PMC Article
Frattini A, Pangrazio A, Susani L, Sobacchi C, Mirolo M, Abinun M, Andolina M, Flanagan A, Horwitz EM, Mihci E, Notarangelo LD, Ramenghi U, Teti A, Van Hove J, Vujic D, Young T, Albertini A, Orchard PJ, Vezzoni P, Villa A
J Bone Miner Res 2003 Oct;18(10):1740-7. doi: 10.1359/jbmr.2003.18.10.1740. PMID: 14584882
Campos-Xavier AB, Saraiva JM, Ribeiro LM, Munnich A, Cormier-Daire V
Hum Genet 2003 Feb;112(2):186-9. Epub 2002 Nov 7 doi: 10.1007/s00439-002-0861-9. PMID: 12522560

Diagnosis

Piret SE, Gorvin CM, Trinh A, Taylor J, Lise S, Taylor JC, Ebeling PR, Thakker RV
Am J Med Genet A 2016 Nov;170(11):2988-2992. Epub 2016 Aug 19 doi: 10.1002/ajmg.a.37755. PMID: 27540713Free PMC Article
Dharamshi HA, Ahmed SA, Mohsin AA, Mustahsan SM, Devi R, Iqbal A, Abidi SM
J Ayub Med Coll Abbottabad 2016 Jan-Mar;28(1):191-3. PMID: 27323593
Ott CE, Fischer B, Schröter P, Richter R, Gupta N, Verma N, Kabra M, Mundlos S, Rajab A, Neitzel H, Kornak U
Bone 2013 Aug;55(2):292-7. Epub 2013 Apr 17 doi: 10.1016/j.bone.2013.04.007. PMID: 23685543
Pangrazio A, Cassani B, Guerrini MM, Crockett JC, Marrella V, Zammataro L, Strina D, Schulz A, Schlack C, Kornak U, Mellis DJ, Duthie A, Helfrich MH, Durandy A, Moshous D, Vellodi A, Chiesa R, Veys P, Lo Iacono N, Vezzoni P, Fischer A, Villa A, Sobacchi C
J Bone Miner Res 2012 Feb;27(2):342-51. doi: 10.1002/jbmr.559. PMID: 22271396Free PMC Article
Othman IS, Ibrahim H, Hii KC, Ong GB, Menon BS
Med J Malaysia 2009 Dec;64(4):325-6. PMID: 20954561

Therapy

Olgaç A, Tümer L, Boyunağa Ö, Kızılkaya M, Hasanoğlu A
J Trop Pediatr 2015 Apr;61(2):146-50. Epub 2015 Feb 11 doi: 10.1093/tropej/fmv001. PMID: 25673572
Anderson SL, Jalas C, Fedick A, Reid KF, Carpenter TO, Chirnomas D, Treff NR, Ekstein J, Rubin BY
Clin Genet 2015 Jul;88(1):74-9. Epub 2014 Jul 31 doi: 10.1111/cge.12448. PMID: 24989235
Martinez C, Polgreen LE, DeFor TE, Kivisto T, Petryk A, Tolar J, Orchard PJ
Bone Marrow Transplant 2010 May;45(5):939-44. Epub 2009 Oct 5 doi: 10.1038/bmt.2009.277. PMID: 19802031Free PMC Article
Othman IS, Ibrahim H, Hii KC, Ong GB, Menon BS
Med J Malaysia 2009 Dec;64(4):325-6. PMID: 20954561
Mohn A, Capanna R, Delli Pizzi C, Morgese G, Chiarelli F
Minerva Pediatr 2004 Feb;56(1):115-8. PMID: 15249921

Prognosis

Dharamshi HA, Ahmed SA, Mohsin AA, Mustahsan SM, Devi R, Iqbal A, Abidi SM
J Ayub Med Coll Abbottabad 2016 Jan-Mar;28(1):191-3. PMID: 27323593
Olgaç A, Tümer L, Boyunağa Ö, Kızılkaya M, Hasanoğlu A
J Trop Pediatr 2015 Apr;61(2):146-50. Epub 2015 Feb 11 doi: 10.1093/tropej/fmv001. PMID: 25673572
Ott CE, Fischer B, Schröter P, Richter R, Gupta N, Verma N, Kabra M, Mundlos S, Rajab A, Neitzel H, Kornak U
Bone 2013 Aug;55(2):292-7. Epub 2013 Apr 17 doi: 10.1016/j.bone.2013.04.007. PMID: 23685543
Pangrazio A, Cassani B, Guerrini MM, Crockett JC, Marrella V, Zammataro L, Strina D, Schulz A, Schlack C, Kornak U, Mellis DJ, Duthie A, Helfrich MH, Durandy A, Moshous D, Vellodi A, Chiesa R, Veys P, Lo Iacono N, Vezzoni P, Fischer A, Villa A, Sobacchi C
J Bone Miner Res 2012 Feb;27(2):342-51. doi: 10.1002/jbmr.559. PMID: 22271396Free PMC Article
Pangrazio A, Poliani PL, Megarbane A, Lefranc G, Lanino E, Di Rocco M, Rucci F, Lucchini F, Ravanini M, Facchetti F, Abinun M, Vezzoni P, Villa A, Frattini A
J Bone Miner Res 2006 Jul;21(7):1098-105. doi: 10.1359/jbmr.060403. PMID: 16813530

Clinical prediction guides

Yuan P, Yue Z, Sun L, Huang W, Hu B, Yang Z, Hu Y, Xiao H, Shi H, Zhou Q, Wang Y
J Bone Miner Metab 2011 Mar;29(2):251-6. Epub 2010 Nov 2 doi: 10.1007/s00774-010-0228-6. PMID: 21042819
Martinez C, Polgreen LE, DeFor TE, Kivisto T, Petryk A, Tolar J, Orchard PJ
Bone Marrow Transplant 2010 May;45(5):939-44. Epub 2009 Oct 5 doi: 10.1038/bmt.2009.277. PMID: 19802031Free PMC Article
Chu K, Koller DL, Snyder R, Fishburn T, Lai D, Waguespack SG, Foroud T, Econs MJ
Bone 2005 Nov;37(5):655-61. Epub 2005 Aug 24 doi: 10.1016/j.bone.2005.06.003. PMID: 16120485
Frattini A, Pangrazio A, Susani L, Sobacchi C, Mirolo M, Abinun M, Andolina M, Flanagan A, Horwitz EM, Mihci E, Notarangelo LD, Ramenghi U, Teti A, Van Hove J, Vujic D, Young T, Albertini A, Orchard PJ, Vezzoni P, Villa A
J Bone Miner Res 2003 Oct;18(10):1740-7. doi: 10.1359/jbmr.2003.18.10.1740. PMID: 14584882
Dini G, Floris R, Garaventa A, Oddone M, De Stefano F, De Marco R, Calcagno E, Faraci M, Claudiani F, Manfredini L, Dallorso S, Lanino E, Morreale G
Bone Marrow Transplant 2000 Jul;26(2):219-24. doi: 10.1038/sj.bmt.1702491. PMID: 10918435

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