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Osteopetrosis autosomal recessive 2(OPTB2)

MedGen UID:
342420
Concept ID:
C1850126
Disease or Syndrome
Synonyms: Autosomal recessive osteopetrosis type 2; 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, Orphanet
Autosomal recessive inheritance refers to genetic conditions that occur only when mutations are present in both copies of a given gene (i.e., the person is homozygous for a mutation, or carries two different mutations of the same gene, a state referred to as compound heterozygosity).
 
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

Cranial hyperostosis
MedGen UID:
318629
Concept ID:
C1832451
Finding
Carious teeth
MedGen UID:
401327
Concept ID:
C1867882
Finding
Mandibular prognathia
MedGen UID:
427817
Concept ID:
CN000285
Finding
Abnormal prominence of the chin related to increased length of the mandible.
Chronic rhinitis due to narrow nasal airway
MedGen UID:
425269
Concept ID:
CN003992
Finding
Persistence of primary teeth
MedGen UID:
501011
Concept ID:
CN005520
Finding
Persistence of the primary teeth beyond the age by which they normally are shed and replaced by the permanent teeth.
Facial paralysis
MedGen UID:
507288
Concept ID:
CN006304
Finding
Complete loss of ability to move facial muscles innervated by the facial nerve (i.e., the seventh cranial nerve).
Mandibular osteomyelitis
MedGen UID:
506094
Concept ID:
CN006684
Finding
Blindness
MedGen UID:
99138
Concept ID:
C0456909
Disease or Syndrome
The inability to see or the loss or absence of perception of visual stimuli. This condition may be the result of EYE DISEASES; OPTIC NERVE DISEASES; OPTIC CHIASM diseases; or BRAIN DISEASES affecting the VISUAL PATHWAYS or OCCIPITAL LOBE.
Optic atrophy
MedGen UID:
504537
Concept ID:
CN000609
Finding
Atrophy of the optic nerve. Optic atrophy results from the death of the retinal ganglion cell axons that comprise the optic nerve and manifesting as a pale optic nerve on fundoscopy.
Intellectual disability
MedGen UID:
334384
Concept ID:
C1843367
Finding
Facial paralysis
MedGen UID:
507288
Concept ID:
CN006304
Finding
Complete loss of ability to move facial muscles innervated by the facial nerve (i.e., the seventh cranial nerve).
Cranial hyperostosis
MedGen UID:
318629
Concept ID:
C1832451
Finding
Mandibular prognathia
MedGen UID:
427817
Concept ID:
CN000285
Finding
Abnormal prominence of the chin related to increased length of the mandible.
Recurrent fractures
MedGen UID:
500939
Concept ID:
CN002502
Finding
The repeated occurence of bone fractures (implying an abnormally increased tendency for fracture).
Genu valgum
MedGen UID:
505373
Concept ID:
CN002582
Finding
The legs angle inward, such that the knees are close together and the ankles far apart.
Diaphyseal sclerosis
MedGen UID:
505435
Concept ID:
CN002742
Finding
An elevation in bone density in one or more diaphyses. Sclerosis is normally detected on a radiograph as an area of increased opacity.
Mandibular osteomyelitis
MedGen UID:
506094
Concept ID:
CN006684
Finding
Osteopetrosis
MedGen UID:
506427
Concept ID:
CN116734
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.
Hepatosplenomegaly
MedGen UID:
504839
Concept ID:
CN001310
Finding
Simultaneous enlargement of the liver and spleen.
Thrombocytopenia
MedGen UID:
52737
Concept ID:
C0040034
Disease or Syndrome
A finding based on laboratory test results that indicate a decrease in number of platelets in a blood specimen.
Anemia
MedGen UID:
56401
Concept ID:
C0162119
Finding
A laboratory test result which indicates decreased levels of hemoglobin in a biological specimen.
Extramedullary hematopoiesis
MedGen UID:
220947
Concept ID:
C1292120
Finding
Pancytopenia
MedGen UID:
504982
Concept ID:
CN001696
Finding
An abnormal reduction in numbers of all blood cell types (red blood cells, white blood cells, and platelets).
Hepatosplenomegaly
MedGen UID:
504839
Concept ID:
CN001310
Finding
Simultaneous enlargement of the liver and spleen.
Facial paralysis
MedGen UID:
507288
Concept ID:
CN006304
Finding
Complete loss of ability to move facial muscles innervated by the facial nerve (i.e., the seventh cranial nerve).
Genu valgum
MedGen UID:
505373
Concept ID:
CN002582
Finding
The legs angle inward, such that the knees are close together and the ankles far apart.

Recent clinical studies

Etiology

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
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. [Epub ahead of print] PMID: 12522560
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
Gerritsen EJ, Vossen JM, van Loo IH, Hermans J, Helfrich MH, Griscelli C, Fischer A
Pediatrics 1994 Feb;93(2):247-53. PMID: 8121736
Gerritsen EJ, Vossen JM, Fasth A, Friedrich W, Morgan G, Padmos A, Vellodi A, Porras O, O'Meara A, Porta F
J Pediatr 1994 Dec;125(6 Pt 1):896-902. PMID: 7996361

Diagnosis

Pangrazio A, Puddu A, Oppo M, Valentini M, Zammataro L, Vellodi A, Gener B, Llano-Rivas I, Raza J, Atta I, Vezzoni P, Superti-Furga A, Villa A, Sobacchi C
Bone 2014 Feb;59:122-6. Epub 2013 Nov 20 doi: 10.1016/j.bone.2013.11.014. [Epub ahead of print] PMID: 24269275Free PMC Article
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. [Epub ahead of print] PMID: 23685543
Sekerci AE, Sisman Y, Ertas ET, Sahman H, Aydinbelge M
J Dent Child (Chic) 2012 May-Aug;79(2):93-9. PMID: 22828766
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

Bosley TM, Salih MA, Alorainy IA, Islam MZ, Oystreck DT, Suliman OS, al Malki S, Suhaibani AH, Khiari H, Beckers S, van Wesenbeeck L, Perdu B, AlDrees A, Elmalik SA, Van Hul W, Abu-Amero KK
Brain 2011 Dec;134(Pt 12):3502-15. Epub 2011 Nov 26 doi: 10.1093/brain/awr302. [Epub ahead of print] PMID: 22120147
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. [Epub ahead of print] PMID: 19802031
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
Gerritsen EJ, Vossen JM, Fasth A, Friedrich W, Morgan G, Padmos A, Vellodi A, Porras O, O'Meara A, Porta F
J Pediatr 1994 Dec;125(6 Pt 1):896-902. PMID: 7996361

Prognosis

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. [Epub ahead of print] PMID: 23685543
Sekerci AE, Sisman Y, Ertas ET, Sahman H, Aydinbelge M
J Dent Child (Chic) 2012 May-Aug;79(2):93-9. PMID: 22828766
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
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. [Epub ahead of print] PMID: 21042819
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

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. [Epub ahead of print] 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. [Epub ahead of print] PMID: 19802031
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. [Epub ahead of print] 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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