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Autosomal recessive osteopetrosis 4(OPTB4)

MedGen UID:
370598
Concept ID:
C1969106
Disease or Syndrome
Synonyms: Infantile Malignant CLCN7-Related Autosomal Recessive Osteopetrosis; infantile malignant CLCN7-related recessive osteopetrosis; Osteopetrosis infantile malignant 2
 
Gene (location): CLCN7 (16p13.3)
 
Monarch Initiative: MONDO:0012676
OMIM®: 611490

Disease characteristics

Excerpted from the GeneReview: CLCN7-Related Osteopetrosis
The spectrum of CLCN7-related osteopetrosis includes infantile malignant CLCN7-related autosomal recessive osteopetrosis (ARO), intermediate autosomal osteopetrosis (IAO), and autosomal dominant osteopetrosis type II (ADOII; Albers-Schönberg disease). ARO. Onset is at birth. Findings may include: fractures; reduced growth; sclerosis of the skull base (with or without choanal stenosis or hydrocephalus) resulting in optic nerve compression, facial palsy, and hearing loss; absence of the bone marrow cavity resulting in severe anemia and thrombocytopenia; dental abnormalities, odontomas, and risk for mandibular osteomyelitis; and hypocalcemia with tetanic seizures and secondary hyperparathyroidism. Without treatment maximal life span in ARO is ten years. IAO. Onset is in childhood. Findings may include: fractures after minor trauma, characteristic skeletal radiographic changes found incidentally, mild anemia, and occasional visual impairment secondary to optic nerve compression. Life expectancy in IAO is usually normal. ADOII. Onset is usually late childhood or adolescence. Findings may include: fractures (in any long bone and/or the posterior arch of a vertebra), scoliosis, hip osteoarthritis, and osteomyelitis of the mandible or septic osteitis or osteoarthritis elsewhere. Cranial nerve compression is rare. [from GeneReviews]
Authors:
Cristina Sobacchi  |  Anna Villa  |  Ansgar Schulz, et. al.   view full author information

Additional description

From MedlinePlus Genetics
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.

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. 

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 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.  https://medlineplus.gov/genetics/condition/osteopetrosis

Clinical features

From HPO
Growth delay
MedGen UID:
99124
Concept ID:
C0456070
Pathologic Function
A deficiency or slowing down of growth pre- and postnatally.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormally increased size of the liver.
Anemia
MedGen UID:
1526
Concept ID:
C0002871
Disease or Syndrome
A reduction in erythrocytes volume or hemoglobin concentration.
Thrombocytopenia
MedGen UID:
52737
Concept ID:
C0040034
Disease or Syndrome
A reduction in the number of circulating thrombocytes.
Reticulocytosis
MedGen UID:
60089
Concept ID:
C0206160
Finding
An elevation in the number of reticulocytes (immature erythrocytes) in the peripheral blood circulation.
Recurrent fractures
MedGen UID:
42094
Concept ID:
C0016655
Injury or Poisoning
The repeated occurrence of bone fractures (implying an abnormally increased tendency for fracture).
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.
Increased bone mineral density
MedGen UID:
10502
Concept ID:
C0029464
Disease or Syndrome
An abnormal increase of bone mineral density, that is, of the amount of matter per cubic centimeter of bones which is often referred to as osteosclerosis. Osteosclerosis can be detected on radiological examination as an increased whiteness (density) of affected bones.
Facial palsy
MedGen UID:
87660
Concept ID:
C0376175
Disease or Syndrome
Facial nerve palsy is a dysfunction of cranial nerve VII (the facial nerve) that results in inability to control facial muscles on the affected side with weakness of the muscles of facial expression and eye closure. This can either be present in unilateral or bilateral form.
Sclerotic vertebral endplates
MedGen UID:
1642576
Concept ID:
C4551970
Finding
Sclerosis (increased density) affecting vertebral end plates.
Splenomegaly
MedGen UID:
52469
Concept ID:
C0038002
Finding
Abnormal increased size of the spleen.
Petechiae
MedGen UID:
10680
Concept ID:
C0031256
Disease or Syndrome
Petechiae are pinpoint-sized reddish/purple spots, resembling a rash, that appear just under the skin or a mucous membrane when capillaries have ruptured and some superficial bleeding into the skin has happened. This term refers to an abnormally increased susceptibility to developing petechiae.
Optic atrophy
MedGen UID:
18180
Concept ID:
C0029124
Disease or Syndrome
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.
Optic disc pallor
MedGen UID:
108218
Concept ID:
C0554970
Finding
A pale yellow discoloration of the optic disc (the area of the optic nerve head in the retina). The optic disc normally has a pinkish hue with a central yellowish depression.
Visual impairment
MedGen UID:
777085
Concept ID:
C3665347
Finding
Visual impairment (or vision impairment) is vision loss (of a person) to such a degree as to qualify as an additional support need through a significant limitation of visual capability resulting from either disease, trauma, or congenital or degenerative conditions that cannot be corrected by conventional means, such as refractive correction, medication, or surgery.

Professional guidelines

PubMed

Sobacchi C, Schulz A, Coxon FP, Villa A, Helfrich MH
Nat Rev Endocrinol 2013 Sep;9(9):522-36. Epub 2013 Jul 23 doi: 10.1038/nrendo.2013.137. PMID: 23877423
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
Del Fattore A, Peruzzi B, Rucci N, Recchia I, Cappariello A, Longo M, Fortunati D, Ballanti P, Iacobini M, Luciani M, Devito R, Pinto R, Caniglia M, Lanino E, Messina C, Cesaro S, Letizia C, Bianchini G, Fryssira H, Grabowski P, Shaw N, Bishop N, Hughes D, Kapur RP, Datta HK, Taranta A, Fornari R, Migliaccio S, Teti A
J Med Genet 2006 Apr;43(4):315-25. Epub 2005 Aug 23 doi: 10.1136/jmg.2005.036673. PMID: 16118345Free PMC Article

Recent clinical studies

Etiology

Xue JY, Grigelioniene G, Wang Z, Nishimura G, Iida A, Matsumoto N, Tham E, Miyake N, Ikegawa S, Guo L
J Bone Miner Res 2022 Feb;37(2):226-235. Epub 2021 Nov 11 doi: 10.1002/jbmr.4462. PMID: 34668226
Rajathi M, Austin RD, Mathew P, Bharathi CS, Srivastava KC
Indian J Dent Res 2010 Oct-Dec;21(4):611-4. doi: 10.4103/0970-9290.74234. PMID: 21187637
Stark Z, Savarirayan R
Orphanet J Rare Dis 2009 Feb 20;4:5. doi: 10.1186/1750-1172-4-5. PMID: 19232111Free PMC Article
Guerrini MM, Sobacchi C, Cassani B, Abinun M, Kilic SS, Pangrazio A, Moratto D, Mazzolari E, Clayton-Smith J, Orchard P, Coxon FP, Helfrich MH, Crockett JC, Mellis D, Vellodi A, Tezcan I, Notarangelo LD, Rogers MJ, Vezzoni P, Villa A, Frattini A
Am J Hum Genet 2008 Jul;83(1):64-76. doi: 10.1016/j.ajhg.2008.06.015. PMID: 18606301Free PMC Article
Waguespack SG, Hui SL, Dimeglio LA, Econs MJ
J Clin Endocrinol Metab 2007 Mar;92(3):771-8. Epub 2006 Dec 12 doi: 10.1210/jc.2006-1986. PMID: 17164308

Diagnosis

Liang H, Li N, Yao RE, Yu T, Ding L, Chen J, Wang J
Mol Genet Genomic Med 2021 Nov;9(11):e1815. Epub 2021 Sep 21 doi: 10.1002/mgg3.1815. PMID: 34545712Free PMC Article
Sobacchi C, Schulz A, Coxon FP, Villa A, Helfrich MH
Nat Rev Endocrinol 2013 Sep;9(9):522-36. Epub 2013 Jul 23 doi: 10.1038/nrendo.2013.137. PMID: 23877423
Khan MN, Datta PK, Hasan MI, Hossain MA, Patwary KH, Ferdous J
Mymensingh Med J 2011 Oct;20(4):715-8. PMID: 22081195
Stark Z, Savarirayan R
Orphanet J Rare Dis 2009 Feb 20;4:5. doi: 10.1186/1750-1172-4-5. PMID: 19232111Free PMC Article
Stoker DJ
Semin Musculoskelet Radiol 2002 Dec;6(4):299-305. doi: 10.1055/s-2002-36728. PMID: 12541186

Therapy

Moscatelli I, Löfvall H, Schneider Thudium C, Rothe M, Montano C, Kertész Z, Sirin M, Schulz A, Schambach A, Henriksen K, Richter J
Hum Gene Ther 2018 Aug;29(8):938-949. Epub 2017 Oct 3 doi: 10.1089/hum.2017.053. PMID: 28726516
Kuroyanagi Y, Kawasaki H, Noda Y, Ohmachi T, Sekiya S, Yoshimura K, Ohe C, Michigami T, Ozono K, Kaneko K
Tohoku J Exp Med 2014 Dec;234(4):309-12. doi: 10.1620/tjem.234.309. PMID: 25504019
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
Krupin T, Sly WS, Whyte MP, Dodgson SJ
Am J Ophthalmol 1985 Apr 15;99(4):396-9. doi: 10.1016/0002-9394(85)90004-2. PMID: 3920916

Prognosis

Dulski J, Souza J, Santos ML, Wszolek ZK
Orphanet J Rare Dis 2023 Jun 22;18(1):160. doi: 10.1186/s13023-023-02772-9. PMID: 37349768Free PMC Article
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
Cao W, Wei W, Yu G, Wu Q, Qin M
J Pediatr Ophthalmol Strabismus 2019 Jan 23;56(1):35-42. Epub 2018 Oct 26 doi: 10.3928/01913913-20180921-01. PMID: 30371911
Chalhoub N, Benachenhou N, Rajapurohitam V, Pata M, Ferron M, Frattini A, Villa A, Vacher J
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Clinical prediction guides

Dulski J, Souza J, Santos ML, Wszolek ZK
Orphanet J Rare Dis 2023 Jun 22;18(1):160. doi: 10.1186/s13023-023-02772-9. PMID: 37349768Free PMC Article
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
Koçak G, Güzel BN, Mıhçı E, Küpesiz OA, Yalçın K, Manguoğlu AE
Gene 2019 Jun 20;702:83-88. Epub 2019 Mar 19 doi: 10.1016/j.gene.2019.02.088. PMID: 30898715
Tfifha M, Gaha M, Gamaoun W, Chemli J, Mabrouk S, Hassayoun S, Zouari N, Jemni H, Abroug S
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Radiology 1992 Apr;183(1):137-44. doi: 10.1148/radiology.183.1.1549660. PMID: 1549660

Recent systematic reviews

Dulski J, Souza J, Santos ML, Wszolek ZK
Orphanet J Rare Dis 2023 Jun 22;18(1):160. doi: 10.1186/s13023-023-02772-9. PMID: 37349768Free PMC Article

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