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Autosomal recessive osteopetrosis 7(OPTB7)

MedGen UID:
436770
Concept ID:
C2676766
Disease or Syndrome
Synonyms: Autosomal recessive osteoclast-poor osteopetrosis with hypogammaglobulinemia; Osteopetrosis osteoclast-poor with hypogammaglobulinemia; TNFRSF11A- 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): TNFRSF11A (18q21.33)
 
Monarch Initiative: MONDO:0012859
OMIM®: 612301
Orphanet: ORPHA178389

Definition

Autosomal recessive osteopetrosis-7 (OPTB7) is an osteoclast-poor form of osteopetrosis with hypogammaglobulinemia. Clinical features include visual impairment, recurrent respiratory infections, poor growth, developmental delay, and increased bone density (Guerrini et al., 2008). For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive osteopetrosis, see OPTB1 (259700). [from OMIM]

Additional description

From MedlinePlus Genetics
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 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. 

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.

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.

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.  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.
Hydrocephalus
MedGen UID:
9335
Concept ID:
C0020255
Disease or Syndrome
Hydrocephalus is an active distension of the ventricular system of the brain resulting from inadequate passage of CSF from its point of production within the cerebral ventricles to its point of absorption into the systemic circulation.
Optic nerve compression
MedGen UID:
78765
Concept ID:
C0271344
Disease or Syndrome
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Motor delay
MedGen UID:
381392
Concept ID:
C1854301
Finding
A type of Developmental delay characterized by a delay in acquiring motor skills.
Hypocalcemic seizures
MedGen UID:
340985
Concept ID:
C1855841
Disease or Syndrome
Lateral ventricle dilatation
MedGen UID:
383904
Concept ID:
C1856409
Pathologic Function
Anemia
MedGen UID:
1526
Concept ID:
C0002871
Disease or Syndrome
A reduction in erythrocytes volume or hemoglobin concentration.
Femur fracture
MedGen UID:
4676
Concept ID:
C0015802
Injury or Poisoning
A break or crush injury of the thigh bone (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.
Multiple rib fractures
MedGen UID:
75784
Concept ID:
C0272567
Injury or Poisoning
More than one fracture of the ribs. Callus formation around multiple rib fractures can produce a row of multiple rounded expansions (beadlike prominences) giving the appearance of beaded ribs. Note that rachitic rosary would have one bead per rib (a swelling at the costochondral junction), while beaded ribs in the context of multiple rib fractures have multiple beads (fractures) along the same rib.
Generalized hypotonia
MedGen UID:
346841
Concept ID:
C1858120
Finding
Generalized muscular hypotonia (abnormally low muscle tone).
Abnormal trabecular bone morphology
MedGen UID:
866611
Concept ID:
C4020957
Anatomical Abnormality
Abnormal structure or form of trabecular bone.
Increased head circumference
MedGen UID:
909477
Concept ID:
C4083076
Finding
An abnormally increased head circumference in a growing child. Head circumference is measured with a nonelastic tape and comprises the distance from above the eyebrows and ears and around the back of the head. The measured HC is then plotted on an appropriate growth chart.
Recurrent pneumonia
MedGen UID:
195802
Concept ID:
C0694550
Disease or Syndrome
An increased susceptibility to pneumonia as manifested by a history of recurrent episodes of pneumonia.
Splenomegaly
MedGen UID:
52469
Concept ID:
C0038002
Finding
Abnormal increased size of the spleen.
Decreased circulating IgA concentration
MedGen UID:
57934
Concept ID:
C0162538
Disease or Syndrome
Decreased levels of immunoglobulin A (IgA).
Decreased circulating total IgM
MedGen UID:
116095
Concept ID:
C0239989
Finding
An abnormally decreased level of immunoglobulin M (IgM) in blood.
Decreased circulating IgG concentration
MedGen UID:
1720114
Concept ID:
C5234937
Finding
An abnormally decreased level of immunoglobulin G (IgG) in blood.
Proptosis
MedGen UID:
41917
Concept ID:
C0015300
Disease or Syndrome
An eye that is protruding anterior to the plane of the face to a greater extent than is typical.
Nystagmus
MedGen UID:
45166
Concept ID:
C0028738
Disease or Syndrome
Rhythmic, involuntary oscillations of one or both eyes related to abnormality in fixation, conjugate gaze, or vestibular mechanisms.
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.
Progressive visual loss
MedGen UID:
326867
Concept ID:
C1839364
Finding
A reduction of previously attained ability to see.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVAutosomal recessive osteopetrosis 7
Follow this link to review classifications for Autosomal recessive osteopetrosis 7 in Orphanet.

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
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Recent clinical studies

Etiology

Funck-Brentano T, Zillikens MC, Clunie G, Siggelkow H, Appelman-Dijkstra NM, Cohen-Solal M
Eur J Med Genet 2024 Jun;69:104936. Epub 2024 Apr 7 doi: 10.1016/j.ejmg.2024.104936. PMID: 38593953
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
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
Aggarwal S
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Hum Genet 2003 Feb;112(2):186-9. Epub 2002 Nov 7 doi: 10.1007/s00439-002-0861-9. PMID: 12522560

Diagnosis

Funck-Brentano T, Zillikens MC, Clunie G, Siggelkow H, Appelman-Dijkstra NM, Cohen-Solal M
Eur J Med Genet 2024 Jun;69:104936. Epub 2024 Apr 7 doi: 10.1016/j.ejmg.2024.104936. PMID: 38593953
McLuckey MN, Imel EA, Forbes-Amrhein MM
Pediatr Radiol 2024 Jun;54(7):1105-1115. Epub 2024 Mar 14 doi: 10.1007/s00247-024-05899-4. PMID: 38483591
Aggarwal S
Gene 2013 Oct 1;528(1):41-5. Epub 2013 May 5 doi: 10.1016/j.gene.2013.04.069. PMID: 23657117
Khan MN, Datta PK, Hasan MI, Hossain MA, Patwary KH, Ferdous J
Mymensingh Med J 2011 Oct;20(4):715-8. PMID: 22081195
de Vernejoul MC
Best Pract Res Clin Rheumatol 2008 Mar;22(1):71-83. doi: 10.1016/j.berh.2007.12.011. PMID: 18328982

Therapy

Doulgeraki A, Bani-Odeh L, Tramma D, Giataganas G, Kirvassilis F, Kollios K, Fotoulaki M
J Pediatr Endocrinol Metab 2023 Jul 26;36(7):712-715. Epub 2023 May 5 doi: 10.1515/jpem-2023-0001. PMID: 37141118
İşeri Nepesov M, Kıral E, Bozan G, Kılıç Ö, Çarman KB, Yarar C, Şaylısoy S, Dinleyici EÇ
J Clin Res Pediatr Endocrinol 2021 Aug 23;13(3):358-361. Epub 2020 Aug 25 doi: 10.4274/jcrpe.galenos.2020.2020.0039. PMID: 32840095Free 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
Driessen GJ, Gerritsen EJ, Fischer A, Fasth A, Hop WC, Veys P, Porta F, Cant A, Steward CG, Vossen JM, Uckan D, Friedrich W
Bone Marrow Transplant 2003 Oct;32(7):657-63. doi: 10.1038/sj.bmt.1704194. PMID: 13130312

Prognosis

McLuckey MN, Imel EA, Forbes-Amrhein MM
Pediatr Radiol 2024 Jun;54(7):1105-1115. Epub 2024 Mar 14 doi: 10.1007/s00247-024-05899-4. PMID: 38483591
Jodeh W, Katz AJ, Hart M, Warden SJ, Niziolek P, Alam I, Ing S, Polgreen LE, Imel EA, Econs MJ
J Clin Endocrinol Metab 2024 Jun 17;109(7):1726-1732. doi: 10.1210/clinem/dgae040. PMID: 38261998Free PMC Article
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
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
Dozier TS, Duncan IM, Klein AJ, Lambert PR, Key LL Jr
Otol Neurotol 2005 Jul;26(4):762-6. doi: 10.1097/01.mao.0000178139.27472.8d. PMID: 16015181

Clinical prediction guides

Jodeh W, Katz AJ, Hart M, Warden SJ, Niziolek P, Alam I, Ing S, Polgreen LE, Imel EA, Econs MJ
J Clin Endocrinol Metab 2024 Jun 17;109(7):1726-1732. doi: 10.1210/clinem/dgae040. PMID: 38261998Free PMC Article
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
Zhang Y, Ji D, Li L, Yang S, Zhang H, Duan X
Theranostics 2019;9(5):1387-1400. Epub 2019 Feb 20 doi: 10.7150/thno.29761. PMID: 30867839Free PMC Article
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
Dozier TS, Duncan IM, Klein AJ, Lambert PR, Key LL Jr
Otol Neurotol 2005 Jul;26(4):762-6. doi: 10.1097/01.mao.0000178139.27472.8d. PMID: 16015181

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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