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Autosomal dominant osteopetrosis 1(OPTA1)

MedGen UID:
335932
Concept ID:
C1843330
Disease or Syndrome
Synonyms: LRP5-Related Autosomal Dominant Osteopetrosis; OPTA1; OSTEOPETROSIS, AUTOSOMAL DOMINANT, TYPE I
SNOMED CT: Autosomal dominant osteopetrosis type 1 (1264041000)
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
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 heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
 
Gene (location): LRP5 (11q13.2)
 
Monarch Initiative: MONDO:0011877
OMIM®: 607634
Orphanet: ORPHA2783

Definition

The osteopetroses are a heterogeneous group of genetic disorders characterized by increased bone density due to impaired bone resorption by osteoclasts. Autosomal dominant osteopetrosis-1 (OPTA1) is characterized by generalized osteosclerosis most pronounced in the cranial vault. Patients are often asymptomatic, but some suffer from pain and hearing loss. It appears to be the only type of osteopetrosis not associated with an increased fracture rate (summary by Van Hul et al., 2002). Genetic Heterogeneity of Autosomal Dominant Osteopetrosis Autosomal dominant osteopetrosis-2 (OPTA2; 166600) is caused by mutation in the CLCN7 gene (602727) on chromosome 16p13. Autosomal dominant osteopetrosis-3 (OPTA3; 618107) is caused by mutation in the PLEKHM1 gene (611466) on chromosome 17q21. [from OMIM]

Additional description

From MedlinePlus Genetics
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.  https://medlineplus.gov/genetics/condition/osteopetrosis

Clinical features

From HPO
Mandibular pain
MedGen UID:
1633770
Concept ID:
C4552061
Sign or Symptom
An unpleasant sensation characterized by physical discomfort (such as pricking, throbbing, or aching) localized to the mandible.
Conductive hearing impairment
MedGen UID:
9163
Concept ID:
C0018777
Disease or Syndrome
An abnormality of vibrational conductance of sound to the inner ear leading to impairment of sensory perception of sound.
Headache
MedGen UID:
9149
Concept ID:
C0018681
Sign or Symptom
Cephalgia, or pain sensed in various parts of the head, not confined to the area of distribution of any nerve.
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.
Thickened cortex of long bones
MedGen UID:
333557
Concept ID:
C1840418
Finding
Abnormal thickening of the cortex of long bones.
Generalized osteosclerosis
MedGen UID:
375162
Concept ID:
C1843331
Finding
An abnormal increase of bone mineral density with generalized involvement of the skeleton.
Calvarial osteosclerosis
MedGen UID:
340927
Concept ID:
C1855657
Finding
An increase in bone density affecting the calvaria (roof of the skull).
Thickened calvaria
MedGen UID:
346823
Concept ID:
C1858452
Finding
The presence of an abnormally thick calvaria.
Abnormal pelvic girdle bone morphology
MedGen UID:
866545
Concept ID:
C4020847
Anatomical Abnormality
An abnormality of the bony pelvic girdle, which is a ring of bones connecting the vertebral column to the femurs.
Abnormality of the vertebral column
MedGen UID:
892426
Concept ID:
C4021789
Anatomical Abnormality
Any abnormality of the vertebral column.
Torus palatinus
MedGen UID:
120594
Concept ID:
C0266981
Finding
A bony protrusion present on the midline of the hard palate.
Elevated serum acid phosphatase
MedGen UID:
326597
Concept ID:
C1839866
Finding

Term Hierarchy

Recent clinical studies

Etiology

Wang Z, Li X, Wang Y, Fu W, Liu Y, Zhang Z, Wang C
Front Endocrinol (Lausanne) 2022;13:819641. Epub 2022 Mar 17 doi: 10.3389/fendo.2022.819641. PMID: 35370969Free PMC Article
Butscheidt S, Rolvien T, Kornak U, Schmidt FN, Schinke T, Amling M, Oheim R
Calcif Tissue Int 2018 Jan;102(1):41-52. Epub 2017 Oct 10 doi: 10.1007/s00223-017-0332-x. PMID: 29018903
Aggarwal S
Gene 2013 Oct 1;528(1):41-5. Epub 2013 May 5 doi: 10.1016/j.gene.2013.04.069. PMID: 23657117
Stark Z, Savarirayan R
Orphanet J Rare Dis 2009 Feb 20;4:5. doi: 10.1186/1750-1172-4-5. PMID: 19232111Free PMC Article
Shapiro F
Clin Orthop Relat Res 1993 Sep;(294):34-44. PMID: 8358940

Diagnosis

Wang Z, Li X, Wang Y, Fu W, Liu Y, Zhang Z, Wang C
Front Endocrinol (Lausanne) 2022;13:819641. Epub 2022 Mar 17 doi: 10.3389/fendo.2022.819641. PMID: 35370969Free PMC Article
Gillani S, Abbas Z
J Ayub Med Coll Abbottabad 2017 Apr-Jun;29(2):350-352. PMID: 28718264
Ozkan AK, Doruk P, Adam M, Celik ZY, Leblebici B
J Back Musculoskelet Rehabil 2015;28(1):197-200. doi: 10.3233/BMR-140486. PMID: 24898439
Stark Z, Savarirayan R
Orphanet J Rare Dis 2009 Feb 20;4:5. doi: 10.1186/1750-1172-4-5. PMID: 19232111Free PMC Article
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

Lu K, Cheng B, Shi Q, Gao XJ, Li C
BMC Musculoskelet Disord 2022 Jul 28;23(1):719. doi: 10.1186/s12891-022-05687-x. PMID: 35902893Free PMC Article
Imel EA, Liu Z, Acton D, Coffman M, Gebregziabher N, Tong Y, Econs MJ
J Bone Miner Res 2019 Aug;34(8):1436-1445. Epub 2019 May 13 doi: 10.1002/jbmr.3715. PMID: 30889272Free PMC Article
Soberón JR Jr, Arzillo S, Myers SL, King JJ
A A Pract 2019 Jan 1;12(1):5-8. doi: 10.1213/XAA.0000000000000828. PMID: 29994871
Whyte MP, Tau C, McAlister WH, Zhang X, Novack DV, Preliasco V, Santini-Araujo E, Mumm S
Bone 2014 Nov;68:153-61. Epub 2014 Jul 23 doi: 10.1016/j.bone.2014.07.019. PMID: 25063546Free PMC Article
Shapiro F
Clin Orthop Relat Res 1993 Sep;(294):34-44. PMID: 8358940

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
Wang Z, Li X, Wang Y, Fu W, Liu Y, Zhang Z, Wang C
Front Endocrinol (Lausanne) 2022;13:819641. Epub 2022 Mar 17 doi: 10.3389/fendo.2022.819641. PMID: 35370969Free PMC Article
Gillani S, Abbas Z
J Ayub Med Coll Abbottabad 2017 Apr-Jun;29(2):350-352. PMID: 28718264
Paterson CR
Baillieres Clin Endocrinol Metab 1997 Apr;11(1):195-213. doi: 10.1016/s0950-351x(97)80601-5. PMID: 9222492
Shapiro F
Clin Orthop Relat Res 1993 Sep;(294):34-44. PMID: 8358940

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
Butscheidt S, Rolvien T, Kornak U, Schmidt FN, Schinke T, Amling M, Oheim R
Calcif Tissue Int 2018 Jan;102(1):41-52. Epub 2017 Oct 10 doi: 10.1007/s00223-017-0332-x. PMID: 29018903
Gillani S, Abbas Z
J Ayub Med Coll Abbottabad 2017 Apr-Jun;29(2):350-352. PMID: 28718264
Coudert AE, Del Fattore A, Baulard C, Olaso R, Schiltz C, Collet C, Teti A, de Vernejoul MC
Lab Invest 2014 Mar;94(3):275-85. Epub 2013 Dec 16 doi: 10.1038/labinvest.2013.140. PMID: 24336069
de Vernejoul MC, Bénichou O
Calcif Tissue Int 2001 Jul;69(1):1-6. Epub 2001 Jun 5 doi: 10.1007/s002230020046. PMID: 11685426

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
Carvalho PHA, Moura LB, Real Gabrielli MF, Cabrini Gabrielli MA, Antonio Pereira Filho V
J Craniomaxillofac Surg 2018 Nov;46(11):1905-1910. Epub 2018 Sep 24 doi: 10.1016/j.jcms.2018.09.004. PMID: 30309794

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