Osteopetrosis, Autosomal recessive 1 (OPTB1)

(OMIM phenotype number #259700)

Autosomal-recessive infantile malignant osteopetrosis is a severe , malignant, and heterogeneous genetic disorder. The autosomal-recessive infantile type is typically fatal during infancy or early childhood if untreated. The major therapeutical option is marrow transplantation. Osteoclasts number is usually normal or high, but their acidification function is defective. The main clinical features are: high bone density, recurrent infections, spontaneous bruising and bleeding, hypersplenism, haemolysis, anemia, delayed eruption of th dentition, blindness, deafness. Autosomal recessive osteopetrosis includes eight subtypes and incidence is estimated at 1/200.000 live births.
Osteopetrosis, Autosomal recessive 1 is a severe and genetically heterogeneous bone disorder with a fatal outcome (within the first decade of life). This disorder usually manifests in the first few months of life with macrocephaly and frontal bossing. The most severe complication, limiting survival, is bone marrow insufficiency. Osteoclasts are present in normal or elevated numbers.


TCIRG1 gene, 11q13.2 (OMIM gene/locus number *604592), encoding the alpha3 subunit of the vacuolar proton pump responsible for proton transport in the resorption lacunae, which mediates the acidification of the bone/osteoclast interface.


Severe form, macrocephaly, frontal bossing, nystagmus, optic atrophy, blindness, deafness, facial palsy, thick and dense skull, narrowness of neural and vascular foramina, genu valgum, dental defects (dental caries, distorted primary molars), loss of trabecular structure, poor/no definition between cortical and medullary bone, osteomyelitis, increased bone density (sclerosis) and generalized high bone mass, pathologic fractures, bone-within-bone appearance, sandwich appearance of vertebral bodies, coxa vara, splayed metaphyses, failure to thrive, hydrocephalus, seizures (tetany), hepato-splenomegaly, bone marrow insufficiency, pancytopenia, anemia.

Main biochemical alterations

Adult/intermediate forms: high CK-BB, high bone ALP. Infantile/severe forms: low Ca, high PTH, high 1,25(OH)2D, high CK-BB, high AP, anemia.


Fig.: Radiographies show: skull (a) and chest (b) of the brother showing sclerotic changes in the base of the skull, dense mastoid and small pituitary fossa, the clavicle, ribs, and scapula bones.

Reproduced from J Bone Miner Metab, Novel mutation of TCIRG1 and clinical pictures of two infantile malignant osteopetrosis patients, 2011;29:251-6, Yuan P, Yue Z, Sun L, et al., with permission of Springer.

Other resource

Osteopetrosis Society (OPETS)


  1. Frattini A, Orchard PJ, Sobacchi C, et al. Defects in TCIRG1 subunit of the vacuolar proton pump are responsible for a subset of human autosomal recessive osteopetrosis.Nat Genet. 2000 Jul;25(3):343-6.
  2. Yuan P, Yue Z, Sun L, et al. Novel mutation of TCIRG1 and clinical pictures of two infantile malignant osteopetrosis patients. J Bone Miner Metab. 2011 Mar;29(2):251-6.
  3. de Vernejoul MC, Kornak U. Heritable sclerosing bone disorders: presentation and new molecular mechanisms. Ann N Y Acad Sci. 2010 Mar;1192:269-77.
  4. Ihde LL, Forrester DM, Gottsegen CJ, et al. Sclerosing bone dysplasias: review and differentiation from other causes of osteosclerosis. 
  5. www.omim.org