Osteopetrosis (OP) is a general term referring to a group of metabolic bone diseases characterized by increased bone mineral density due to impairment of osteoclast development or function. About a dozen types of OP have been described to date, and they comprise a clinical spectrum ranging from very mild to severe disease phenotypes which are fatal in the first year of life.
The presentation of OP varies largely. While the majority of autosomal recessive types of the disease is related to severe symptoms with an early onset and rapid deterioration, autosomal dominant OP tends to follow a milder course and may not become symptomatic until adulthood  . In general, the following conditions contribute to the clinical picture :
- The absence of functional osteoclasts interferes with skeletal growth and bone remodeling, giving rise to skeletal deformities that may be apparent at birth. Such deformities include, but are not limited to, dysmorphic facial features and dental abnormalities.
- Rather than conferring strength, the excessively dense bone architecture belies a structural brittleness that predisposes to fracture and osteomyelitis. Also, OP patients tend to suffer from bone pain worsening with activity.
- The progressive thickening of the skull interferes with the development and function of the brain and may result in increased intracranial pressure. Affected individuals may present with headaches, nausea and vomiting, seizures and a broad spectrum of other neurological symptoms. Failure to thrive may be observed in pediatric patients.
- Furthermore, the lack of bone resorption leads to the narrowing of cranial nerve foramina and subsequent neurological deficits. Visual and hearing impairment are among the most common presenting symptoms, and patients may develop blindness or deafness. Trigeminal and facial neuralgia have also been described.
- The expansion of bone into marrow cavities impedes normal hematopoiesis, giving rise to cytopenias and symptoms thereof. In an attempt to compensate for the loss of medullary spaces, extramedullary hematopoiesis is stimulated, and patients may be found to have hepatomegaly and splenomegaly.
Moreover, mutations inducing OP may interfere with a variety of other biological processes, thereby exacerbating the aforedescribed conditions and expanding the spectrum of symptoms. Primary neurodegeneration, for instance, may further contribute to developmental delays and progressive neurological disorders, while hypogammaglobulinemia may render patients with leukopenia highly susceptible to infections.
It should be kept in mind that there is considerable heterogeneity in the presentation of distinct types of OP, but the age of symptom onset and the severity of the disease may vary even within a family affected by a single variant of the disease.
Entire Body System
- Proportionate Short Stature
Clinical features include proportionate short stature, vision impairment, esotropia, exophthalmos, mild hearing loss, and hepatosplenomegaly. Pancytopenia was present and the patient had frequent illnesses. [ncbi.nlm.nih.gov]
- Recurrent Respiratory Infections
There was history of recurrent respiratory infections. He was the second product of third degree consanguineous marriage. On general examination, the patient was thin built, short statured. [mjdrdypu.org]
- Failure to Thrive
We report a 3-month-old male child presented with chest infections, failure to thrive and hepatosplenomegaly and diagnosed with osteopetrosis associated with acute myeloid leukaemia M3 type (AML-M3). [ncbi.nlm.nih.gov]
Those who survive childbirth present with general failure to thrive, bone marrow failure or characteristic facies. [radiopaedia.org]
Case A 38 days-old girl was admitted to our clinic with irritability and failure to thrive. [turkjem.org]
Jaw & Teeth
- Dental Caries
Disease General Considerations Rare hereditary disorder Defective osteoclast function with failure of proper reabsorption produces sclerotic bone Structurally weak Types Infantile autosomal recessive type Failure to thrive Premature senility in facies Dental [learningradiology.com]
All primary teeth were completely erupted, and multiple caries on deciduous molars were observed. Periapical radiographic images revealed dental caries were observed in all primary teeth. [journal.kapd.org]
caries One of the commonest presentations is with ocular disturbance: failure to establish fixation, nystagmus or strabismus 4. [radiopaedia.org]
Liver, Gall & Pancreas
We noted more severe radiological findings in patients with TCIRG1 and RANK mutations, including fractures, osteopetrorickets, hydrocephalus, and hepatomegaly. [ncbi.nlm.nih.gov]
The younger sibling had splenomegaly of 10 cm below left sub-costal margin in its axis but no hepatomegaly. The older sibling had both hepatomegaly of 3 cm and splenomegaly of 8 cm. [bmcresnotes.biomedcentral.com]
[…] in the newborn period 516 Hepatomegaly in children General overview 517 Hepatomegaly with portal hypertention and obstructive jaundice 519 Liver calcifications in the pediatric age 520 Copyright [books.google.com]
[…] osteopetrosis include: Breakable bones Bruising and Bone pain Carpal tunnel syndrome Osteoarthritis of various joints Paralysis of various nerves due to nerve compression or damage to nerves due adjacent bone fractures Loss of muscle control Large liver/spleen (hepatomegaly [dovemed.com]
Brunquell PJ (1982) Osteopetrosis, optic atrophy and hepatomegaly. N Engl J Med 307:735–743 Google Scholar 5. Case Records of the Massachusetts General Hospital (1982) N Engl J Med 307:735–743 Google Scholar 6. [doi.org]
- Hearing Impairment
Osteopetrosis is a rare inherited metabolic bone disorder characterized by extensive sclerosis of skeletons, visual and hearing impairment, hepatosplenomegaly and anemia. [ncbi.nlm.nih.gov]
Visual and hearing impairment are among the most common presenting symptoms, and patients may develop blindness or deafness. Trigeminal and facial neuralgia have also been described. [symptoma.com]
impairment, hepatosplenomegaly and anemia. [bmcresnotes.biomedcentral.com]
impairment Deafness Hearing defect [ more ] 0000365 Hypocalcemia Low blood calcium levels 0002901 Hypophosphatemia Low blood phosphate level 0002148 Lymphadenopathy Swollen lymph nodes 0002716 Macrocephaly Increased size of skull Large head Large head [rarediseases.info.nih.gov]
National Osteoporosis Foundation (2003) Physician's Guide to Prevention and Treatment of Osteoporosis. Belle Mead, NJ: Excerpta Medica. [els.net]
Related Journals of Osteopetrosis Journal of Osteoporosis and Physical Activity, Orphanet Journal of Rare Diseases, The New England Journal of Medicine, Human Molecular Genetics and Pan African Medical Journal [imedpub.com]
Even though high bone density disorders are different than low, most of these disorders are treated similarly to osteoporosis, with often the same medications. [healthcentral.com]
CONTINUE SCROLLING OR CLICK HERE FOR RELATED SLIDESHOW QUESTION What is another medical term for osteoporosis? See Answer Health Solutions From Our Sponsors [medicinenet.com]
- Bone Disorder
Dysosteosclerosis (DSS) is the form of osteopetrosis distinguished by the presence of skin findings such as red-violet macular atrophy, platyspondyly and metaphyseal osteosclerosis with relative radiolucency of widened diaphyses. [ncbi.nlm.nih.gov]
The radiographic appearance of the skeleton is the basis of OP diagnosis, both in suspected cases and as a starting point for the workup of incidental findings. Generalized osteosclerosis identifiable on standard radiographs is pathognomonic of OP, as are other signs of deficiencies in the remodeling of osseous tissues: Parallel bands of dense bone may be observed - particularly in the pelvic girdle - and are often described as "bone within a bone", whereas zonal differences in the vertebral bone density allow for the recognition of a "rugger jersey spine". Erlenmeyer flask deformities are most easily recognized in the long bones of the extremities, which often show metaphyseal flaring and cortical thinning. Additionally, evidence of multiple new and healing fractures may be found.
Additional studies may be conducted if doubts remain as to the underlying disease, but this is rarely necessary. While standard analyses of blood samples are recommended to assess the patient's electrolyte status, the measurement of osteoclast-derived tartrate-resistant acid phosphatase and creatine kinase isoenzyme BB gains importance in the absence of radiographic findings, namely to support a suspected diagnosis of mild OP . Furthermore, bone biopsies may be realized to distinguish between osteoclast-rich and osteoclast-poor variants of the disease .
In any case, the diagnosis should be confirmed by means of molecular biological studies, the results of which may have therapeutic and prognostic implications . The patient's age at symptom onset, the presence of associated features, and the results of genealogical analyses may hint at a particular subtype of OP and should thus guide decisions related to genetic testing.
- Parathyroid Hormone Increased
Differential Diagnoses Hypoparathyroidism Myeloproliferative Disease Lead Toxicity in children Pseudohypoparathyroidism Lab Investigations Decreased calcium Elevated parathyroid hormone Increased acid phosphatase – due to increased release from defective [boneandspine.com]
The only cure for OP is allogeneic hematopoietic stem cell transplantation (HSCT), which has greatly improved its outcome. Successful HSCT allows for the engraftment of donor-derived osteoclast precursors, which further differentiate and give rise to mature osteoclasts that may fulfill their function in bone resorption . However, certain conditions may render OP patients unfit for the procedure, which in itself is not without risks. HSCT is contraindicated in those with neurodegenerative disease, namely in those with autosomal recessive OP types 2, 4, and 5 . Other patients with severe OP should undergo HSCT as soon as possible in order to prevent irreversible damage to the nervous system. While osteosclerosis, bone marrow failure, and extramedullary hematopoiesis can be prevented and reverted by HSCT, this does not apply to neurological sequelae resulting from abnormal bone remodeling. Additionally, the risk of engraftment failure and delayed hematological reconstitution strongly increases if HSCT is performed after the age of 10 months. This is at least partially due to limited or nearly absent bone marrow space in advanced stages of the disease . Such is the necessity of an early diagnosis and timely treatment of OP that the possibility of HSCT in utero is currently tested in preclinical studies . Further hopes for treatment options are placed in gene therapy .
Beyond that, all patients diagnosed with OP should receive supportive care according to their individual needs .
Patients diagnosed with autosomal dominant OP usually have a normal life expectancy , whereas autosomal recessive OP tends to be fatal within the first 10 years of life  . The latter applies unless the condition is successfully treated with HSCT, although diverse factors may affect the outcome. The prognosis of the individual patient largely depends on the specific type of OP, on the course of the disease in that particular case, and any complications that contribute to morbidity and may result in mortality. To give but two examples, autosomal recessive OP type 3 is compatible with long-term survival, and autosomal dominant OP has been described as becoming severe in childhood  .
Based on the pattern of inheritance, three main types of OP are distinguished: autosomal recessive OP, autosomal dominant OP, and X-linked OP, with each being further classified according to the causal mutation. Autosomal recessive OP tends to be fatal in childhood and is sometimes referred to as the malignant variant of OP. Symptoms of autosomal dominant OP, however, don't usually develop until adolescence or adulthood. The disease follows a milder cause and is thus also known as the benign form of OP. A possible reason for the apparent dichotomy of genotype-phenotype correlations in OP may be that dominant gene defects resulting in severe disease and early mortality are unable to persist in the population. Notwithstanding, OP is far from being a black-and-white issue, and there are non-classical and intermediate phenotypes to be observed in both autosomal recessive and autosomal dominant types of the disease. Incomplete penetrance and variable expressivity significantly limit the ability to correlate genotypes and clinical phenotypes, and the possibility of modifying genes exerting influences on these relationships cannot be ruled out . What's more, the list of OP-inducing genes given in summary is unlikely to be exhaustive, and up to 10% of OP patients remain without a clear genetic diagnosis .
The incidence of autosomal dominant OP has been estimated at 1 in 20,000 live births, while the autosomal recessive type is diagnosed in 1 in 250,000 persons only. Finally, X-linked OP is an increasingly rare entity and there are only isolated case reports available in the literature .
High degrees of parental consanguinity, geographic isolation, and founder effects contribute to particularly high OP incidence in Costa Rica, the Middle East, and the Västerbotten county in Sweden, among others. In Costa Rica, only two mutations of the TCIRG1 gene are behind the vast majority of OP cases, while a milder form of OP is predominant in Arab countries. Here, mutations of the CA2 gene are rather common and OP with tubular acidosis is diagnosed at a higher rate. OP of intermediate severity has regularly been reported in the Swedish county of Västerbotten and could recently be related to SNX10 mutations .
OP has long since been assumed to be the result of deficiencies in osteoclast function. Mutations of distinct genes could be related to the osteoclasts' inability to resorb bone and mineralized cartilage, thereby confirming the original hypothesis of OP pathogenesis. Biopsy specimens obtained from OP patients generally revealed abundant osteoclasts severely impaired in their resorptive function - but some patients seemed to suffer from osteoclast-poor variants of the disease .
It has not been until 2007 that the importance of RANK/RANKL signaling for osteoclast maturation has been understood and the puzzle of osteoclast-poor could be resolved  . RANKL is the main osteoclast differentiation factor and is expressed by osteoblasts and stromal stem cells, while RANK is to be found on the surface of osteoclasts and their precursors. Binding of RANKL to RANK promotes the differentiation of osteoclast precursors into multinucleated, active osteoclasts. Any disruption of this process entails a lack of mature osteoclasts and thus deficiencies in bone resorption in an osteoclast-poor environment.
The prenatal diagnosis of OP is feasible and affected families are highly recommended to receive genetic counseling. Severe OP may be recognized prenatally even in the setting of unknown mutations, since the respective types of the disease result in skeletal malformations and fractures to be identified in prenatal imaging .
OP is an umbrella term for the following disorders of bone metabolism :
- Autosomal recessive osteopetrosis 1, also referred to as infantile malignant osteopetrosis type 1, is caused by mutations of the TCIRG1 gene
- Autosomal recessive osteopetrosis 2 is related to mutations of the TNFSF11 or RANKL gene
- Autosomal recessive osteopetrosis 3, also described as autosomal recessive osteopetrosis with tubular acidosis or carbonic anhydrase II deficiency, is induced by mutations of the CA2 gene
- Autosomal recessive osteopetrosis 4, also referred to as infantile malignant osteopetrosis type 2, is induced by mutations of the CLCN7 gene
- Autosomal recessive osteopetrosis 5, also known as infantile malignant osteopetrosis type 3, has been linked to mutations of the OSTM1 gene
- Autosomal recessive osteopetrosis 6 is related to mutations of the PLEKHM1 gene
- Autosomal recessive osteopetrosis 7, also called autosomal recessive osteopetrosis with hypogammaglobulinemia, is caused by mutations of the TNFRSF11A or RANK gene
- Autosomal recessive osteopetrosis 8, has only recently been associated with mutations of the SNX10 gene
- Autosomal dominant osteopetrosis type 1 is related to mutations of the LRP5 gene
- Autosomal dominant osteopetrosis type 2, also known as Albers-Schönberg disease, is allelic to autosomal recessive OP 4
- Autosomal dominant osteopetrosis type 3 is allelic to autosomal recessive OP 6
- X-linked osteopetrosis is part of the anhidrotic ectodermal dysplasia-immunodeficiency-osteopetrosis-lymphedema syndrome, which is related to mutations of the IKBKG gene
This article aims at giving a general overview of metabolic bone diseases associated with osteoclast dysfunction and increases in bone mineral density. It is beyond the scope of this work to provide detailed information on specific types of osteopetrosis, and the interested reader is referred to the corresponding descriptions available on this platform.
Osteopetrosis is a general term referring to a heterogeneous group of metabolic bone disorders. About a dozen entities have been defined to date, and they differ with regards to the patient's age at symptom onset, the severity of the disease and the foreseeable outcome. Clinical, imaging, and genetic findings must be considered to reach a reliable diagnosis and to formulate a treatment plan. Hematopoietic stem cell transplantation may constitute the only chance for cure, and although the procedure is not without risks, it must be carried out as early as possible in patients with severe osteopetrosis. Those with milder forms of the disease receive supportive care. The latter may include medical therapy to diminish bone formation and promote bone resorption, to compensate for electrolyte imbalances, and to alleviate symptoms.
- Del Fattore A, Cappariello A, Teti A. Genetics, pathogenesis and complications of osteopetrosis. Bone. 2008; 42(1):19-29.
- Sobacchi C, Schulz A, Coxon FP, Villa A, Helfrich MH. Osteopetrosis: genetics, treatment and new insights into osteoclast function. Nat Rev Endocrinol. 2013; 9(9):522-536.
- Wu CC, Econs MJ, DiMeglio LA, et al. Diagnosis and Management of Osteopetrosis: Consensus Guidelines From the Osteopetrosis Working Group. J Clin Endocrinol Metab. 2017; 102(9):3111-3123.
- Stark Z, Savarirayan R. Osteopetrosis. Orphanet J Rare Dis. 2009; 4:5.
- Penna S, Capo V, Palagano E, Sobacchi C, Villa A. One Disease, Many Genes: Implications for the Treatment of Osteopetroses. Front Endocrinol (Lausanne). 2019; 10:85.
- Tondelli B, Blair HC, Guerrini M, et al. Fetal liver cells transplanted in utero rescue the osteopetrotic phenotype in the oc/oc mouse. Am J Pathol. 2009; 174(3):727-735.
- Askmyr M, Flores C, Fasth A, Richter J. Prospects for gene therapy of osteopetrosis. Curr Gene Ther. 2009; 9(3):150-159.
- Awad M, Al-Ashwal AA, Sakati N, Al-Abbad AA, Bin-Abbas BS. Long-term follow up of carbonic anhydrase II deficiency syndrome. Saudi Med J. 2002; 23(1):25-29.
- Waguespack SG, Hui SL, Dimeglio LA, Econs MJ. Autosomal dominant osteopetrosis: clinical severity and natural history of 94 subjects with a chloride channel 7 gene mutation. J Clin Endocrinol Metab. 2007; 92(3):771-778.
- Palagano E, Menale C, Sobacchi C, Villa A. Genetics of Osteopetrosis. Curr Osteoporos Rep. 2018; 16(1):13-25.
- Stattin EL, Henning P, Klar J, et al. SNX10 gene mutation leading to osteopetrosis with dysfunctional osteoclasts. Sci Rep. 2017; 7(1):3012.
- Guerrini MM, Sobacchi C, Cassani B, et al. Human osteoclast-poor osteopetrosis with hypogammaglobulinemia due to TNFRSF11A (RANK) mutations. Am J Hum Genet. 2008; 83(1):64-76.
- Sobacchi C, Frattini A, Guerrini MM, et al. Osteoclast-poor human osteopetrosis due to mutations in the gene encoding RANKL. Nat Genet. 2007; 39(8):960-962.