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 [1] [2]. In general, the following conditions contribute to the clinical picture [3]:

• 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.

• Pain

  Here, we present a case a 46 year-old woman complained low back pain for 15 years. The patient lacked any history of direct trauma and her pain was radiating to her left leg, increasing with physical activity, she had no pain at nights. [ncbi.nlm.nih.gov]

  The patient was complaining from a six-month low back pain that was not cured in previous visits as general practitioners hypothesized that this pain is associated with his underlying disease or is musculoskeletal. [omicsonline.org]

  First published: 02 March 2015 The patient, a 68‐year‐old man, presented with pain on motion of his left knee and occasional self‐limited diffuse back pain. [onlinelibrary.wiley.com]

• Recurrent Infection

  Due to depressed marrow function, this disorder can cause anemia, hepatosplenomegaly, recurrent infections and osteomyelitis of jaw. Excessive bone deposition in skull base leads to narrowing of foramina and cranial nerve compression. [ncbi.nlm.nih.gov]

  LAD-III is associated with recurrent infections and mucosal bleeding. [hematology.org]

  infection, massive hemorrhage, terminal leukemia) Benign adult autosomal dominant type 50% asymptomatic Recurrent fractures Mild anemia Cranial nerve palsy (rarely) Prognosis: normal X-ray findings Diffuse osteosclerosis Cortical thickening with medullary [learningradiology.com]

  Affected individuals also have a malfunctioning immune system (immunodeficiency), which allows severe, recurrent infections to develop. [ghr.nlm.nih.gov]

• Lymphedema

  In addition to abnormally dense bones, the X-linked form of the disorder is characterized by abnormal swelling caused by a buildup of fluid (lymphedema) and a condition called anhydrotic ectodermal dysplasia that affects the skin, hair, teeth, and sweat [ghr.nlm.nih.gov]

  This is known as OL-EDA-ID, an abbreviation of the symptoms the condition causes — osteopetrosis, lymphedema (abnormal swelling), anhidrotic ectodermal dysplasia (a condition affecting the skin, hair, teeth, and sweat glands), and immunodeficiency. [verywellhealth.com]

  Fatal in early childhood.Classical radiographic features of osteopetrosis are present.Osteopetrosis, lymphedema, anhidrotic ectodermal dysplasia and immunodeficiency (OLEDAID). [ncbi.nlm.nih.gov]

• Failure to Thrive

  pancytopenia; bleeding; infection; failure to thrive; growth retardation; proptosis; blindness; deafness; hydrocephalus Infancy Poor Marble bone disease Autosomal recessive Abnormal osteoclastic bone resorption No bone marrow failure; renal tubular [aafp.org]

  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]

• Austin Flint Murmur

  Flint オースチン・フリント Austin Flint murmur オースチン・フリント雑音 Austin Flint （1812-1886）American physician Ayerza アイエルザ Ayerza's syndrome アイエルザ症候群 Babinski バビンスキー Babinski's phenomenon バビンスキー現象 JosephJules François Félix Babinski （1857 - 1932） Polish neurologist パリ [jams.med.or.jp]

• 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]

  Fluoride applications can be done to decrease the susceptibility to dental caries [4]. Dental abnormalities may be attributed to the pathological changes in osteopetrosis. Patients with the disease seem to be especially susceptible to caries. [ncbi.nlm.nih.gov]

  caries One of the commonest presentations is with ocular disturbance: failure to establish fixation, nystagmus or strabismus 4. [radiopaedia.org]

• Hepatomegaly

  We noted more severe radiological findings in patients with TCIRG1 and RANK mutations, including fractures, osteopetrorickets, hydrocephalus, and hepatomegaly. [ncbi.nlm.nih.gov]

  […] 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]

  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]

  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]

  […] 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]

• 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]

  Hearing impairment in association with distal renal tubular acidosis among Saudi children. J Laryngol Otol. 1995;109:930–4. 7. Becelli R, Sassano P. The maxillofacial functional and esthetic surgical aspects in a case of osteopetrosis. [aafp.org]

  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]

• Osteoporosis

  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]

  High risk of fractures is a major concern for people living with osteoporosis. Once a patient suffers an osteoporosis-related fracture his or her risk of a future fracture increases up to 10 times. [urduexpresslive.com]

• Bone Disorder

  SUMMARY: Osteopetrosis is a group of genetic bone disorders. [ncbi.nlm.nih.gov]

  Since we rarely get this question, I thought we'd discuss bone disorders that can cause an excess build up of bone. [healthcentral.com]

• Back Pain

  Here, we present a case a 46 year-old woman complained low back pain for 15 years. The patient lacked any history of direct trauma and her pain was radiating to her left leg, increasing with physical activity, she had no pain at nights. [ncbi.nlm.nih.gov]

  The patient was complaining from a six-month low back pain that was not cured in previous visits as general practitioners hypothesized that this pain is associated with his underlying disease or is musculoskeletal. [omicsonline.org]

  The most common problems for which patients present to the Emergency Department are neurological disorders, including stroke, syncope, back pain and headache. [books.google.com]

  First published: 02 March 2015 The patient, a 68‐year‐old man, presented with pain on motion of his left knee and occasional self‐limited diffuse back pain. [onlinelibrary.wiley.com]

• Hip Dislocation

  […] disname=Osteopetrosis v t e Congenital malformations and deformations of musculoskeletal system ( Q65-Q79, 754-756 ) Limbs hip : Dislocation of hip / Hip dysplasia - Upington disease feet ( Club foot, Flat feet, Pes cavus ) systemic dislocations Larsen [wikidoc.org]

  She presented initially with hip dislocation and was subsequently observed to have hypotonia and motor delay. She also had normal stature, as well as joint laxity and soft skin. Her bone mineral density was also low for her age. [emedicine.medscape.com]

• Cerebral Calcification

  Abstract Carbonic anhydrase-II deficiency is an autosomal recessive disorder with a triad of cerebral calcification, osteopetrosis and renal tubular acidosis (often combined proximal and distal). [sjkdt.org]

  The onset of cerebral calcification may have been delayed but was not prevented in one child. [bloodjournal.org]

  Major characteristics of this disorder include cerebral calcification, osteopetrosis and distal renal tubular acidosis. [aafp.org]

  The autosomal recessive type is common in children and has three forms: severe (malignant), mild (intermediate), and the one associated with cerebral calcification and renal tubular acidosis. [annsaudimed.net]

  calcification Prognosis: survival beyond middle age is uncommon (death due to recurrent infection, massive hemorrhage, terminal leukemia) Benign adult autosomal dominant type 50% asymptomatic Recurrent fractures Mild anemia Cranial nerve palsy (rarely [learningradiology.com]

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 [3]. Furthermore, bone biopsies may be realized to distinguish between osteoclast-rich and osteoclast-poor variants of the disease [4].

In any case, the diagnosis should be confirmed by means of molecular biological studies, the results of which may have therapeutic and prognostic implications [3]. 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.

• Increased Bone Density

  General imaging differential considerations include: heavy metal poisoning (e.g. lead) melorheostosis hypervitaminosis D pyknodysostosis fibrous dysplasia of skull or face generalized increased bone density (mnemonic) generalized increased bone density [radiopaedia.org]

  Osteopetrosis is a heterogeneous disorder characterized by abnormal bone remodeling and increased bone density primarily due to defective osteoclast resorption. [ncbi.nlm.nih.gov]

  X-rays showed the thick bones with increased bone density [Figure 2]b. [mjdrdypu.org]

  […] disease characterized by increased bone density. [pure.au.dk]

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 [5]. 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 [2]. 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 [5]. 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 [6]. Further hopes for treatment options are placed in gene therapy [7].

Beyond that, all patients diagnosed with OP should receive supportive care according to their individual needs [3].

Patients diagnosed with autosomal dominant OP usually have a normal life expectancy [4], whereas autosomal recessive OP tends to be fatal within the first 10 years of life [2] [5]. 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 [8] [9].

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 [3]. 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 [10].

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 [10].

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 [11].

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 [2].

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 [12] [13]. 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 [4].

OP is an umbrella term for the following disorders of bone metabolism [1]:

• 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.

1. Del Fattore A, Cappariello A, Teti A. Genetics, pathogenesis and complications of osteopetrosis. Bone. 2008; 42(1):19-29.
2. 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.
3. 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.
4. Stark Z, Savarirayan R. Osteopetrosis. Orphanet J Rare Dis. 2009; 4:5.
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.
6. 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.
7. Askmyr M, Flores C, Fasth A, Richter J. Prospects for gene therapy of osteopetrosis. Curr Gene Ther. 2009; 9(3):150-159.
8. 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.
9. 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.
10. Palagano E, Menale C, Sobacchi C, Villa A. Genetics of Osteopetrosis. Curr Osteoporos Rep. 2018; 16(1):13-25.
11. Stattin EL, Henning P, Klar J, et al. SNX10 gene mutation leading to osteopetrosis with dysfunctional osteoclasts. Sci Rep. 2017; 7(1):3012.
12. 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.
13. 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.