Autosomal dominant osteopetrosis type 2 (OPTA2) is a rather mild form of hereditary osteopetrosis. OPTA2 is also referred to as Albers-Schönberg disease and is allelic to autosomal recessive osteopetrosis 4 (OPTB4), a type of malignant infantile osteopetrosis. Both are caused by mutations in the CLCN7 gene. In OPTA2, symptom onset is generally delayed until adulthood, with incidental diagnoses being common. Notwithstanding, more severe phenotypes have been observed, and suggest the influence of as-of-yet unknown genetic or environmental factors that determine where an individual patient fits in the continuum of CLCN7-related disease.
Classical OPTA2 may include complaints due to skeletal involvement but is neither related to visual impairment nor neurological symptoms. Patients tend to be asymptomatic for prolonged periods of time and the disease is not usually diagnosed until adulthood, when diagnostic imaging is realized for non-related reasons. Patients who become symptomatic may present with susceptibility to fractures or unspecific, radiating bone pain. Fractures may occur after minor traumas, and pain is generally not related to potential triggers. Bone pain may worsen during physical exercise and often reduces during inactivity and sleep .
Heterogeneous presentation has repeatedly been described in families affected by OPTA2, and a minor share of patients has been reported to suffer from intermediate or severe osteopetrosis . Symptom onset in childhood, recurrent fractures, vision loss and pancytopenia due to the progressive narrowing of cranial nerve foramina and medullary spaces, respectively, have been observed in these cases. Tooth crowding and mandibular osteomyelitis have rarely been diagnosed . In this context, it should be noted that patients with classical OPTA2 and more severe phenotypes may coexist in the same family .
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[…] body height Small stature [ more ] 0004322 5%-29% of people have these symptoms Abnormal leukocyte morphology 0001881 Blindness 0000618 Bone marrow hypocellularity Bone marrow failure 0005528 Carious teeth Dental cavities Tooth cavities Tooth decay [ [rarediseases.info.nih.gov]
But the shape of the skull, abnormal bony swellings over the body gave us a clue regarding the actual diagnosis. Summary A case of Osteopetrosis with bilateral exophthalmos and optic atrophy in a 8 years old boy is reported. [ijo.in]
Patients may have a rather long medical history, with unspecific bone pain persisting for decades . However, OPTA2-related bone pain is not usually disabling and may not even be reported by the affected individual until specifically asked about it. Incidental diagnoses are common and are typically made during the workup of other disorders or preventive bone density screenings. More severe OPTA2 is associated with specific symptoms, such as neurological deficits or hematological anomalies, that prompt a targeted search for causes.
In any case, radiological studies form the basis of OPTA2 diagnosis. Images of the affected bones reveal osteosclerotic changes and increased bone density, whereby OPTA2 preferentially affects the base of the skull, vertebrae, pelvis, and long bones of the appendicular skeleton   :
- Cranial nerve palsies may be related to the progressive obturation of the respective foramina and canals. The optic nerve is most frequently affected, but atrophy of the facial and auditory nerve have also been described.
- With regards to the spinal column, the term "rugger jersey spine" has been coined to describe the alternating appearance of sclerotic and radiolucent stripes, which are owing to increased bone density in the upper and lower end plates.
- Deficiencies in the remodeling of the pelvic bones, namely the iliac wings, often give rise to the appearance of "bone within a bone".
- Sclerotic changes and segmental enlargement are readily recognizable in the long bones of the extremities.
The tentative diagnosis of OPTA2 should be confirmed by means of genetic studies. The detailed characterization of the genotypes of the patient, their parents, and further relatives allows for genealogical analyses and genetic counseling and is particularly important in the light of persisting knowledge gaps regarding the factors that contribute to the course of the disease. It should be beared in mind that the molecular diagnosis of CLCN7-related osteopetrosis may not coincide with the clinical suspicion .
With regards to the spinal column, the term "rugger jersey spine" has been coined to describe the alternating appearance of sclerotic and radiolucent stripes, which are owing to increased bone density in the upper and lower end plates. [symptoma.com]
CHORUS Collaborative Hypertext of Radiology Musculoskeletal system About CHORUS Disclaimer Copyright marble bones, brittle bones, osteosclerosis fragilis abnormally dense bones brittle, fracture easily "rugger jersey" spine may be cause of anemia (d/t [gamuts.net]
The spine images show the classic sandwich vertebrae sign (differentiate by some from the rugger jersey spine). The femur demonstrates increased sclerosis and an Erlenmeyer flask deformity. References Butteriss DJ, Clarke M, Birchall D. [roentgenrayreader.blogspot.com]
Del Fattore et al. reported generalised osteosclerosis in 43% of the cases, rugger jersey spine was noted in 52.3% of the patients, and 33.3% patients had bone-in-bone appearance . [hindawi.com]
Hematopoietic stem cell transplantation offers the only chance for cure of hereditary osteopetrosis and heterogeneous in severely affected patients without irreversible damage to the nervous system. The vast majority of OPTA2 patients doesn't meet this criterion, displays a milder phenotype and hence is not eligible for stem cell transplantations, which continue to be associated with significant morbidity and mortality . These patients are instead provided with symptomatic care according to their individual needs  :
- A multidisciplinary approach is required to manage skeletal complications, such as fractures, arthritis, and osteomyelitis.
- Cytopenias may require the transfusion of blood products. Furthermore, corticosteroids may be administered to stimulate hematopoiesis.
- The surgical decompression of the optic nerve may delay vision loss but is hardly able to prevent it.
Notwithstanding, hematopoietic stem cell transplantation should be considered in those with severe phenotypes .
Intensive research is carried out on new approaches to treating OPTA2. In this context, RNA interference therapy has yielded the most promising results. The silencing of the mutated gene may induce a condition of pseudo-haplosufficiency and rescue the healthy phenotype. RNA interference therapy has been proven to be effective and safe in animal models for OPTA2 and may soon progress to be tested in clinical trials .
OPTA2 patients have a normal life expectancy but may be faced with a series of orthopedic problems . Spine curvature disorders may be provoked by vertebral osteopetrosis, and involvement of the pelvic bones may result in coxarthritis. Likewise, susceptibility to pathological fractures persists, and patients may experience long-bone bowing .
In the rare cases where OPTA2 is associated with cranial nerve palsies and bone marrow failure, the prognosis is less favorable. Atrophy of the optic nerve eventually results in blindness, and damage to other cranial nerves is likewise irreversible .
OPTA2 is inherited in an autosomal dominant manner and has been linked to mutations in the CLCN7 gene. CLCN7 is located at 16p13.3 and encodes for voltage-gated chloride channel 7 or ClC-7, an ion exchanger that localizes to the cell membrane and membranes of organelles. Mutations of CLCN7 have also been stated to account for OPTB4, hence pathogenic variants of this gene may differently affect the expression and function of ClC-7. In this context, mutations exerting a dominant negative affect have been related to OPTA2, while loss-of-function mutations in CLCN7 have been postulated to not cause abnormalities in heterozygous individuals. Homozygosity for such mutations, however, has been demonstrated to trigger OPTB4 .
So much for the generally accepted differentiation of black and white, of mild OPTA2 and malignant infantile OPTB4. The growing amount of clinical data paints a more complex picture and suggests a continuum from classical, dominant OPTA2 to intermediate forms to severe, recessive OPTB4 . Genotype-phenotype correlations existing in this broad spectrum of CLCN7-related osteopetrosis are poorly understood. There may be additional factors of genetic or environmental nature that affect the course of the disease but that have not yet been identified and considered in the classification of hereditary osteopetroses. The understanding of these factors is further hampered by the variable expressivity of determined mutations: The same mutations have been described in heterozygous OPTA2 and homozygous OPTB4 patients, have been found in asymptomatic carriers, and have been linked to more or less severe disease . The general penetrance of pathogenic mutations in CLCN7 has been estimated at 66-94%  .
The incidence of autosomal dominant osteopetrosis has been estimated at 1 in 20,000 live births, but the respective diseases are likely to be underdiagnosed: They present with a relatively benign clinical picture, with many patients being asymptomatic and only detected by incidental radiological examination. According to available data, OPTA2 is the most common form of osteopetrosis . OPTA2 has been diagnosed in patients of distinct ethnicities and seems to be prevalent in all parts of the world. Men and women are likewise affected, and the disease is usually diagnosed in mid-adulthood. Symptom onset as early as the first decade of life has been described in isolated cases, though .
ClC-7 is a membrane-bound protein that mediates the exchange of two chloride ions against one proton, thereby affecting the electrical and chemical potentials across the respective membrane. In osteoclasts, ClC-7 is to be found in the membrane of lysosomes, which eventually fuse with a specific zone of the cell membrane to release their content into the extracellular space, namely into resorption lacunae . The latter are formed when osteoclasts adhere to bone tissue and constitute a confined area that facilitates the resorption of the osseous matrix. In order to dissolve bone minerals, an acidic environment must be created in those resorption lacunae, and this is achieved by means of proton secretion. An electrogenic V-type ATPase takes care of proton secretion but requires assistance in maintaining the electrical potential across the newly formed ruffled border. This assistance is provided by ClC-7, which mediates chloride transport across the ruffled border into the extracellular space. The role of protons being "partially recovered" by ClC-7 is less clear; this mechanism seems to be of minor importance for the maintenance of the electrical shunt that assures the function of the electrogenic ATPase, as has been demonstrated in mice carrying mutations that uncouple ClC-7-mediated chloride transport from proton countertransport .
The function of lysosomes in non-osseous tissues may similarly depend on ClC-7. Mice lacking this ion channel display osteopetrosis, retinal degeneration, and lysosomal storage disease in the central nervous system and proximal tubules of the kidney. And while similar findings are made in patients suffering from autosomal recessive osteopetrosis due to chloride channelopathies, OPTA2 seem to benefit from heterozygosity and a remaining share of functional ClC-7. As ClC-7 forms dimers, heterozygous dominant-negative mutations of CLCN7 reduce the level of wildtype channels to 25%. This may suffice for the function of lysosomes in the retina, brain, and kidneys. Homozygosity for pathogenic mutations, as observed in OPTB4, does not allow for the synthesis of active ion exchangers .
Of note, the aforedescribed process requires functional ClC-7 and osteopetrosis-associated transmembrane protein 1 . The latter is encoded by the OSTM1 gene and may also be referred to as the β subunit of chloride channel 7. Mutations in the OSTM1 gene have been linked to autosomal recessive osteopetrosis, and the respective type of the disease has been named autosomal recessive osteopetrosis 5 .
In order to provide the best possible genetic counseling and to shed more light on the complex correlations between CLCN7 mutations and phenotypes of OPTA2, affected individuals and, at the very least, first-degree relatives should undergo thorough genetic testing. The knowledge gained may then be used to identify carriers and to make prenatal diagnoses.
Hereditary osteopetroses are a heterogeneous group of disorders. There are at least eight types of autosomal recessive osteopetrosis, which manifests early in life and is also referred to as malignant infantile osteopetrosis, and there is autosomal dominant osteopetrosis. The latter follows a milder course and is more common than the former, with the vast majority of cases corresponding to CLCN7-related OPTA2. Indeed, what has formerly been referred to as autosomal dominant osteopetrosis type 1 is now known to be secondary to mutations in the gene encoding the low-density lipoprotein receptor-related protein 5, hence it is no longer considered a "true form" of autosomal dominant osteopetrosis. Rare variants of autosomal dominant osteopetrosis have been related to mutations in the PLEKHM1 gene and have been designated autosomal dominant osteopetrosis type 3 .
The patient originally described in 1904 by Albers-Schönberg most likely suffered from OPTA2, hence the term "Albers-Schönberg disease" is now reserved for this type of osteopetrosis. Current challenges in OPTA2 research consist in the establishment of genotype-phenotype correlations, the identification of additional factors that affect disease severity and progression, and the development of a specific pharmacological therapy .
Autosomal dominant osteopetrosis type 2 (OPTA2) is a rather frequent hereditary disorder. The disease is underdiagnosed because most patients remain asymptomatic until mid- to advanced adulthood. When diagnostic imaging is carried out for unrelated reasons, sclerotic changes in the skull, vertebrae, pelvis, and long bones of the appendicular skeleton may be noted, prompting a further workup and an eventual diagnosis of OPTA2. Patients who become symptomatic may present with fractures upon minor physical impact, bone pain, or long-term sequelae of skeletal anomalies, such as spine curvature disorders, arthritis of the hip joint, and osteomyelitis of the mandible.
In rare cases, OPTA2 may manifest in childhood. Pathological fractures are the most common symptom of early-onset OPTA2, but patients may also present with progressive visual impairment or cytopenias as a sign of bone marrow failure.
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