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CLCN7-Related Osteopetrosis

Includes: Autosomal Dominant Osteopetrosis Type II (ADOII), Infantile Malignant CLCN7-Related Autosomal Recessive Osteopetrosis (ARO), Intermediate Autosomal Osteopetrosis (IAO)

, MD, PhD, , MD, and , MD, PhD.

Author Information
, MD, PhD
INSERM U606
Hôpital Lariboisière
Paris, France
, MD
Universitätsklinik für Kinder- und Jugendmedizin
Ulm, Germany
, MD, PhD
Institut für Medizinische Genetik
Charité Universitätsmedizin
Berlin, Germany

Initial Posting: ; Last Update: June 20, 2013.

Summary

Disease characteristics. The spectrum of CLCN7-related osteopetrosis includes infantile malignant CLCN7-related recessive osteopetrosis (ARO), intermediate autosomal osteopetrosis (IAO), and autosomal dominant osteopetrosis type II (ADOII, Albers-Schoenberg disease).

  • Onset of ARO is in infancy; findings may include fractures; poor growth; sclerosis of the skull base (with or without choanal stenosis or hydrocephalus) resulting in optic nerve compression, facial palsy, and hearing loss; absence of the bone marrow cavity resulting in severe anemia and thrombocytopenia; dental abnormalities, odontomas, and risk for mandibular osteomyelitis; and hypocalcemia with tetanic seizures and secondary hyperparathyroidism. Without treatment maximal life span in ARO is ten years.
  • Onset of IAO is in childhood; findings may include fractures after minor trauma, characteristic skeletal radiographic changes found incidentally, mild anemia, and occasional visual impairment secondary to optic nerve compression. Life expectancy in IAO is usually normal.
  • Onset of ADOII is usually late childhood or adolescence; findings may include fractures (in any long bone and/or the posterior arch of a vertebra); scoliosis; hip osteoarthritis; osteomyelitis of the mandible or septic osteitis or osteoarthritis elsewhere. Cranial nerve compression is rare.

Diagnosis/testing. Diagnosis of CLCN7-related osteopetrosis usually relies on radiographic changes that are pathognomonic in ARO (generalized osteosclerosis, club-shaped long bones, osteosclerosis of the skull base, bone-within-bone appearance) and characteristic in ADOII (osteosclerosis of the spine ("sandwich vertebra" appearance), bone-within-bone appearance (mainly iliac wings), Erlenmeyer-shaped femoral metaphysis, mild osteosclerosis of the skull base, transverse bands of osteosclerosis in long bones). CLCN7 is the only gene in which mutations are known to cause CLCN7-related osteopetrosis.

Management. Treatment of manifestations:

  • ARO. Calcium supplementation for hypocalcemic convulsions; management of calcium homeostasis per the individual’s needs; erythrocyte or platelet transfusions as needed; antibiotics for leukocytopenia; immunoglobulins for hypogammaglobulinemia; surgical decompression of the optic nerve; treatment of fractures by an experienced orthopedist; dental care with attention to tooth eruption, ankylosis, abscesses, cysts, fistulas.
  • ADOII. Orthopedic treatment for fractures and arthritis with attention to potential post-surgical complications (delayed union or non-union of fractures, infection); fractures near joints may require total joint arthroplasty.

Prevention of primary manifestations: ARO. Hematopoietic stem cell transplantation (HSCT) can be curative; however, cranial nerve dysfunction is usually irreversible, and progressive neurologic sequelae occur in children with the neuronopathic form even after successful HSCT.

Prevention of secondary complications:

  • ARO. Restricted intake of calcium and vitamin D just before, during, and following HSCT to prevent hypercalcemia.
  • ADOII. Good routine dental care and oral hygiene to help prevent osteomyelitis of the mandible.

Surveillance: ARO. Complete blood count and ophthalmologic examination at least once a year; follow-up per the transplantation center following HSCT.

Agents/circumstances to avoid: ADOII. Activities with high fracture risk.

Genetic counseling. ARO is inherited in an autosomal recessive manner; ADOII is inherited in an autosomal dominant manner; about 40% of IAO is inherited in an autosomal recessive manner and about 60% in an autosomal dominant manner.

  • Autosomal recessive inheritance. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Individuals with ARO in general only reproduce if successfully treated by HSCT.
  • Autosomal dominant inheritance. Most individuals diagnosed with autosomal dominant CLCN7-related osteopetrosis have an affected parent. The proportion of cases caused by de novo mutations is unknown. Each child of an individual with autosomal dominant CLCN7-related osteopetrosis has a 50% chance of inheriting the mutation.

Prenatal diagnosis for pregnancies at increased risk for ADOII and ARO is possible if the disease-causing mutation(s) has/have been identified in the family.

Diagnosis

Clinical Diagnosis

The spectrum of CLCN7-related osteopetrosis includes:

  • Infantile malignant CLCN7-related autosomal recessive osteopetrosis (ARO)
  • Intermediate autosomal osteopetrosis (IAO)
  • Autosomal dominant osteopetrosis type II (ADOII, Albers-Schoenberg disease).

Table 1. Diagnostic Features of the Subtypes of CLCN7-Related Osteopetrosis

FindingSubtype of CLCN7-Related Osteopetrosis
ARO 1IAO 2 ADOII 3
Radiographic changesPathognomonic 4 Characteristic 5 Characteristic 6
HypocalcemiaSevere to absentAbsentAbsent
AnemiaSevere to absentMild to absentAbsent
ThrombocytopeniaSevere to absentAbsentAbsent
Visual impairmentFrequentRareVery rare
CNS involvementSevere to absentAbsent Absent

1. ARO = infantile malignant autosomal CLCN7-related recessive osteopetrosis

2. IAO = intermediate autosomal CLCN7-related osteopetrosis

3. ADOII = autosomal dominant osteopetrosis type II

4. Generalized osteosclerosis, club-shaped long bones, sclerosis of the skull base, bone-within-bone appearance

5. Findings similar to ARO, already present in early childhood, but less severe

6. Findings include:

• Osteosclerosis of the spine ("sandwich vertebrae")

• Bone within bone appearance, mainly in iliac wings

• Erlenmeyer-shaped femoral metaphysis

• Mild osteosclerosis of the skull base

• Transverse bands of osteosclerosis in long bones

Testing

Serum concentrations of the BB-isoenzyme of creatine kinase (CK) and tartrate resistant acid phosphatase (TRAP). Increases in the serum concentrations of these two enzymes have been reported as biologic markers of ADOII. They could reflect increased osteoclast numbers and could help identify affected individuals who do not have diagnostic radiographic findings [Waguespack et al 2002, Alatalo et al 2004, Del Fattore et al 2006].

Molecular Genetic Testing

Gene. CLCN7 is the only gene in which mutations are known to cause CLCN7-related osteopetrosis.

The proportion of all osteopetrosis caused by mutation of CLCN7 is summarized in Table 2.

Table 2. Proportion of Osteopetrosis Phenotype Caused by Mutation of CLCN7

Osteopetrosis Phenotype# of CLCN7 Mutations% of Osteopetrosis Caused by Mutation of CLCN7
Infantile malignant CLCN7-related autosomal recessive osteopetrosis (ARO)213%
Intermediate autosomal CLCN7-related osteopetrosis (IAO)140%
160%
Autosomal dominant osteopetrosis type II (ADOII)175% 2

1. Campos-Xavier et al [2003], Frattini et al [2003] , Pangrazio et al [2010]

2. Del Fattore et al [2006] found CLCN7 mutations in 78% of ADOII cases; Frattini et al [2003] found CLCN7 mutations in 72% of ADOII cases. In other cohorts, rates may be higher [unpublished observations]. It remains possible that mutations in another gene cause the ADOII phenotype in a subset of cases.

Table 3. Summary of Molecular Genetic Testing Used in CLCN7-Related Osteopetrosis

Gene 1 Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
CLCN7Sequence analysisSequence variants 4~95% 5
Deletion/duplication analysis 7Partial, whole-gene, or contiguous gene deletions 6Unknown

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5. Mutations in CLCN7 account for approximately 13% of all ARO and 100% of all IAO described to date [Frattini et al 2003].

6. Example of homozygous 101-kb contiguous gene deletion including exons 7-25 of CLCN7 [Pangrazio et al 2012]

7. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

To confirm/establish the diagnosis in a proband. Bone marrow aspirates and bone biopsy histology may be performed to confirm and classify the disease.

  • CLCN7-related osteopetrosis is generally characterized by high levels of osteoclasts and persistence of cartilage in bone trabeculae.
  • If osteoclast-poor disease is seen, molecular genetic testing of genes involved in osteoclast differentiation (TNFSF11, TNFRSF11A) should be considered.

Autosomal recessive osteopetrosis (ARO) should be considered in those with symptoms beginning in early childhood, x-rays that show general osteosclerosis, and hypocalcemia and hematologic abnormalities.

  • Testing should begin with sequence analysis of TCIRG1
  • If sequencing of TCIRG1 does not confirm the diagnosis, sequence analysis of CLCN7 should be considered next.
  • In individuals with a clear ARO phenotype in whom a single heterozygous mutation in CLCN7 is identified, deletion/duplication analysis of CLCN7 should be considered to evaluate for a microdeletion or microduplication. In the case of a homozygous deletion of CLCN7, no PCR products will be obtained for the affected exons; confirmation requires deletion/duplication analysis.
  • If molecular genetic testing of CLCN7 does not confirm the diagnosis, sequencing of SNX10, TNFSF11, TNFRSF11A and OSTM1 (see Differential Diagnosis) should be considered.

Intermediate autosomal osteopetrosis (IAO) should be considered in those with symptoms beginning after age six years (usually fractures) and x-rays that show less pronounced osteosclerosis (i.e., typical sandwich appearance of the vertebrae).

Autosomal dominant osteopetrosis type II (ADOII) is characterized by a broad range of possible manifestations. The diagnostic measures should be in accordance with the individual clinical signs, and may include:

  • A blood cell count
  • Abdominal ultrasonography
  • Ophthalmologic examination
  • In severely affected individuals with early onset, the diagnostic work-up is the same as for ARO.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutations in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Clinical Description

Natural History

Infantile Malignant CLCN7-Related Autosomal Recessive Osteopetrosis (ARO)

ARO is a systemic, life-threatening disorder. Without treatment, maximal life span is ten years. Possible clinical manifestations of ARO:

  • Fractures. The nearly complete absence of osteoclastic bone resorption caused by the loss of chloride channel protein 7 (also known as ClC-7) leads to osteosclerosis of the whole skeleton within the first few months after birth (Figure 1). Because of defective microarchitecture, the bones become brittle, resulting in recurrent fractures (usually of the long bones).
  • Reduced growth. Growth retardation is variable because resorption of cartilage and bone at the growth plate is a prerequisite for longitudinal growth. In severely affected children, body length at age 12 months is as much as 5 cm below the third centile.
  • Skull. In some severely affected children, macrocephaly and frontal bossing develop within the first year. This is not necessarily paralleled by sclerosis of the cranial vault. The sclerosis of the skull base often leads to choanal stenosis. Additionally, the skull changes can cause hydrocephalus.
  • Neurologic complications. Visual impairment beginning shortly after birth is common. In most cases it is caused by optic nerve compression within the osteosclerotic skull base.

    A prominent and large anterior fontanel is common and sometimes associated with hydrocephalus, possibly caused by obstruction of cerebral blood flow and cerebrospinal fluid (CSF) circulation as a result of hyperostosis.

    Facial palsy caused by facial nerve entrapment is an uncommon manifestation.

    Seizures can result from hypocalcemia.
  • Neuronopathic form. If seizures appear together with normal serum calcium concentration and developmental delay, a neuronopathic form has to be considered. In these cases the neuronal phenotype resembles neuronal ceroid-lipofuscinosis [Steward 2003]. In this subset of very severely affected children, primary degeneration of the retina and CNS occurs. It is important to differentiate these rare primary neurologic manifestations of the neuronopathic form of ARO, which has a poor prognosis, from more common secondary lesions resulting from hyperostosis of the skull base. It is noteworthy that pathologic EEG changes with a characteristic pattern of very frequent multifocal spikes and sharp waves usually precede the clinical symptoms and brain MRI findings of neurodegeneration [A Schulz, unpublished results].

    The basis of the neuronopathic form of ARO is as yet incompletely understood, but neurologic complications seem to be more common and more severe in persons with CLCN7 mutations than in those with TCIRG1 mutations [Pangrazio et al 2010; A Schulz, unpublished results]. This is mirrored by neurodegeneration in CLCN7-null mice [Kasper et al 2005].
  • Otologic manifestations. According to Dozier et al [2005], 78% of individuals with ARO showed variable hearing loss. Poor pneumatization of the mastoid bone and narrowing of the external auditory canal, eustachian tube, and internal auditory canal frequently lead to otitis media, conductive and sensorineural hearing loss, and facial nerve paralysis [Dozier et al 2005].
  • Dental. Oral problems in ARO are delayed tooth eruption, hypodontia, malformed teeth, enamel hypoplasia, hypomineralization of enamel and dentin, the presence of odontomas, and severe mandibular osteomyelitis. Even if the primary dentition is impaired, the secondary dentition can be normal after successful stem cell transplantation [Jalevik et al 2002, Helfrich 2005, Luzzi et al 2006].
  • Hypocalcemia. Hypocalcemia may result in tetanic seizures and secondary hyperparathyroidism.
  • Anemia and thrombocytopenia. The absence of the bone marrow cavity leads to extramedullary hematopoiesis, hepatosplenomegaly, anemia, and thrombocytopenia. The bleeding associated with thrombocytopenia can be severe and life threatening, especially in the CNS.
  • Immune function. Immune function may be impaired. Leukocytosis, present in the early stage of the disease, can become leukocytopenia. In conjunction with the frequently observed choanal stenosis, impaired immune function may lead to chronic rhinitis. Defective superoxide generation by granulocytes and monocytes has been reported in ARO [Wilson & Vellodi 2000].
Figure 1

Figure

Figure 1. ARO x-rays

Intermediate Autosomal Osteopetrosis (IAO)

IAO is characterized by childhood onset with a milder course than ARO. Life expectancy is normal in most cases. Children may present with fractures after minor trauma or characteristic changes on x-rays obtained for other clinical indications. Hematologic signs are milder than those in ARO and are usually restricted to anemia. Although CNS involvement is usually absent, visual impairment secondary to optic nerve encroachment can occur [Campos-Xavier et al 2003, Frattini et al 2003].

Autosomal Dominant Osteopetrosis Type II (ADOII)

Although ADOII is sometimes called "benign osteopetrosis," as many as 60%-80% of individuals with radiologic signs of ADOII experience clinical problems (see Figure 2).

Figure 2

Figure

Figure 2. ADOII x-rays

Reprinted from Benichou et al [2000] with permission from Elsevier

Onset of clinical and radiologic manifestations of ADOII is usually in late childhood or adolescence, although earlier occurrence has been reported. Osteosclerosis of the spine predominates, with a "sandwich vertebra" appearance, a diagnostic criterion for ADOII. Most affected individuals have a "bone-within-bone" appearance primarily in the iliac wings, but also in other bones. Transverse bands of sclerosis, perpendicular to the main axis, are often observed in long bones. Increase in the skull base density can be seen [Benichou et al 2000, Cleiren et al 2001].

Clinical findings vary even within the same family [Chu et al 2006]. In three families in which most affected individuals had mild ADOII, early-onset disease, anemia, and blindness caused by optic nerve compression was observed in some affected family members; this phenotype has been called "intermediate osteopetrosis" because of its overlap with mild ARO.

The main complications affect the skeleton:

  • Fractures occur in about 80% of affected individuals in the largest study, with a mean of three fractures per person. Some individuals had more than ten fractures. The most frequently affected bone is the femur, but fractures occur in any long bone and in the posterior arch of the vertebrae, thereby inducing spondylolisthesis.
  • Scoliosis is seen in a number of cases.
  • Hip osteoarthritis is common (27%) and could be caused by the excessive toughness of the subchondral bone.
  • Osteomyelitis of the mandible is often associated with dental abscess or caries [Benichou et al 2000]. Septic osteitis or osteoarthritis at other localizations can also occur.

Cranial nerve compression caused by osteosclerosis of the skull base is rare. Hearing loss and visual loss occurs in fewer than 5% of affected individuals.

Genotype-Phenotype Correlations

Except for the following, no clear genotype-phenotype correlation exists, including analysis of the polymorphisms.

  • Nonsense mutations in CLCN7 are more likely to cause ARO.
  • The proportion of mutations in the C-terminal CBS-domains of the chloride channel type 7 is higher in ADOII than in ARO.

Penetrance

Depending on the population studied, penetrance ranges from 60% to 90% in families with ADOII [Bollerslev 1989, Benichou et al 2000, Waguespack et al 2003].

Anticipation

Anticipation is not observed.

Nomenclature

The other term used for ADOII is Albers-Schönberg disease.

Prevalence

The prevalence of ADOII has been estimated at approximately 1:100,000.

ARO is probably less common.

Differential Diagnosis

Autosomal recessive osteopetrosis. See Osteopetrosis, Autosomal Recessive: OMIM Phenotypic Series, a table of similar phenotypes that are genetically diverse.

  • ARO secondary to TCIRG1 mutations. Approximately 50% of ARO is caused by mutations in TCIRG1. ARO caused by TCIRG1 mutations is difficult to distinguish from CLCN7-related disease [Frattini et al 2000, Kornak et al 2000]. The frequency of developmental delay and seizures is higher in osteopetrosis caused by mutations in CLCN7.
  • Osteoclast-poor ARO. Osteoclast-poor ARO is characterized by onset within the first year of life and typical ARO manifestations. Investigation of a bone biopsy is prerequisite for a reliable diagnosis. However, TNFSF11 (RANKL) mutations cause a slight T-cell defect and TNFRSF11A (RANK) mutations can lead to hypogammaglobulinemia similar to a common variable immune deficiency (CVID) [Sobacchi et al 2007, Guerrini et al 2008]. Ruling out an RANKL-related ARO is crucial since HSC transplantation is not successful in affected individuals.
  • ARO with renal tubular acidosis (RTA). The onset of ARO with RTA is usually later than in the malignant infantile form of ARO and the disease course is milder. In addition to the generalized osteosclerosis, cerebral calcifications are typical and may be associated with intellectual disability [Jacquemin et al 1998]. Mutations are found in CA2, the gene encoding carbonic anhydrase type II [Bolt et al 2005].
  • ARO secondary to OSTM1 mutations. Approximately 2% of ARO is caused by mutations in OSTM1. OSTM1 mutations seem to cause an extremely severe form of ARO with frequent CNS involvement [Pangrazio et al 2006]. Deletions in the OSTM1 locus have also been observed [Ott et al 2013].
  • ARO secondary to PLEKHM1 mutations. Two individuals with PLEKHM1 mutations have been described to date. The phenotype appears to be very mild and can regress with increasing age [van Wesenbeeck et al 2007].
  • ARO secondary to SNX10 mutations. Approximately 4% of ARO is caused by mutations in SNX10. This form of ARO seems to be slightly less severe than the CLCN7-related form. However, loss of vision, anemia and bone fragility are frequently observed justifying therapy by HSCT [Aker et al 2012, Pangrazio et al 2013].

Autosomal dominant osteopetrosis. See Osteopetrosis, Autosomal Dominant: OMIM Phenotypic Series, a table of similar phenotypes that are genetically diverse.

  • Autosomal dominant osteopetrosis type I (ADOI). Osteosclerosis in ADOI is most pronounced in the skull vault and does not lead to sandwich vertebrae. It is debated whether this disease entity should be called endosteal hyperostosis or high bone mass disorder, as osteopetrosis should be reserved for osteoclast-related disorders. ADOI is not associated with an increased fracture rate. Mutations in LRP5 are causative [Van Wesenbeeck et al 2003].

Other

  • Pyknodysostosis. Affected individuals usually have small stature (adult height <150 cm), frontal bossing, a persistent (open) anterior fontanel, and acroosteolysis of the terminal phalanges [Vanhoenacker et al 2000]. The bones are generally sclerotic and prone to fractures. Pyknodysostosis is caused by mutations in CTSK, the gene encoding cathepsin K [Gelb et al 1996].
  • SOST-related sclerosteosis, including Van Buchem disease and sclerosteosis, is characterized by moderate to gross skull hyperostosis leading to cranial nerve dysfunction, mandibular enlargement, and generalized osteosclerosis. Sclerosteosis also comprises syndactyly and tall stature and can be lethal as a result of increased intracranial pressure [Hamersma et al 2003].
  • Craniometaphyseal dysplasia (CMD). The clinical hallmark of CMD is skull hyperostosis leading to deep-set eyes and paranasal bossing. Facial nerve palsy is common and occurs more frequently than optic nerve compression [Braun et al 2001]. The femur shows a modeling defect, but no osteosclerosis. Susceptibility to fractures is not increased. Mutations in ANKH are causative [Nurnberg et al 2001].

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Guidelines for diagnosis, therapy, and follow up are available at www.ebmt.org.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with infantile malignant CLCN7-related autosomal recessive osteopetrosis (ARO), the following evaluations are recommended:

  • Full blood cell count to evaluate for leukocytosis or leukocytopenia, thrombocytopenia, and anemia with low reticulocyte count
  • Investigation of calcium concentrations in blood and urine to evaluate for hypocalcemia and secondary hyperparathyroidism
  • Ultrasonography of abdomen to evaluate for hepatosplenomegaly
  • MRT and/or CT of the neurocranium to evaluate for narrowed neuroforamina, hydrocephalus, brain abnormalities in neuronopathic form of OP
  • Ophthalmologic examination including VEPs to evaluate for optic nerve atrophy
  • Otorhinolaryngologic examination including AEPs to evaluate for choanal stenosis
  • EEG to detect pathologic changes associated with neurodegeneration; neurologic examination to evaluate development
  • Medical genetics consultation

Treatment of Manifestations

ARO

Hypocalcemic convulsions, occurring in a substantial number of neonates as the first disease manifestation, should be treated by calcium supplementation. The management of calcium homeostasis may be difficult and recommendations are conflicting: whereas physiologic doses of calcium and vitamin D have been used to treat children with osteopetrosis who have rickets, restriction of calcium and vitamin D has been used to prevent progression of disease and hypercalcemic crisis following hematopoietic stem cell transplantation (HSCT). Treatment needs to take into account the particular situation of the affected individual.

Bone marrow failure may require erythrocyte or platelet transfusions (irradiated products). In the case of leukocytopenia and/or hypogammaglobulinemia, which may develop in a subset of individuals, antibiotics and immunoglobulins may be given in a prophylactic or therapeutic manner.

Newly diagnosed individuals should be transferred as soon as possible to a pediatric center experienced in allogeneic stem cell transplantation in this disease.

Sensory and neurologic manifestations require the collaboration of pediatricians, pediatric neurologists, ophthalmologists, and psychologists. Surgical decompression of the optic nerve, a difficult procedure, has been performed with some success to prevent vision loss [Hwang et al 2000].

Fractures require treatment and surveillance by an experienced bone surgeon or orthopedist in collaboration with the treating pediatrician.

Dental. Without HSCT, most children do not reach the age at which secondary dentition erupts. Children undergoing early HSCT may have normal secondary dentition despite defective primary dentition [Jalevik et al 2002].

In some cases, defective tooth eruption, ankylosis, abscesses, and the formation of cysts and fistulas may require surgical intervention. Special attention is required to prevent mandibular osteomyelitis and extreme brittleness of the alveolar bone [Luzzi et al 2006].

ADOII

Orthopedic treatment is often required for fractures and arthritis. Post-surgical complications such as delayed union or non-union of fractures and infections are common (50%) because of the brittleness of the bones. Fractures near joints may require total joint arthroplasty [Strickland & Berry 2005].

Prevention of Primary Manifestations

ARO

Hematopoietic stem cell transplantation (HSCT). Since the defective osteoclasts in osteopetrosis are of hematopoietic origin, allogeneic HSCT can be curative. Most manifestations (bone sclerosis, bone marrow failure, and extramedullary hematopoiesis) can be prevented or reversed by HSCT.

Secondary sensorineurologic impairments caused by nerve compression may be prevented by early transplantation, but not reversed when they are already present.

Primary neurologic problems and retinal degeneration developing in the neuronopathic form of ARO, however, are independent of the bone disease and therefore cannot be improved or prevented by HSCT. Persons with ARO resulting from CLCN7 mutations who do not develop neurologic complications after HSCT have been reported [Pangrazio et al 2010; A Schulz and U Kornak, unpublished results].

It is highly important but difficult to exclude individuals with the neuronopathic form from this invasive treatment. On the other hand, HSCT should be performed as soon as possible in the majority of those without primary neurologic sequelae to prevent irreversible secondary complications, including visual impairment. The evaluation of affected individuals and treatment by HSCT should therefore be performed in experienced pediatric centers after multidisciplinary evaluation to assess the severity of the disease and individual prognostic factors.

A registry of individuals with infantile osteopetrosis who have undergone HSCT has been created on behalf of the European Society for Immunodeficiences (ESID) and the Inborn Errors Working Party of the EBMT (IEWP-EBMT). According to this registry, the five-year disease-free survival rate in a cohort of 125 affected individuals who underwent HSCT is 88% for recipients of a genotype HLA-identical HSCT, 80% for recipients of a graft from a matched unrelated donor, and 66% for recipients of a graft from a related HLA-haplotype-mismatched donor [Schulz et al 2002; A Schulz et al, unpublished results]. This is a significant improvement over older data [Martin et al 2000, Driessen et al 2003].

Note: Because TCIRG1 mutations are more often the cause of ARO than are CLCN7 mutations, the majority of HSCTs have been performed in infants with TCIRG1 rather than CLCN7 mutations. However there seems to be no significant difference in treatment outcome between individuals with TCIRG1 and CLCN7 mutations [A Schulz et al, unpublished results].

The incidence of severe complications post-HSCT is high, particularly when alternative stem cell sources are used. Complications include rejection, delayed hematopoietic reconstitution, venous occlusive disease, pulmonary hypertension, and hypercalcemic crisis [Steward et al 2004; Corbacioglu et al 2006; Shroff et al 2012].

Cranial nerve dysfunction (visual impairment caused by optic nerve atrophy) is irreversible in most cases. In the authors' series including about 30 individuals, about two thirds of affected individuals were visually impaired after successful transplantation [A Schulz, unpublished results].

Progressive neurologic sequelae, developmental delay, and repeated seizures occur in a subset of individuals after successful HSCT [Steward 2003]. Severe neurologic manifestations other than visual impairment have been seen in about 10% of individuals in the authors' series [A Schulz, unpublished results].

Other. Conservative treatment strategies include stimulation of host osteoclasts with calcium restriction, calcitrol, steroids, parathyroid hormone, and interferon [Kocher & Kasser 2003]. Since evidence for a favorable outcome in severe osteopetrosis is limited and because side effects are severe (particularly in infants), these drugs may be administered in special situations only.

Prevention of Secondary Complications

ARO. Restricted intake of calcium and vitamin D just before, during, and following HSCT to prevent hypercalcemia is recommended.

ADOII. Good routine dental care and oral hygiene may help prevent osteomyelitis of the mandible.

Surveillance

ARO

  • The possible manifestations and complications of osteopetrosis require repeat investigations; however, no general recommendations are available for the extent and frequency of investigations. A blood cell count and an ophthalmologic examination should be performed once a year at a minimum in all individuals with ARO.
  • In individuals who have undergone HSCT, surveillance should be coordinated by the transplantation center; chimerism analysis should be performed repeatedly, as secondary graft failures have been reported. However, such individuals may be free of disease manifestation even in the case of stable mixed chimerism, if a substantial part of blood cells are donor derived (coexistence of hematopoietic cells of donor and recipient origin).

ADOII. In ADOII, skeletal manifestations do not progress and therefore no special surveillance is necessary.

Agents/Circumstances to Avoid

ARO. Avoidance of calcium and vitamin D is not generally recommended.

ADOII

  • Activities with high fracture risk should be avoided.
  • Orthopedic surgery should only be performed when absolutely necessary and the surgeon should be aware of potential complications and difficulties in handling osteopetrotic bone.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Studies have been initiated to investigate the relation of genotype and clinical outcome after stem cell transplantation (for current information, see the European Society of Immunodeficiencies (ESID) and European Group of Bone Marrow Transplantation (EBMT) Web sites).

Parents and patients should be informed about possible complications of the disease and recommendations for prevention should be given accordingly (e.g., severe CNS bleeding in patients with thrombocytopenia, pathologic fractures). Because of the heterogeneity of the disease, recommendations should be given on an individual basis.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

CLCN7-related osteopetrosis is inherited in an autosomal recessive or autosomal dominant manner.

Risk to Family Members — Autosomal Recessive Osteopetrosis

Parents of a proband

  • The parents of an affected child are obligate heterozygotes and therefore carry one mutant allele.
  • Heterozygotes (carriers) are asymptomatic; however, no systematic studies have been performed to evaluate for subtle changes in bone mass.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband

  • Individuals with ARO in general only reproduce if successfully treated by hematopoietic stem cell transplantation (HSCT).
  • The offspring of an individual with autosomal recessive CLCN7-related osteopetrosis are obligate heterozygotes (carriers) for a disease-causing mutation in CLCN7.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing for at-risk family members is possible if the disease-causing mutations in the family are known.

Risk to Family Members — Autosomal Dominant Osteopetrosis

Parents of a proband

  • Most individuals diagnosed with autosomal dominant CLCN7-related osteopetrosis have an affected parent.
  • A proband with autosomal dominant CLCN7-related osteopetrosis may have the disorder as the result of a new mutation of CLCN7. The proportion of cases caused by de novo mutations is unknown.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include x-ray investigation of the skeleton and molecular genetic testing if the mutation in the proband has been identified. Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of failure by health care professionals to recognize the syndrome and/or a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.

Sibs of a proband

Offspring of a proband. Each child of an individual with autosomal dominant CLCN7-related osteopetrosis has a 50% chance of inheriting the mutation.

Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent is affected, his or her family members are at risk.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing mutation(s) have been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks' gestation) or chorionic villus sampling (usually performed at ~10-12 weeks' gestation).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for conditions which (like CLCN7-related osteopetrosis) do not affect intellect and have some treatment available are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although decisions about prenatal testing are the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation(s) have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Paget Foundation
    120 Wall Street
    Suite 1602
    New York NY 10005-4001
    Phone: 800-237-2438 (toll-free); 212-509-5335
    Fax: 212-509-8492
    Email: Pagetfdn@aol.com
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
    1 AMS Circle
    Bethesda MD 20892-3675
    Phone: 877-226-4267 (toll-free); 301-565-2966 (TTY)
    Fax: 301-718-6366
    Email: niamsinfo@mail.nih.gov
  • European Society for Immunodeficiencies (ESID) Registry
    Dr. Gerhard Kindle
    University Medical Center Freiburg Centre of Chronic Immunodeficiency
    UFK, Hugstetter Strasse 55
    79106 Freiburg
    Germany
    Phone: 49-761-270-34450
    Email: registry@esid.org
  • International Skeletal Dysplasia Registry
    Cedars-Sinai Medical Center
    116 North Robertson Boulevard, 4th floor (UPS, FedEx, DHL, etc)
    Pacific Theatres, 4th Floor, 8700 Beverly Boulevard (USPS regular mail only)
    Los Angeles CA 90048
    Phone: 310-423-9915
    Fax: 310-423-1528

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. CLCN7-Related Osteopetrosis: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for CLCN7-Related Osteopetrosis (View All in OMIM)

166600OSTEOPETROSIS, AUTOSOMAL DOMINANT 2; OPTA2
602727CHLORIDE CHANNEL 7; CLCN7
611490OSTEOPETROSIS, AUTOSOMAL RECESSIVE 4; OPTB4

Molecular Genetic Pathogenesis

ARO, IAO, and ADOII are caused by osteoclast dysfunction. The osteoclast is a highly specialized cell with the unique ability to resorb large amounts of mineralized bone tissue. Like macrophages, osteoclasts are giant multinuclear cells formed by fusion of mononuclear hematopoietic precursors that subsequently differentiate under the influence of M-CSF and RANKL.

After attaching to the bone surface, a sealing zone that isolates the resorption lacuna from the extracellular environment is formed. Large quantities of acidic vesicles then fuse with the plasma membrane juxtaposed to the bone surface to create the ruffled membrane. This structure is exclusively found in osteoclasts and secretes large amounts of acid into the resorption lacuna, which therefore is also referred to as an "extracellular lysosome" [Teitelbaum & Ross 2003]. The low pH is required to dissolve the bone mineral and for the optimal activity of acid hydrolases that degrade the bone matrix, particularly cathepsin K.

Most forms of human osteopetrosis for which the genetic causes have been identified so far are the result of defects in the acid secretion mechanism. The ClC-7 chloride channel resides in lysosomal vesicles and in the ruffled membrane and is thought to transport negative charges in parallel to the protons pumped into the resorption lacuna by the ruffled membrane v-type H+-ATPase [Kornak et al 2001].

TCIRG1 encodes an important subunit of this H+-ATPase and carbonic anhydrase type II (CAII) generates the necessary protons in the osteoclast cytoplasm; thus, defects in these genes also cause osteopetrosis.

Mutations in CLCN7 lead to a loss of chloride channel function of varying degree. In the most severe cases of ARO, chloride channel protein 7 (ClC-7) is absent. As illustrated by a knockout mouse model, which shows degeneration of the CNS and the retina, a complete loss of the protein entails a strong risk for the neuronopathic form of ARO [Kornak et al 2001, Steward 2003, Kasper et al 2005].

The less severe forms of osteopetrosis are thought to be caused by mutations that incompletely inactivate the protein. Mutations found in ADOII apparently have dominant negative effects. It has been shown that these mutations affect chloride channel function, as has been described for the Thomsen type of myotonia congenita, caused by dominant mutations in CLCN1 [Jentsch et al 2005b]. Some CLCN7 mutations have been reported to alter expression and subcellular localization of the protein. Electrophysiologic measurement of a ClC-7 variant localizing to the plasma membrane demonstrated that ADOII-causing mutations do not necessarily impair chloride currents, but do result in abnormal gating behavior of the channel [Leisle et al 2011].

Normal allelic variants. The most relevant CLCN7 transcript (NM_001287.5; CCDS 32361.1) contains a coding region of 2418 bp subdivided into 25 exons. The most common coding single-nucleotide polymorphism (SNP) is rs12926089, which leads to the amino acid exchange p.Val418Met. Although clearly not pathogenic, this polymorphism has been found to be associated with bone mineral density in postmenopausal women [Pettersson et al 2005]. A prominent intronic polymorphism is a 50-bp variable number tandem repeat (VNTR) in intron 8, which ranges in length from 100 to 450 bp. This polymorphism is also associated with bone mineral density in postmenopausal women as well as with resorption markers and with the penetrance of dominant CLCN7 mutations [Kornak et al 2006].

Pathogenic allelic variants. Fifteen percent of the mutations found in ARO are nonsense and 85% are missense mutations. Approximately 25% of these mutations reside in the C-terminal CBS domains of the protein. In ADOII, nonsense mutations are found in 6%; 72% are missense mutations. Twelve percent are deletions, 6% are insertions, and 6% are frameshift mutations. Almost 50% of these mutations are found in the C-terminal CBS domains [Pangrazio et al 2012] (CLCN7 Mutation Database). Also a homozygous deletion has been identified in one individual with ARO [Pangrazio et al 2012].

Table 4. CLCN7 Allelic Variants Discussed in This GeneReview

Class of Variant AlleleDNA Nucleotide Change Protein Amino Acid ChangeReference Sequences
Normalc.1252G>Ap.Val418MetNM_001287​.5
NP_001278​.1
Pathogenicc.296A>Gp.Tyr99Cys
c.643G>Ap.Gly215Arg
c.2299C>Tp.Arg767Trp

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

Normal gene product. CLCN7 encodes the 805-amino acid chloride channel protein 7 (also known as ClC-7), which resides in late endosomes and lysosomes of most cell types. In osteoclasts, the protein is translocated to the ruffled membrane. Like the other CLC channels, ClC-7 contains two C-terminal CBS domains, supposed to be involved in protein-protein interaction. This interaction may facilitate the formation of the functional channel dimers. It has been shown recently that CLC channels are not pure chloride channels but rather function as chloride/proton antiporters [Jentsch et al 2005a].

Abnormal gene product. A complete loss of the ClC-7 protein abolished osteoclast resorptive activity in mice with Clcn7/− osteoclasts; similarly, some individuals with malignant infantile osteopetrosis had one null allele [Kornak et al 2001]. The vast majority of mutations associated with ARO lead to only minor changes in ClC-7 protein levels. No abnormal subcellular distribution has yet been described as a consequence of CLCN7 mutations. It can be assumed that the majority of mutations associated with ADOII alter the electrophysiologic properties of the channel, thereby reducing the chloride conductance under physiologic conditions. This is thought to lead to an attenuation of osteoclast activity of varying degrees, giving rise to the variability of the clinical course [Chu et al 2006, Del Fattore et al 2006].

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Suggested Reading

  1. Helfrich MH. Osteoclast diseases. Microsc Res Tech. 2003;61:514–32. [PubMed: 12879419]
  2. Proceedings and abstracts of the First International Symposium on Osteopetrosis: biology and therapy. October 23-24, 2003. Bethesda, Maryland, USA. J Bone Miner Res. 2004;19:1356–75. [PubMed: 15768481]
  3. Tolar J, Teitelbaum SL, Orchard PJ. Osteopetrosis. N Engl J Med. 2004;351:2839–49. [PubMed: 15625335]
  4. Van Hul W, Vanhoenacker F, Balemans W, Janssens K, De Schepper AM. Molecular and radiological diagnosis of sclerosing bone dysplasias. Eur J Radiol. 2001;40:198–207. [PubMed: 11731208]

Chapter Notes

Author Information

Guidelines for diagnosis, therapy, and follow up for this disorder are available at www.ebmt.org (pdf) and from author Ansgar Schulz, MD at ansgar.schulz@uniklinik-ulm.de.

Revision History

  • 20 June 2013 (me) Comprehensive update posted live
  • 14 October 2010 (me) Comprehensive update posted live
  • 12 February 2007 (me) Review posted to live Web site
  • 8 September 2006 (uk) Original submission
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