NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

CLCN7-Related Osteopetrosis

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

Author Information
, MS
CNR-IRGB, Milan Unit
Humanitas Clinical and Research Center
Rozzano, Italy
, MD, PhD
CNR-IRGB, Milan Unit
Humanitas Clinical and Research Center
Rozzano, Italy
, MD
Universitätsklinik für Kinder- und Jugendmedizin
Ulm, Germany
, MD, PhD
Institut für Medizinische Genetik und Humangenetik
Charité Universitätsmedizin
Berlin, Germany

Initial Posting: ; Last Update: June 9, 2016.

Summary

Clinical 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-Schönberg 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, and osteomyelitis of the mandible or septic osteitis or osteoarthritis elsewhere. Cranial nerve compression is rare.

Diagnosis/testing.

CLCN7-related osteopetrosis is suspected with identification of 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). Identification of pathogenic variants in CLCN7 establishes the diagnosis.

Management.

Treatment of manifestations:

  • ARO. Calcium supplementation for hypocalcemic convulsions; management of calcium homeostasis per individual 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, and 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. In general, individuals with ARO 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 pathogenic variants is unknown. Each child of an individual with autosomal dominant CLCN7-related osteopetrosis has a 50% chance of inheriting the pathogenic variant.

Prenatal diagnosis for pregnancies at increased risk for ADOII and ARO is possible if the pathogenic variant(s) have been identified in the family.

GeneReview Scope

CLCN7-Related Osteopetrosis: Included Phenotypes

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-Schönberg disease).

Suggestive Findings

A CLCN7-related osteopetrosis should be suspected in individuals with osteosclerosis noted on radiographs, which may be accompanied by hypocalcemia and resulting convulsions, anemia, thrombocytopenia, visual impairment, and/or CNS involvement (see Table 1).

Table 1.

Diagnostic Features of the Subtypes of CLCN7-Related Osteopetrosis

FindingSubtype of CLCN7-Related Osteopetrosis
ARO 1IAO 2ADOII 3
Radiographic changesPathognomonic 4Characteristic 5Characteristic 6
HypocalcemiaSevere to absentAbsentAbsent
AnemiaSevere to moderateMild to absentAbsent
ThrombocytopeniaSevere to absentAbsentAbsent
Visual impairmentFrequentRareVery rare
CNS involvementSevere to absentAbsentAbsent
Age of onset of symptomsBirthFirst 2 yearsFirst 10 years
1.

ARO = infantile malignant autosomal CLCN7-related autosomal recessive osteopetrosis

2.

IAO = intermediate autosomal 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

Establishing the Diagnosis

The diagnosis of a CLCN7-related osteopetrosis is established in a proband through the identification of biallelic pathogenic variants or a heterozygous pathogenic variant in CLCN7 by molecular genetic testing (see Table 3).

Molecular testing approaches can include single-gene testing and use of a multi-gene panel.

  • Single-gene testing. Sequence analysis of CLCN7 is performed first followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found.
  • A multi-gene panel that includes CLCN7 and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and over time. (2) Some multi-gene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multi-gene panel provides the best opportunity to identify the genetic cause of the condition at the most reasonable cost. (3) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing based tests.

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

Table 2.

Proportion of Osteopetrosis Phenotype Caused by Pathogenic Variants in CLCN7

Osteopetrosis Phenotype# of CLCN7 Pathogenic Variants% of Osteopetrosis Caused by Pathogenic Variants in CLCN7
Infantile malignant CLCN7-related autosomal recessive osteopetrosis (ARO)213%
Intermediate autosomal osteopetrosis (IAO)240% 1
160% 1
Autosomal dominant osteopetrosis type II (ADOII)175% 2
1.
2.

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

Table 3.

Molecular Genetic Testing Used in CLCN7-Related Osteopetrosis

Gene 1Test MethodProportion of Probands with a Pathogenic Variant 2 Detectable by This Method
CLCN7Sequence analysis 3~95% 4
Gene-targeted deletion/duplication analysis 5Unknown 6, 7
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice-site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Virtually all pathogenic variants reported in the literature have been identified by sequencing of the gene, the majority by classical Sanger sequencing, more recently also by whole-exome or gene panel-based sequencing [Author observation].

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used can include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

6.

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

7.

No data on detection rate of gene-targeted deletion/duplication analysis are available.

Clinical Characteristics

Clinical Description

Infantile Malignant CLCN7-Related Autosomal Recessive Osteopetrosis (ARO)

ARO is a systemic, life-threatening disorder. Without treatment, life span is approximately ten years (although rare exceptions of far longer survival have occurred). Possible clinical manifestations of ARO:

  • Fractures. The near-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. Resorption of cartilage and bone at the growth plate is a prerequisite for longitudinal growth; its absence results in variable growth retardation. 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. Skull changes may also 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 must 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 are more common and more severe in persons with CLCN7 pathogenic variants than in those with TCIRG1-related ARO [Pangrazio et al 2010; A Schulz, unpublished results], while all individuals with OSTM1-related ARO have CNS involvement. This is mirrored by neurodegeneration in Clcn7- and Ostm1-null mice [Kasper et al 2005, Lange et al 2006]. Ostm1 is a beta subunit of ClC-7 and is required for its transport activity [Leisle et al 2011].
  • 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 [Jälevik 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 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]. Recently, recessive hypomorphic intronic pathogenic variants in TCIRG1 have been reported in an intermediate form of the disease [Sobacchi et al 2014, Palagano et al 2015]. These variants caused aberrant splicing, but also allowed the production of a limited amount of normal transcript sufficient to dampen the severity of the disease usually associated with pathogenic variants in TCIRG1. In fact, three individuals with such variants at the homozygous state reached adulthood in relatively good health, the major issues being recurrent non-traumatic fractures [Palagano et al 2015].

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 2.

ADOII x-rays

Reprinted from Bénichou 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 [Bénichou 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 were 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 [Bénichou et al 2000]. 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 [Bénichou 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:

  • Pathogenic nonsense variants and indel and splicing defects in CLCN7 are more likely to cause ARO [Author, personal observation].
  • The proportion of pathogenic variants in the C-terminal cystathionine β-synthase (CBS) domains of the chloride channel type 7 is higher in ADOII than in ARO [Author, personal observation].

Penetrance

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

Prevalence

The prevalence of ADOII has been estimated at up to 1:20,000 [Bénichou et al 2001]. The disease is probably underdiagnosed in milder cases.

ARO is less common, with a prevalence around 1:250,000. Higher frequencies are reported in specific geographic areas, most likely as a result of a founder effect: one in 3500 newborns in Chuvashiya and one in 14,000 newborns in the Mari population in Russia [Bliznetz et al 2009]; about 5.4:100,000 births in the Middle East [Souraty et al 2007]. Higher frequencies are also registered in Costa Rica [Sobacchi et al 2001] and in the Swedish province of Västerbotten [Pangrazio et al 2013].

Differential Diagnosis

Autosomal recessive osteopetrosis

  • ARO secondary to TCIRG1 pathogenic variants (OMIM). More than 50% of ARO is caused by pathogenic variants in TCIRG1. ARO caused by TCIRG1 pathogenic variants can be distinguished from CLCN7-related disease [Frattini et al 2000, Kornak et al 2000] based on the higher frequency of neurodevelopmental delay and seizures in the latter form of osteopetrosis.
  • 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 (OMIM) pathogenic variants cause a slight T-cell defect and TNFRSF11A (OMIM) pathogenic variants can lead to hypogammaglobulinemia similar to a common variable immune deficiency (CVID) [Sobacchi et al 2007, Guerrini et al 2008]. Ruling out a TNFSF11 -related ARO is crucial since HSC transplantation is not successful in these affected individuals.
  • ARO with renal tubular acidosis (RTA) (OMIM). 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]. Pathogenic variants are found in CA2, the gene encoding carbonic anhydrase 2 [Bolt et al 2005].
  • ARO secondary to OSTM1 pathogenic variants (OMIM). Approximately 4% of ARO is caused by pathogenic variants in OSTM1. OSTM1 pathogenic variants cause an extremely severe form of ARO with CNS involvement [Pangrazio et al 2006]. Deletions in the OSTM1 locus have also been observed [Ott et al 2013].
  • ARO secondary to PLEKHM1 pathogenic variants (OMIM). Two individuals with PLEKHM1 pathogenic variants 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 pathogenic variants (OMIM). Approximately 4% of ARO is caused by pathogenic variants in SNX10; in particular, “Västerbottenian osteopetrosis” is caused by pathogenic variants in this gene. This form of ARO appears to be slightly less severe than the CLCN7-related form. However, loss of vision, anemia, and bone fragility are frequently observed, warranting the use of HSCT [Aker et al 2012, Pangrazio et al 2013].

See Osteopetrosis, autosomal recessive: OMIM Phenotypic Series to view genes associated with this phenotype in OMIM

Mild ARO

  • ARO secondary to intronic TCIRG1 pathogenic variants (OMIM). A mild form of ARO can be caused by deep intronic or splice-site variants in TCIRG1 [Sobacchi et al 2014, Palagano et al 2015]. This form can be very similar to CLCN7-related IAO or ADOII.

Autosomal dominant osteopetrosis

  • Autosomal dominant osteopetrosis type I (ADOI) (OMIM). 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. Pathogenic variants in LRP5 are causative [Van Wesenbeeck et al 2003].

See Osteopetrosis, autosomal dominant: OMIM Phenotypic Series to view genes associated with this phenotype in OMIM.

Other

  • Pyknodysostosis (OMIM). Affected individuals usually have small stature (adult height <150 cm), frontal bossing, wormian bones, a persistent (open) anterior fontanel, and acroosteolysis of the terminal phalanges [Vanhoenacker et al 2000]. The bones are generally sclerotic and prone to fractures. In some patients the clinical presentation can resemble IAO [Pangrazio et al 2014]. Pyknodysostosis is caused by pathogenic variants in CTSK, the gene encoding cathepsin K [Gelb et al 1996], and is inherited in an autosomal recessive manner.
  • SOST-related sclerosing bone dysplasias, 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]. The SOST-related sclerosing bone dysplasias are inherited in an autosomal recessive manner.
  • Autosomal dominant craniometaphyseal dysplasia (AD-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. Pathogenic variants in ANKH are causative [Nürnberg et al 2001].
  • Autosomal recessive craniometaphyseal dysplasia (AR-CMD) (OMIM). Affected individuals show typical features of CMD (macrocephaly, hearing loss, skull hyperostosis with paranasal bossing, metaphyseal widening) but less pronounced calvarial thickening [Iughetti et al 2000]. Due to diaphyseal osteosclerosis the disorder can occasionally resemble mild forms of osteopetrosis. Pathogenic variants in GJA1 are causative [Hu et al 2013].
  • Dysosteosclerosis. Short stature, sandwich vertebrae, platyspondyly, metaphyseal widening and sclerosis, and often also diaphyseal thickening are characteristic of dysosteosclerosis. Campeau et al [2012] identified biallelic SLC29A3 (OMIM) variants in two individuals with dysosteosclerosis. The phenotype caused by deep intronic TCIRG1 pathogenic variants can look similar [U Kornak, unpublished observation].
  • Leukocyte adhesion deficiency type III (LAD-III) (OMIM). Affected individuals present with recurrent infections and a bleeding diathesis regardless of platelet or leukocyte count. Pathogenic variants in FERMT3 (encoding fermitin family homolog 3) are causative. In some individuals with LAD-III, a high bone density can be found, since fermitin family homolog 3 (also referred to as kindlin-3) signaling is required for osteoclast-mediated bone resorption [Crazzolara et al 2015].

Management

Recently updated guidelines for diagnosis, therapy, and follow up are available online.

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
  • MRI and/or CT of the neurocranium to evaluate for narrowed neuroforamina, hydrocephalus, and brain abnormalities in neuronopathic form of osteopetrosis
  • Ophthalmologic examination including VEPs to evaluate for optic nerve atrophy
  • Otorhinolaryngologic examination to evaluate for choanal stenosis
  • EEG to detect pathologic changes associated with neurodegeneration; neurologic examination to evaluate development
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Due to the difference in severity, treatment strategies for ARO and ADOII differ. IAO lies between these two forms and has a variable prognosis. Therefore, treatment options must be evaluated on an individual basis.

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 [Jälevik 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 neurosensory 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 pathogenic variants who do not develop neurologic complications 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.

The outcome of HSCT in ARO has been analyzed in a retrospective survey of the European Society of Immunodeficiencies (ESID) and the European Group of Bone Marrow Transplantation (EBMT) [Sobacchi et al 2013]. The five-year disease-free survival was estimated at 88% for genoidentical transplants, 80% for matched unrelated transplants, and 66% for haploidentical transplants [Sobacchi et al 2013]. In a recently published report of 193 patients transplanted in various centers by a cyclophosphamide-based regimen, the five-year probabilities of survival were 62% after HLA-matched sib transplantation and 42% after alternative donor transplantation [Orchard et al 2015]. A further improved outcome was most recently reported from three large transplant centers using a fludarabine-based conditioning regimen [Natsheh et al 2016; Schulz and Moshous, personal communication].

Note: Because TCIRG1 pathogenic variants are more often the cause of ARO than are CLCN7 pathogenic variants, the majority of HSCTs have been performed in infants with TCIRG1 rather than CLCN7 pathogenic variants. However, there appears to be no significant difference in treatment outcome between individuals with TCIRG1 and CLCN7 pathogenic variants [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, calcitriol, 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.

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.

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 (i.e., 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

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

It is appropriate to clarify the genetic status of apparently asymptomatic older and younger sibs of an affected individual by molecular genetic testing of the CLCN7 pathogenic variant(s) in the family in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures.

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] websites).

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 (i.e., carriers of one CLCN7 pathogenic variant).
  • 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.
  • Heterozygotes (carriers) are asymptomatic; however, no systematic studies have been performed to evaluate for subtle changes in bone mass.
  • The limited data available suggest that in the presence of infantile malignant CLCN7-related recessive osteopetrosis (ARO), a similar presentation of the disease is expected in individuals of the same family; in particular, if the neuronopathic form of the disease was present in the proband, a primary CNS involvement is likely to be present in other affected sibs [Sobacchi, unpublished observation].

Offspring of a proband

  • In general, individuals with ARO reproduce only 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 pathogenic variant in CLCN7.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a pathogenic variant in CLCN7.

Carrier (Heterozygote) Detection

Carrier testing for at-risk relatives requires prior identification of the CLCN7 pathogenic variants in the family.

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 CLCN7 pathogenic variant. The proportion of cases caused by de novo pathogenic variants is unknown.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant include x-ray investigation of the skeleton and molecular genetic testing for the pathogenic variant identified in the proband. 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.

Note: If the parent is the individual in whom the pathogenic variant first occurred, s/he may have somatic mosaicism for the variant and may be mildly/minimally affected.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband's parents:
    • If a parent of the proband is affected or has the CLCN7 pathogenic variant, the risk to the sibs of inheriting the variant is 50%.
    • When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
    • If the pathogenic variant found in the proband cannot be detected in the DNA of one of the parents, the risk to sibs is low, but greater than that of the general population because of the possibility of germline mosaicism. Germline mosaicism has not been reported.
  • The clinical severity of autosomal dominant osteopetrosis type II (ADOII) may vary within a family.

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

Other family members. The risk to other family members depends on the status of the proband's parents. If a parent has the CLCN7 pathogenic variant, his or her family members may be at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant or clinical evidence of the disorder, it is likely that the proband has a de novo pathogenic variant. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could 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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the CLCN7 pathogenic variant(s) have been identified in an affected family member, prenatal testing and preimplantation genetic diagnosis for a pregnancy at increased risk for CLCN7-related osteopetrosis are possible options.

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.

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.

  • The OsteoPETrosis Society (OPETS)
    Phone: 980-292-3921
    Email: osteopetrosispatient@gmail.com; janecastello.opets@gmail.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
  • National Library of Medicine Genetics Home Reference
  • European Society for Immunodeficiencies (ESID) Registry
    Dr. Gerhard Kindle
    University Medical Center Freiburg Centre of Chronic Immunodeficiency
    Engesserstr. 4
    79106 Freiburg
    Germany
    Phone: 49-761-270-34450
    Email: esid-registry@uniklinik-freiburg.de
  • International Skeletal Dysplasia Registry
    UCLA
    615 Charles E. Young Drive
    South Room 410
    Los Angeles CA 90095-7358
    Phone: 310-825-8998
    Email: AZargaryan@mednet.ucla.edu

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

GeneChromosome LocusProteinLocus SpecificHGMD
CLCN716p13​.3Chloride channel protein 7CLCN7 databaseCLCN7

Data are compiled from the following standard references: gene from HGNC; chromosome locus, locus name, critical region, complementation group from OMIM; protein 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 acts as a 2Cl-/1H+ exchanger transporting negative charges into the resorption lacuna in parallel to the protons pumped in this extracellular space by the ruffled membrane v-type H+-ATPase [Kornak et al 2001, Leisle et al 2011].

TCIRG1 encodes an important subunit of this H+-ATPase and carbonic anhydrase 2, encoded by CA2, generates the necessary protons in the osteoclast cytoplasm; thus, defects in these genes also cause osteopetrosis.

Pathogenic variants 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 pathogenic variants that incompletely inactivate the protein. Pathogenic variants found in ADOII apparently have dominant-negative effects. It has been shown that these pathogenic variants affect chloride channel function, as has been described for the Thomsen type of myotonia congenita, caused by dominant pathogenic variants in CLCN1 [Jentsch et al 2005b]. Some CLCN7 pathogenic variants 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 pathogenic variants do not necessarily impair chloride currents, but do result in abnormal gating behavior of the channel [Leisle et al 2011].

Gene structure. The most relevant CLCN7 transcript (NM_001287.5, CCDS 32361.1) contains a coding region of 2418 bp subdivided into 25 exons. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic allelic variants. Pathogenic variants found in ARO comprise nonsense variants (7.4%), frameshifts caused by splicing defects and indels (25.5%), in-frame deletions (0.01%) and missense variants (66%). Approximately 28.7% of these pathogenic variants reside in the C-terminal CBS domains of the protein. A homozygous contiguous gene deletion has also been identified in one individual with ARO [Pangrazio et al 2012]. In ADOII, pathogenic variants comprise nonsense variants (2.5%), frameshifts (12.5%), inframe deletions (2.5%) and missense variants (82.5%). Approximately 45% of these pathogenic variants are found in the C-terminal CBS domains [Sobacchi, unpublished].

Table 4.

CLCN7 Allelic Variants Discussed in This GeneReview

Variant ClassificationDNA Nucleotide ChangePredicted Protein ChangeReference Sequences
Benignc.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 authors. 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.

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, assumed to be involved in protein-protein interaction. This interaction may facilitate the formation of the functional channel dimers. CLC channels are not pure chloride channels but rather function as chloride/proton antiporters [Jentsch et al 2005a]. The OSTM1 protein is a subunit of the functional CLC channels and influences their behavior [Lange et al 2006, Leisle et al 2011]. When driven to the plasma membrane the protein complex shows slow gating and outwardly rectifying chloride currents [Leisle et al 2011].

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 situation for missense variants is less clear. Only a minority of ClC-7 mutants have been tested for their stability and subcellular distribution. The tested pathogenic missense variants show variable effects [Schulz et al 2010, Leisle et al 2011]. Among the pathogenic variants associated with ADOII tested in vitro (10 of 40 total variants), the majority alter the electrophysiologic properties of the channel [Leisle et al 2011]. Interestingly, some of these variants showed normal current amplitudes and even accelerated gating. These alterations are thought to lead to the variable attenuation of osteoclast activity – giving rise to the variability of the clinical course [Chu et al 2006, Del Fattore et al 2006].

References

Literature Cited

  1. Aker M, Rouvinski A, Hashavia S, Ta-Shma A, Shaag A, Zenvirt S, Israel S, Weintraub M, Taraboulos A, Bar-Shavit Z, Elpeleg O. An SNX10 mutation causes malignant osteopetrosis of infancy. J Med Genet. 2012;49:221–6. [PubMed: 22499339]
  2. Bénichou O, Cleiren E, Gram J, Bollerslev J, de Vernejoul MC, Van Hul W. Mapping of autosomal dominant osteopetrosis type II (Albers-Schönberg disease) to chromosome 16p13.3. Am J Hum Genet. 2001;2001;69:647–54. [PMC free article: PMC1235505] [PubMed: 11468688]
  3. Bénichou OD, Laredo JD, de Vernejoul MC. Type II autosomal dominant osteopetrosis (Albers-Schönberg disease): clinical and radiological manifestations in 42 patients. Bone. 2000;26:87–93. [PubMed: 10617161]
  4. Bliznetz EA, Tverskaya SM, Zinchenko RA, Abrukova AV, Savaskina EN, Nikulin MV, Kirillov AG, Ginter EK, Polyakov AV. Genetic analysis of autosomal recessive osteopetrosis in Chuvashiya: the unique splice site mutation in TCIRG1 gene spread by the founder effect. Eur J Hum Genet. 2009;17:664–72. [PMC free article: PMC2986262] [PubMed: 19172990]
  5. Bollerslev J. Autosomal dominant osteopetrosis: bone metabolism and epidemiological, clinical, and hormonal aspects. Endocr Rev. 1989;10:45–67. [PubMed: 2666111]
  6. Bolt RJ, Wennink JM, Verbeke JI, Shah GN, Sly WS, Bökenkamp A. Carbonic anhydrase type II deficiency. Am J Kidney Dis. 2005;46(A50):e71–3. [PubMed: 16265785]
  7. Braun HS, Nurnberg P, Tinschert S. Metaphyseal dysplasia: a new autosomal dominant type in a large German kindred. Am J Med Genet. 2001;101:74–7. [PubMed: 11343343]
  8. Campeau PM, Lu JT, Sule G, Jiang MM, Bae Y, Madan S, Högler W, Shaw NJ, Mumm S, Gibbs RA, Whyte MP, Lee BH. Whole-exome sequencing identifies mutations in the nucleoside transporter gene SLC29A3 in dysosteosclerosis, a form of osteopetrosis. Hum Mol Genet. 2012;21:4904–9. [PMC free article: PMC3607481] [PubMed: 22875837]
  9. Campos-Xavier AB, Saraiva JM, Ribeiro LM, Munnich A, Cormier-Daire V. Chloride channel 7 (CLCN7) gene mutations in intermediate autosomal recessive osteopetrosis. Hum Genet. 2003;112:186–9. [PubMed: 12522560]
  10. Chu K, Snyder R, Econs MJ. Disease status in autosomal dominant osteopetrosis type 2 is determined by osteoclastic properties. J Bone Miner Res. 2006;21:1089–97. [PubMed: 16813529]
  11. Cleiren E, Bénichou O, Van Hul E, Gram J, Bollerslev J, Singer FR, Beaverson K, Aledo A, Whyte MP, Yoneyama T, deVernejoul MC, Van Hul W. Albers-Schonberg disease (autosomal dominant osteopetrosis, type II) results from mutations in the ClCN7 chloride channel gene. Hum Mol Genet. 2001;10:2861–7. [PubMed: 11741829]
  12. Corbacioglu S, Hönig M, Lahr G, Stöhr S, Berry G, Friedrich W, Schulz AS. Stem cell transplantation in children with infantile osteopetrosis is associated with a high incidence of VOD, which could be prevented with defibrotide. Bone Marrow Transplant. 2006;38:547–53. [PubMed: 16953210]
  13. Crazzolara R, Maurer K, Schulze H, Zieger B, Zustin J, Schulz AS. A new mutation in the KINDLIN-3 gene ablates integrin-dependent leukocyte, platelet, and osteoclast function in a patient with leukocyte adhesion deficiency-III. Pediatr Blood Cancer. 2015;62:1677–9. [PubMed: 25854317]
  14. Del Fattore A, Peruzzi B, Rucci N, Recchia I, Cappariello A, Longo M, Fortunati D, Ballanti P, Iacobini M, Luciani M, Devito R, Pinto R, Caniglia M, Lanino E, Messina C, Cesaro S, Letizia C, Bianchini G, Fryssira H, Grabowski P, Shaw N, Bishop N, Hughes D, Kapur RP, Datta HK, Taranta A, Fornari R, Migliaccio S, Teti A. Clinical, genetic, and cellular analysis of 49 osteopetrotic patients: implications for diagnosis and treatment. J Med Genet. 2006;43:315–25. [PMC free article: PMC2563229] [PubMed: 16118345]
  15. Dozier TS, Duncan IM, Klein AJ, Lambert PR, Key LL Jr. Otologic manifestations of malignant osteopetrosis. Otol Neurotol. 2005;26:762–6. [PubMed: 16015181]
  16. Frattini A, Orchard PJ, Sobacchi C, Giliani S, Abinun M, Mattsson JP, Keeling DJ, Andersson AK, Wallbrandt P, Zecca L, Notarangelo LD, Vezzoni P, Villa A. Defects in TCIRG1 subunit of the vacuolar proton pump are responsible for a subset of human autosomal recessive osteopetrosis. Nat Genet. 2000;25:343–6. [PubMed: 10888887]
  17. Frattini A, Pangrazio A, Susani L, Sobacchi C, Mirolo M, Abinun M, Andolina M, Flanagan A, Horwitz EM, Mihci E, Notarangelo LD, Ramenghi U, Teti A, Van Hove J, Vujic D, Young T, Albertini A, Orchard PJ, Vezzoni P, Villa A. Chloride channel ClCN7 mutations are responsible for severe recessive, dominant, and intermediate osteopetrosis. J Bone Miner Res. 2003;18:1740–7. [PubMed: 14584882]
  18. Gelb BD, Shi GP, Chapman HA, Desnick RJ. Pycnodysostosis, a lysosomal disease caused by cathepsin K deficiency. Science. 1996;273:1236–8. [PubMed: 8703060]
  19. Guerrini MM, Sobacchi C, Cassani B, Abinun M, Kilic SS, Pangrazio A, Moratto D, Mazzolari E, Clayton-Smith J, Orchard P, Coxon FP, Helfrich MH, Crockett JC, Mellis D, Vellodi A, Tezcan I, Notarangelo J, Rogers MJ, Vezzoni P, Villa A, Frattini A. Humanosteoclast-poor osteopetrosis with hypogammaglobulinemia due to TNFRSF11A (RANK) mutations. Am J Hum Genet. 2008;83:64–76. [PMC free article: PMC2443850] [PubMed: 18606301]
  20. Hamersma H, Gardner J, Beighton P. The natural history of sclerosteosis. Clin Genet. 2003;63:192–7. [PubMed: 12694228]
  21. Helfrich MH. Osteoclast diseases and dental abnormalities. Arch Oral Biol. 2005;50:115–22. [PubMed: 15721137]
  22. Hu Y, Chen IP, de Almeida S, Tiziani V, Do Amaral CM, Gowrishankar K, Passos-Bueno MR, Reichenberger EJ. A novel autosomal recessive GJA1 missense mutation linked to Craniometaphyseal dysplasia. PLoS One. 2013;8:e73576. [PMC free article: PMC3741164] [PubMed: 23951358]
  23. Hwang JM, Kim IO, Wang KC. Complete visual recovery in osteopetrosis by early optic nerve decompression. Pediatr Neurosurg. 2000;33:328–32. [PubMed: 11182645]
  24. Iughetti P, Alonso LG, Wilcox W, Alonso N, Passos-Bueno MR. Mapping of the autosomal recessive (AR) craniometaphyseal dysplasia locus to chromosome region 6q21-22 and confirmation of genetic heterogeneity for mild AR spondylocostal dysplasia. Am J Med Genet. 2000;95:482–91. [PubMed: 11146471]
  25. Jacquemin C, Mullaney P, Svedberg E. Marble brain syndrome: osteopetrosis, renal acidosis and calcification of the brain. Neuroradiology. 1998;40:662–3. [PubMed: 9833897]
  26. Jälevik B, Fasth A, Dahllöf G. Dental development after successful treatment of infantile osteopetrosis with bone marrow transplantation. Bone Marrow Transplant. 2002;29:537–40. [PubMed: 11960278]
  27. Jentsch TJ, Maritzen T, Zdebik AA. Chloride channel diseases resulting from impaired transepithelial transport or vesicular function. J Clin Invest. 2005a;115:2039–46. [PMC free article: PMC1180548] [PubMed: 16075045]
  28. Jentsch TJ, Poet M, Fuhrmann JC, Zdebik AA. Physiological functions of CLC. Annu Rev Physiol. 2005b;67:779–807. [PubMed: 15709978]
  29. Kasper D, Planells-Cases R, Fuhrmann JC, Scheel O, Zeitz O, Ruether K, Schmitt A, Poet M, Steinfeld R, Schweizer M, Kornak U, Jentsch TJ. Loss of the chloride channel ClC-7 leads to lysosomal storage disease and neurodegeneration. EMBO J. 2005;24:1079–91. [PMC free article: PMC554126] [PubMed: 15706348]
  30. Kocher MS, Kasser JR. Osteopetrosis. Am J Orthop. 2003;32:222–8. [PubMed: 12772872]
  31. Kornak U, Kasper D, Bosl MR, Kaiser E, Schweizer M, Schulz A, Friedrich W, Delling G, Jentsch TJ. Loss of the ClC-7 chloride channel leads to osteopetrosis in mice and man. Cell. 2001;104:205–15. [PubMed: 11207362]
  32. Kornak U, Schulz A, Friedrich W, Uhlhaas S, Kremens B, Voit T, Hasan C, Bode U, Jentsch TJ, Kubisch C. Mutations in the a3 subunit of the vacuolar H(+)-ATPase cause infantile malignant osteopetrosis. Hum Mol Genet. 2000;9:2059–63. [PubMed: 10942435]
  33. Lange PF, Wartosch L, Jentsch TJ, Fuhrmann JC. ClC-7 requires Ostm1 as a beta-subunit to support bone resorption and lysosomal function. Nature. 2006;440:220–3. [PubMed: 16525474]
  34. Leisle L, Ludwig CF, Wagner FA, Jentsch TJ, Stauber T. ClC-7 is a slowly voltage-gated 2Cl(-)/1H(+)-exchanger and requires Ostm1 for transport activity. EMBO J. 2011;30:2140–52. [PMC free article: PMC3117652] [PubMed: 21527911]
  35. Luzzi V, Consoli G, Daryanani V, Santoro G, Sfasciotti GL, Polimeni A. Malignant infantile osteopetrosis: dental effects in paediatric patients. Case reports. Eur J Paediatr Dent. 2006;7:39–44. [PubMed: 16646644]
  36. Natsheh J, Drozdinsky G, Simanovsky N, Lamdan R, Erlich O, Gorelik N, Or R, Weintraub M, Stepensky P. Improved outcomes of hematopoietic stem cell transplantation in patients with infantile malignant osteopetrosis using fludarabine-based conditioning. Pediatr Blood Cancer. 2016;63:535–40. [PubMed: 26485304]
  37. Nürnberg P, Thiele H, Chandler D, Höhne W, Cunningham ML, Ritter H, Leschik G, Uhlmann K, Mischung C, Harrop K, Goldblatt J, Borochowitz ZU, Kotzot D, Westermann F, Mundlos S, Braun HS, Laing N, Tinschert S. Heterozygous mutations in ANKH, the human ortholog of the mouse progressive ankylosis gene, result in craniometaphyseal dysplasia. Nat Genet. 2001;28:37–41. [PubMed: 11326272]
  38. Ott C-E, Fischer B, Schröter P, Richter R, Gupta N, Verma N, Kabra M, Mundlos S, Rajab A, Neitzel H, Kornak U. Severe neuronopathic autosomal recessive osteopetrosis due to homozygous deletions affecting OSTM1. Bone. 2013;55:292–7. [PubMed: 23685543]
  39. Orchard PJ, Fasth AL, Le Rademacher J, He W, Boelens JJ, Horwitz EM, Al-Seraihy A, Ayas M, Bonfim CM, Boulad F, Lund T, Buchbinder DK, Kapoor N, O'Brien TA, Perez MA, Veys PA, Eapen M. Hematopoietic stem cell transplantation for infantile osteopetrosis. Blood. 2015;126:270–6. [PMC free article: PMC4497967] [PubMed: 26012570]
  40. Palagano E, Blair HC, Pangrazio A, Tourkova I, Strina D, Angius A, Cuccuru G, Oppo M, Uva P, Van Hul W, Boudin E, Superti-Furga A, Faletra F, Nocerino A, Ferrari MC, Grappiolo G, Monari M, Montanelli A, Vezzoni P, Villa A, Sobacchi C. Buried in the Middle but Guilty: Intronic Mutations in the TCIRG1 Gene Cause Human Autosomal Recessive Osteopetrosis. J Bone Miner Res. 2015;30:1814–21. [PubMed: 25829125]
  41. Pangrazio A, Fasth A, Sbardellati A, Orchard PJ, Kasow KA, Raza J, Albayrak C, Albayrak D, Vanakker OM, De Moerloose B, Vellodi A, Notarangelo LD, Schlack C, Strauss G, Kühl JS, Caldana E, Iacono NL, Susani L, Kornak U, Schulz A, Vezzoni P, Villa A, Sobacchi C. SNX10 mutations define a subgroup of human autosomal recessive osteopetrosis with variable clinical severity. J Bone Miner Res. 2013;28:1041–9. [PubMed: 23280965]
  42. Pangrazio A, Frattini A, Valli R, Maserati E, Susani L, Vezzoni P, Villa A, Al-Herz W, Sobacchi C. A homozygous contiguous gene deletion in chromosome 16p13.3 leads to autosomal recessive osteopetrosis in a Jordanian patient. Calcif Tissue Int. 2012;91:250–4. [PubMed: 22847576]
  43. Pangrazio A, Poliani PL, Megarbane A, Lefranc G, Lanino E, Di Rocco M, Rucci F, Lucchini F, Ravanini M, Facchetti F, Abinun M, Vezzoni P, Villa A, Frattini A. Mutations in OSTM1 (grey lethal) define a particularly severe form of autosomal recessive osteopetrosis with neural involvement. J Bone Miner Res. 2006;21:1098–105. [PubMed: 16813530]
  44. Pangrazio A, Pusch M, Caldana E, Frattini A, Lanino E, Tamhankar PM, Phadke S, Lopez AG, Orchard P, Mihci E, Abinun M, Wright M, Vettenranta K, Bariae I, Melis D, Tezcan I, Baumann C, Locatelli F, Zecca M, Horwitz E, Mansour LS, Van Roij M, Vezzoni P, Villa A, Sobacchi C. Molecular and clinical heterogeneity in CLCN7-dependent osteopetrosis: report of 20 novel mutations. Hum Mutat. 2010;31:E1071–80. [PubMed: 19953639]
  45. Pangrazio A, Puddu A, Oppo M, Valentini M, Zammataro L, Vellodi A, Gener B, Llano-Rivas I, Raza J, Atta I, Vezzoni P, Superti-Furga A, Villa A, Sobacchi C. Exome sequencing identifies CTSK mutations in patients originally diagnosed as intermediate osteopetrosis. Bone. 2014;59:122–6. [PMC free article: PMC3885796] [PubMed: 24269275]
  46. Schulz P, Werner J, Stauber T, Henriksen K, Fendler K. The G215R mutation in the Cl-/H+-antiporter ClC-7 found in ADO II osteopetrosis does not abolish function but causes a severe trafficking defect. PLoS One. 2010;5:e12585. [PMC free article: PMC2935355] [PubMed: 20830208]
  47. Shroff R, Beringer O, Rao K, Hofbauer L, Schulz A. Denosumab for post-transplantation hypercalcemia in osteopetrosis. N Engl J Med. 2012;367:1766–7. [PubMed: 23113501]
  48. Sobacchi C, Frattini A, Orchard P, Porras O, Tezcan I, Andolina M, Babul-Hirji R, Baric I, Canham N, Chitayat D, Dupuis-Girod S, Ellis I, Etzioni A, Fasth A, Fisher A, Gerritsen B, Gulino V, Horwitz E, Klamroth V, Lanino E, Mirolo M, Musio A, Matthijs G, Nonomaya S, Notarangelo LD, Ochs HD, Superti Furga A, Valiaho J, van Hove JL, Vihinen M, Vujic D, Vezzoni P, Villa A. The mutational spectrum of human malignant autosomal recessive osteopetrosis. Hum Mol Genet. 2001;10:1767–73. [PubMed: 11532986]
  49. Sobacchi C, Frattini A, Guerrini MM, Abinun M, Pangrazio A, Susani L, Bredius R, Mancini G, Cant A, Bishop N, Grabowski P, Del Fattore A, Messina C, Errigo G, Coxon FP, Scott DI, Teti A, Rogers MJ, Vezzoni P, Villa A Helfrich MH. Osteoclast-poor human osteopetrosis due to mutations in the gene encoding RANKL. Nat Genet. 2007;39:960–2. [PubMed: 17632511]
  50. Sobacchi C, Pangrazio A, Lopez AG, Gomez DP, Caldana ME, Susani L, Vezzoni P, Villa A. As little as needed: the extraordinary case of a mild recessive osteopetrosis owing to a novel splicing hypomorphic mutation in the TCIRG1 gene. J Bone Miner Res. 2014;29:1646–50. [PMC free article: PMC4258090] [PubMed: 24535816]
  51. Souraty N, Noun P, Djambas-Khayat C, Chouery E, Pangrazio A, Villa A, Lefranc G, Frattini A, Mégarbané A. Molecular study of six families originating from the Middle-East and presenting with autosomal recessive osteopetrosis. Eur J Med Genet. 2007;50:188–99. [PubMed: 17400532]
  52. Steward CG. Neurological aspects of osteopetrosis. Neuropathol Appl Neurobiol. 2003;29:87–97. [PubMed: 12662317]
  53. Steward CG, Pellier I, Mahajan A, Ashworth MT, Stuart AG, Fasth A, Lang D, Fischer A, Friedrich W, Schulz AS. Severe pulmonary hypertension: a frequent complication of stem cell transplantation for malignant infantile osteopetrosis. Br J Haematol. 2004;124:63–71. [PubMed: 14675409]
  54. Strickland JP, Berry DJ. Total joint arthroplasty in patients with osteopetrosis: a report of 5 cases and review of the literature. J Arthroplasty. 2005;20:815–20. [PubMed: 16139724]
  55. Teitelbaum SL, Ross FP. Genetic regulation of osteoclast development and function. Nat Rev Genet. 2003;4:638–49. [PubMed: 12897775]
  56. Van Wesenbeeck L, Cleiren E, Gram J, Beals RK, Bénichou O, Scopelliti D, Key L, Renton T, Bartels C, Gong Y, Warman ML, De Vernejoul MC, Bollerslev J, Van Hul W. Six novel missense mutations in the LDL receptor-related protein 5 (LRP5) gene in different conditions with an increased bone density. Am J Hum Genet. 2003;72:763–71. [PMC free article: PMC1180253] [PubMed: 12579474]
  57. Van Wesenbeeck L, Odgren PR, Coxon FP, Frattini A, Moens P, Perdu B, MacKay CA, Van Hul E, Timmermans JP, Vanhoenacker F, Jacobs R, Peruzzi B, Teti A, Helfrich MH, Rogers MJ, Villa A, Van Hul W. Involvement of PLEKHM1 in osteoclastic vesicular transport and osteopetrosis in incisors absent rats and humans. J Clin Invest. 2007;117:919–30. [PMC free article: PMC1838941] [PubMed: 17404618]
  58. Vanhoenacker FM, De Beuckeleer LH, Van Hul W, Balemans W, Tan GJ, Hill SC, De Schepper AM. Sclerosing bone dysplasias: genetic and radioclinical features. Eur Radiol. 2000;10:1423–33. [PubMed: 10997431]
  59. Waguespack SG, Koller DL, White KE, Fishburn T, Carn G, Buckwalter KA, Johnson M, Kocisko M, Evans WE, Foroud T, Econs MJ. Chloride channel 7 (ClCN7) gene mutations and autosomal dominant osteopetrosis, type II. J Bone Miner Res. 2003;18:1513–8. [PubMed: 12929941]
  60. Wilson CJ, Vellodi A. Autosomal recessive osteopetrosis: diagnosis, management, and outcome. Arch Dis Child. 2000;83:449–52. [PMC free article: PMC1718540] [PubMed: 11040159]

Suggested Reading

  1. de Vernejoul MC, Kornak U. Heritable sclerosing bone disorders: presentation and new molecular mechanisms. Ann N Y Acad Sci. 2010;1192:269–77. [PubMed: 20392246]
  2. Sobacchi C, Schulz A, Coxon FP, Villa A, Helfrich MH. Osteopetrosis: genetics, treatment and new insights into osteoclast function. Nat Rev Endocrinol. 2013;9:522–36. [PubMed: 23877423]
  3. Tolar J, Teitelbaum SL, Orchard PJ. Osteopetrosis. N Engl J Med. 2004;351:2839–49. [PubMed: 15625335]
  4. Villa A, Guerrini MM, Cassani B, Pangrazio A, Sobacchi C. Infantile malignant, autosomal recessive osteopetrosis: the rich and the poor. Calcif Tissue Int. 2009;84:1–12. [PubMed: 19082854]

Chapter Notes

Author Information

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

Author History

Marie-Christine de Vernejoul, MD, PhD; Hôpital Lariboisière (2007-2016)
Uwe Kornak, MD, PhD (2007-present)
Ansgar Schulz, MD (2007-present)
Cristina Sobacchi, MS (2016-present)
Anna Villa, MD, PhD (2016-present)

Revision History

  • 9 June 2016 (ha) Comprehensive update posted live
  • 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
Copyright © 1993-2016, University of Washington, Seattle. All rights reserved.

For more information, see the GeneReviews Copyright Notice and Usage Disclaimer.

For questions regarding permissions: ude.wu@tssamda.

Bookshelf ID: NBK1127PMID: 20301306

Views

  • PubReader
  • Print View
  • Cite this Page
  • Disable Glossary Links

Related information

  • MedGen
    Related information in MedGen
  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed
  • Gene
    Locus Links

Similar articles in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...