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CLCN7-Related Osteopetrosis

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

Author Information and Affiliations

Initial Posting: ; Last Update: January 20, 2022.

Estimated reading time: 31 minutes

Summary

Clinical characteristics.

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

  • ARO. Onset is at birth. Findings may include: fractures; reduced 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.
  • IAO. Onset 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.
  • ADOII. Onset 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.

The diagnosis of a CLCN7-related osteopetrosis is established in a proband with suggestive findings and biallelic pathogenic variants or a heterozygous pathogenic variant in CLCN7 identified by molecular genetic testing.

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. Newly diagnosed individuals should be transferred as soon as possible to a pediatric center experienced in allogeneic stem cell transplantation in this disease. The collaboration of pediatricians, pediatric neurologists, ophthalmologists, and psychologists is required to determine best treatment of neurologic and ophthalmic issues, which may include surgical decompression of the optic nerve and hearing aids. Treatment of fractures by an experienced orthopedist and 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. Medical treatment for arthritis with anti-inflammatory agents; transfusions for anemia and thrombocytopenia; surgical optic nerve decompression, hearing aids, and regular dental care and good oral hygiene.

Prevention of primary manifestations: In 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.

Surveillance: Complete blood count, ophthalmologic examination, and audiologic evaluation at least once a year; dental evaluation every 6-12 months or as directed. For ARO, follow up as directed by the transplantation center following HSCT.

Agents/circumstances to avoid: In ADOII, activities with high fracture risk. Orthopedic surgery should only be performed when absolutely necessary.

Genetic counseling.

CLCN7-related osteopetrosis is inherited in an autosomal recessive or autosomal dominant manner: ARO is inherited in an autosomal recessive manner; about 40% of IAO is inherited in an autosomal recessive manner and about 60% in an autosomal dominant manner; and ADOII is inherited in an autosomal dominant manner.

  • Autosomal recessive inheritance. If both parents are known to be heterozygous for a CLCN7 pathogenic variant associated with autosomal recessive osteopetrosis, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial CLCN7 pathogenic variants. Carrier testing for at-risk relatives requires prior identification of the CLCN7 pathogenic variants in the family.
  • Autosomal dominant inheritance. Most individuals diagnosed with autosomal dominant CLCN7-related osteopetrosis have an affected parent. Each child of an individual with autosomal dominant osteopetrosis has a 50% chance of inheriting the pathogenic variant.

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

GeneReview Scope

CLCN7-Related Osteopetrosis: Included Phenotypes

Phenotype 1Synonym
Autosomal recessive osteopetrosis (ARO)Infantile malignant CLCN7-related autosomal recessive osteopetrosis
Intermediate autosomal osteopetrosis (IAO)
Autosomal dominant osteopetrosis type II (ADOII)Albers-Schönberg disease
1.

For other genetic causes of these phenotypes see Differential Diagnosis.

Diagnosis

The spectrum of CLCN7-related osteopetrosis includes the following:

  • Autosomal recessive osteopetrosis (ARO; infantile malignant CLCN7-related autosomal recessive osteopetrosis)
  • 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 central nervous system involvement (Table 1).

Table 1.

Diagnostic Features of the Subtypes of CLCN7-Related Osteopetrosis

FindingSubtype of CLCN7-Related Osteopetrosis
AROIAOADOII
Radiographic changesPathognomonic 1Characteristic 2Characteristic 3
HypocalcemiaSevere to absentAbsentAbsent
AnemiaSevere to moderateMild to absentAbsent
ThrombocytopeniaSevere to absentAbsentAbsent
Visual impairmentFrequentRareVery rare
CNS involvementSevere to absent 4AbsentAbsent
Age of onset of symptomsBirthFirst 2 yearsFirst 10 yrs
InheritanceARAR or ADAD

ADOII = autosomal dominant osteopetrosis type II; ARO = infantile malignant CLCN7-related autosomal recessive osteopetrosis; CNS = central nervous system; IAO = intermediate autosomal osteopetrosis

1.

Generalized osteosclerosis, club-shaped long bones, sclerosis of the skull base, bone-within-bone appearance; these signs are observed in all types of ARO.

2.

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

3.

Findings:
• 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

4.

Typical signs of CNS involvement:
• Delayed psychomotor development
• Loss of abilities
• Seizures (can be also due to hypocalcemia)
• On MRI: global brain atrophy, cortical abnormalities, and in rare individuals, heterotopias

Establishing the Diagnosis

The diagnosis of a CLCN7-related osteopetrosis is established in a proband with suggestive findings and biallelic pathogenic variants or a heterozygous pathogenic variant in CLCN7 identified by molecular genetic testing (see Table 2).

Note: Identification of biallelic CLCN7 variants of uncertain significance, of one known CLCN7 pathogenic variant and one CLCN7 variant of uncertain significance, or of a heterozygous CLCN7 variant of uncertain significance does not establish or rule out a diagnosis of this disorder.

Because the phenotype of a CLCN7-related osteopetrosis may be indistinguishable from other inherited sclerosing bone dysplasias resulting from impaired osteoclast function, recommended molecular genetic testing approaches include use of a multigene panel or comprehensive genomic testing.

Note: Single-gene testing (sequence analysis of CLCN7, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.

An osteopetrosis multigene panel that includes CLCN7 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Comprehensive genomic testing does not require the clinician to determine which genes is likely involved. Exome sequencing is most commonly used; genome sequencing is also possible.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 2.

Molecular Genetic Testing Used in CLCN7-Related Osteopetrosis

Gene 1MethodProportion of Pathogenic Variants 2 Detectable by Method
CLCN7 Sequence analysis 3~99% 4, 5
Gene-targeted deletion/duplication analysis 6Rare 7
1.
2.

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

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or 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.

Data derived from the subscription-based professional view of Human Gene Mutation Database [Stenson et al 2020]

5.

A noncoding deep intronic variant in CLCN7 causing autosomal recessive osteopetrosis was reported to have been missed on genome sequencing [Chorin et al 2020].

6.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may 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.

7.

A homozygous 101-kb contiguous gene deletion including exons 7-25 of CLCN7 has been reported [Pangrazio et al 2012].

Clinical Characteristics

Clinical Description

To date, approximately 300 individuals have been identified with a pathogenic variant in CLCN7 [Stenson et al 2020]. The three different associated phenotypes are described in this section.

Infantile Malignant CLCN7-Related Autosomal Recessive Osteopetrosis (ARO)

ARO is a systemic, life-threatening disorder. Onset of symptoms is at birth. Without treatment, life span is approximately ten years (although rare exceptions of far longer survival have occurred). Note: Many of the most complete clinical descriptions of ARO were published prior to the discovery of the causative gene.

Possible clinical manifestations of ARO include the following.

Skeletal findings

  • Fractures. The near-complete absence of osteoclastic bone resorption 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.
Figure 1.

Figure 1.

Autosomal recessive osteopetrosis radiographs

Calcium and blood cell findings

  • 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 central nervous system (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].

CNS involvement

  • Neurologic complications
    • Visual impairment beginning shortly after birth is common. In most individuals it is caused by optic nerve compression within the osteosclerotic skull base.
    • Skull changes may also cause hydrocephalus.
    • A prominent and large anterior fontanelle is common and sometimes associated with hydrocephalus, possibly caused by obstruction of cerebral blood flow and cerebrospinal fluid 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 individuals 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. If the onset is very early brain development can be disturbed, resulting in structural brain anomalies and heterotopias [Rössler et al 2021]. 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].

Other

  • 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 [Kantaputra et al 2012, Wang et al 2016, Zhang et al 2019].

Intermediate Autosomal Osteopetrosis (IAO)

IAO is characterized by childhood onset with a milder course than ARO. Life expectancy is normal in most individuals. 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 (Figure 2).

Figure 2.

Figure 2.

Autosomal dominant osteopetrosis type II radiographs Reprinted from Bénichou et al [2000] with permission from Elsevier

Onset of radiologic and clinical 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 [Waguespack et al 2007]. 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 60%-80% of affected individuals, with a mean of three fractures per person [Bénichou et al 2000, Waguespack et al 2007]. 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 individuals.
  • Hip osteoarthritis is common (up to 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, Waguespack et al 2007]. 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 up to 19% of affected individuals.

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified.

Penetrance

Penetrance ranges from 60% to 90% in families with ADOII [Waguespack et al 2007].

Prevalence

The prevalence of ADOII has been estimated at up to 1:20,000 [Bénichou et al 2000]. The disease is probably underdiagnosed in those with milder phenotypes.

ARO is less common, with an estimated prevalence of 1:250,000.

Differential Diagnosis

Pathogenic variants in CLCN7 account for 13% of the infantile autosomal recessive osteopetrosis (ARO), 40% of the recessive intermediate autosomal osteopetrosis (IAO), 60% of the dominant IAO, and 99% of the autosomal dominant osteopetrosis type II (ADOII) [Authors, personal observation].

ARO

Table 3.

Other Types of Autosomal Recessive Osteopetrosis

GeneDisorderClinical CharacteristicsFeatures Distinguishing this Disorder from CLCN7-Related ARO
CA2 ARO w/renal tubular acidosis (RTA) (OMIM 259730)Generalized osteosclerosis. Cerebral calcifications are typical & may be assoc w/ID. 1Onset of ARO w/RTA is usually later than in infantile malignant form of ARO & disease course is milder.
OSTM1 OSTM1-related ARO (OMIM 259720)~4% of ARO is caused by pathogenic variants in OSTM1. Extremely severe form of ARO w/CNS involvement 2 that is indistinguishable from most severe forms of CLCN7-related ARO.OSTM1-related ARO is frequently assoc w/structural brain anomalies.
PLEKHM1 PLEKHM1-related ARO (OMIM 611497)Very rare, can look like ADOIIPLEKHM1-related ARO appears to be very mild & can regress w/↑ age. 3 One person w/PLEKHM1-related ARO caused by a heterozygous pathogenic variant has been described. 4
SNX10 SNX10-related ARO (OMIM 615085)~4% of ARO is caused by pathogenic variants in SNX10; in particular, "Västerbottenian osteopetrosis" is caused by SNX10 pathogenic variants. Loss of vision, anemia, & bone fragility are frequently observed, warranting use of HSCT. 5SNX10-related ARO appears to be slightly less severe than CLCN7-related ARO.
TCIRG1 TCIRG1-related ARO (OMIM 259700)>50% of ARO is caused by pathogenic variants in TCIRG1.Higher frequency of neurodevelopmental delay & seizures in CLCN7-related ARO than in TCIRG1-related ARO. 6 Noncoding TCIRG1 variants can cause milder phenotype that resembles ADOII.
TNFRSF11A Osteoclast-poor ARO (OMIM 612301)Characterized by onset w/in 1st yr of life & typical ARO manifestations. Investigation of bone biopsy is prerequisite for reliable diagnosis.TNFSF11 pathogenic variants cause a slight T-cell defect & TNFRSF11A pathogenic variants can lead to hypogammaglobulinemia similar to a common variable immune deficiency. 7 It is crucial to rule out TNFSF11- & TNFRSF11A-related ARO, as HSCT is not successful in these persons.
TNFSF11 Osteoclast-poor ARO (OMIM 259710)

ADOII = autosomal dominant osteopetrosis type II; ARO = autosomal recessive osteopetrosis; CNS = central nervous system; ID = intellectual disability; HSCT = hematopoietic stem cell transplantation

1.
2.
3.
4.
5.
6.
7.

A mild form of ARO can be caused by deep intronic or splice site variants in TCIRG1 (OMIM 259700) [Sobacchi et al 2014, Palagano et al 2015]. This form can be very similar to CLCN7-related IAO or ADOII.

Autosomal Dominant Osteopetrosis (ADO)

Heterozygous pathogenic variants in LRP5 are associated with ADO type I (ADOI) (OMIM 607634). In ADOI, osteosclerosis is most pronounced in the skull vault and does not lead to sandwich vertebrae. ADOI is not associated with an increased fracture rate. (Note: 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.)

Other

Table 4.

Other Disorders to Consider in the Differential Diagnosis of CLCN7-Related Osteopetrosis

GeneDisorder/PhenotypeMOIComment
ANKH AD craniometaphyseal dysplasia AD
  • Clinical hallmark is skull hyperostosis → deep-set eyes & paranasal bossing. Facial nerve palsy is common & more frequent than optic nerve compression.
  • The femur shows a modeling defect, but no osteosclerosis. Susceptibility to fractures is not ↑.
CSF1R Brain anomalies, neurodegeneration, & dysosteosclerosis (BANDDOS) (OMIM 618476)ARCharacterized by structural brain anomalies & a primary neurodegenerative phenotype. Like other forms of dysosteosclerosis, affected persons have platyspondyly.
CTSK Pycnodysostosis AR
  • Short-limbed short stature, typical facial appearance (convex nasal ridge & small jaw w/obtuse mandibular angle), osteosclerosis w/↑ bone fragility, acroosteolysis of distal phalanges, delayed closure of cranial sutures, & dysplasia of clavicle
  • In some affected persons clinical presentation can resemble IAO. 1
FERMT3 Leukocyte adhesion deficiency type III (OMIM 612840)ARAffected persons present w/recurrent infections & bleeding diathesis regardless of platelet or leukocyte count. In some, high bone density can be found, since fermitin family homolog 3 signaling is required for osteoclast-mediated bone resorption. 2
GJA1 AR craniometaphyseal dysplasia (OMIM 218400)AR
  • Typical features of craniometaphyseal dysplasia (macrocephaly, hearing loss, skull hyperostosis w/paranasal bossing, metaphyseal widening) but less pronounced calvarial thickening 3
  • Due to diaphyseal osteosclerosis; can occasionally resemble mild forms of osteopetrosis
LRP6 High bone mass phenotype 4ADEndosteal hyperostosis similar to ADOI but w/hypodontia
LRRK1 Osteosclerotic metaphyseal dysplasia (OSMD) 5AR
  • While the disorder name differs, LRRK1-related OSMD is a typical recessive osteopetrosis w/dysfunctional osteoclasts. No neurologic complications.
  • LRRK1-related OSMD is milder than CLCN7-related ARO & can be best compared to IAO.
SLC29A3 Dysosteosclerosis 6AR
  • Assoc w/platyspondyly (a distinguishing feature). Disorder appears to be osteoclast-poor. No neurologic complications.
  • SLC39A3-related dysosteosclerosis is milder than CLCN7-related ARO & is best compared to IAO.
SOST SOST-related sclerosing bone dysplasias, incl van Buchem disease & sclerosteosisARModerate-to-gross skull hyperostosis → cranial nerve dysfunction, mandibular enlargement, & generalized osteosclerosis. Sclerosteosis also comprises syndactyly & tall stature & can be lethal as a result of ↑ intracranial pressure.

AD = autosomal dominant; ADO = autosomal dominant osteopetrosis; AR = autosomal recessive; ARO = autosomal recessive osteopetrosis; IAO = intermediate autosomal osteopetrosis; MOI = mode of inheritance

1.
2.
3.
4.
5.
6.

Management

General guidelines for diagnosis, therapy, and follow up are available for all forms of osteopetrosis; see Author Information.

Due to the difference in severity, the evaluation, treatment, and surveillance recommendations for infantile malignant CLCN7-related autosomal recessive osteopetrosis (ARO) and CLCN7-related autosomal dominant osteopetrosis type II (ADOII) differ. The CLCN7-related intermediate autosomal osteopetrosis (IAO) phenotype lies between these two forms and has variable manifestations and prognosis. Therefore, management options for CLCN7-related IAO must be evaluated on an individual basis.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with ARO, the evaluations summarized in Table 5 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 5.

Recommended Evaluations Following Initial Diagnosis in Individuals with Infantile Malignant CLCN7-Related Autosomal Recessive Osteopetrosis (ARO)

System/ConcernEvaluationComment
Osteosclerosis Baseline radiographic skeletal survey
Choanal stenosis Otorhinolaryngologic exam to evaluate for choanal stenosis assoc w/sclerosis of skull base
Hypocalcemia &
secondary hyper-
parathyroidism
Calcium concentrations in blood & urine
Anemia &
thrombocytopenia
CBC w/reticulocyte count
Abdominal ultrasoundEvaluate for hepatosplenomegaly assoc w/extrameduallry hematopoeisis.
Neurologic
complications
MRI &/or CT of neurocranium to evaluate for narrowed neuroforamina, hydrocephalus, & brain abnormalities in neuronopathic form of osteopetrosis
EEGEvaluate for evidence of neurodegeneration.
Baseline neurodevelopmental assessment
Visual impairment Ophthalmologic exam incl VEPs to evaluate for optic nerve atrophy assoc w/optic nerve compression w/in skull base
Hearing loss Baseline audiologic assessment
Genetic
counseling
By genetics professionals 1To inform affected persons & their families re nature, MOI, & implications of CLCN7-related ARO to facilitate medical & personal decision making
Family support
& resources
Assess need for:

ARO = autosomal recessive osteopetrosis; MOI = mode of inheritance; VEP = visual evoked potential

1.

Medical geneticist, certified genetic counselor, certified advanced genetic nurse

To establish the extent of disease and needs in an individual diagnosed with ADOII, the evaluations summarized in Table 6 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 6.

Recommended Evaluations Following Initial Diagnosis in Individuals with CLCN7-Related Autosomal Dominant Osteopetrosis Type II

System/ConcernEvaluationComment
Osteosclerosis Baseline radiographic skeletal survey
Anemia & thrombocytopenia CBC w/reticulocyte count
Neurologic complications MRI &/or CT of neurocranium to evaluate for narrowed neuroforamina
Visual impairment Ophthalmologic exam incl VEPs to evaluate for optic nerve atrophy assoc w/optic nerve compression w/in skull base
Hearing loss Baseline audiologic assessment
Genetic counseling By genetics professionals 1To inform affected persons & their families re nature, MOI, & implications of CLCN7-related ADOII to facilitate medical & personal decision making

ADOII = autosomal dominant osteopetrosis type II; MOI = mode of inheritance; VEP = visual evoked potential

1.

Medical geneticist, certified genetic counselor, certified advanced genetic nurse

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.

Table 7.

Treatment of Manifestations in Individuals with Infantile Malignant CLCN7-Related Autosomal Recessive Osteopetrosis (ARO)

Manifestation/
Concern
TreatmentConsiderations/Other
Hypocalcemic
convulsions
Calcium supplementation 1
Bone marrow
failure
Erythrocyte or platelet transfusions (irradiated products) as neededIn case of leukocytopenia &/or hypogammaglobulinemia, which may develop in a subset of persons, antibiotics & immunoglobulins may be given in a prophylactic or therapeutic manner.
Newly diagnosed persons should be transferred as soon as possible to pediatric center experienced in allogeneic HSCT in this disease.See Prevention of Primary Manifestations.
Neurologic
issues
The collaboration of pediatricians, pediatric neurologists, ophthalmologists, & psychologists is required to determine best treatment.
Visual
impairment
Surgical decompression of optic nerve, a difficult procedure, has been performed w/some success to prevent vision loss in those w/ARO in general [Hwang et al 2000].
Hearing loss Hearing aids
Fractures Treatment by orthopedist w/experience w/ARO in collaboration w/treating pediatrician
Dental issues Treatment as needed by dentistOral surgery may be needed for defective tooth eruption, ankylosis, abscesses, & formation of cysts & fistulas.

ARO = autosomal recessive osteopetrosis; HSCT = hematopoietic stem cell transplantation

1.

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 HSCT. Treatment needs to take into account the particular situation of the affected individual.

Table 8.

Treatment of Manifestations in Individuals with CLCN7-Related Autosomal Dominant Osteopetrosis Type II (ADOII)

Manifestation/ConcernTreatmentConsiderations/Other
Fractures Treatment by orthopedist w/experience w/ADOIIFractures near joints may require total joint arthroplasty [Strickland & Berry 2005].
Arthritis Medical treatment w/anti-inflammatory agents
Anemia & thrombocytopenia Transfusions
Visual impairment Surgical optic nerve decompression
Hearing loss Hearing aids
Dental issues Regular dental care & good oral hygiene

ADOII = autosomal dominant osteopetrosis type II

Prevention of Primary Manifestations

Infantile Malignant CLCN7-Related 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.

  • Restricted intake of calcium and vitamin D just before, during, and following HSCT to prevent hypercalcemia is recommended.
  • Secondary neurosensory impairments caused by nerve compression may be prevented by early transplantation, but not reversed when they are already present.
    Cranial nerve dysfunction (visual impairment caused by optic nerve atrophy) is irreversible in most individuals. In the authors' series including about 30 individuals, about two thirds of affected individuals were visually impaired after successful transplantation [A Schulz, unpublished results]. Even-Or et al [2022] report blindness in 26% of a group with ARO associated with mutation of different genes.
  • 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; Gaytán-Morales et al 2021; A Schulz & U Kornak, unpublished results].
    It is highly important but difficult to exclude individuals with the neuronopathic form from this invasive treatment [Rössler et al 2021]. 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.
  • 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 following transplant have been seen in about 10% of individuals in the authors' series [A Schulz, unpublished results]. However, it must be stressed that individuals with ARO who do not have primary CNS involvement can be cured by HSCT [Gaytán-Morales et al 2021].
  • Reported outcomes of HSCT
    • 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].
    • 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 HLA-identical donor transplants, 80% for HLA-matched unrelated donor transplants, and 66% for HLA-haplotype-mismatched related donor transplants [Sobacchi et al 2013].
    • In a published report of 193 individuals 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 reported from three large transplant centers using a fludarabine-based conditioning regimen [Natsheh et al 2016; Schulz & Moshous, personal communication].
    • In HLA-haploidentical HSCT, the implementation of post-transplant cyclophosphamide according to a modified Baltimore protocol achieved promising results. Therefore, this protocol was included in the recently updated treatment guidelines of the EBMT/ESID inborn errors working party [Lankester et al 2021].

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].

Surveillance

Table 9.

Recommended Surveillance for Individuals with Infantile Malignant CLCN7-Related Autosomal Recessive Osteopetrosis (ARO)

System/ConcernEvaluationFrequency
Bone marrow failure CBCAnnually at a minimum
Visual loss Ophthalmic exam
Hearing loss Audiologic eval
Dental issues Dental evalEvery 6-12 mos or as directed
Potential for graft failure after HSCT Transplant center surveillanceAs directed by specialists

CBC = complete blood count; HSCT = hematopoietic stem cell transplantation

Table 10.

Recommended Surveillance for Individuals with CLCN7-Related Autosomal Dominant Osteopetrosis Type II (ADOII)

System/ConcernEvaluationFrequency
Anemia & thrombocytopenia CBCAt least annually
Visual loss Ophthalmic exam
Hearing loss Audiologic eval
Dental issues Dental evalEvery 6-12 mos or as directed

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.

For hematopoietic stem cell donation (relatives of a proband with CLCN7-related ARO). Any relative considering stem cell donation should undergo molecular genetic testing to clarify their genetic status. Whenever possible, related donors who do not have a familial CLCN7 pathogenic variant are preferred.

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

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe 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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of 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; it is not meant to address all personal, cultural, or ethical issues that may arise 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:

Autosomal Recessive Inheritance – Risk to Family Members

Parents of a proband

  • The parents of an affected child are presumed to be heterozygous for a CLCN7 pathogenic variant.
  • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a CLCN7 pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • Individuals who are heterozygous for a CLCN7 pathogenic variant associated with ARO are asymptomatic; however, no systematic studies have been performed to evaluate for subtle changes in bone mass.

Sibs of a proband

  • If both parents are known to be heterozygous for a CLCN7 pathogenic variant associated with autosomal recessive osteopetrosis, each sib of an affected individual has at conception a 25% chance of inheriting biallelic CLCN7 pathogenic variants and being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial CLCN7 pathogenic variants.
  • The limited data available suggest that in the presence of ARO, a similar presentation of the disorder is expected in individuals with biallelic CLCN7 pathogenic variants in the same family; in particular, if the neuronopathic form of the disorder is present in the proband, a primary central nervous system involvement is likely to be present in other affected sibs [Sobacchi, unpublished observation].
  • Individuals who are heterozygous for a CLCN7 pathogenic variant associated with autosomal recessive osteopetrosis are asymptomatic; however, no systematic studies have been performed to evaluate for subtle changes in bone mass.

Offspring of a proband

  • The offspring of an individual with autosomal recessive CLCN7-related osteopetrosis are obligate heterozygotes (carriers) for a pathogenic variant in CLCN7.
  • In general, individuals with ARO reproduce only if successfully treated by hematopoietic stem cell transplantation.

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

Carrier Detection

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

Autosomal Dominant Inheritance – Risk to Family Members

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 de novo pathogenic variant. The proportion of individuals with CLCN7-related osteopetrosis caused by a de novo pathogenic variant is unknown.
  • If the proband appears to be the only affected family member (i.e., a simplex case), recommendations for the evaluation of parents include x-ray investigation of the skeleton and molecular genetic testing for the pathogenic variant identified in the proband. Evaluation of the parents is used to confirm their genetic status and to allow reliable recurrence risk counseling.
  • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of reduced penetrance, failure by health care professionals to recognize the syndrome, and/or a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband).

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 and/or is known to have the CLCN7 pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Because ADOII is associated with both intrafamilial clinical variability and reduced penetrance (see Penetrance), a sib who inherits a CLCN7 pathogenic variant associated with autosomal dominant CLCN7-related osteopetrosis may be more or less severely affected than the proband.
  • If the proband has a known CLCN7 pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
  • If the parents have not been tested for the CLCN7 pathogenic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for CLCN7-related osteopetrosis because of the possibility of reduced penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism.

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.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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.

Prenatal Testing and Preimplantation Genetic Testing

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

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

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
  • MedlinePlus
  • 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
  • Network for Rare Osteopathies (NetsOs)
    CeSER
    Alexandrinenstraße 5
    Germany
    Phone: 49 (0)234 509-2601
    Fax: 49 (0)234 509-2688
    Email: ceser@klinikum-bochum.de
  • European Society for Immunodeficiencies (ESID) Registry
    Dr. Gerhard Kindle
    University Medical Center Freiburg Centre of Chronic Immunodeficiency
    Engesserstrasse 4
    79106 Freiburg
    Germany
    Phone: 49-761-270-34450
    Email: esid-registry@uniklinik-freiburg.de
  • UCLA International Skeletal Dysplasia Registry (ISDR)
    Phone: 310-825-8998

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-Specific DatabasesHGMDClinVar
CLCN7 H(+)/Cl(-) exchange transporter 7 CLCN7 database CLCN7 CLCN7

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) 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 Pathogenesis

CLCN7-related osteopetrosis is caused by osteoclast dysfunction. The osteoclast is a highly specialized cell with the unique ability to resorb large amounts of mineralized bone tissue. 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" [Sobacchi et al 2013]. The low pH is required to dissolve the bone mineral and for the optimal activity of acid hydrolases that degrade the bone matrix.

CLCN7 encodes the ClC-7 chloride channel, which 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].

Mechanism of disease causation. Pathogenic variants in CLCN7 lead to a loss of chloride channel function of varying degree. In the most severe autosomal recessive osteopetrosis phenotype, the ClC-7 chloride channel is absent, while the autosomal dominant osteopetrosis type II phenotype-causing pathogenic variants do not necessarily impair chloride currents, but do result in abnormal gating behavior of the channel [Leisle et al 2011].

Table 11.

Notable CLCN7 Pathogenic Variants

Reference SequencesDNA Nucleotide ChangePredicted Protein ChangeComment [Reference]
NM_001287​.6
NP_001278​.1
c.643G>Ap.Gly215ArgRecurrent pathogenic variants assoc w/ADOII [Cleiren et al 2001]
c.856C>Tp.Arg286Trp

ADOII = autosomal dominant osteopetrosis type II

Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

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

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 ed.mlu-kinilkinu@zluhcs.ragsna.

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

  • 20 January 2022 (ha) Comprehensive update posted live
  • 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 live
  • 8 September 2006 (uk) Original submission

References

Literature Cited

  • 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]
  • 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]
  • Bo T, Yan F, Guo J, Lin X, Zhang H, Guan Q, Wang H, Fang L, Gao L, Zhao J, Xu C. Characterization of a relatively malignant form of osteopetrosis caused by a novel mutation in the PLEKHM1 gene. J Bone Miner Res. 2016;31:1979–87. [PubMed: 27291868]
  • Brance ML, Brun LR, Cóccaro NM, Aravena A, Duan S, Mumm S, Whyte MP. High bone mass from mutation of low-density lipoprotein receptor-related protein 6 (LRP6). Bone. 2020;141:115550. [PubMed: 32730923]
  • 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]
  • Chorin O, Yachelevich N, Mohamed K, Moscatelli I, Pappas J, Henriksen K, Evrony GD. Transcriptome sequencing identifies a noncoding, deep intronic variant in CLCN7 causing autosomal recessive osteopetrosis. Mol Genet Genomic Med. 2020;8:e1405. [PMC free article: PMC7549584] [PubMed: 32691986]
  • 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]
  • 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]
  • 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]
  • Dozier TS, Duncan IM, Klein AJ, Lambert PR, Key LL Jr. Otologic manifestations of malignant osteopetrosis. Otol Neurotol. 2005;26:762–6. [PubMed: 16015181]
  • Even-Or E, Schiesel G, Simanovsky N. NaserEddin A, Zaidman I, Elpeleg O, Mor-Shaked H, Stepensky P. Clinical presentation and analysis of genotype-phenotype correlations in patients with malignant infantile osteopetrosis. Bone. 2022;154:116229. [PubMed: 34624559]
  • 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]
  • 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]
  • Gaytán-Morales JF, Castorena-Villa I, Mendoza-Camargo FO, Cortés-Flores DC, Gómez-Domíguez YA, Montenegro-Chahar PD, García-Maldonado P, Parra-Ortega I. Hematopoietic stem cell transplantation in a patient with osteopetrosis and mutation in CLCN7: long-term follow-up. Bol Med Hosp Infant Mex. 2021;78:225–33. [PubMed: 33651788]
  • 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. Human osteoclast-poor osteopetrosis with hypogammaglobulinemia due to TNFRSF11A (RANK) mutations. Am J Hum Genet. 2008;83:64–76. [PMC free article: PMC2443850] [PubMed: 18606301]
  • Howaldt A, Nampoothiri S, Quell LM, Ozden A, Fischer-Zirnsak B, Collet C, de Vernejoul MC, Doneray H, Kayserili H, Kornak U. Sclerosing bone dysplasias with hallmarks of dysosteosclerosis in four patients carrying mutations in SLC29A3 and TCIRG1. Bone. 2019;120:495–503. [PubMed: 30537558]
  • Howaldt A, Hennig AF, Rolvien T, Rössler U, Stelzer N, Knaus A, Böttger S, Zustin J, Geißler S, Oheim R, Amling M, Howaldt HP, Kornak U. Adult osteosclerotic metaphyseal dysplasia with progressive osteonecrosis of the jaws and abnormal bone resorption pattern due to a LRRK1 splice site mutation. J Bone Miner Res. 2020;35:1322–32. [PubMed: 32119750]
  • 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]
  • Hwang JM, Kim IO, Wang KC. Complete visual recovery in osteopetrosis by early optic nerve decompression. Pediatr Neurosurg. 2000;33:328–32. [PubMed: 11182645]
  • Jacquemin C, Mullaney P, Svedberg E. Marble brain syndrome: osteopetrosis, renal acidosis and calcification of the brain. Neuroradiology. 1998;40:662–3. [PubMed: 9833897]
  • Jónsson H, Sulem P, Kehr B, Kristmundsdottir S, Zink F, Hjartarson E, Hardarson MT, Hjorleifsson KE, Eggertsson HP, Gudjonsson SA, Ward LD, Arnadottir GA, Helgason EA, Helgason H, Gylfason A, Jonasdottir A, Jonasdottir A, Rafnar T, Frigge M, Stacey SN, Th Magnusson O, Thorsteinsdottir U, Masson G, Kong A, Halldorsson BV, Helgason A, Gudbjartsson DF, Stefansson K. Parental influence on human germline de novo mutations in 1,548 trios from Iceland. Nature. 2017;549:519–22. [PubMed: 28959963]
  • Kantaputra PN, Thawanaphong S, Issarangporn W, Klangsinsirikul P, Ohazama A, Sharpe P, Supanchart C. Long-term survival in infantile malignant autosomal recessive osteopetrosis secondary to homozygous p.Arg526Gln mutation in CLCN7. Am J Med Genet A. 2012;158A:909–16. [PubMed: 22419446]
  • 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]
  • 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]
  • Lankester AC, Albert MH, Booth C, Gennery AR, Güngör T, Hönig M, Morris EC, Moshous D, Neven B, Schulz A, Slatter M, Veys P, et al. EBMT/ESID inborn errors working party guidelines for hematopoietic stem cell transplantation for inborn errors of immunity. Bone Marrow Transplant. 2021;56:2052–62. [PMC free article: PMC8410590] [PubMed: 34226669]
  • 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]
  • 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]
  • Nicoli ER, Weston MR, Hackbarth M, Becerril A, Larson A, Zein WM, Baker PR 2nd, Burke JD, Dorward H, Davids M, Huang Y, Adams DR, Zerfas PM, Chen D, Markello TC, Toro C, Wood T, Elliott G, Vu M. Undiagnosed Diseases Network, Zheng W, Garrett LJ, Tifft CJ, Gahl WA, Day-Salvatore DL, Mindell JA, Malicdan MCV. Lysosomal storage and albinism due to effects of a de novo CLCN7 variant on lysosomal acidification. Am J Hum Genet. 2019;104:1127–38. [PMC free article: PMC6562152] [PubMed: 31155284]
  • 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]
  • 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]
  • 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]
  • Rössler U, Hennig AF, Stelzer N, Bose S, Kopp J, Søe K, Cyganek L, Zifarelli G, Ali S, von der Hagen M, Strässler ET, Hahn G, Pusch M, Stauber T, Izsvák Z, Gossen M, Stachelscheid H, Kornak U. Efficient generation of osteoclasts from human induced pluripotent stem cells and functional investigations of lethal CLCN7-related osteopetrosis. J Bone Miner Res. 2021;36:1621–35. [PubMed: 33905594]
  • 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]
  • 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]
  • 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]
  • 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]
  • Rahbari R, Wuster A, Lindsay SJ, Hardwick RJ, Alexandrov LB, Turki SA, Dominiczak A, Morris A, Porteous D, Smith B, Stratton MR, Hurles ME, et al. Timing, rates and spectra of human germline mutation. Nat Genet. 2016;48:126–33. [PMC free article: PMC4731925] [PubMed: 26656846]
  • 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]
  • 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]
  • 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]
  • Sobacchi C, Schulz A, Coxon FP, Helfrich MH. Osteopetrosis: genetics, treatment and new insights into osteoclast function. Nat Rev Endocrinol. 2013;9:522–36. [PubMed: 23877423]
  • Stenson PD, Mort M, Ball EV, Chapman M, Evans K, Azevedo L, Hayden M, Heywood S, Millar DS, Phillips AD, Cooper DN. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting. Hum Genet. 2020;139:1197–207. [PMC free article: PMC7497289] [PubMed: 32596782]
  • Steward CG. Neurological aspects of osteopetrosis. Neuropathol Appl Neurobiol. 2003;29:87–97. [PubMed: 12662317]
  • 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]
  • 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]
  • 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]
  • Waguespack SG, Hui SL, Dimeglio LA, Econs MJ. Autosomal dominant osteopetrosis: clinical severity and natural history of 94 subjects with a chloride channel 7 gene mutation. J Clin Endocrinol Metab. 2007;92:771–8. [PubMed: 17164308]
  • Wang H, Pan M, Ni J, Zhang Y, Zhang Y, Gao S, Liu J, Wang Z, Zhang R, He H, Wu B, Duan X. ClC-7 deficiency impairs tooth development and eruption. Sci Rep. 2016;6:19971. [PMC free article: PMC4734291] [PubMed: 26829236]
  • Wilson CJ, Vellodi A. Autosomal recessive osteopetrosis: diagnosis, management, and outcome. Arch Dis Child. 2000;83:449–52. [PMC free article: PMC1718540] [PubMed: 11040159]
  • Zhang Y, Ji D, Li L, Yang S, Zhang H. Duan. ClC-7 regulates the pattern and early development of craniofacial bone and tooth. Theranostics. 2019;9:1387–400. [PMC free article: PMC6401512] [PubMed: 30867839]
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