CLCN7-Related Osteopetrosis

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.

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

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

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.

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].

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.

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.

ARO

Table 3.

Other Types of Autosomal Recessive Osteopetrosis

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

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)

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

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)

Table 8.

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

Prevention of Primary Manifestations

Surveillance

Table 9.

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

Table 10.

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

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.

Mode of Inheritance

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

• Infantile malignant CLCN7-related autosomal recessive osteopetrosis (ARO) is inherited in an autosomal recessive manner.
• About 40% of CLCN7-related intermediate autosomal osteopetrosis (IAO) is inherited in an autosomal recessive manner and about 60% in an autosomal dominant manner.
• CLCN7-related autosomal dominant osteopetrosis type II (ADOII) is inherited in an 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:
  • One of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017].
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• 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.

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:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• 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.

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

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

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