Clinical characteristics.

Cohen syndrome is characterized by early-onset hypotonia, developmental delay, and moderate-to-profound intellectual disability; at least 20% of individuals are unable to communicate verbally. In infancy and childhood weight gain is poor due to feeding difficulties. However, in the early teen years rapid weight gain (without a change in appetite, food intake, or activity) leads to significant truncal obesity; short stature is common. Ophthalmologic findings include early childhood onset of progressive high myopia and retinal dystrophy. Mild-to-moderate neutropenia, present in almost all individuals, may be associated with recurrent infections and/or aphthous ulcers. Joint laxity can lead to kyphosis and scoliosis. Individuals with Cohen syndrome are described as having a cheerful and friendly disposition.

Diagnosis/testing.

The diagnosis of Cohen syndrome is established in a proband with suggestive findings and biallelic pathogenic variants in VPS13B identified by molecular genetic testing.

Management.

Treatment of manifestations: Early educational intervention and physical, occupational, and speech therapy to help address developmental delay and hypotonia; spectacle correction for refractive errors and low vision services for the visually impaired; treatment of recurrent infections per standard care (with caution regarding medications that could decrease neutrophil count); treatment of scoliosis and kyphosis by an experienced orthopedist.

Surveillance: Routing monitoring of growth and weight gain, developmental progress and educational needs, neurologic findings for emergence of new issues, ophthalmologic findings, possible emergence of scoliosis or kyphosis, and neutropenia and infection risk.

Genetic counseling.

Cohen syndrome is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a VPS13B pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the VPS13B pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.

Suggestive Findings

Cohen syndrome should be suspected in probands with the following clinical findings and family history.

Clinical findings

• Non-progressive global developmental delay / intellectual disability
• Hypotonia
• Retinal dystrophy appearing by mid-childhood
• Progressive high myopia
• Acquired microcephaly
• Neutropenia

Imaging findings. Brain MRI is typically normal.

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of Cohen syndrome is established in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in VPS13B identified by molecular genetic testing (see Table 1).

Note: (1) Per American College of Medical Genetics and Genomics (ACMG) / Association for Molecular Pathology variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of biallelic VPS13B variants of uncertain significance (or of one known VPS13B pathogenic variant and one VPS13B variant of uncertain significance) does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype. Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Clinical Description

To date, more than 300 individuals have been identified with biallelic pathogenic variants in VPS13B [Falk et al 2004, Kolehmainen et al 2004, Mochida et al 2004, Taban et al 2007, Peeters et al 2008, Balikova et al 2009, Momtazmanesh et al 2020]. The following description of the phenotypic features associated with Cohen syndrome is based on these reports.

Phenotypic features of Cohen syndrome are variable and include developmental delay, hypotonia, progressive retinal dystrophy and myopia, acquired microcephaly, joint laxity, characteristic facial features, truncal obesity, cheerful disposition, and neutropenia. The spectrum of these clinical findings ranges from severe to milder.

Note: Certain statistics presented here are from the National Cohen Syndrome Database (NCSD) in which approximately 50% of individuals are Old Order Amish; the diagnosis of Cohen syndrome has been confirmed by molecular genetic testing in most individuals [H Wang, personal observation].

Hypotonia. Half of mothers whose children are included in the NCSD recalled reduced fetal movement during an otherwise normal pregnancy. Most newborns with Cohen syndrome are hypotonic; feeding and breathing difficulties, likely related to hypotonia, are common during the first days of life.

Hypotonia, present in all infants by age one year [Kivitie-Kallio & Norio 2001], appears to improve over time regardless of intervention. Joint laxity and additional musculoskeletal features including kyphosis, scoliosis, and pes planovalgus are likely related to hypotonia. However, a clumsy gait seems to be more disease specific and common [Kivitie-Kallio et al 2000, Chandler et al 2003a].

Developmental delay. All children have delayed developmental milestones in the first year of life. Individuals in the NCSD showed fairly consistent findings on certain developmental milestones compared with other cohorts with Cohen syndrome (see Table 3) [Kivitie-Kallio & Norio 2001, Chandler et al 2003a, Nye et al 2005]. Overall, children with Cohen syndrome attain developmental milestones at a slower rate than average; however, once achieved, psychomotor skills do not regress. At least 20% of individuals are unable to communicate verbally. The degree of developmental delay varies considerably, even among sibs [Horn et al 2000].

Intellectual disability. While cognitive ability varies, most affected individuals are in the moderate-to-profound range of intellectual disability [Kivitie-Kallio et al 1999b, Chandler et al 2003b, Karpf et al 2004]. While the ability to function independently is generally poor, socialization skills are relatively less impaired. Individuals with Cohen syndrome are typically described as having a "cheerful and friendly disposition."

Ophthalmologic

• Progressive high myopia. Individuals with Cohen syndrome had a first ophthalmologic visit at an average age of 4.5 years, when they received their first pair of glasses.
  The progressive myopia and late-onset lens subluxation that occur in some individuals result from progressive laxity of zonules and progressive rounding up of the lens (spherophakia). Older individuals can have tremulousness of the iris (iridodonesis) because of lens subluxation and/or microspherophakia.
• Retinal dystrophy. Defective dark adaptation / night blindness (nyctalopia) indicating rod involvement was typically noticed after age seven years. However, studies of children younger than age five years had both abnormal retinal findings and changes on the electroretinogram (ERG) [Chandler et al 2002] as well as marked progression of retinal dystrophy over time, with many individuals developing a bull's-eye maculopathy indicating cone involvement and optic nerve atrophy likely secondary to the retinal degeneration.
  More than 70% of individuals in the NCSD fall often or trip easily, most likely because of constriction of peripheral visual fields secondary to retinal dystrophy.
  Of ten individuals from nine families of Italian ancestry, nine had retinal dystrophy and eight had high myopia [Katzaki et al 2007]. Although 20% of individuals in a Greek cohort developed significant visual impairment [Douzgou et al 2011, Douzgou & Petersen 2011], progression to complete blindness has not been reported in other ethnic groups to the authors' knowledge.
• Other ophthalmologic findings include astigmatism, strabismus, microcornea, microphthalmia, sluggish pupillary reaction, iris atrophy and oval pupil, cataracts, coloboma of the retina or lids, congenital ptosis, and exophthalmos [Taban et al 2007].
  Several individuals have developed cystoid macular edema that responds well to treatment with topical dorzolamide drops [Sevik et al 2021; E Traboulsi, personal observation]. Some individuals have developed glaucoma [Li et al 2018] and retinal detachments [E Traboulsi, personal observation].
  Corneal changes and early-onset cataracts are frequently observed in individuals of Greek ancestry but not in other ethnic groups [Douzgou et al 2011, Douzgou & Petersen 2011].

Short stature. About 65% of individuals in the NCSD have short stature. Adult height in six individuals from three families was at or below the 3rd centile [Peeters et al 2008]. In ten individuals ages five to 52 years from nine families, seven had short stature and eight had truncal obesity; BMI ranged from 21.8 to 32.2 [Katzaki et al 2007]. Extensive evaluations of pituitary, adrenal, and thyroid function in individuals of Finnish descent showed no significant abnormalities [Kivitie-Kallio et al 1999a].

The prevalence of growth hormone deficiency in Cohen syndrome is unknown. Three individuals who had growth hormone deficiency displayed catch-up growth following initiation of growth hormone replacement therapy [H Wang, personal observation].

Truncal obesity. More than 80% of individuals in the NCSD were reported to be underweight during early childhood but overweight afterward. Although poor weight gain is common in infancy and early childhood due to the feeding difficulties and frequent infections, children subsequently become significantly overweight in their teenage years. The obesity tends to be truncal.

The average age of onset of obesity is 11.3 years (14.6 years in individuals of Amish descent and 8.4 years in individuals of non-Amish ancestry). This change usually occurs rapidly over a period of four to six months, with a weight gain of 10-15 kg even though appetite and food intake are not increased and activity is not decreased during this time [H Wang, personal observation].

Neurobehavioral/psychiatric manifestations. Psychological evaluations identified maladaptive and autistic-type behavior in some individuals [Kivitie-Kallio et al 1999b, Chandler et al 2003b, Karpf et al 2004]. Detailed psychometric and behavioral analyses did not identify any severe behavioral problems in six affected adults but confirmed a wide range of dysfunction related to the degree of intellectual disability and visual impairment [Peeters et al 2008]. Aggression and self-injury have been observed occasionally [H Wang, personal observation].

Neutropenia. Neutropenia, observed in all age groups, is usually moderate to mild (i.e., 500-1,200 per microliter) [H Wang, personal observation]. It may be the first presenting manifestation in some younger individuals before other clinical features fully develop [Marti et al 2025]. Low-normal neutrophil counts are common in individuals who do not have frank neutropenia. Because the neutropenia may not necessarily result in an overall low white blood cell count, it may be overlooked for years in some individuals.

While neutropenia is not cyclic and usually not life-threatening [Kivitie-Kallio et al 1997; H Wang, personal observation], some individuals have recurrent infections and aphthous ulcers [Falk et al 2004].

More than 80% of children in the NCSD have had more than five episodes of otitis media per year and most of them had tympanostomy tubes placed during early childhood. Most children also had an average of 2.5 lifetime episodes of pneumonia.

More than 65% of individuals experience repeated oral mucosal ulcers and gingival infections for which prophylactic granulocyte colony-stimulating factor (G-CSF) therapy has commonly been used.

Results of bone marrow examinations reported by Kivitie-Kallio & Norio [2001] showed a normocellular or hypercellular marrow, with a left-shifted granulopoiesis in about half of affected individuals [Kivitie-Kallio & Norio 2001].

While neutropenia may contribute to the compromised immune function in some individuals, it is unknown if it is the sole cause. The frequency and severity of infections does not appear to correlate with absolute neutrophil count (ANC), as individuals with and without frequent infections have an ANC in the same range as those without increased infections (500-1,200 per microliter).

Hematologic malignancies have not been reported.

Other immune disturbances. De Ravel et al [2002] reported rheumatoid arthritis in one individual. Uveitis and recurrent pericarditis have been seen in a few affected individuals [H Wang, personal observation].

Neurologic. Seizures have been reported in some individuals [Coppola et al 2003, Atabek et al 2004]. Anecdotally, two individuals in the NCSD cohort with epilepsy requiring anti-seizure medications seem to have more severe disease as characterized by more severe intellectual disability and an inability to communicate verbally. Most individuals, however, particularly those older than age five years in the Finnish cohort, were reported to have low-voltage EEGs without irritative spikes or epileptiform foci [Kivitie-Kallio et al 1999b].

Microcephaly usually develops during or after age one year.

Brain MRI of 18 individuals found normal gray and white matter signal intensity but a relatively enlarged corpus callosum compared to 26 controls [Kivitie-Kallio et al 1998]; however, this finding appeared to be subtle and nonspecific.

Distinctive facial features. Typical Cohen syndrome facial features (including thick scalp hair, low posterior hairline, thick eyebrows, long and thick eyelashes, high-arched and wave-shaped palpebral fissures, broad nasal tip, smooth or short philtrum, prominent upper central incisors, and hypotonic appearance) have been described in different ethnicities. Together the short philtrum and prominent upper central incisors result in an open-mouth appearance (see Figure 1).

Figure 1.

Distinctive facial features in two individuals with Cohen syndrome with thick scalp hair, thick eyebrows, wave-shaped eyes, and broad nasal tip. Note that the short philtrum and prominent upper central incisors result in an open-mouth appearance. A. 30-year-old (more...)

Although Horn et al [2000] and Falk et al [2004] also found that while the facial gestalt is quite consistent among affected individuals within a particular ethnic group, it appears to be inconsistent across different ethnicities; e.g., lack of the frontonasal angle together with a short philtrum made the nose appear "overly long" in a cohort from Greece [Bugiani et al 2008]. Nonetheless, taking into consideration that reported individuals have been evaluated by different clinicians, these distinctive facial features present in individuals from different ethnic backgrounds is noteworthy.

Craniofacial and nasopharyngeal abnormalities that can cause management difficulties with anesthesia include micrognathia and high and narrow palate.

Cardiovascular. Although the cardiovascular system is not commonly affected, cardiac evaluation in 22 individuals of Finnish descent identified decreased left ventricular function with advancing age [Kivitie-Kallio et al 1999a].

Other

• Most infants (95% of those of Amish ancestry and 65% of non-Amish ancestry) have an unusually high-pitched and weak cry. Overall, 80% of parents with children in the NCSD recall this cry resembling that of a kitten mewing. However, this unique cry is frequently overlooked by clinicians and has not been reported in the medical literature. Although the cause is unknown, laryngeal abnormalities postulated to cause the "mewing cry" seen in cri-du-chat syndrome have also been observed in some individuals with Cohen syndrome [Chandler et al 2003a].
• Constipation is common in all age groups and often needs management with use of stool softeners and laxatives [H Wang, personal observation].

Genotype-Phenotype Correlations

No clinically relevant genotype-phenotype correlations have been identified.

Nomenclature

Cohen et al [1973] described a pattern of abnormalities – intellectual deficiency, hypotonia, obesity, high nasal bridge, and prominent central incisors – observed in a pair of sibs and one unrelated individual. Norio et al [1984] observed six individuals of Finnish descent with the same disorder, known by them as "Pepper syndrome," from the family name.

Cohen-like syndrome or "Jewish-type Cohen" was first reported in a cohort of individuals from Israel [Sack & Friedman 1986]. The concept has since been challenged [Chandler & Clayton-Smith 2002]. The originally reported 39 individuals of Jewish descent in 32 families were macrocephalic and tall with generalized obesity, as opposed to being microcephalic and short with truncal obesity as seen in classic Cohen syndrome. Furthermore, the individuals reported with "Jewish-type Cohen" or Cohen-like syndrome did not have neutropenia or chorioretinal dystrophy – manifestations that are found in all affected individuals of Finnish ancestry [Norio et al 1984]. In fact, no VPS13B pathogenic variants have been found in individuals with "Jewish-type Cohen" or Cohen-like syndrome [Kolehmainen et al 2004]; the authors therefore conclude that these individuals have a clinical and genetic etiology that is distinct from Cohen syndrome. It is notable that this historical mislabeling has caused significant confusion in the characterization of the Cohen syndrome phenotype.

Cohen syndrome may also be referred to as VPS13B-related neurodevelopmental disorder. This term is based on the naming approach proposed by Biesecker et al [2021], in which mendelian disorders are designated by combining the mutated gene and resulting phenotype.

Prevalence

About 300 individuals have been reported with Cohen syndrome since the first described by Cohen et al [1973]. The disorder has been confirmed on almost all continents and in a wide variety of ethnic groups [Falk et al 2004, Hennies et al 2004, Kolehmainen et al 2004, Mochida et al 2004, Kondo et al 2005, Katzaki et al 2007, Taban et al 2007, Bugiani et al 2008, Peeters et al 2008, Balikova et al 2009, Hashmi et al 2020, Kaushik et al 2020, Momtazmanesh et al 2020, Hu et al 2021, Karimzadeh et al 2021, Hussain et al 2023].

Founder variants

• Finnish population. The 2-bp deletion c.3348_3349delCT accounts for 75% of pathogenic alleles in Finland [Kolehmainen et al 2003]. The phenotype in individuals with this founder variant is comparable to that seen in individuals of non-Finnish descent [Chandler et al 2003a].
• Old Order Amish population. The two Old Order Amish founder pathogenic variants, c.8459T>C in exon 46 and c.9260dupT in exon 51, occur on the same allele and segregate together. Since the first report of Cohen syndrome in the Ohio Geauga Old Order Amish settlement by Falk et al [2004], more than 50 affected individuals have been identified in this highly consanguineous, isolated population of approximately 25,000 people, indicating a prevalence as high as one in 500. These two founder variants are also found with high prevalence in Amish settlements in Kentucky, New York, Pennsylvania, and Wisconsin. Collectively, more than 100 individuals have been identified with the same founder variants, indicating a broader impact.

Evaluations Following Initial Diagnosis

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

Treatment of Manifestations

There is no cure for Cohen syndrome. Supportive care is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 6).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 7 are recommended.

Evaluation of Relatives at Risk

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

Therapies Under Investigation

Search ClinicalTrials.gov 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

Cohen syndrome is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are presumed to be heterozygous for a VPS13B pathogenic variant.
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a VPS13B 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, it is possible that 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]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• If both parents are known to be heterozygous for a VPS13B pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. The offspring of an individual with Cohen syndrome are obligate heterozygotes (carriers) for a pathogenic variant in VPS13B.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a VPS13B pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the VPS13B pathogenic variants in the family.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk 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 carriers or are at risk of being carriers.
• Carrier testing should be considered for the reproductive partners of known carriers, particularly if both partners are of the same ancestry. Founder variants have been identified in Finnish and Amish populations (see Table 8).

Prenatal Testing and Preimplantation Genetic Testing

Once the VPS13B pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

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

Molecular Pathogenesis

VPS13B encodes intermembrane lipid transfer protein VPS13B, a large transmembrane protein that localizes mainly to the Golgi complex, where it is involved in maintenance of the Golgi structure, vesicle-mediated protein sorting, and intracellular trafficking. It also plays a role in endosomal-lysosomal transport. Loss-of-function pathogenic variants in VPS13B impair Golgi integrity and disrupt glycosylation of proteins, leading to abnormal processing and trafficking of cellular proteins and lipids between Golgi, endosomes, lysosomes, and plasma membranes. This affects multiple cell types, particularly neurons, immune cells, and retinal cells, which are highly dependent on proper protein processing. As such, deficiency of VPS13B results in the multisystem manifestations of Cohen syndrome, particularly affecting the brain, retina, immune system, and metabolism. For a more in-depth discussion of the molecular mechanisms of VPS13B functioning, see Seifert et al [2015] and Ugur et al [2024].

Mechanism of disease causation. Loss of function

Missing variants. If molecular genetic testing has identified only one VPS13B pathogenic variant in the proband, additional possibilities to consider include the following:

• The proband does not have Cohen syndrome.
• Gene-targeted deletion/duplication analysis can be considered to detect exon and whole-gene deletions or duplications.
• The proband has a missing variant on the other allele that has not yet been detected or is undetectable by current methods (see Establishing the Diagnosis regarding intronic variants [Boschann et al 2020]).

Author Notes

Dr Heng Wang is a board-certified pediatrician and Medical Director of DDC Clinic, Center for Special Needs Children in Middlefield, Ohio. The Center is a unique collaboration between Amish communities, medical professionals, and research scientists, and it has become widely recognized as a leading facility for the diagnosis and treatment of several rare genetic disorders, including Cohen syndrome.

Dr Wang and his team at DDC Clinic currently manage more than 150 patients with Cohen syndrome worldwide. Since the early 2000s, he has worked with this large cohort, conducting both clinical and laboratory research, particularly on natural history and treatment protocols.

In addition to his clinical responsibilities, Dr Wang directs the DDC Clinic's CLIA-certified molecular diagnostics laboratory. Under his leadership, the laboratory has employed cutting-edge technology to make Cohen syndrome diagnosis more affordable, particularly benefiting the Amish community. Dr Wang is widely published and is a frequent speaker on Cohen syndrome at medical conferences and family gatherings across the globe.

In 2004, Dr Wang's team at DDC Clinic hosted the first annual Cohen Syndrome Family Gathering. By 2008, the Cohen Syndrome Association was formally established with the goal of raising awareness and educating both parents and medical professionals about this rare condition. Dr Wang has served on the Association's Medical Advisory Board since its inception.

Website for Dr Wang

Dr Baozhong Xin is a Research Scientist and Technical Director of the CLIA-certified molecular diagnostics laboratory at DDC Clinic. With more than 20 years of experience diagnosing rare and ultra-rare genetic conditions, including Cohen syndrome, he brings extensive expertise to the clinic's research and diagnostic programs. His work has contributed to improving the accuracy, efficiency, and accessibility of molecular genetic testing for diverse patient populations.

Dr Xin welcomes inquiries about molecular genetic testing for Cohen syndrome.

Website for Dr Xin

Dr Elias I Traboulsi is a clinical geneticist whose practice is restricted to diagnosis and management of patients with inherited eye diseases and those with inherited systemic diseases with ocular manifestations such as Cohen syndrome. His research interests relate to the clinical manifestations, natural history, and support and treatment of such patients.

Dr Traboulsi is actively involved in clinical research regarding individuals with Cohen syndrome. He would be happy to communicate with persons who have any questions regarding diagnosis of Cohen syndrome or other considerations.

Website for Dr Traboulsi

Acknowledgments

We are very grateful for the patients and families affected by Cohen syndrome for whom we have had the privilege to provide professional services. Much knowledge of clinical findings and insight into management has been gleaned from them over years. Without their continued support, this chapter would not be possible. We are also thankful to the colleagues who worked with us in our clinical services and research throughout the years, as well as the knowledge gained from other experts on Cohen syndrome.

Author History

Marni J Falk, MD; The Children's Hospital of Philadelphia (2006-2025)
Elias I Traboulsi, MD, MEd (2006-present)
Heng Wang, MD, PhD (2006-present)
Christine Wensel, MS (2016-present)
Baozhong Xin, PhD (2025-present)

Revision History

• 4 December 2025 (bp) Comprehensive update posted live
• 21 July 2016 (sw) Comprehensive update posted live
• 10 March 2011 (me) Comprehensive update posted live
• 29 August 2006 (me) Review posted live
• 18 April 2006 (mjf) Original submission

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