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Cockayne syndrome

This is part of Rare diseases.

Diagnosis: Cockayne syndrome

Synonyms: --

Innehåll


Publication date: 2012-06-14
Version: 4.0

The disease

Cockayne syndrome (CS) is named after the English paediatrician Edward Alfred Cockayne, who described the disorder in 1936. It is a progressive condition that affects the function of many organs in the body. Characteristic features include photosensitivity (abnormal sensitivity to sunlight), short stature, and an appearance of premature ageing.

The syndrome was previously divided into three different variants. A new classification has been suggested (2010), in which the syndrome is divided into four subtypes: three juvenile and one adult form. The juvenile variants include one severe, early onset form (previously known as CS 2; also known as COFS or Pena-Shokeir syndrome), one intermediate (previously known as CS 1, classical form), and one mild form (formerly known as CS 3, atypical form). The fourth, adult form is a mild variant of the syndrome.

Occurrence

The total number of individuals with Cockayne syndrome is not known, but a few cases have been diagnosed in Sweden. An estimated number of 1-3 children per million, up to the age of 16, has been given in the international medical literature.

Cause

For the body to grow, its cells have to divide. Cells also have to be renewed continuously. Every time a cell divides, the entire genetic set-up, consisting of 23 pairs of chromosomes, must be exactly replicated. This means that for the two new cells to have one full genome each, approximately 25,000 genes are copied. To prevent faulty copies from being transferred to the new cells, the procedure involves a number of checkpoints which ensure that only normal copies are created and prevent the creation of cells with defective (mutated) genes. This monitoring is carried out by specific proteins. Other proteins are responsible for repairing defective genes.

Cockayne syndrome is caused by a mutation in the gene ERCC8 or the gene ERCC6. ERCC8 mutations are most common, representing 80 per cent of all cases. ERCC8 is located on chromosome 5 (5q12), and ERCC6 is located on chromosome 10 (10q11). These genes code for (regulate the production of) proteins that are important for DNA repair in the cell nucleus. In healthy individuals, defective genes are repaired and the division of damaged cells is blocked. In individuals with Cockayne syndrome, the repair function does not operate normally. One consequence is that damaged cells cause organs to malfunction. It has hitherto not been possible to predict the severity of Cockayne syndrome based on the underlying mutation.

Cockayne syndrome is similar to other conditions that are also caused by mutations in genes that regulate DNA repair in the cell nucleus, for example xeroderma pigmentosum (XP), cerebro-oculo-facio-skeletal syndrome (COFS), and trichotiodystrophy (TTD). These conditions may be difficult to differentiate, both clinically and genetically, but XP is associated with an increased risk of cancer, and people with TTD have brittle hair and nails, symptoms which are not typical of Cockayne syndrome.

Heredity

The inheritance pattern of Cockayne syndrome is autosomal recessive. This means that both parents are healthy carriers of a mutated gene. When two healthy carriers have a child, there is a 25 per cent risk that the child will inherit the mutated genes (one from each parent) in which case he or she will have the disease. In 50 per cent of cases the child inherits only one mutated gene (from one parent only) and, like both parents, will be a healthy carrier of the mutated gene. In 25 per cent of cases the child will not have the disease and will not be a carrier of the mutated gene.

Autosomal recessive inheritance of genetic traits

A person with an inherited autosomal recessive disease has two mutated genes. If this person has a child with a person who is not a carrier of the mutated gene, all the children will inherit the mutated gene but they will not have the disorder. If a person with an inherited autosomal recessive disease has children with a healthy carrier of the mutated gene (who has one single copy of the mutated gene) there is a 50 per cent risk of the child having the disorder, and a 50 per cent risk of the child being a healthy carrier of the mutated gene.

Symptoms

Cockayne syndrome usually progresses slowly, with the symptoms increasing over a period of 10 to 20 years, sometimes longer. The most common symptoms are photosensitivity, small head circumference (microcephaly), short stature, low weight, developmental delay, premature ageing, hearing loss, visual impairment, and increasing mobility problems. The syndrome is divided into four types based on age of onset and symptoms, but there are no strict demarcations between the different forms. The juvenile forms are associated with a shortened life expectancy.

Severe, early-onset Cockayne syndrome (previously referred to as CS2)

This is the most severe form of the syndrome, and the life expectancy of these children is on average five years. Growth failure is evident from the neonatal period. Congenital cataracts may be present. The head is abnormally small at birth and growth gradually tapers off. The syndrome is also associated with progressive joint problems, such as contractures (malpositionings) and abnormal curvature of the spine (scoliosis). Some children do not learn to sit or speak. Feeding difficulties are common and it may be difficult to provide the child with sufficient nourishment, increasing the risk of weight loss. It is sometimes difficult to differentiate the severe form of Cockayne syndrome from COFS syndrome.

Intermediate form (previously known as CS 1, classical form)

In the intermediate, classical form the child develops relatively normally during the first year of life. Most of these children learn to walk, but between the ages of one and two growth failure becomes evident, as well as delayed motor and intellectual development. Neurological symptoms appear successively, with a jerky, unsteady pattern of movement (ataxia) and trembling (tremors). Spastic muscle tension in the legs and feet are common. Similar changes in the muscles active in flexing and stretching the knees often lead to a posture with semi-flexed knees.

As in the severe form, these children may have feeding difficulties and there may be problems providing sufficient nutrition, increasing the risk of weight loss.

Many young people with the syndrome gradually develop renal failure and high blood pressure. Some individuals also have epilepsy.

Children with Cockayne syndrome have intellectual disabilities that range from mild to severe. Individuals with intellectual disability require more time to understand and learn new skills. They have difficulties processing information and dealing with new situations. It may also be hard to generalize information or to see interconnections between details and broader patterns. Under these circumstances it may take a little longer to express one’s wishes, thoughts, and feelings. If the intellectual disability is moderate to severe, language development will also be impaired. It is therefore important that people interacting with the child are familiar with their non-verbal means of communication such as gestures and mimics.

The eyes are often affected. Changes in the optic nerves and retinas (retinopathy) are common. Cataracts (opacity of the lens) may occur and can, if left untreated, eventually lead to blindness. Fundoscopic examination can reveal “pepper and salt” changes of the retina (retinitis pigmentosa). Hearing loss as a result of damage to the inner ear (sensorineural hearing impairment) is another common feature.

Children with the syndrome have short stature. They are thin, and their arms and legs are disproportionately long. They also have a characteristic appearance of premature ageing. The skin is frail, slightly wrinkled and sensitive to light, and the hair tends to be thin and dry. Over time, sun exposure causes characteristic skin changes, but there is no evidence of increased predisposition to skin cancer. The head is small and the eyes deeply set as a result of the brain failing to grow normally. One or two teeth may fail to appear or erupt later than normal. Dental problems, with a large numbers of cavities, are common.

Individuals with this form of Cockayne syndrome live into their teens or young adulthood. The prognosis is highly contingent on the severity of the disease and the general state of health of the particular person.

Mild form (previously known as CS 3, atypical form)

Children and adults with the mild form have the characteristic symptoms of the syndrome: short stature, intellectual disability, hearing loss, impaired vision, and light sensitivity. They are milder, however, and manifest later, sometimes making the diagnosis difficult. The average life expectancy of individuals with the mild form of the syndrome is early middle age.

Adult form

A few adults have photosensitivity as their main symptom, associated with a specific ERCC6 mutation.

Diagnosis

Cockayne syndrome is diagnosed on the basis of a combination of growth failure, a characteristic appearance, photosensitivity, increasing neurological symptoms (unsteady gait, shakiness), and the typical progression of the disease.

In Cockayne syndrome the brain becomes increasingly calcified - both the central, grey matter of the large brain or cerebrum (the basal ganglia) and the small brain or cerebellum. An expansion of the cerebral cavities (the ventricles) also occurs as a result of the gradual atrophy of the brain. It is possible to detect the calcification in a computed tomography scan (CT scan), and magnetic resonance imaging (MRI) usually demonstrates atrophic changes of the white matter of the brain.

The peripheral nerves also undergo changes, and neurophysiological tests may indicate a decrease of the nerve conduction velocities.

Hearing loss can be established in a screening test (audiometry). Congenital cataracts and retinal changes may be present and an eye examination reveals typical changes in the optic nerves and retinal abnormalities.

Specialized laboratories can test skin hypersensitivity by irradiating cultured skin cells with ultraviolet light.

The diagnosis can also be confirmed by a DNA analysis. Carrier diagnosis, pre-natal diagnosis, and embryo diagnosis are possible if the mutation in the family has been identified.

At the same time that the diagnosis is made, the family should be offered genetic counselling.

Treatment/interventions

There is currently no cure for the syndrome, and efforts are directed at relieving symptoms.

In children with the severe, early-onset form or the intermediate form of Cockayne syndrome, eating, sucking, and swallowing problems are common. Gastroesophageal reflux is also common, a condition in which the stomach contents leak into the lower part of the oesophagus. These problems may result in weight loss and failure to thrive. A speech pathologist can provide oral motor exercises and sensory stimulation for these children, and a dietician will assist in calculating an adequate calorie intake and give advice on a well-balanced diet. Tube feeding is sometimes needed. In many children a direct connection between the abdominal wall and the stomach, a PEG (percutaneous endoscopic gastrostomy), is necessary to facilitate feeding.

Regular monitoring of kidney function is effective for detecting any abnormalities, thereby preventing renal failure.

Epilepsy can be treated with medication.

Eye problems will need to be checked and followed up by an ophthalmologist, who will also assess vision and the need for visual aids. Cataracts are treated surgically.

Hearing is checked by an audiologist. The hearing health care services assist in the fitting of hearing aids and provide assistive listening devices.

Sensitivity to sunlight may pose practical problems. Individuals with Cockayne syndrome must avoid prolonged exposure to direct sunlight. During the sunny part of the year it is important to use high-factor protective sunscreen. Clothing can also provide effective protection from the sun, and a hat or cap should be used to protect the head and face. A dermatologist can provide further advice and treatment. X-ray examinations should be avoided as far as possible. If X-ray is necessary, radiation doses should be kept low.

Habilitation, including hearing and vision habilitation, is essential for stimulating development and compensating for functional limitations. Early contact should be established with a habilitation team, which includes professionals with special expertise in how disability affects everyday life, health and development. Support and treatment take place within the medical, educational, psychological, social and technical fields. Help includes assessment, treatment, the provision of aids, information on the specific disability, and counselling. It also includes information on all available support offered in the community, as well as advice on adjustments to the home environment and other places where the child spends time. The family may also need help in coordinating different measures.

These measures focus on existing needs, may vary over time and occur in collaboration with individuals close to the child. Exercises are needed for stimulating the development of motor skills, to compensate for functional limitations associated with ataxia, and for preventing contractures. Communication skills vary in children with Cockayne syndrome. For some children it is important to work with different types of augmentative and alternative communication (AAC). Parents as well as other people close to the child need to learn different AAC forms to support understanding.

The parents may need psychological support, both at the time of diagnosis and later. Children and young people with the syndrome should also be offered psychological support, adapted to the needs of the individual.

There should be close contact with the local authority where different kinds of help including personal assistance, a contact family or short-term accommodation can be arranged to make daily life easier.

Early contact should be established with paediatric dental specialists for assessment. Owing to an increased risk of caries, most children with the syndrome require additional preventative dental care in the form of fluoride treatment and help with oral hygiene.

Adults with Cockayne syndrome need continued habilitation and support in their daily lives. This may take the form of support and care in accommodation offering specialist services and daily activities.

Practical advice

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National and regional resources in Sweden

Paediatric clinics at Sweden’s university hospitals have the expertise to diagnose and follow-up children and young people with Cockayne syndrome.

Resource personnel

Associate Professor Niklas Darin, The Queen Silvia Children’s Hospital, SE-416 85 Gothenburg, Sweden. Tel: +46 31 343 40 00.

Courses, exchanges of experience, recreation

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Organizations for the disabled/patient associations

FUB, The Swedish National Association for Children, Young People and Adults with Intellectual Disabilities, Gävlegatan 18 C, Box 6436, SE-113 82 Stockholm, Sweden. Tel: +46 8 508 866 00, fax: +46 8 508 866 66, email: fub@fub.se, www.fub.se.

Courses, exchanges of experience for personnel

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Research and development (R&D)

There is considerable international interest in clinical issues, genetics, and molecular genetics related to this group of disorders. No research that deals specifically with Cockayne syndrome is currently carried out in Sweden.

Information material

An information leaflet on Cockayne syndrome summarising the information in this database text is available free of charge from the customer service department of the Swedish National Board of Health and Welfare (in Swedish only, article number 2012-2-31.) Address: SE-120 88 Stockholm, Sweden. Tel: +46 75 247 38 80, fax: +46 35 19 75 29, email: publikationsservice@socialstyrelsen.se. Postage will be charged for bulk orders.

Literature

Cockayne EA. Dwarfism with retinal atrophy and deafness. Arch Dis Child 1936; 11: 148.

Greenhaw GA, Hebert A, Duke-Woodside ME, Butler IJ, Hecht JT, Cleaver JE et al. Xeroderma pigmentosum and Cockayne syndrome: overlapping clinical and biochemical phenotypes. Am J Hum Genet 1992; 50: 677-689.

Kamenisch Y, Berneburg M. Progeroid syndromes and UV-induced oxidative DNA damage. J Investig Dermatol Symp Proc 2009; 14: 8-14.

Latini P, Frontini M, Caputo M, Gregan J, Cipak L, Filippi S et al. CSA and CSB proteins interact with p53 and regulate its Mdm2-dependent ubiquitination. Cell Cycle 2011; 10: 3719-3730.

Lehmann AR. DNA repair-deficient diseases, xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy. Biochimie 2003; 85: 1101-1111.

Leibeling D, Laspe P, Emmert S. Nucleotide excision repair and cancer. J Mol Histol 2006; 37: 225-238.

Nance MA, Berry SA. Cockayne syndrome: review of 140 cases. Am J Med Genet 1992; 42: 68-84. Review.

Natale V. A comprehensive description of the severity groups in Cockayne syndrome. Am J Med Genet Part A 2011; 155: 1081-1095.

Rapin I, Lindenbaum Y, Dickson DW, Kraemer KH, Robbins JH. Cockayne syndrome and xeroderma pigmentosum. Neurology 2000; 55: 1442-1449.

Spivak G. The many faces of Cockayne syndrome. Proc Natl Acad Sci USA 2004; 101: 15273-15274.

Suzumura H, Arisaka O. Cerebro-oculo-facio-skeletal syndrome. Adv Exp Med Biol 2010; 685: 210-214.

Database references

OMIM (Online Mendelian Inheritance in Man)
www.ncbi.nlm.nih.gov/omim 
Search: cockayne syndrome

GeneReviews (University of Washington)
www.genetests.org (find GeneReviews, then Titles)
Search: cockayne syndrome

Document information

The Swedish Information Centre for Rare Diseases produced and edited this information material.

The medical expert who wrote the draft of this information material is Associate Professor Mårten Kyllerman, The Queen Silvia Children’s Hospital, Gothenburg, Sweden.

The relevant organisations for the disabled/patient associations have been given the opportunity to comment on the content of the text.

An expert group on rare diseases, affiliated with the University of Gothenburg, approved the material prior to publication.

Publication date: 2012-06-14
Version: 4.0
Publication date of the Swedish version: 2012-03-07

For enquiries contact The Swedish Information Centre for Rare Diseases, The Sahlgrenska Academy at the University of Gothenburg, Box 400, SE-405 30 Gothenburg, Sweden. Tel: +46 31 786 55 90, email: ovanligadiagnoser@gu.se.

 

About the database

This knowledge database provides information on rare diseases and conditions. The information is not intended to be a substitute for professional medical care, nor is it intended to be used as a basis for diagnosis or treatment.