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Coffin-Lowry syndrome

This is part of Rare diseases.

Diagnosis: Coffin-Lowry syndrome

Synonyms: --


Date of publication: 2013-11-01
Version: 1.1

The disease

Coffin-Lowry syndrome is associated with intellectual disability, short stature, skeletal abnormalities, heart problems, impaired hearing and sudden attacks of muscle weakness. In general, men experience more severe symptoms than women.

American paediatrician Grange S Coffin was the first to identify the syndrome in 1966 when he described two unrelated boys with intellectual disabilities, short stature, hypermobile joints and characteristic facial features. In 1971, British geneticist Robert Brian Lowry identified a further five individuals with similar clinical profiles in Canada.

Occurrence

There are no firm figures for how common Coffin-Lowry syndrome is in Sweden, but it is estimated that there is an incidence of two to three individuals per 100,000 inhabitants.

Cause

Approximately 50 per cent of people with the syndrome have a mutation in the RPS6KA3 gene located on the short arm of chromosome X (Xp22.2-p22.1). This gene controls production of (codes for) the RSK2 protein (ribosomal S6 kinase 2). RSK2 is an enzyme which helps control activity in other genes essential for the survival of nerve cells. These signal paths play an important role in learning and memory. The mutation results in an absence, or inadequate levels, of this protein.

Currently, RPS6KA3 is the only gene which has been identified as causing Coffin-Lowry syndrome.

Heredity

The inheritance pattern of Coffin-Lowry syndrome is X-chromosome dominant. This means that the genetic mutation is located on the X chromosome and that a female carrier (with the mutation on one of her two X chromosomes) often has mild symptoms or none at all, while males (with the mutation on their sole X chromosome) have more severe symptoms.

Figur: X-linked dominant inheritance via a female carrier with the disease

In between 70 and 80 per cent of people with the disease, the condition arises sporadically, meaning that it is caused by a new mutation. This means that the genetic mutation occurs for the first time in the individual concerned and is not inherited from either parent. However, the new genetic mutation will be hereditary and an adult with this mutation risks passing on the mutated gene to his/her children.

Parents with a child with a new mutation generally do not have an increased risk of having another child with the disorder. However, it is not possible to entirely rule out the occurrence of germinal mosaicism, whereby some of the gametes (reproductive cells) of one of the parents carry the mutation.

Between 20 and 30 per cent of all children with Coffin-Lowry syndrome have inherited the genetic mutation from their mothers, who may be asymptomatic or have mild physical symptoms and an intellectual impairment.

A woman who carries the mutated gene has a 50 per cent chance of passing it on to her children. Even if the mother’s symptoms are mild, her daughter’s symptoms can be severe. Sons and daughters who have inherited the normal version of their mother’s two RPS6KA3 genes do not have the syndrome and do not pass on the mutation.

It is unlikely that men with the syndrome will become fathers. However, in the event that they do, men with Coffin-Lowry syndrome will pass on the mutated gene to all their daughters. Their sons will not be affected as males inherit a Y chromosome from their fathers.

Symptoms

Every person with Coffin-Lowry syndrome has a unique combination of symptoms, which are commonly more severe in men than women. Symptoms include intellectual disability, short stature, abnormalities of the skeleton and connective tissue, heart problems, characteristic facial features and sudden attacks of muscle weakness. All the above symptoms can present in female carriers.

At birth, children with the syndrome are often of normal weight and size. Newborns may have less than normal muscle tone (hypotonus) and hypermobile joints. Other early signs can be soft hands with short, tapered fingers.

During the first years of life it becomes apparent that the child is not growing or developing normally. The development of motor and language skills is delayed and the child learns to sit, crawl and walk later than average.

The facial features characteristic of the syndrome become more pronounced as the child becomes older. These features include a broad forehead, widely spaced eyes (hypertelorism), downward-slanting eyes, skin folds covering the inner corner of the eye (epicanthal fold), a short, broad nose with a low nasal bridge, protruding nostrils, a broad nasal septum which can make the nostrils appear small, thick lips, a large mouth which is often open, large ears and a small head (microcephalus). The lower jaw is unusually small (micrognathia) when the child is young, but becomes prominent with time (prognathia).

The hands are often large and soft with hypermobile joints and short, broad fingers with narrow nails. A single palmar crease in the hand may also manifest. The lower arms may be large and soft as a result of unusual deposits of subcutaneous fat.

Other symptoms include soft, elastic skin, muscle weakness, hypermobile joints, flat feet, umbilical and inguinal hernia, pouches (diverticula) within the bowel wall, rectal prolapse and delayed closure of the frontal fontanelle.

The syndrome is often associated with moderate to severe intellectual disability. In female carriers, intelligence levels range from normal to severe intellectual disability. All boys with the condition develop speech late and with varying degrees of impairment. Listening skills are usually better developed than speech. The children are described as happy and sociable, although self-destructive behaviour may also occur. Symptoms within the autism spectrum may present, and female carriers often have psychiatric symptoms. Psychosis and obsessive-compulsive disorder may also present in people with the syndrome.

In the brain, reduced brain volume, structural defects and dilated ventricles are common.

SIDE attacks (stimulus induced drop episodes) are experienced by approximately 20 per cent of people with the syndrome. These can be described as a sudden loss of muscle strength (atonic seizures and cataplexy) or an attack of muscle stiffness (hyperekplexia). Episodes are triggered by an unexpected sound or sudden physical contact, usually present for the first time at school age, and affect both girls and boys. They are of very short duration and do not involve a loss of consciousness, but they are associated with a risk of fall-related injuries.

Approximately five per cent of people with the syndrome have epilepsy. A combination of epileptic seizures and SIDE attacks is common, the specific combination often varying with time. Individuals with the syndrome may also have sleep apnea.

Approximately 30 per cent of people with the condition have impaired hearing, which is caused by the inability of the nervous system to pass sound impulses from the inner ear to the brain (sensorineural hearing loss). Problems with vision are uncommon but may manifest in the form of cataracts or atrophy of the retina and optic nerve. Inflammation of the eyelids (blepharitis) may also occur.

Approximately 50 per cent of boys and 33 per cent of girls with the syndrome have severely deformed spines (kyphosis and scoliosis). The rib cage may also have skeletal abnormalities including pectus carinatum (pigeon chest), pectus excavatum (funnel chest) and a divided sternum. Skeletal deterioration may be rapid, especially during periods of growth, and is often more noticeable in the teens. Often a gradual deterioration continues in adulthood as skeletal deformities do not stabilise when the child stops growing. A consequence for the individual may be limited mobility, which in turn can affect the heart and lungs, causing early death.

Congenital narrowing of the spinal canal (spinal stenosis), combined with an increasing calcification of the ligaments, can affect the spinal cord and cause neurological symptoms including increasing spasticity and paralysis. These may in turn cause contractures and severe gait-related problems. Posture may be affected, with a pronounced forward stoop developing over time.

Heart defects occur in approximately 15 per cent of boys with the syndrome, less frequently in girls, and may affect life expectancy. Some heart defects, including mitral valve insufficiency or prolapse, affect the heart valves. Other conditions are associated with cardiac musculature (cardiomyopathy), and dilation of the aorta and pulmonary artery (aneurysm). Lung diseases, including emphysema and pneumonia, are common.

Dental anomalies are common. Both deciduous (milk) teeth and permanent teeth can erupt, and fall out, later than normal. In the case of milk teeth, normal root resorption may not occur before teeth are shed. In some children, tooth buds may be entirely absent. Bite abnormalities (malocclusions), in particular open bite and underbite, are often found in children with the syndrome and the palate may be unusually high. The tongue may have a central groove.

When children with the syndrome are born they are often of normal size and weight, but later become disproportionately short of stature with unusually short legs. Many individuals also have a small head.

Adults with Coffin-Lowry syndrome often have problems with stiffness and pain, as well as neurological problems caused by skeletal abnormalities. Some people with the syndrome may have a shortened life expectancy. This applies in particular to those individuals with heart or lung defects, epilepsy, spinal stenosis and/or severe kyphoscoliosis.

Diagnosis

Diagnosis is made on the basis of clinical signs and symptoms. Skeletal X-rays help in identifying characteristics of the condition, including delayed skeletal maturity, thickened skull, large sinuses, narrow pelvis, calcifications in the ligaments of the spine (ligamenta flava), kyphoscoliosis and other abnormalities of the vertebrae and the bones of the hand.

A diagnosis based on a DNA analysis of the RPS6KA3 gene is possible, although a normal result does not eliminate the diagnosis as currently (2013) only approximately 40 per cent of people with the condition have a mutation. At the time of diagnosis it is important that the family should be offered genetic counselling. Carrier and prenatal diagnostics, as well as pre-implantation genetic diagnostics (PGD) in association with IVF (in vitro fertilization), are available to families where the mutation is known.

Treatment/interventions

There is no cure for Coffin-Lowry syndrome, and efforts are directed at alleviating symptoms and compensating for disabilities.

It is important to identify heart defects and skeletal abnormalities at an early stage in order to prevent the development of serious complications. As severe spinal deformities are common, check-ups of the spine should be carried out at regular intervals throughout life. X-ray examinations may need to be repeated in order to make exact measurements of abnormalities and assess whether they are becoming more pronounced. Sometimes a surgical corset may be useful. If spinal abnormalities become too pronounced, an operation may be necessary.

Ultrasonography is one method of diagnosing congenital heart defects. The type and severity of the disorder determine treatment. Some types of heart defects require surgery while others can be treated by medication. As heart defects may first present later in life, ultrasound scans (sonograms) should be carried out on repeated occasions.

In order to prevent SIDE attacks people with the syndrome should be protected as far as possible from situations which trigger the attacks. In order to prevent injury, treatment with medication including valproic acid, clonazepam or selective serotonin re-uptake inhibitors (SSRIs), may be necessary. Epilepsy may require medication. Neurological problems including spasticity and paralysis, which may be caused by damage to the spinal cord, may result in some people with the syndrome requiring a wheelchair and other aids.

Regular clinical examinations, including neurological check-ups and growth monitoring, should be carried out. Any issues with food and excess weight should be investigated, followed up and treated.

Early tests of vision and hearing are necessary, and both should be regularly monitored. Early detection of such impairments makes the planning of communication strategies easier. Impaired hearing can sometimes be improved with hearing aids or by surgically inserting a cochlear implant (CI).

Children should have contact with a pedodontist (children’s dentist) and receive extensive, preventive dental care.

Children and young people with Coffin-Lowry syndrome require early habilitation. A habilitation team includes professionals with special expertise in how disability affects everyday life, health and development. Help is available within the medical, educational, psychological, social and technical fields. Habilitation may include assessments, treatment, assistance with choice of aids, information about disabilities and counselling. It also includes information about support offered by the local authority as well as advice on the way home and other environments can be adapted to the child’s needs. The whole family should be offered support.

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

Speech and language impairments are investigated by a speech and language therapist, and individually-designed programmes are drawn up to stimulate the child’s language and communication skills. Language skills may also be stimulated by AAC (augmentative and alternative communication), a collective term for non-verbal communication. Impaired hearing affects the choice of communication medium, and hearing habilitation is important for the development of the child’s language and communication skills. Being able to make themselves understood can reduce any behavioural abnormalities, although children with the condition may still require medical treatment.

Adults with Coffin-Lowry syndrome may require continued individual habilitation and support in their daily lives. This may take the form of support and care in accommodation offering specialist services and daily activities.

If the mother of the affected child also has symptoms of the disease it is important to support her in order to ensure that she can cope with the situation.

Practical advice

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National and regional resources in Sweden

Clinical genetics departments located at Swedish university hospitals are a national resource.

Regional Centre for Rare Diseases, Clinical Genetics, L4:03, Karolinska University Hospital, Solna, SE-171 76 Stockholm, Sweden. Coordinator: Eva Ekblom, tel: +46 8 517 756 26, email: sallsyntadiagnoser@karolinska.se.

Expertise in orofacial problems can be found at Mun-H-Center, Institute of Odontology in Gothenburg, Medicinaregatan 12A, SE-413 90 Gothenburg, Sweden. Tel: +46 31 750 92 00, fax: +46 31 750 92 01, email mun-h-center@vgregion.se, www.mun-h-center.se.

Resource personnel

Associate Professor Ann Nordgren, Clinical Genetics, Karolinska University Hospital Solna, SE-171 76 Stockholm, Sweden. Tel: +46 8 517 753 18, fax: +46 8 32 77 34.

Courses, exchanges of experience, recreation

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Organizations for the disabled/patient associations etc.

FUB, The Swedish National Association for Children, Young People and Adults with Intellectual Disabilities, Industrivägen 7 (visitors address), Box 1181, SE-171 23 Solna, Sweden. Tel: +46 8 508 866 00, fax: +46 8 508 866 66, email: fub@fub.se, www.fub.se.

The Association of People with Short Stature in Sweden - DHR, Eneby-Näs Framnäs Hage, SE-590 40 Kisa, Sweden. Tel: +46 494 421 41, email: info@fkv.se, www.fkv.se.

Courses, exchanges of experience for personnel

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Research and development

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Information material

Short summaries of all the database texts are available as leaflets, in Swedish only. They can be printed out or ordered by selecting the Swedish version, and then clicking on the leaflet icon which will appear under "Mer hos oss" in the column on the right-hand side. 

Literature

Coffin GS, Siris E, Wegienka LC. Mental retardation with osteocartilaginous anomalies. Am J Dis Child 1966; 112: 205-213.

Coffin GS. Postmortem findings in the Coffin-Lowry syndrome. Genet Med 2003: 5: 187-193.

Delaunoy JP, Dubos A, Marques Pereira P, Hanauer A. Identification of novel mutations in the RSK2 gene (RPS6KA3) in patients with Coffin-Lowry syndrome. Clin Genet 2006; 70: 161-166.

Harum KH, Alemi L, Johnston MV. Cognitive impairment in Coffin-Lowry syndrome correlates with reduced RSK2 activation. Neurology 2001; 56: 207-214.

Horn D, Delaunoy JP, Kunze J: Prenatal diagnosis in Coffin-Lowry syndrome demonstrates germinal mosaicism confirmed by mutation analysis. Prenat Diagn 2001; 21: 881-884.

Hunter AGW. Coffin-Lowry syndrome: a 20-year follow-up and review of long-term outcomes. Am J Med Genet 2002; 111: 345-355.

Jacquot S, Merienne K, Pannetier S, Blumenfeld S, Schinzel A, Hanauer A. Germline mosaicism in Coffin-Lowry syndrome. Eur J Hum Genet 1998; 6: 578-582.

Jin S, Hahn JS, Hanauer A. Stimulus-induced drop episodes in Coffin–Lowry syndrome. Eur J Med Genet 2012; 55: 335-337.

Lowry B, Miller JR, Fraser F. A new dominant gene mental retardation syndrome. Am J Dis Child 1971; 121: 496-500.

Marques Pereira P, Schneider A, Pannetier S, Heron D, Hanauer A. Coffin-Lowry syndrome. Europ J Hum Genet 2010; 18: 627-633.

Massin MM, Radermecker MA, Verloes A, Jacquot S, Grenade T. Cardiac involvement in Coffin-Lowry syndrome. Acta Paediat 1999; 88: 468-470.

Mehmood T, Schneider A, Sibille J, Marques Pereira P, Pannetier S, Ammar MR et al. Transcriptome profile reveals AMPA receptor dysfunction in the hippocampus of the Rsk2-knockout mice, an animal model of Coffin-Lowry syndrome. Hum Genet 2011; 129: 255-269.

Norderyd J, Aronsson J. Hypoplastic root cementum and premature loss of primary teeth in Coffin-Lowry syndrome: a case report. Int J Paediatr Dent 2012; 22: 154-156.

Simensen RJ, Abidi F, Collins JS, Schwartz CE, Stevenson RE. Cognitive function in Coffin-Lowry syndrome. Clin Genet 2002; 61: 299-304.

Stephenson JB, Hoffman MC, Russell AJ, Falconer J, Beach RC, Tolmie JL et al. The movement disorders of Coffin-Lowry syndrome. Brain Dev 2005; 27: 108-113.

Trivier E, De Cesare D, Jacquot S, Pannetier S, Zackai E, Young I et al. Mutations in the kinase Rsk-2 associated with Coffin-Lowry syndrome. Nature 1996; 384: 567-570.

Wilson WG, Kelly TE. Early recognition of the Coffin-Lowry syndrome. Am J Med Genet 1981; 8: 215-220.

Zeniou M, Ding T, Trivier E, Hanauer A. Expression analysis of RSK gene family members: the RSK2 gene, mutated in Coffin Lowry syndrome, is prominently expressed in brain structures essential for cognitive function and learning. Hum Mol Genet 2002; 11: 2929-2940.

Database references

OMIM (Online Mendelian Inheritance in Man)
www.ncbi.nlm.nih.gov/omim 
Search: coffin-lowry syndrome, CLS

GeneReviews (University of Washington)
www.genetests.org (select “GeneReviews”, then “Titles”)
Search: coffin-lowry syndrome

Orphanet, (European database)
www.orpha.net 
Search: Coffin-Lowry 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 Ann Nordgren, Karolinska University Hospital, Stockholm, 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.

Date of publication: 2013-11-01
Version: 1.1
Publication date of the Swedish version: 2013-01-22

For enquiries contact The Swedish Information Centre for Rare Diseases, The Sahlgrenska Academy at the University of Gothenburg, Box 422, SE-405 30 Gothenburg, Sweden. Tel: +46 31 786 55 90, email: ovanligadiagnoser@gu.se.

 

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