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Late-onset spondyloepiphyseal dysplasia

This is part of Rare diseases.

Diagnosis: Late-onset spondyloepiphyseal dysplasia

Synonyms: Spondyloepiphyseal dysplasia tarda

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Publication date: 2013-03-15
Version: 3.0

The disease

Late-onset spondyloepiphyseal dysplasia (the tarda form) is a disorder of skeletal development. The condition is hereditary and was first described in 1927 by Swedish orthopaedist Harald Nilsonne.

Disorders of skeletal development, or skeletal dysplasias, cause bone abnormalities and deformities. The severity of the deformities increases as the child grows and gains weight. Some skeletal dysplasias affect the whole skeleton, while others only affect parts, such as the ends of the long bones (epiphysis) or the growth zones (metaphysis). Abnormalities can affect bone, cartilage or connective tissue. Individuals with skeletal dysplasia are usually of short stature.

More than 200 inherited skeletal dysplasias are currently recognised. Information on several of them, including achondroplasia, diastrophic dysplasia, congenital spondyloepiphyseal dysplasia, multiple epiphyseal dysplasia, and pseudo-achondroplasia, is available in the Rare Disease Database of the Swedish Board of Health and Welfare.

Skeletal dysplasias are a complicated group of disorders in terms of both diagnosis and treatment. As treatment regimes, patterns of inheritance, and prognoses differ, it is essential to establish a correct diagnosis.

Occurrence

In Sweden, 1-2 children with late-onset spondyloepiphyseal dysplasia are born every year. There are approximately 40-50 individuals with the disorder in Sweden.

Cause

The disorder is caused by a mutation (a structural defect) in a gene that contributes to the production of collagen fibres in bone, cartilage, and connective tissue. The mutation impairs the development of bone, cartilage, and connective tissue, and normal bone growth is disrupted. This results in short stature and progressive spinal deformities and joint problems.

There is one form of the disorder with X-linked recessive inheritance and one form with autosomal dominant inheritance. The X-linked form is caused by mutations in a gene known as TRAPPC2 (SEDL), located on the short arm of the X chromosome (Xp22.2). This gene regulates the development of cartilage and bone growth. The autosomal dominant form results from a mutation in a gene located on chromosome 12 (12q13.11), which codes for collagen type II. This gene is known as COL2A1.

Heredity

The X-linked recessive variant is the most prevalent form of the disorder. The X chromosome is one of the chromosomes which determines sex. Men have one X chromosome and one Y chromosome, while women have two X chromosomes. Inherited X-linked recessive disorders usually occur only in men, being passed down via a healthy female carrier who has one normal and one mutated gene. Sons of female carriers of a mutated gene run a 50 per cent risk of inheriting the disease and daughters run the same risk of being healthy carriers of a mutated gene.

Figure: X-linked recessive inheritance  via a healthy female carrier

A man with an inherited X-linked recessive disease cannot pass it on to his sons, but all his daughters will be carriers of the mutated gene.

Figure: Figure: X-linked recessive inheritance via a male carrier with the disease

In rare cases the pattern of inheritance in late-onset spondyloepiphyseal dysplasia is autosomal dominant. This means that one of the parents has the disease, and so has one normal gene and one mutated gene. Sons and daughters of this parent have a 50 per cent risk of inheriting the disease. Children who do not inherit the mutated gene do not have the disease and do not pass it down.

Figure: Autosomal dominant inheritance

Symptoms

The only sign of late-onset spondyloepiphyseal dysplasia in newborns is a short neck. The syndrome is usually not suspected until between the ages of 4 and 12, when the symptoms become more apparent. These children have short stature, short trunk, chest-wall deformities, and lordosis (swayback). An X-ray examination will reveal malformed, flattened vertebrae. The intervertebral disc spaces are also narrowed. The ends of the arm and leg long bones (the condyles) are often deformed as a consequence of bone and joint inflammations.

Late-onset spondyloepiphyseal dysplasia does not affect intellectual development.

Walking is delayed and the child will have a mildly waddling gait. Knock-knees or bow-legs are common. Spinal deformities may present as early as by the age of 10. The condition tends to progress over the years, and many individuals have problems with back pain.

The mobility of the large joints is often increasingly restricted. Hips, knees, and elbows stiffen and become more difficult to extend. Hip joint deformities and premature degenerative arthritis often cause considerable pain and disability from an early age. The final adult height of women with the disorder is 140-150 cm, while men attain a height of between 145 and 165 cm.

The neck is short with flattened cervical vertebrae and the tooth-like projection on the upper side of the second cervical vertebra (the dens axis) is sometimes underdeveloped. This may result in increased pressure on the spinal cord, which, in the worst cases, can lead to progressive leg paralysis. The first signs of spinal cord injury are often subtle and easily overlooked. They include diffuse leg pain, fatigue, and decline in physical function.

Before surgery under general anaesthesia the anaesthetist must be informed about the condition, as there may be complications associated with intubation (when a tube is inserted into the airways to facilitate breathing during surgery), as the head is forced back during this procedure. Surgery should always be preceded by X-ray examination of the cervical column.

Diagnosis

The diagnosis is usually based on clinical manifestations in combination with a skeletal X-ray. The radiographic findings include flattened vertebrae, calcified intervertebral disc spaces, and hip and knee joint abnormalities.

The diagnosis can frequently be confirmed by DNA analysis of a blood sample. At the time of diagnosis 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 in families where the mutation is known.

Treatment/interventions

There is no cure for late-onset spondyloepiphyseal dysplasia, but a great deal can be done to provide support and compensate for disabilities.

Hip joint defects and arthritis sometimes require surgical intervention. Spinal defects are treated with a corset brace, but may require surgery.

As well as contact with a paediatric orthopaedist, the child requires early habilitation to stimulate development as much as possible and help compensate for disabilities. The family should be included in the process. A habilitation team includes professionals with special expertise in different aspects of the disability and how it affects everyday life, health and development. Support and treatment are offered within the medical, educational, psychological, social and technical fields. All interventions focus on the existing needs of the child and family, and are adapted as the child grows older. Habilitation is carried out in collaboration with individuals close to the child and includes evaluation, treatment, assessing the need for aids, information about the disability, and counselling.

The environment should be adapted early to meet the child’s needs. This will help compensate for loss of functionality and help prevent wear on the joints. The habilitation team can provide advice about making adjustments to the home and other places where the child spends time, as well as on how to avoid strain on the joints.

Children and young people of short stature are to be treated age-appropriately and like their peers. Parents should be offered contact with other parents of children of short stature, and the children themselves should also be offered the opportunity to meet children in the same situation. Children as well as parents may also need to meet adults of short stature to learn more about their situation. Psychological support adapted to age and maturity should be available continuously while the child is growing up.

Adults with the syndrome may require continued individual habilitation and support in their daily lives. Adjustments to the home and the working environment are often essential. Ambulation problems are common. In addition to an electric wheelchair a specially adapted car may eventually be necessary.

In pregnancy, women with the very rare autosomal dominant form of the disorder should be in contact with specialist maternity care services. Many of these women experience increasing breathing difficulties. Early delivery by caesarean section two to four weeks before the due date is often necessary.

Occupational guidance is needed, as well as adjustments to the work environment. The employment services and the Swedish Social Insurance Agency can provide information and support.

Practical advice

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National and regional resources in Sweden

Diagnostics is performed at regional hospital paediatric clinics. If the diagnosis is inconclusive, investigations can be carried out at the National Centre for Skeletal Dysplasias, located at Uppsala University Children’s Hospital where the Swedish Centre for Deformities and Syndromes is also located. Both these centres also coordinate interventions for children and adults.

The skeletal dysplasia team at the Astrid Lindgren Children’s Hospital has wide experience of monitoring children and young people with skeletal dysplasia. The team consists of representatives from the following areas: respiratory physiology, neurosurgery, neuroradiology, skeletal radiology, paediatric orthopaedics, paediatric endocrinology, physiotherapy, urinary incontinence therapy and clinical genetics. Contacts are research nurse Lo Neumeyer, tel: +46 8 517 775 81, and chief physician Lars Hagenäs, Astrid Lindgren’s Children’s Hospital, SE-171 76 Stockholm, Sweden. Tel: +46 8 517 700 00.

Resource personnel

Professor Göran Annerén, The Rudbeck Laboratory, Uppsala University Hospital, SE-751 85 Uppsala, Sweden. Tel: +46 18 611 59 42, fax: +46 18 55 40 25.

Professor emeritus Karl-Henrik Gustavson, The Rudbeck Laboratory, Uppsala University Hospital, SE-751 85 Uppsala, Sweden. Tel: +46 18 471 48 53, fax: +46 18 55 40 25.

Associate Professor Lars Rehnberg, Astrid Lindgren Children’s Hospital, SE-171 76 Stockholm, Sweden. Tel: +46 8 517 777 00.

Senior physician Lars Hagenäs, Paediatric Endocrinology Laboratory, Astrid Lindgren Children’s Hospital, SE-171 76 Stockholm, Sweden. Tel: +46 8 517 700 00.

Courses, exchanges of experience, recreation

Uppsala University Children’s Hospital arranges special theme days for children with skeletal dysplasia and their parents.

Family camps and other activities are arranged by RBU (see under “Organizations for the disabled/patient associations”).

The Association for People of Short Stature in Sweden-DHR, arranges theme days (see under “Organizations for the disabled/patient associations”).

Organizations for the disabled/patient associations etc.

The Association for People of Short Stature in Sweden-DHR, chair Gunilla Hyltén-Cavallius, Södra Forsåkersgatan 44, SE-431 63 Mölndal, Sweden. Tel: +46 31 27 45 74, email: fkv@telia.comwww.fkv.se.
The association is in contact with similar organizations in several countries and cooperates closely with associations in the Nordic countries.

RBU, The Swedish National Association for Disabled Children and Young People, St Eriksgatan 44, Box 8026, SE-104 20 Stockholm, Sweden. Tel: +46 8 677 73 00, fax: +46 8 677 73 09, email: info@rbu.se, www.rbu.se.

Courses, exchanges of experience for personnel

Uppsala University Children’s Hospital arranges special theme days for children with skeletal dysplasia and their parents.

Research and Development

There is ongoing clinical and DNA-based research about skeletal dysplasias at Uppsala University Hospital. Contact person is Professor emeritus Karl-Henrik Gustavson (see under “Resource personnel”).

Information material

An information leaflet on late-onset spondyloepiphyseal dysplasia that summarises the information in this database text is available free of charge from the Publishers Department of the Swedish National Board of Health and Welfare (in Swedish only, article number 2001-126-1131.) Address: SE-106 30 Stockholm, Sweden. Fax: +46 35 19 75 29, email: publikationsservice@socialstyrelsen.se, or tel: +46 75 247 38 80. Postage will be charged for bulk orders.

The booklet “Barn och ungdomar med kortväxthet” (1999, in Swedish only). Order from RBU (see under “Organizations for the disabled/patient associations”). It can also be downloaded from: www.rbu.se.

Kort men inte liten (In Swedish only). A fact book about short stature by Pernilla Gesén, Eva Schreiber and Ulla-Karin-Karlsson. Order from the Association for People of Short Stature in Sweden-DHR (see under “Organizations for the disabled/patient associations”).

Mindre vanliga människor. A book by and about individuals with growth restriction disorders (1996, in Swedish only). Published by Utbildningsförlaget Brevskolan on behalf of the Association for People of Short Stature in Sweden-DHR (see under “Organizations for the disabled/patient associations”). Edited by Gerd Andersson, Rune Larsson, and Eva Schreiber.

Literature

Bar-Yosef U, Ohana E, Hershkowitz E, Perlmuter S, Ofir R, Birk OS.
X-linked spondyloepiphyseal dysplasia tarda: a novel SEDL mutation in a Jewish Ashkenazi family and clinical intervention considerations. Am J Med Genet 2004; 125: 45-48.

Fiedler J, Le Merrer M, Mortier G, Heuertz S, Faivre L, Brenner RE. X-linked spondyloepiphyseal dysplasia tarda: Novel and recurrent mutations in 13 European families. Hum Mutat 2004; 24: 103.

Dreyer SD, Zhou G, Lee B. The long and the short of it: developmental genetics of the skeletal dysplasias. Clinical Genetics 1998; 54: 464-473.

Gedeon AK, Colley A, Jamieson R, Thompson EM, Rogers J, Sillence D et al. Identification of the gene (SEDL) causing X-linked spondyloepiphyseal dysplasia tarda. Nature Genetics 1999; 22: 400-404.

Gustavson K-H, Annerén G, Axelsson O, Eriksson L, Gustafsson J, Lönnerholm T et al. Skelettdysplasi. Läkartidningen 1992; 38: 3425-3430.

Hall CM. International nosology and classification of constitutional disorders of bone (2001). Am J Med Genet 2002; 113: 65-77.

Horton WA. Molecular genetics of the human chondrodysplasias. Eur J Hum Genet 1995; 3: 357-373.

Jagell S, Gustavson K-H. Skelettdysplasi hos barn kan ge allvarliga komplikationer. Läkartidningen 1984; 81: 2157.

Ritvaniemi P, Sokolov BP, Williams CJ, Considine E, Yurgenev L, Meerson EM et al. A single base mutation in the type II procollagen gene (COL2A1) that converts glycine alpha 1-247 to serine in a family with late-onset spondyloepiphyseal dysplasia. Hum Mutat 1994; 3: 261-267.

Savarirayan R, Thompson E, Gécz J. Spondyloepiphyseal dysplasia tarda (SEDL, MIM #313400). Eur J Hum Genet 2003; 11: 639-642.

Schantz K, Andersen PE Jr, Justesen P. Spondyloepiphyseal dysplasia tarda: report of a family with autosomal dominant transmission. Acta Orthop Scand 1988; 59: 716-719.

Shaw MA, Brunetti-Pierri N, Kádasi L, Kovácová V, Van Maldergem L, De Brasi D et al. Identification of three novel SEDL mutations, including mutation in the rare, non-canonical splice site of exon 4. Clin Genet 2003; 64: 235-242.

Whyte MP, Gottesman GS, Eddy MC, McAlister WH. X-linked recessive spondyloepiphyseal tarda: clinical and radiographic evaluation in a 6-generation kindred and review of the literature. Medicine 1999; 78: 9-25.

Database references

OMIM (Online Mendelian Inheritance in Man)
www.ncbi.nlm.nih.gov/omim 
Search for the X-linked recessive form: spondyloepiphyseal dysplasia, X-linked
Search for the autosomal dominant form: spondyloepiphyseal dysplasia tarda

GeneReviews (University of Washington)
www.genetests.org (find GeneReviews, then Titles)
Search: spondyloepiphyseal dysplasia tarda, X-linked

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 Professor emeritus Karl-Henrik Gustavson, Uppsala University Hospital, 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: 2013-03-15
Version: 3.0
Publication date of the Swedish version: 2012-11-29

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.