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WAGR syndrome

This is part of Rare diseases.

Diagnosis: WAGR syndrome

Synonyms: Wilms tumour, aniridia, genital abnormalities and retardation; WAGR

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Date of publication: 2014-04-29
Version: 3.0

ICD 10 code

Q87.8

The disease

WAGR is an acronym indicating the symptoms included in the syndrome. W stands for Wilms tumour (a malignant kidney tumour primarily affecting small children), A is for aniridia (partial or total absence of the iris), G is for genital abnormalities and R stands for mental retardation. The syndrome can also be associated with obesity in which case another letter, O, is added to make WAGRO.

The American oncologist Robert Miller published the first full description of the syndrome in 1964.

Occurrence

Every year, approximately two children with aniridia are born in Sweden. Of these, fewer than 10 per cent have WAGR syndrome. New cases of WAGR syndrome can be estimated at approximately two per one million population, meaning that in Sweden on average one child is born with the condition every five years.

Cause

WAGR syndrome is caused by a loss of chromosomal material (a deletion) on the short arm of chromosome 11 (11p13). This deleted material normally contains several genes critical to foetal and infant development. In cases of WAGR syndrome, there is only one copy of these genes, rather than the normal two.

Two genes which play major roles in determining symptoms are PAX6, which when deleted causes aniridia, and WT1, which when deleted causes Wilms tumour.

The deletion of another gene located in this area, BDNF (brain-derived neurotrophic factor), is associated with mental disability and a tendency to obesity.

Symptoms vary depending on which genes are affected and the extent of the deletions.

Heredity

The syndrome is most often caused by a new mutation, meaning that the deletion occurs in an individual for the first time and is not inherited from either parent. Consequently, parents with a child with a new mutation generally have a low risk of having another child with the disorder. However, the new genetic mutation will be hereditary and an adult with this deletion risks passing on the deletion to his/her children.

In isolated cases, the deletion is inherited from one of the parents. The inheritance pattern of WAGR syndrome is autosomal dominant. This means that one of the parents has the disease, and so has one normal gene and one chromosome with a deletion. Sons and daughters of this parent have a 50 per cent risk of inheriting the disease. Children who do not inherit the deletion do not have the disease and do not pass it down.

Figure: Autosomal dominant inheritance

In rare cases the deletion is caused by a chromosome translocation, which is inherited from one of the parents. Here, there is an increased risk of having more children with the syndrome.

Symptoms

Eyes

Immediately after birth it is usually possible to see that the irises in a child with WAGR syndrome are almost entirely absent (aniridia). The pupils are dilated and do not react to light. The absence of the iris leads to impaired vision, over-sensitivity to light (photophobia), involuntary eye movements (nystagmus), and squinting (strabismus). Glaucoma and cataracts may also occur. In the Rare Disease Database of the Swedish Board of Health and Welfare you can find separate information on congenital aniridia.

The kidneys and genitals

Impaired function of gene WT1 greatly increases the risk (more than 50 per cent compared with 0.01 per cent for children who do not have WAGR syndrome) of a child with the syndrome developing Wilms tumour. This is a malignant kidney tumour commonly diagnosed in young children, usually before the age of five. Usually the parents notice that the child has a sensitive swelling in the stomach. Some children experience pains in the stomach and some pass blood in the urine. Impaired function of the WT1 gene can also lead to abnormalities in the development of the genitals. The testicles of boys with the syndrome often do not descend to the scrotum and the opening of the uretha is abnormally placed (hypospadias). A few girls with the syndrome have abnormalities of the uterus and ovaries. At birth, it has been difficult to determine the sex of some children with the syndrome.

Development

Approximately three-quarters of people with the condition have mental disabilities. In most cases this is mild or moderate. Autism spectrum conditions or behaviours associated with autism may present, as can behavioural abnormalites and psychiatric problems.

Other points

Other symptoms, including renal failure and pancreatic, occur more frequently in children with WAGR syndrome. Children with the syndrome run an increased risk of becoming obese, which is presumed to be an effect of the deletion of certain genes. (See under “Cause.”)

Diagnosis

An opthamologist can often diagnose aniridia when the child is very young, but it is not possible to diagnose WAGR syndrome so early without a DNA analysis as the condition’s other symptoms do not manifest clearly at this age. For that reason, before the diagnosis of aniridia is made genetic tests should be carried out. Most children with aniridia do not have WAGR syndrome, but the inherited and considerably more common form of aniridia, which is caused solely by a mutation in gene PAX6 . The cause of WAGR syndrome is a deletion of chromosomal material which includes several genes, among which are the PAX6 gene and the WT1 gene.

Larger deletions and translocations of 11p13 can be established by chromosome analysis, but when deletions are small they are best diagnosed using FISH, MLPA or array CGH analyses.

At the time of diagnosis it is important that the family is offered genetic counselling. Carrier and prenatal diagnosis, as well as pre-implantation genetic diagnosis (PGD) in association with IVF (in vitro fertilization), are available in families where the mutation is known.

Treatment/interventions

There is no cure for the syndrome, but symptoms can be relieved in various ways. Much can be done to support the individual and compensate as much as possible for functional limitations. Treatment and support measures vary as the combination and severity of symptoms differ from person to person. Children with WAGR syndrome require contact with several different medical specialists. It is therefore important that a paediatrician acts a coordinator.

Eyes

Children with the syndrome should be seen at an early stage by a paediatric ophthalmologist. Different investigative methods and tests make it possible to establish which abnormalities of the eye the child has, and how they will affect vision. Every eye clinic collaborates with a low vision centre, where different aids to vision can be tried out and adjusted to the individual. Over-sensitivity to light means that the child often requires protective glasses. These protective glasses can also be made to correct any refractive vision problems. Coloured contact lenses which filter out different amounts of light can be tried in some instances. Squints are treated by covering the normal eye with a patch in order to train the affected eye.

Glaucoma is treated with eye drops and surgery. Eye drops reduce pressure in the eye and prevent further damage to the optic nerve fibres. Cataracts are treated surgically.

The kidneys and genitals

As the risk of developing Wilms tumours is far higher than normal, children require regular kidney examinations as they are growing up. Ultrasonography examinations are commonly carried out at frequent intervals (every third month) until the child is six, and subsequently every six months. If a tumour is suspected, further investigations and treatment should be carried out at a paediatric oncology centre. Treatment is usually a combination of chemotherapy (cytotoxic medication) and surgery. Sometimes radiation therapy is also required. The prognosis is very good if the tumour is detected early.

Regular monitoring of kidneys and kidney function should continue in adulthood. Kidney function is monitored using X-rays, ultrasound and blood tests. The frequency of screening depends on the condition of the kidneys. It is important to prevent the child developing urinary tract infections which may exacerbate existing kidney damage. Some individuals may require dialysis or a kidney transplant.

Children with WAGR syndrome should be examined by a paediatric urologist, as they may have malformations in the urinary tract and genitals. Hypospadias and undescended testicles require surgical intervention.

Obesity

It is important that the families of children who risk becoming obese have early contact with a dietician.

Habilitation

In order to stimulate the child’s development and help compensate for loss of function, the family requires early contact with a habilitation team. A habilitation team 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 and includes visual habilitation. Help includes assessment, treatment, the provision of aids, information on the specific disability, and counselling. It also includes information about support offered by public services as well as advice on the way accommodation and other environments can be adapted to the child’s needs. Parents and siblings and others close to the child may also receive support.

All habilitation planning is based on the needs of the child and the family. It may vary over time and is always planned in collaboration with individuals close to the child. Children with an intellectual disability require specialist educational provision to facilitate the development of reading and writing skills. Some may need to be educated in a special school which can provide specialist expertise.

Local Swedish public agencies can offer different forms of support to facilitate the family’s everyday life. Respite care can, for example, take the form of a contact family or short-term accommodation outside the home. In cases of severe disability, the help of a personal care assistant can give the person with WAGR syndrome the opportunity to lead a more active life.

Adults with WAGR syndrome require continued medical monitoring of kidney function and continued contact with a low vision centre. They may also require continued individual habilitation and support in their daily lives. This may take the form of support and care in accommodation with special services and daily activities.

Practical advice

The website of Aniridia Sweden, www.aniridi.se, provides useful advice for parents of children with aniridia.

National and regional resources in Sweden

The diagnosis is made in collaboration with departments of clinical genetics at Sweden’s university hospitals. Departments of clinical genetics are located at: Skåne University Hospital, Sahlgrenska University Hospital in Gothenburg, Linköping University Hospital, Karolinska University Hospital in Stockholm, Uppsala University Hospital and Norrland University Hospital in Umeå.

The Swedish National Agency for Special Needs Education and Schools (www.spsm.se) is a country-wide, public authority. The organization’s role is to give special support to local and other authorities with responsibility for daycare, pre-schools, schools, independent educational establishments regulated by public authorities, and adult education. National resource centres with specialist expertise carry out investigations, organize visits for children and young people and provide information and training for parents, teachers and other personnel. Swedish Resource Centres for the Visually Impaired are located in Stockholm and Örebro.

Resource Centre for the Visually Impaired - Stockholm, Rålambsvägen 32 B, Box 12161, SE-102 26 Stockholm, Sweden. Tel: +46 10 437 50 00, email: rc.syn.stockholm@spsm.se.

Resource Centre for the Visually Impaired - Örebro, Eriksbergsgatan 3, SE-702 30 Örebro. Box 9024, SE-700 09 Örebro, Sweden.Tel: +46 10 473 50 00, email: rc.syn.orebro@spsm.se.

Resource personnel

Associate Professor Elisabeth Syk Lundberg, Clinical Genetics, Karolinska University Hospital, SE-171 76 Stockholm, Sweden. Tel: +46 8 51 77 53 80, fax: +46 8 32 77 34.

Associate Professor Niklas Pal, Astrid Lindgren Children’s Hospital, Karolinska University Hospital, SE-171 76 Stockholm, Sweden. Tel: +46 8 517 780 84.

Professor Agneta Nordenskjöld, Paediatric Surgery, Astrid Lindgren Children’s Hospital, Karolinska University Hospital, SE-171 76 Stockholm, Sweden. Tel: +46 8 517 777 05.

Courses, exchanges of experience, recreation

Aniridia Sweden organizes annual events for children and adults with aniridia to encourage the exchange of relevant information and experiences. The association also supports networks for members with WAGR syndrome. See under “Organizations for the disabled/patient associations etc.”

Organizations for the disabled/patient associations etc.

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.

Aniridia Sweden, www.aniridi.se, email: info@aniridi.se. The network is chaired by Neven Milivojevic, Bygatan 19, Floor 6, SE-171 49 Solna, Sweden. Tel: +46 70 639 00 68. The Aniridia Network in Sweden is a national association for people with aniridia and their families. People with WAGR syndrome and their friends and family are also welcome to become members.

SRF, The Swedish Association of the Visually Impaired, Sandsborgsvägen 52, SE-122 88 Enskede, Sweden. Tel: +46 8 39 90 00, fax: +46 8 39 93 22, email: info@srf.nu, www.srf.nu.

The Swedish Kidney Association, Sturegatan 4 A, Box 1386, SE-172 31 Sundbyberg, Sweden. Tel: +46 8 546 40 500, fax: +46 8 546 40 504, email: info@njurforbundet.se, www.njurforbundet.se.

Rare Diseases Sweden, Sturegatan 4A, Box 1386, SE-172 27 Sundbyberg, Sweden. Tel: +46 8 764 49 99, email: info@sallsyntadiagnoser.se, www.sallsyntadiagnoser.se. Rare Diseases Sweden is a national association representing people with rare diseases and varying disabilities.

There is also a European Aniridia network, Aniridia Europe, www.aniridia.eu.

The address of the International WAGR Syndrome Association is www.wagr.org.

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. These leaflets may be ordered or printed out. (See under “Mer hos oss” in the right hand column.)

For information in English go to the website of The International WAGR Syndrome Association, www.wagr.org.

There is a relevant book in English: Aniridia and WAGR syndrome: A guide for patients and their families (2010), by Jill Ann Nerby, Jessica J Otis. ISBN 0195389301.

Literature

Breslow NE, Norris R, Norkool PA, Kang T, Beckwith JB, Perlman EJ. Characteristics and outcomes of children with the Wilms Tumor-Aniridia syndrome: A report from the National Wilms Tumor Study Group. J Clin Oncol 2003; 21: 4579-4585.

Clericuzio CL. Clinical phenotypes and Wilms tumour. Med Pediatr Oncol 1993; 21: 182-187.

Clericuzio C, Hingorani M, Crolla JA, van Heyningen V, Verloes A. Clinical utility gene card for: WAGR syndrome. Eur J Hum Genet 2011; 19(4): doi: 10.1038/ejhg.2010.220. Epub 2011 Jan 12.

Edén U, Beijar C, Riise R, Tornqvist K. Aniridia among children and teenagers in Sweden and Norway. Acta Opthalmol 2008; 86: 730-734.

Fischbach B, Trout K, Lewis J, Luis C, Sika M. WAGR syndrome: a clinical review of 54 cases. Pediatrics 2005; 116: 984-988.

Fraumeni JF, Glass AG. Wilms’ tumour and congenital aniridia. J Am Med Assoc 1968; 206: 825-828.

Han JC, Liu QR, Jones M, Levinn RL, Menzie CM, Jefferson-George KS et al. Brain-derived neutrophic factor and obesity in the WAGR syndrome. N Engl J Med 2008; 359: 918-927.

Han JC, Thurm A, Golden Williams C, Joseph LA, Zein WM, Brooks BP et al. Association of brain-derived neurotrophic factor (BDNF) haploinsufficiency with lower adaptive behaviour and reduced cognitive functioning in WAGR/11p13 deletion syndrome. Cortex 2013; 49: 2700-2710.

Miller RW, Fraumeni JF Jr, Manning MD. Association of Wilms’ tumour with aniridia, hemihypertrophy and other congenital malformations. N Engl J Med 1964; 270: 922-927.

Nelson LB, Spaeth GL, Nowinski TS, Margo CE, Jackson L. Aniridia, a review. Surv Ophtalmol 1984; 28: 621-642.

Riccardi VM, Sujansky E, Smith AC, Francke U. Chromosomal imbalance in the aniridia-Wilms’ tumour association: 11p interstitial deletion. Pediatrics 1978; 61: 604-610.

Xu S, Han JC, Morales A, Menzie CM, Williams K, Fan YS. Characterization of 11p14-p12 deletion in WAGR syndrome by array CGH for identifying genes contributing to mental retardation and autism. Cytogenet Genome Res 2008; 122: 181-187.

Database references

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

GeneReviews (University of Washington)
www.genetests.org (select GeneReviews)
Search: WAGR syndrome

Orphanet, www.orpha.net 
Search: WAGR 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 Professor Elisabeth Syk Lundberg, Karolinska University Hospital, Stockholm, Sweden.

Professor Agneta Nordenskjöld and Senior Physician Niklas Pal, both of Astrid Lindgren Children’s Hospital, Stockholm, have also contributed.

The relevant organizations 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: 2014-04-29
Version: 5.0
Publication date of the Swedish version: 2014-01-23

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.

 

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.