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Wilms tumor, aniridia, genitourinary anomalies and range of developmental delay (WAGR) syndrome: for patients


Synonyms of WAGR syndrome

  • Chromosome 11p deletion syndrome
  • WAGR complex

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Overview

WAGR syndrome is a rare condition affecting 1 in 500,000 to 1 in 1 million people.[1] It is caused by genetic changes to genes located on chromosome 11. WAGR syndrome affects multiple body systems. WAGR is an acronym which describes its main features: 

  • Wilms tumour (a childhood kidney cancer)
  • Aniridia 
  • Genitourinary abnormalities (anomalies of the reproductive organs and urinary tract) 
  • Range of developmental delays

Affected individuals usually have two or more of the above features. Most cases are not inherited, but develop spontaneously within the patient themselves (when they were developing in the womb during pregnancy).

WAGR syndrome is typically diagnosed at birth or in early infancy when aniridia is first noticed, prompting further examination and investigations. Approximately one-third of children with non-inherited aniridia are diagnosed with WAGR syndrome.[1] Apart from the four main features, there are other conditions associated with WAGR syndrome as well. These conditions include medical, behavioural, and neurodevelopmental disorders.[1]

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The condition

Symptoms

1) Wilms tumour (nephroblastoma)

Wilms tumour is the most common kidney cancer in childhood. Patients affected by WAGR syndrome are at 45-60% increased risk of developing Wilms tumour.[2-4] Of those who develop Wilms tumour, 98% do so by age seven.[5]

2) Aniridia

Comparison between an eye affected by aniridia which has no iris and a normal eye which has a hazel coloured iris.
An eye affected by aniridia where the iris absent (A) and an eye with a fully developed iris (B)

Aniridia is present in almost all cases of WAGR syndrome.[1] It is characterised by an under-developed or absent iris in both eyes. Other structures of the eye could be affected as well, such as the cornea, the trabecular meshworklensfoveaoptic disc and overall size of the eye (microphthalmia). The symptoms experienced by patients depend on the structures affected and vary in severity. The most common symptoms associated with aniridia are glare, light sensitivity, poor vision and nystagmus.

3) Genitourinary anomalies

Both males and females with WAGR syndrome may have abnormal development of their reproductive organs (gonads) and urinary tract. During pregnancy, a baby boy’s testes are normally developed in the abdomen before moving down into the scrotum about 1 to 2 months before birth. However, this might not occur in males with WAGR syndrome, leading to a condition called undescended testes or cryptorchidism. This is the most common abnormality in male WAGR patients (60% of cases).[3] Another feature in males with WAGR syndrome is hypospadias, where the opening of the penis is not at the tip.

In females, genitourinary abnormalities can manifest as underdeveloped ovaries (streak ovaries) or malformation of the womb or vagina.

These features can affect urination, fertility and more importantly, children from both sexes with underdeveloped gonads are at increased risk of developing a rare type of cancer called gonadoblastoma.

In some patients with WAGR syndrome, the external genitals might not have fully developed, leading to difficulty in sexual assignment at birth (ambiguous genitalia).

4) Range of developmental delays

70% of patients with WAGR syndrome have developmental delay, learning difficulties, or intellectual disability (defined as IQ<74). Most patients are mildly to moderately affected, but the range of disability varies.[1] Some patients are profoundly delayed, while others have normal intellect.

In addition, WAGR syndrome can be associated with attention-deficit disorder (ADD), attention-deficit hyperactivity disorder (ADHD), autism spectrum disorder, anxiety, depression, and obsessive-compulsive disorder (OCD).

5) Other associated features

Apart from the four main features, a variety of other conditions have been reported in WAGR syndrome:

  • Chronic kidney disease

It affects approximately 60% of patients with WAGR syndrome, most often developing in adolescence or young adulthood. The cause of kidney disease is FSGS (focal segmental glomerulosclerosis). FSGS attacks the kidney’s filtering units (glomeruli) causing serious scarring which leads to permanent kidney damage. Symptoms of FSGS include high blood pressure and protein in the urine. FSGS may progress to kidney failure, requiring dialysis or kidney transplant.[4]

  • Central auditory processing disorder (CAPD)

90% of patients with WAGR syndrome have some degree of CAPD. It affects the brain’s ability to filter and interpret sounds.[6]

  • Early onset obesity (before the age of 10)

50% of patients with WAGR syndrome have a deletion of one copy of the BDNF gene.[7] Loss of one copy of this gene is associated with early onset obesity. Symptoms of BDNF gene deletion include constant hunger, food-seeking behaviour, and a decreased behavioural response to pain.[8]

  • Dyslipidaemia (elevated levels of fat in the blood)
  • Sleep disorders and sleep apnoea

These conditions are common in WAGR syndrome.[9] People with WAGR syndrome may have small or absent pineal glands, an organ in the brain which produces a hormone called melatonin. This hormone helps the brain to know when to sleep and when to wake up. Too little melatonin may result in difficulty falling asleep or staying asleep. Sleep apnoea is a disorder in which breathing repeatedly stops and starts. Sleep apnoea may cause high blood pressure or heart problems, and may increase the risk of developing type 2 diabetes.

This list of associated features is not exhaustive. Please visit the International WAGR Syndrome Association (IWSA) website for more information.

Cause

WAGR syndrome is caused by deletion of a section of genetic material on chromosome 11. This deletion occurs during the formation of the sperm or egg or in the early stages of the baby’s development in the womb. This section of genetic material involves the PAX6 and WT1 genes as well as many other genes.

The PAX6 gene provides instructions for the development of multiple vital organs during early pregnancy including the eyes, the brain and the spinal cord.[10] When the gene is not working properly, the development of these vital organs are affected, leading to some main features seen in WAGR syndrome such as aniridia and intellectual disability.

The WT1 gene is responsible for the development of the kidneys and gonads before birth. After birth, it provides instructions for a protein that maintains normal growth of kidney cells.[11] Absence of the WT1 gene results in kidney malformation and unregulated growth of these cells, increasing the risk of developing Wilms tumour. It also leads to abnormal development of the gonads and genitals, causing genitourinary anomalies.

The BDNF gene provides instructions for making a protein found in the brain and spinal cord called brain-derived neurotrophic factor. This protein helps regulate synaptic plasticity, which is important for learning and memory, and is found in regions of the brain that control eating, drinking, and body weight, as well as perception of pain.[12] People with deletion of this gene may have learning difficulties, early onset obesity, and a decreased response to pain.

More research is needed to determine whether other genes that are deleted in patients with WAGR syndrome are responsible for other features of the disorder.

How is it diagnosed?

WAGR syndrome is suspected based on the four main clinical features although not every feature has to be present. The diagnosis is confirmed with genetic testing by identifying deletions in the PAX6 and WT1 genes.

How is it inherited?

WAGR syndrome most often develops spontaneously during the early stages of the baby’s development in the womb. In very rare cases, it can be inherited through complex genetic abnormalities in an unaffected parent.

If your child is affected by WAGR syndrome, it is advisable to see a genetic counsellor to obtain more information and advice on inheritance and family planning options.

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Treatment

Is there any treatment?

There is currently no treatment for the gene deletions causing WAGR syndrome. Treatment is mainly focused on alleviating the presenting symptoms. Frequent observations are advised so that any associated physical or mental issues can be addressed at the earliest instance. Children affected with WAGR syndrome should be managed by a multidisciplinary team of healthcare professionals.

1) Wilms tumour

Children with confirmed WAGR syndrome should have an ultrasound scan of their abdomen performed every 3 months from birth or diagnosis until the age of 8 to detect for Wilms tumour.[1] After age 8, surveillance continues throughout life with variable intervals based on each country’s protocol.

If Wilms tumour is diagnosed, the affected child is referred to a paediatric oncologist for treatment. Treatment may include a combination of chemotherapy, radiation therapy and surgery depending on the location and stage of the tumour. Lifelong observation of kidney function through blood tests is advised.[4]

2) Aniridia

Patients affected with WAGR syndrome are normally monitored by an ophthalmologist for visual development and eye conditions typically associated with aniridia, such as glaucomacataract and aniridia-related keratopathy. Regular check-ups are important to monitor these conditions so that treatment, either in the form of eye drops or surgery can be initiated as soon as possible to preserve sight. Patients with visual impairment are referred to low vision services to help optimise their vision.

The usually transparent cornea is now covered with blood vessels from the conjunctiva, causing it to be opaque.
Aniridia-related keratopathy (ARK):
The usually transparent cornea is now opaque after being replaced by tissues from the conjunctiva

3) Genitourinary anomalies

This is usually managed by a urologist or a gynaecologist.

  • Undescended testes/cryptorchidism

An operation called orchidopexy can be performed to move the undescended testes to the scrotum. Untreated cryptorchidism can result in fertility issues and increased risk of testicular cancer.

  • Hypospadias

An operation can be performed to create a new opening at the tip of the penis. Although it is not a life-threatening problem, surgery is usually performed for reproductive purposes or to correct problems with urination.

  • Abnormal development of gonads

Due to the increased risk of gonadoblastoma, children with WAGR syndrome should be regularly evaluated to detect abnormalities in the gonads. In males, this risk may be decreased by orchidopexy surgery. If this is not possible, the testicle may be removed. Females, may be managed by monitoring the ovaries with ultrasound or MRI (magnetic resonance imaging) and with blood tests. As the ovaries might not be able to produce adequate level of hormones for the development of puberty and menstruation, hormone replacement therapy might be required.

4) Range of developmental delays

Timely referral to practitioners familiar with developmental surveillance and intervention for children with visual impairment (VI), such as developmental paediatricians as well as a Qualified Teacher of children and young people with Visual Impairment (QTVI) is crucial to optimise their developmental potential.

The Developmental Journal for babies and young children with visual impairment (DJVI) is a structured early intervention programme designed to track developmental and vision progress from birth to three years of age. It is mainly used by qualified healthcare professionals working in services providing support to babies and young children with VI in conjunction with the child’s parents. Children with VI may be referred to specialist services such as the developmental vision clinic in the Great Ormond Street Hospital for Children or other specialist developmental services for further management.

In addition, children may also require other forms of support in the community to cater to their complex health, developmental and social needs. These are usually delivered through specialist centres working alongside community paediatric services. A multitude of professionals might be involved such as:

  • Community nurses 
  • Speech and language therapists 
  • Occupational health therapists 
  • Physiotherapists 
  • Social workers 
  • Child and adolescent mental health service (CAMHS) 
  • Schools (see education support)

As children may be seen by many different services, parents may find it helpful to speak to their paediatrician to help coordinate care.

This is based on current UK practice and might differ in other countries.

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5) Chronic kidney disease

Early diagnosis of kidney disease and aggressive treatment with medication may preserve kidney function for long periods in some patients. When kidney function declines below the level needed to sustain life, dialysis or kidney transplant is required.[4]

6) Central Auditory Processing Disorder (CAPD)

Environmental modifications at home and at school, such as the use of listening devices, and working with a speech and language therapist.

7) BDNF gene deletion

Some patients may respond to careful control of calorie intake and increased physical activity. Restricting access to food may be necessary. Patients with decreased response to pain should be observed closely for altered behaviour that may indicate injury or illness, such as limping or refusing to use an arm or a hand, swelling or redness of the skin, or fever.

9) Dyslipidaemia

Patients may benefit from medication to lower the level of lipids (fats) in the blood. Patients affected by WAGR syndrome should also avoid propofol (a common medication given during general anaesthesia) if possible. This is because propofol, even when used short-term, has been shown to increase lipid level in the blood, which may in turn cause acute inflammation of the pancreas (acute pancreatitis).[13]

10) Sleep disorders and sleep apnoea

Supplemental melatonin is helpful for some people with WAGR syndrome and sleep disorders. Sleep apnoea may be treated with CPAP (continuous positive airway pressure), a machine which uses a hose and mask or nosepiece to deliver constant and steady air pressure.

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Current research in WAGR syndrome

Updates on the current research involving WAGR syndrome can be found on the International WAGR Syndrome Association’s “Recent Research” page.

Related links

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Referral to a specialist centre

If you are based in the UK and would like to be seen in the nearest specialist centre for your eye condition, either to receive a more comprehensive genetic management or just to find out more about current research, you can approach your GP to make a referral or alternatively arrange for a private appointment. 

More information can be found in our “How to see a genetic eye specialist?” page.

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Further information and support

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A patient’s perspective

Families talking about their experience with WAGR syndrome

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References

  1.  Moosajee M, Hingorani M, Moore AT. PAX6-Related Aniridia. In: GeneReviews®[Internet]. University of Washington, Seattle; 2018
  2.   Muto R, Yamamori S, Ohashi H, Osawa M. Prediction by FISH analysis of the occurrence of Wilms tumor in aniridia patients. Am J Med Genet. 2002;108(4):285-289
  3.  Fischbach BV, Trout KL, Lewis J, Luis CA, Sika M. WAGR syndrome: a clinical review of 54 cases. Pediatrics. 2005;116(4):984-988
  4.  Breslow NE, Norris R, Norkool PA, et al. 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(24):4579-4585
  5.  Beckwith JB. Nephrogenic rests and the pathogenesis of Wilms tumor: developmental and clinical considerations. Am J Med Genet. 1998;79(4):268-273
  6.  Bobilev AM, Hudgens-Haney ME, Hamm JP, et al. Early and late auditory information processing show opposing deviations in aniridia. Brain Res. 2019;1720:146307
  7.  Han JC, Liu QR, Jones M, et al. Brain-derived neurotrophic factor and obesity in the WAGR syndrome. N Engl J Med. 2008;359(9):918-927
  8.  Sapio MR, Iadarola MJ, LaPaglia DM, et al. Haploinsufficiency of the brain-derived neurotrophic factor gene is associated with reduced pain sensitivity. Pain. 2019;160(5):1070-1081
  9.  Hanish AE, Butman JA, Thomas F, Yao J, Han JC. Pineal hypoplasia, reduced melatonin and sleep disturbance in patients with PAX6 haploinsufficiency. J Sleep Res. 2016;25(1):16-22
  10.  US National Libray of Medicine. PAX6 gene. https://ghr.nlm.nih.gov/gene/PAX6. Published 2019. Updated July 2014. Accessed 30/10/19
  11.  US National Libray of Medicine. WT1 gene. https://ghr.nlm.nih.gov/gene/WT1. Published 2019. Updated September 2018. Accessed 30/10/19
  12.  U.S. National Library of Medicine. BDNF gene. https://ghr.nlm.nih.gov/gene/BDNF. Published 2019. Updated March 2013. Accessed 10 November 2019
  13.  ●Gottschling S, Meyer S, Krenn T, et al. Effects of short-term propofol administration on pancreatic enzymes and triglyceride levels in children. Anaesthesia. 2005;60(7):660-663. doi:https://doi.org/10.1111/j.1365-2044.2005.04231.x

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Updated on December 1, 2020
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