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


Synonyms of WAGR syndrome

  • Chromosome 11p deletion syndrome
  • WAGR complex

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Overview

Prevalence
  • 1 in 500,000[1]
Inheritance
  • de novo sporadic is most common
  • Rarely autosomal dominant
Genes involved (OMIM No.)Deletion of chromosome 11p13:
Main features
  • Increased risk of Wilms tumour (45-60%)
  • Aniridia
  • Genitourinary anomalies (Cryptorchidism, hypospadias, streak ovaries, increased risk of gonadoblastoma)
  • Range of developmental delays
Other features
  • Chronic kidney disease
  • Behavioural and neurodevelopmental disorders
  • Neurological abnormalities
  • Early onset obesity
  • Dyslipidaemia
  • Sleep disorders and sleep apnoea
Key investigationsOcularSystemic
  • Renal ultrasound
  • Audiology
  • MRI brain imaging
Molecular diagnosis
  • Chromosomal microarray to exclude WT1 and PAX6 deletion
ManagementOcular
  • Supportive
  • Correct refractive errors, prevent amblyopia
  • Monitor for glaucoma, cataract and keratopathy
Systemic
  • Serial 3 monthly renal USS till age of 8 for confirmed WT1 deletions
  • Multidisciplinary approach to other associated systemic issues
Therapies under research

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Clinical phenotype

Main features

1) Wilms tumour (nephroblastoma)

Patients affected by WAGR syndrome are at 45-60% increased risk of developing Wilms tumour.[2][3] Compared to patients with isolated Wilms tumour not associated with a WT1 gene deletion, WAGR patients often have a younger age of diagnosis and tend to have bilateral involvement.[4] Of those who develop Wilms tumour, 98% do so by age seven.[5]

In the early stages, Wilms tumour usually does not cause any symptoms. Later on, patients might experience haematuria, abdominal pain and swelling, anaemia, low-grade fever, loss of appetite, weight loss and lethargy. About 30% of children with Wilms tumour also have hypertension.

2) Aniridia

Iris hypoplasia with associated lens opacity

Aniridia is almost universally present in WAGR patients and tends to be severe.[1] It is usually the first sign detected by clinicians at birth or early infancy, leading to further examination and investigations. Approximately 1/3 of patients presenting with aniridia have WAGR syndrome.

Patients with aniridia typically have impaired vision (VA 6/30 or worse) and photophobia but milder forms of aniridia with subtle changes to the iris architecture, good vision, and normal foveal structure do occur.[6]

3) Genitourinary anomalies

Both males and females might suffer from abnormal development of their gonads, external genitalia and urinary tract.

Cryptorchidism is the most common manifestation among males with WAGR syndrome (60% of cases) followed by hypospadias. In females, uterine abnormalities such as bicornate uterus and streak ovaries can occur. These gonadal malformations lead to an increased risk of gonadoblastoma development in WAGR patients.

Other features include:

  • Ambiguous genitalia
  • Uretheral strictures
  • Ureteric abnormalities

4) Range of developmental delay

Children with WAGR syndrome may experience developmental delays in various aspects, such as gross and/or fine motor skills, speech and intellectual disability. However, the severity and the developmental aspect(s) that are affected are highly variable among patients.

Other associated features

1) 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). Symptoms of FSGS include high blood pressure and protein in the urine. FSGS may progress to kidney failure, requiring dialysis or kidney transplant[4]

2) Behavioural, neurodevelopmental, and psychiatric disorders

These are common in patients with WAGR syndrome. They may include attention-deficit disorder (ADD), attention-deficit hyperactivity disorder (ADHD), autism spectrum disorder, anxiety, depression, and obsessive-compulsive disorder (OCD).

3) Neurological abnormalities

Hyper- or hypotonia and seizures are commonly found in WAGR patients.

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.[7]

5) Early onset obesity (before the age of 10) and dyslipidaemia

50% of patients with WAGR syndrome have a deletion of one copy of the BDNF gene.[8] 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.[9]

6) Sleep disorders and sleep apnoea

These conditions are common in WAGR syndrome.[10] People with WAGR syndrome may have small or absent pineal glands, disrupting the production of melatonin. 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.

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Genetics

WAGR syndrome is associated with contiguous gene deletions involving both PAX6 and the adjacent WT1 gene on chromosome 11p13.

The PAX6 gene encodes highly conserved transcriptional factors that are involved in the early development of the eye, brain, olfactory bulb, neural tube, pancreas and gut in the embryo.[6] 99% of isolated aniridia are due to mutations in this gene.[1]

The WT1 gene encodes the Wilms tumour 1 protein that is involved in the development of kidneys and gonads before birth. Postnatally, the WT1 protein regulates renal cell division, differentiation and apoptosis. Deletion of the WT1 gene leads to unregulated cell growth and thus increases the risk Wilms tumour formation.

The BDNF gene encodes for a protein found in the brain and spinal cord. 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. People with deletion of this gene may have learning difficulties, early onset obesity, and a decreased response to pain.[9]

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Key investigations

Ocular

1) Optical coherence tomography (OCT)

OCT can be used to detect fovea hypoplasia and support a clinical diagnosis of aniridia, especially where iris defects may be subtle. Anterior segment OCT can help delineate anterior segment structures even in the presence of corneal opacity.

OCT scan of the macula showing the absence of a pit which is normally present in normal individuals.
OCT scan of the left macula of a PAX6 aniridia patient

2) High-frequency ultrasound biomicroscopy (UBM)

This is usually performed in infants (under general anaesthesia) presenting with corneal opacity or corneal oedema associated with congenital glaucoma. Iris hypoplasia and other anterior segment abnormalities can be identified through this modality.

3) Ultrasound B-scan

This should be performed routinely to assess axial length (AL) due to the association of PAX6 aniridia with microphthalmia. It is defined as AL < 19mm in infants at 1 year of age or <21mm in adults. 

4) Electrophysiology

To assess level of vision and exclude other causes of nystagmus such as ocular or oculocutaneous albinism

Systemic

Children presenting with aniridia should be investigated and monitored for WAGR syndrome by a paediatrician until absence of WT1 deletion is proven through genetic testing.  Investigations usually include:

  • Renal ultrasound
  • Audiology
  • MRI brain imaging
  • Endocrine assessment (if indicated)
  • Sleep assessment (if indicated)

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Diagnosis

Patients are usually referred due to the presence of aniridia. Therefore, general ophthalmologists should be vigilant about its association with Wilms tumour and other systemic features.

New patients should be under joint care with a paediatrician and have genetic testing done urgently either by a clinical geneticist or an ophthalmologist specialising in genetic eye disease.

Patients should be tested for WT1 and PAX6 deletions with chromosomal microarray in the first instance to exclude WAGR syndrome. If this is negative, PAX6 is then screened using sequence analysis to identify a causative mutation as per isolated aniridia.

Related links

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Management

Patients diagnosed with WAGR syndrome often have complex physical, mental and social needs. Therefore, a multidisciplinary approach is key.

Ocular

Aniridia

Patients with aniridia should be followed-up regularly by a glaucoma specialist as they are at increased risk of developing secondary glaucoma. They may also need input, monitoring and intervention from the cornea specialists if they have evidence of limbal stem cell deficiency and their cornea is affected by epithelial defects and scarring.

Related links

Systemic

1) Wilms tumour

Patients with confirmed WT1 gene deletion should be referred to a paediatrician for Wilms tumour surveillance. Serial 3 monthly renal ultrasound scans are performed until the age of 8 where the risk of tumour development is low. Patients who did not get or refused genetic testing should be monitored similarly. The same is applied to aniridia patients until absence of WT1 gene deletion is confirmed.

If Wilms tumour is diagnosed, treatment usually involves a combination of nephrectomy, chemotherapy and radiotherapy. Due to the significant risk of renal failure especially in patients with bilateral Wilms tumour,[4] lifelong monitoring of renal function and blood pressure is recommended.

2) Genitourinary anomalies

This is usually managed by a combination of urologists, gynaecologists and endocrinologists. Various surgical and/or hormonal approaches can be explored on an individual basis.

3) Developmental delays, behavioural and psychiatric disorders, neurological abnormalities

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.

4) 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]

5) Neurological abnormalities

Physiotherapy is helpful for problems with muscle tone, coordination, and strength.

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.

8) Dyslipidaemia

Patients may benefit from lipid lowering medications. In addition, individuals affected by WAGR syndrome should avoid propofol for general anaesthesia induction if possible as it has been shown even short-term use can increase serum triglyceride levels and cause acute pancreatitis.[11]

9) 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) machine.

Family management and counselling

WAGR syndrome usually arise sporadically but very rarely, it is inherited with an autosomal dominant pattern due to mosaicism in either parent.

Patients and families require genetic counselling and can seek advice for family planning including prenatal testing and preimplantation genetic diagnosis.

Emotional and social support

Eye Clinic Liaison Officers (ECLOs) act as an initial point of contact for newly diagnosed patients in clinic. They provide emotional and practical support to help patients deal with their diagnosis and maintain independence. They work closely with the local council’s sensory support team and are able to advise on the broad range of services provided, such as visual rehabilitation, home assessment, work and access to qualified teachers for children with visual impairment (QTVI) among other services.

Related links

Referral to a specialist service

In the UK, patients should be referred to their local genomic ophthalmology (if available) or clinical genetics services to receive a more comprehensive genetic management of their conditions (genetic testing and genetic counselling) and having the opportunity to participate in clinical research.

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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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Further information and support

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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.  Hingorani M, Hanson I, Van Heyningen V. Aniridia. European Journal of Human Genetics. 2012;20(10):1011
  7.  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
  8.  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
  9.  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
  10.  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
  11.  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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