Results of NIH Study

Joan Han, MD

Lead Investigator
Study of Aniridia, WAGR Syndrome, and 11p Deletions
National Institutes of Health
2006-2014

Director
Pediatric Obesity Program
Le Bonheur Children’s Hospital

Associate Professor
Division of Pediatric Endocrinology
Department of Pediatrics
University of Tennessee Health Science Center
Memphis, Tennessee

office phone: 901-287-6408
office fax: 901-287-4478

EMAIL: jhan14@uthsc.edu

Summary of Results
National Institutes of Health
Study of WAGR syndrome, 11p Deletions, and Aniridia
2006 – 2014
Genotyping Methods

In clinical practice, high-resolution karyotype and fluorescence in situ hybridization are typically used for diagnosis. However, these methods can be costly, and inaccessible in developing countries. a novel quantitative fluorescent PCR method for rapid and inexpensive screening of genomic copy number variations for the diagnosis of WAGR syndrome and other deletion/duplication syndromes.

Rapid and inexpensive screening of genomic copy number variations using a novel quantitative fluorescent PCR method. Stofanko M, Han JC, Elsea SH, Pena HB, Gonçalves-Dornelas H, Pena SD. Dis Markers. 2013;35(6):589-94. doi: 10.1155/2013/704917. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3830787

Obesity

The NIH research team observed that haploinsufficiency (having one copy of a gene instead of two) for the gene that encodes for brain-derived neurotrophic factor (BDNF) is associated with childhood-onset obesity in persons with WAGR syndrome. Their findings demonstrated that BDNF is important for energy homeostasis in humans.

Brain-Derived Neurotrophic Factor and Obesity in the WAGR Syndrome. Han JC, Liu QR, Jones M, Levinn RL, Menzie CM, Jefferson-George KS, Adler-Wailes DC, Sanford EL, Lacbawan FL, Uhl GR, Rennert OM, Yanovski JA. N Engl J Med 2008;359(9):918-27. http://www.ncbi.nlm.nih.gov/pubmed/18753648

Pain Perception

Mice with Bdnf haploinsufficiency are not only hyperphagic (abnormally excessive appetite) and obese, but also exhibit reduced thermal pain response. The NIH research team observed that BDNF haploinsufficiency in patients with WAGR syndrome is associated with significantly reduced scores on a parent-completed questionnaire assessing behavior responses to injuries or illnesses considered painful to most people. These findings suggest that BDNF plays a role in human pain perception.

These findings were reported in the supplementary appendix 1 of the publication on obesity (N Engl J Med 2008;359(9):918-27). http://www.nejm.org/doi/suppl/10.1056/NEJMoa0801119/suppl_file/nejm_han_918sa1.pdf

Cognition and Behavior

Mice with Bdnf haploinsufficiency exhibit learning deficits and social behavior abnormalities. The NIH research team observed that, among patients with WAGR syndrome, BDNF haploinsufficiency is associated with a 20-pointed lower intelligence quotient and 15-point lower Vineland Adaptive Behavior Composite score than among individuals without the haploinsufficiency. BDNF haploinsufficiency was also associated with greater social impairment, the percentage meeting criteria for autism on the Autism Diagnostic Interview-Revised, but not for diagnosis of true autism based on Autism Diagnostic Observation Schedule and the clinical judgment of a child psychologist. These findings support a role for BDNF in human neuro-cognitive development. Brain MRI revealed hypoplastic (small or underdeveloped) corpus callosum in 31% of patients but the rates were similar in those with and without BDNF haploinsufficiency suggesting that some other gene in the chromosome 11p region is important for corpus callosum development.

Association of brain-derived neurotrophic factor (BDNF) haploinsufficiency with lower adaptive behaviour and reduced cognitive functioning in WAGR/11p13 deletion syndrome. Han JC1, Thurm A, Golden Williams C, Joseph LA, Zein WM, Brooks BP, Butman JA, Brady SM, Fuhr SR, Hicks MD, Huey AE, Hanish AE, Danley KM, Raygada MJ, Rennert OM, Martinowich K, Sharp SJ, Tsao JW, Swedo SE. Cortex. 2013 Nov-Dec;49(10):2700-10. doi: 10.1016/j.cortex.2013.02.009. Epub 2013 Feb 19. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3762943/

Sleep and Melatonin Production

The aniridia of WAGR syndrome is caused by PAX6 haploinsufficiency. This gene is also believed to play a role in the development of the pineal gland, a structure in the brain which controls circadian rhythm and produces the sleep hormone melatonin. The NIH research group observed that patients with WAGR syndrome or isolated aniridia had smaller pineal volumes, decreased melatonin production, and increased sleep disturbance. These findings suggest that PAX6 plays an important role in pineal development and function.

PAX6 Haploinsufficiency: Pineal Hypoplasia, Reduced Melatonin, & Sleep Disturbance. Hanish AE, Butman JA, Caplan Y, Tsang M, Thomas F, Yao J, Han JC. SLEEP (28th Annual Meeting of the Associated Professional Sleep Societies) in Minneapolis, MN, June 2014. Unpublished findings presented as preliminary data in abstract format at a medical conference.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4823177/

Cranial Nerves

The NIH research team observed that absence or incomplete development of nerves in the brain, specifically nerves associated with smell (CN I) and outward eye gaze (CN VI), is not uncommon in patients with WAGR syndrome. This suggests that the genes on chromosome 11 around the WAGR region are important for the development of these nerves in the brain.

Agenesis of the Olfactory (CN1) and Abducens (CN VI) Nerves in WAGR Syndrome. Butman JA, Zein WM, Fuhr SR, Huey AE, Crossman JR, Tsang MM, Bowles KE, Sharp SJ, Tsao JW, Brooks BP, Han JC. Society of Neuroradiology 49th Annual Meeting in Seattle, Washington in June 2011. Unpublished findings presented as preliminary data in abstract format at a medical conference. Poster 133 on page 417 of : http://www.asnr2.org/proceedings/2011.pdf

Differences in Brain Structure

The NIH research team observed structural brain differences between patients with WAGR syndrome and patients with isolated aniridia. The findings suggest that other genes on chromosome 11 besides PAX6, the gene that causes aniridia, may contribute to brain structure.

Morphologic Alterations in Brain Structure in Patients with WAGR/11p Deletion Syndrome. McEntee JE, Butman JA, Pham DL, Fuhr SR, Huey AE, Sharp SJ, Tsao JW, Han JC. Morphologic alterations in brain structure in patients with WAGR/11p deletion syndrome. Organization for Human Brain Mapping’s 17th Annual Meeting in Quebec City, Canada, June 26-30, 2011. Abstract 334 on page 124 of: http://www.humanbrainmapping.org/files/2011MeetingFiles/HBM2011AbstractBook.pdf Unpublished findings presented as preliminary data in abstract format at a medical conference.

Short Stature

The NIH research team observed shorter stature in patients with WAGR syndrome, and that this did not appear to be associated with growth hormone deficiency, but rather with an inadequate growth spurt during puberty.

Childhood Stature in WAGR Syndrome. RL Levinn, JC Han, CA Wijesinghe, JK Gustafson, JM Checchi, DC Adler-Wailes, KS Jefferson-George, OM Rennert, JA Yanovski, Unit on Growth & Obesity, PDEGEN, NICHD, NIH, Bethesda, MD. Endocrine Society’s 90th Annual Meeting, San Francisco, CA, June 2008.Unpublished findings presented as preliminary data in abstract format at a medical conference.

Craniofacial Abnormalities

Patients with WAGR syndrome frequently have narrow, high arched palates, dental crossbites, and narrowing of the pharynx.

WAGR Syndrome: Oral and Craniofacial Characteristics. Domingo DL, Tomona N, Danley KM, Tune MK, Han JC. American Society of Human Genetics 59th Annual Meeting, Honolulu, HI, October 20-24, 2009. Unpublished findings presented as preliminary data in abstract format at a medical conference. http://www.ashg.org/2009meeting/abstracts/fulltext/f10790.htm

Susceptibility to Pancreatitis

Patients with WAGR syndrome have higher rates of pancreatitis than individuals in the general population. The risk for pancreatitis is increased particularly if the patient has elevated triglycerides. The PAX6 gene appears to play an important role in pancreas development; therefore, PAX deletion may be an additional predisposing risk factor for pancreatitis. Propofol, an anesthetic agent that is delivered in an oil suspension, can transiently increase triglyceride levels. One patient in the NIH study was observed to develop acute pancreatitis after receiving propofol. It is advisable to monitor amylase, lipase, and triglycerides in patients with WAGR syndrome, and to avoid the administration of propofol in the setting of baseline abnormalities in these laboratory values.

Acute Pancreatitis after Propofol Administration in a Child with WAGR Syndrome. Danley KM, Henderson WA, Ibrahim T, Hadigan CM, Han JC. North American Society for Pediatric Gastroenterology, Hepatology and Nutrition Annual Meeting, National Harbor, MD, November 2009. Unpublished findings presented as preliminary data in abstract format at a medical conference.

Hearing and Auditory Processing

The NIH Research team found sensorineural hearing loss in 5%, abnormal brainstem response in 50%, and auditory processing deficits in 92% of patients with WAGR syndrome.
Auditory Function in WAGR Syndrome and Isolated Aniridia. Kokx M, Zalewski CK, King KA, Brady SM, Hanish AE, Hicks MD, Huey AE, Fuhr SR, Danley KM, Brewer CC, Han JC. 40th Annual Scientific and Technology Conference of the American Auditory Society in Scottsdale, AZ, March 2013. Poster #29 – DX02: https://aas.memberclicks.net/assets/docs/aas_2013_poster_abstracts.pdf?mcid_token=36108aed-843a-477d-a9b9-c9469c6b1707