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Pineal hypoplasia and decreased melatonin in patients with PAX6 haploinsufficiency due to WAGR syndrome or PAX6 mutations

Thursday, October 11, 2012 — Poster Session III

10:00 a.m. – Noon

Natcher Conference Center, Building 45




  • A.E. Hanish
  • J.A. Butman
  • A.E. Huey
  • M.D. Lee
  • E. Yin
  • L.A. Hunter
  • M.D. Hicks
  • T. Singh
  • M. Tsang
  • J.C. Han


Background: Aniridia can be caused by isolated PAX6 haploinsufficiency (+/-) due to mutations or heterozygous deletion as part of WAGR/11p deletion syndrome. Pineal gland hypoplasia has been previously reported, but melatonin has not been studied in humans with PAX6 mutations. Methods: 39 WAGR subjects, 13 PAX6+/- subjects, and 20 controls were evaluated as inpatients. Pineal was evaluated by brain MRI. Serum melatonin and urine 6-sulfatoxymelatonin (6SM) were measured by ELISA. The Child Sleep Habits Questionnaire (CSHQ) was administered for subjects <13y. Results: The prevalence of pineal gland hypoplasia was higher in WAGR (58%) and PAX6+/- (45%) vs. controls (0%, p<0.01). Midnight melatonin was ~2-fold lower in WAGR and PAX6+/- vs. controls (p<0.01). Midnight melatonin was ~2-fold lower in those with vs. without pineal hypoplasia (p=0.02). Morning urinary 6SM level (reflecting nighttime production) was ~4-fold lower in WAGR and PAX6+/- as compared to controls (p<0.01). CSHQ score was ~30% higher for WAGR/PAX6+/-vs. controls, but not statistically different (p=0.08). Conclusions: Pineal hypoplasia occurred in 55% of WAGR/PAX6+/- subjects, and was associated with lower melatonin production. In WAGR/PAX6+/- children, there was a trend toward greater sleep disturbance. Our findings support the view that PAX6 plays an important role in pineal development and function.

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