Pineal hypoplasia, reduced melatonin and sleep disturbance in patients with PAX6 haploinsufficiency

In rodent studies, paired box 6 (PAX6) appears to play an important role in the development of the pineal, the primary source of the circadian regulating hormone, melatonin. Pineal hypoplasia has been previously reported in patients with PAX6 haploinsufficiency (+/-); however, pineal measurement, melatonin concentrations and sleep quality have not been reported. This cross-sectional descriptive study examined pineal volume, melatonin secretion and sleep disturbance in 37 patients with PAX6+/- (age 15.3 ± 9.9 years) and 17 healthy controls (16.0 ± 7.2 years), within an inpatient setting at the Clinical Research Center of the National Institutes of Health, Bethesda, Maryland, USA. Pineal volume was evaluated by magnetic resonance imaging. Diurnal serum cortisol, serum melatonin and urine 6-sulphatoxymelatonin concentrations were measured by enzyme-linked immunosorbent assay. The Child Sleep Habits Questionnaire was administered for patients <13 years old. Pineal volume was fivefold lower in PAX6+/- versus controls (mean ± SD: 25 ± 15 versus 129 ± 50 μL, P < 0.001). Midnight serum cortisol was similar in PAX6+/- versus controls (P = 0.14). Midnight serum melatonin was > twofold lower in PAX6+/- versus controls [median (25th-75th): 28 (22-42) versus 71 (46-88) pg mL^-1, P < 0.001]. First morning void urinary 6-sulphatoxymelatonin was fourfold lower in PAX6+/- versus controls [11 (6-26) versus 45 (34-61) ng mg^-1 Cr, P = 0.001]. Child Sleep Habits Questionnaire score was higher in PAX6+/- versus controls (48 ± 6 versus 41 ± 5, P = 0.03). The current findings suggest that PAX6+/- is associated with smaller pineal size, lower melatonin secretion and greater parental report of sleep disturbances in children. Further studies are needed to explore the potential use of melatonin replacement for improving sleep quality in patients with PAX6+/-.