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Aniridia is a severe eye disease characterized by iris hypoplasia; both sporadic cases and familial cases with an autosomal dominant inheritance exist. Mutations in the PAX6 gene have been shown to be the genetic cause of the disease. Some of the sporadic cases are caused by large chromosomal deletions, some of which also include the Wilms tumor gene (WAGR syndrome), resulting in an increased risk of developing Wilms tumor. Based on the unique registration of both cancer and aniridia cases in Denmark, we have made the most accurate risk estimate to date for Wilms tumor in sporadic aniridia. We have found that patients with sporadic aniridia have a relative risk of 67 (confidence interval: 8.1-241) of developing Wilms tumor. Among patients investigated for mutations, Wilms tumor developed in only two patients out of 5 with the Wilms tumor gene (WT1) deleted. None of the patients with smaller chromosomal deletions or intragenic mutations were found to develop Wilms tumor. Our observations suggest a smaller risk for Wilms tumor than previous estimates, and that tumor development requires deletion of WT1. We report a strategy for the mutational analysis of aniridia cases resulting in the detection of mutations in 68% of sporadic cases and 89% of familial cases. We also report four novel mutations in PAX6, and furthermore, we have discovered a new alternatively spliced form of PAX6.

The hypothesis that low-level lead absorption is a risk factor for learning disabilities in school children was examined in the municipality of Aarhus, Denmark. During 1982-1983, a total of 1,302 children in the first grade (54% of the eligible population) delivered shed deciduous teeth. The lead concentration in the circumpulpal dentin was used as an indicator of the cumulated lead absorption, and 200 cases (high-lead) and controls (low-lead) were selected, and matched for socioeconomic group and gender. The parents were interviewed regarding the child's development and past medical history. Possible confounders were identified and controlled for in a logistic multivariate model. The influence of lead absorption became statistically significant only after exclusion of the children with proven medical risk factors, thereby the adjusted odds ratio in the weighted analysis was changed from 2.2 to 4.3. Thus, in a Scandinavian low-level lead-polluted area, lead absorption appears to be a risk factor for learning disabilities.

Cerebellar ataxia, areflexia, pes cavus, optic atrophy and sensorineural hearing impairment (CAPOS) is a rare clinically distinct syndrome caused by a single dominant missense mutation, c.2452G>A, p.Glu818Lys, in ATP1A3, encoding the neuron-specific alpha subunit of the Na+/K+-ATPase α3. Allelic mutations cause the neurological diseases rapid dystonia Parkinsonism and alternating hemiplegia of childhood, disorders which do not encompass hearing or visual impairment. We present detailed clinical phenotypic information in 18 genetically confirmed patients from 11 families (10 previously unreported) from Denmark, Sweden, UK and Germany indicating a specific type of hearing impairment-auditory neuropathy (AN). All patients were clinically suspected of CAPOS and had hearing problems. In this retrospective analysis of audiological data, we show for the first time that cochlear outer hair cell activity was preserved as shown by the presence of otoacoustic emissions and cochlear microphonic potentials, but the auditory brainstem responses were grossly abnormal, likely reflecting neural dyssynchrony. Poor speech perception was observed, especially in noise, which was beyond the hearing level obtained in the pure tone audiograms in several of the patients presented here. Molecular modelling and in vitro electrophysiological studies of the specific CAPOS mutation were performed. Heterologous expression studies of α3 with the p.Glu818Lys mutation affects sodium binding to, and release from, the sodium-specific site in the pump, the third ion-binding site. Molecular dynamics simulations confirm that the structure of the C-terminal region is affected. In conclusion, we demonstrate for the first time evidence for auditory neuropathy in CAPOS syndrome, which may reflect impaired propagation of electrical impulses along the spiral ganglion neurons. This has implications for diagnosis and patient management. Auditory neuropathy is difficult to treat with conventional hearing aids, but preliminary improvement in speech perception in some patients suggests that cochlear implantation may be effective in CAPOS patients.

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A total of 245 newly shed deciduous incisors were obtained from 114 first-grade children who each contributed more than one tooth. Lead concentrations averaged about fivefold higher in circumpulpal dentin than in the whole tooth, but the two parameters showed little correlation. A considerable intraindividual variation in lead levels was partly related to tooth type. In particular, whole upper central incisors contained more lead than did other incisors, but the reverse applied to circumpulpal dentin lead concentration. As whole-tooth and circumpulpal lead concentrations may represent different compartments, tooth lead analyses must be interpreted accordingly. Lead levels in circumpulpal dentin would appear to be a meaningful indicator of long-term lead retention in population studies of children.

Blood lead concentrations were measured in a group of children from a group of 9- to 10-year-old school children in Aarhus, Denmark. The study group was selected as a high-level and a low-level lead group, as identified by the lead concentration in the circumpulpal dentine in deciduous teeth shed 2-3 years previously. The validity of the blood sampling technique was investigated in adult volunteers, and lead was determined by electrothermal atomic absorption. Capillary blood sampling by a finger-stick method was preferred, as the slight contamination caused by this technique was deemed acceptable. The children with the highest dentine lead levels (n = 70), had blood lead concentrations of 0.08-0.63 mumol/l and a geometric mean of 0.28 mumol/l. The children with lowest dentine levels (n = 76) had blood lead concentrations of 0.08-0.70 mumol/l and a geometric mean of 0.18 mumol/l. The blood lead concentrations were compared with interview data on behaviour, family habits, diet, parents' tobacco smoking and occupation, water lead measurements, and traffic counts. A total of 20% of the variation in blood lead was explained by parents' tobacco smoking, the child's number in the sibship, gender, and consumption of canned food at home.