Forty-six of 93 children with neurofibromatosis type 1 (NF1) were found to satisfy the diagnostic criteria for attention-deficit-hyperactivity disorder (ADHD). Detailed comparisons were made among 20 children with NF1 and ADHD (12 males, 8 females; mean age 10.7 years, SD 2.2), 26 control children with NF1 (15 males, 11 females; mean age 11.3 years, SD 2.3), 14 control children with ADHD (7 males; mean age 9.9 years, SD 1.9), and 14 normally developing control children (7 males; mean age 11.2 years, SD 2.8). Children with NF1 and ADHD had the lowest IQ scores among the four groups. Test of Variables of Attention (TOVA) scores were poorer in the NF1-ADHD and ADHD control groups than in the two non-ADHD groups. Those with NF1 and ADHD were rated significantly poorer on the Child Behavior Checklist (CBCL) than were the NF1 control group. By administrating low doses (5 to 15 mg) of methylphenidate to the NF1-ADHD group, significantly improved TOVA scores were obtained. One-year follow-up yielded significantly improved CBCL scores. Our results show a high incidence of ADHD in NF1 and support an association between ADHD and learning and social problems in children with NF1. It was demonstrated that stimulant medication can lead to improvement in cognitive, academic, and social problems of children with NF1 and ADHD.

A total of 500 unselected unrelated neurofibromatosis 1 (NF1) patients were screened for deletions of the NF1 gene. After excluding 67 patients with known intragenic NF1 mutations, the remaining 433 were genotyped using six intragenic and one distal microsatellite marker for the NF1 gene. A total of 28 patients were hemi- or homozygous for all seven markers and were thus considered as candidates for NF1 deletion with a calculated probability of 99.99%. Metaphase or interphase cells were available from 23 of these 28 individuals for molecular cytogenetics. Fluorescence in situ hybridization (FISH) confirmed an NF1 deletion in 22 (96%) of the 23 patients. Thus, a constitutional deletion of the NF1 gene is responsible for the disease phenotype in at least 4.4% of the 500 unselected NF1 patients. Genotyping using multiple microsatellite markers may provide a simple, inexpensive, and efficient strategy for screening deletions of the NF1 gene, and can as well be applied for other large genes.

Forty-six of 93 children with neurofibromatosis type 1(NF1) were found to satisfy the diagnostic criteria for attentiondeficit-hyperactivity disorder (ADHD). Detailed comparisons were made among 20 children with NF1 and ADHD (12 males, 8 females; mean age 10.7 years, SD 2.2), 26 control children with NF1 (15 males, 11 females; mean age 11.3 years, SD 2.3), 14 control children with ADHD (7 males; mean age 9.9 years, SD 1.9), and 14 normally developing control children (7 males; mean age 11.2 years, SD 2.8).Children with NF1 and ADHD had the lowest IQ scores among the four groups. Test of Variables of Attention (TOVA) scores were poorer in the NF1-ADHD and ADHD control groups than in the two non-ADHD groups. Those with NF1 and ADHD were rated significantly poorer on the Child Behavior Checklist (CBCL) than were the NF1 control group. By administrating low doses (5 to 15 mg) of methylphenidate to the NF1-ADHD group, significantly improved TOVA scores were obtained. One-year follow-up yielded significantly improved CBCL scores. Our results show a high incidence of ADHD in NF1 and support an association between ADHD and learning and social problems in children with NF1. It was demonstrated that stimulant medication can lead to improvement in cognitive, academic, and social problems of children with NF1 and ADHD.

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More than half of neurofibromatosis 2 (NF2) patients represent de novo mutations which could have occurred at either pre-zygotic or post-zygotic stages. A post-zygotic mutation can result in mosaicism. In four sporadic NF2 patients, we found NF2 mutations in only a portion of corresponding leukocytes. In two other sporadic patients, no mutations were found in leukocytes but constitutional NF2 mutations were suggested by identical mutations in different tumors from each patient. We screened leukocyte DNA from a total of 16 inherited and 91 sporadic NF2 patients, and found NF2 mutations in 13 (81%) of the former and in 46 (51%) of the latter cases. The 30% difference in the rate of detection of mutations ( P = 0.051) might be partially explained by mosaicism in a portion of sporadic NF2 patients who carry the mutations in such a fashion that their leukocytes are unaffected. Among sporadic cases, we found mutations more frequently in patients with severe phenotypes (59%) than in patients with mild phenotypes (23%) (difference of 36%, P = 0.007). Mosaicism might be more common in the latter patient group since small populations of mutation-bearing cells can in some cases result in mild phenotypes and can also lead to difficulties in identifying mutations. No mutations were found in eight patients suspected of having NF2. Mosaicism with an extremely small population of affected cells may explain the incomplete phenotypes in some of these patients and the lack of mutations in their leukocytes. These findings suggest that mosaicism is relatively common in NF2 and may have important implications for diagnosis, prognosis and genetic counseling.