ClinVar

Upadhyaya et al. (2003) described a Portuguese family in which 3 members had clinical features of neurofibromatosis type I (NF1; 162200) and each had a different underlying defect in the NF1 gene. A 12-year-old boy who had multiple cafe-au-lait spots on his trunk and legs as well as developmental delay had a heterozygous 1.5-Mb deletion including the entire NF1 gene. The mutation was associated with the maternally derived chromosomal haplotype. His 10-year-old brother, who exhibited multiple cafe-au-lait spots and macrocephaly but whose development was within the normal range, was heterozygous for a CGA-to-TGA transition in exon 22 of the NF1 gene, resulting in an arg1241-to-ter mutation (613113.0031). This mutation had previously been described; its recurrence was thought to have been mediated by 5-methylcytosine deamination because it occurred in a hypermutable CpG dinucleotide. The brothers' 26-year-old female first cousin once removed (a first cousin of their father) exhibited multiple cafe-au-lait spots, bilateral Lisch nodules, and multiple dermal neurofibromas. She also showed severe scoliosis and several plexiform neurofibromas in the clavicular region, but her development was within the normal range. She was found to carry a frameshift mutation, 5406insT (613113.0032), in exon 29 of the NF1 gene. None of the parents had any clinical evidence of NF1 and none had a mutation in the NF1 gene. There was also no evidence of mosaicism. Upadhyaya et al. (2003) speculated about the mechanism of this unusual situation.