Clinical Expression of NF1 in Monozygotic Twins

Twin studies can be a valuable tool in understanding variable expression in NF1. Evidence is accumulating that monozygotic (MZ) twins are not truly “identical” and may have multiple phenotypic differences as well as differences related to postzygotic and epigenetic events. There have been at least 45 pairs of confirmed MZ twins with NF1 reported in the medical literature. Phenotypic differences as extreme as complete discordance for NF1 diagnosis have been found to be due to somatic mutation. Multiple studies have shown MZ twins to be much more similar in numbers of cafe-au-lait spots and cutaneous neurofibromas than are siblings or more distant relatives, suggesting that germline modifying genes play a significant role in regulating these features. Learning disabilities, ADHD, and speech disorder are highly concordant in MZ twins, again implying a major role for germline genes. Valuable information has also come from traits that are discordant in co-twins. The majority of neoplasms, including optic pathway gliomas and malignant peripheral nerve sheath tumors (MPNSTs), fell into this category, consistent with sporadic second-hit events that are known to occur in those tumors. With only a few exceptions, plexiform neurofibromas occurred in different areas of the body when concordant in co-twins. Most dystrophic skeletal complications, such as dystrophic scoliosis or tibial pseudarthrosis, were discordant in MZ twins, suggesting nonhereditary events. Other possible causes of variable NF1 expression suggested by twin studies include epigenetic differences, NF1 promoter methylation differences, and postzygotic mutations of NF1 or other genes.