Neurofibromatosis type 1 is a genetic skeletal disorder

In the article by Superti-Furga et al. [2007] entitled, ‘‘Nosology and classification of genetic skeletal disorders: 2006 revision,’’ the Nosology Group of the International Skeletal Dysplasia Society provide a comprehensive list of genetic skeletal disorders. The working group proposed four criteria for inclusion and these are as follows: (1) Significant skeletal involvement, corresponding to the definition of skeletal dysplasias, metabolic bone disorders, dysostoses, and skeletal malformation and/or reduction syndromes; (2) Publication and/or listing in OMIM (meaning that observations should not find their way into the Nosology before they achieve peerreviewed publication status); (3) Genetic basis proven by pedigree or very likely based on homogeneity of phenotype in unrelated families; (4) Nosologic autonomy confirmed by molecular or linkage analysis and/or distinctive diagnostic features and observation in multiple individuals or families [Superti-Furga et al., 2007]. Neurofibromatosis type 1 (NF1) was not included in the list of disorders even though it fulfills the above-mentioned criteria. NF1 clearly fulfills the 2nd criterion as it is listed in OMIM (OMIMþ162200). NF1 also fulfills the 3rd criterion as multiple pedigrees show a well-documented autosomal dominant inheritance pattern with full penetrance. NF1 also fulfills the 4th criterion as nosologic autonomy has been confirmed by molecular analysis [Cawthon et al., 1990; Wallace et al., 1990; Viskochil et al., 1993], and NF1 has an established clinical diagnostic criteria system [Neurofibromatosis, 1988; Gutmann et al., 1997]. The 1st criterion is much more subjective and open to interpretation.Wepropose thatNF1has significant skeletal involvement thus fulfilling the 1st criterion. Although NF1 is typically thought of as a neurocristopathy or phacomatosis, skeletal abnormalities are frequently observed in NF1. One of the seven diagnostic criteria focuses solely on the distinct skeletal manifestations of NF1, and reads: ‘‘A distinctive osseous lesion such as sphenoid dysplasia or thinning of long bone cortex, with or without pseudarthrosis’’ [Neurofibromatosis, 1988]. One NF clinic reported that 38% of NF1 individuals had one or more orthopedic finding [Crawford and Schorry, 1999]. Skeletal manifestations of NF1 include long bone dysplasia with and without pseudarthrosis, sphenoid wing dysplasia, bone cysts, pectus deformities, relative macrocephaly, short stature for familial background, and dystrophic scoliosis with vertebral scalloping, vertebral wedging, spinal canal narrowing, vertebral body narrowing, and ribpenciling [Crawford and Bagamery, 1986; Crawford and Schorry, 1999, 2006; Durrani et al., 2000; Vitale et al., 2002; Ramachandran et al., 2004; Tsirikos et al., 2004]. Long bone dysplasia is likely the skeletal finding most specific to NF1 as 50–80% of individuals with tibial pseudarthrosis are reported to have NF1 [Sofield, 1971; Morrissy et al., 1981; Gilbert and Brockman, 1995]. The long bone abnormalities in NF1 typically present as anterolateral bowing of the long bone with the apex of the bowing at the distal third. Radiographic findings generally consist of cortical thickening and medullary narrowing of the diaphysis at the apex of the bowing. In some cases, the long bone bowing will progress to fracture and non-union, or psuedarthrosis. The long bone pseudarthrosis is difficult to treat requiring multiple surgical interventionswith amputation in many cases