The Skeleton Abnormalities in Patients with Neurofibromatosis Type 1: Important Consequences of Abnormal Gene Function

Neurofibromatosis type 1 [Nf-1, OMIM #1622001], formerly known as von Recklinghausen disease, is one of the most frequent disorders affecting mankind, inherited as an autosomal dominant trait. The relatively high prevalence, with an incidence at birth of approximately one in 2500 to 3500 live births, and a progressive nature of the disorder, notable for its phenotypic variability with almost 100% penetrance, as well as high proportion of sporadic cases (almost 50% of de novo mutations), constitute for the clinical magnitude of this disease. Multiple café au lait spots [CALs], axillary and inguinal freckling, multiple discrete cutaneous neurofibromas [NFM] and more prominent plexiform neurofibromas [PNF], and iris Lisch nodules constituted for the cardinal signs of the disease. Learning disabilities and attention deficits states, but usually with normal intelligence in adulthood, are present in at least 50% of individuals with Nf-1. Neurofibromatosis type 1 belongs to the group of disorders with significantly increased risk of tumorigenesis. The other significant manifestations of Nf-1 include bone dysplasias, clinically presented as progressive dystrophic scoliosis, vertebral dysplasia, overgrowth and tibial dysplasia with pseudarthrosis, and vasculopathy. Pubertal development is usually normal, but precocious puberty, especially in those with an optic chiasm glioma, as well as delayed puberty, may commonly occur in children with Nf-1. The life expectancy of Nf-1 patients is assumed to be reduced by 15 years. The most important causes of early death in these patients are malignant peripheral nerve sheath tumors and severe complications of vasculopathy (Friedman et al., 1999; Jett & Friedman, 2010; Larizza et al., 2009). Despite the possibility of molecular testing, the diagnosis of Nf-1 is still based on clinical findings and is usually unequivocal in all but the young children (DeBella et al., 2000b). The diagnostic criteria for Nf-1 (Tabl. 1) were developed by the US National Institutes of Health (National Institute of Health [NIH], 1988) and are generally accepted worldwide for routine clinical use (Ferner et al., 2007; Williams et al., 2009). The disease is characterizes by extreme clinical variability, not only between unrelated, but also among affected individuals within a