Neurofibromatosis Type 1: Cognitive and Behavioral Phenotype: Diagnosis and Treatment

Abstract

Neurofibromatosis type 1 (Nf1) is a neurocutaneous disorder with a prevalence of approximately 1 in 2,500–3,500 individuals (Ferner et al. 2007). The physical manifestations of Nf1, such as café au lait spots, axillary freckling, iris hamartomas (Lisch nodules), osseous lesions (sphenoid wing dysplasia, pseudoarthrosis), and benign as well as malignant neural tumors (neurofibromas, optic gliomas), are well recognized (Castle et al. 2003; Ferner et al. 2007). National Institutes of Health (NIH) criteria are currently used for clinical diagnosis (1988) (Table 31.1). The clinical severity of this disorder is quite variable, and approximately 20% of children with Nf1 will later have considerable physical complications (Castle et al. 2003; Ferner et al. 2007; Williams et al. 2009). Other clinical manifestations are abnormalities of the cardiovascular, gastrointestinal, renal, and endocrine systems, facial and body disfigurement, cognitive deficit, and malignancies of the peripheral nerve sheath and central nervous system. The tumors that occur in Nf1 are dermal and plexiform neurofibromas, optic gliomas, malignant peripheral nerve sheath tumors (MPNSTs), pheochromocytomas, and rhabdomyosarcomas (Castle et al. 2003). Children with Nf1 have an increased risk of developing myeloid disease, particularly juvenile chronic myeloid leukemia. Some 30%–40% of Nf1 patients develop plexiform neurofibromas (Szudek, Evans, and Friedman 2003). Malignant peripheral nerve sheath tumors are present in 5%–10% of cases (Evans et al. 2002), often in preexisting plexiform neurofibromas (Castle et al. 2003). Although many see the predisposition to cancer as the major concern regarding Nf1, some of the more prevalent features are not directly related to tumors (Acosta, Gioia, and Silva 2006). Cognitive dysfunction, academic difficulties, and school failure, occur in 40%–80% (Hyman, Arthur, and North 2006; Krab et al. 2008; North et al. 1997). These complications affect the day-to-day life of these children, and are the largest cause of lifetime morbidity in the pediatric Nf1 population (Acosta et al. 2006). These deficits impact on long-term adaptation to society (Acosta et al. 2006; Barton and North 2007; Krab et al. 2008; Krab et al. 2009).