Clinical complications of Neurofibromatosis Type 1
Skin features of NF1 Café-Au-Lait Spots (CALS) are the most common manifestation of NF1. They are often present at birth or become visible during the first few months of life, and usually appear before the age of two. By the age of five, over 95% of NF1 children have CALS and these increase in size and number throughout life (Korf, 1992). The typical CALS have sharp, well defined borders and become darker in sun-exposed areas. Although CALS are present in the general population, it is only six or more CALS which indicate a strong likelihood of the presence of the disease.
Skinfold freckling represents the second most common feature of NF1. It is present in approximately 80% of patients, with the majority having multiple sites of freckling. This freckling generally appears before the age of five and is often present in the axilla, inguinal regions, and submammary regions in women. In obese individuals with NF1, freckling is often seen between skin folds.
Discrete neurofibromas are benign tumours arising from nerves that contain neural elements and an overgrowth of small blood vessels and fibrous connective tissue. They do not usually develop until preadolescence, and increase during adolescence and young adult years. Early neurofibromas may appear as “divots” in the skin, with reddening of the skin due to dilation or proliferation of overlying capillaries. Cutaneous neurofibromas occur within the dermis and epidermis and movement of the skin results in movement of the tumour.
In contrast, subcutaneous neurofibromas lie underneath the dermis and the skin moves over them. Subcutaneous neurofibromas are discrete, firm, generally have a spherical or oval shape and are often tender to palpation.
Over 50% of children with NF1 have neurofibromas, with the majority having more than one. The occurrence of neurofibromas increases as the patients get older, and over 95% of patients with NF1 have neurofibromas in adulthood (Young et al., 2002). The earlier neurofibromas appear, the more likely the individual is to develop a high tumour load with age. Discrete neurofibromas are usually not premalignant lesions and rarely transform into malignant tumours (neurofibrosarcomas).
Plexiform neurofibromas arise from hamartamatous overgrowth of groups of deep or superficial nerves and are present in approximately 30% of patients with NF1. They appear as a soft-tissue mass under the skin, often following the course of a peripheral nerve. They may be superficial, deep, or nodular. Hyperpigmentation of the overlying skin may occur, as well as hypertrophy or deformity of the involved area. Plexiform neurofibromas may cause severe cosmetic disfigurement or compression or overgrowth of other structures. Large plexiform neurofibromas are congenital in origin and are usually obvious by the age of two years.
Plexiform neurofibromas have a potential for malignant transformation (Korf, 1999). Approximately 3% of lesions may develop into highly malignant peripheral nerve sheath tumours, accounting for the increase lifetime risk of malignancy in patients with NF1 (King, Debaun, Riccardi & Gutmann, 2000; Waggoner, Towbin, Gottesman & Gutmann, 2000).
Eye abnormalities in NF1 Lisch nodules are harmless iris hamartomas. They are rare in children under six, yet become increasingly frequent in older patients. Over 50% of NF1 children have Lisch nodules and there is an increasing frequency of these lesions in older patients, with over 98% of adults with NF1 having them. Lisch nodules do not portend other ocular manifestations of NF1 or visual compromise. They can be seen by a slit- lamp examination, and present as three-dimensional translucent masses punctuated by melanin containing cells. Lisch nodules are pathognomonic of NF1, and are an extremely useful diagnostic tool which is frequently used for screening parents of affected children. Optic pathway gliomas are the most common central nervous system tumours in patients with NF1 (Listernick, Louis, Packer & Gutmann, 1997). They are present in 15-20% of patients on neuroimaging, however only 30-50% of these tumours become symptomatic.
Histologically optic gliomas are low grade pilocytic astrocytomas and it is not known why some tumours progress rapidly to cause symptoms while others remain quiescent for many years. Common symptoms of optic pathway tumours are decreased visual acuity, visual field defects, proptosis, strabismus and hypothalamic dysfunction. A study of precocious puberty in NF1 found all cases were associated with optic pathway tumours with primary or secondary involvement of the hypothalamus (Habiby, Silverman, Listernick & Charrow, 1995). The first sign of precocious puberty in young children with NF1 may be an acceleration of linear growth. Thus advanced bone age is an indication for cranial imaging to investigate a possible hypothalamic tumour.
Listernick and colleagues (1994) examined the natural history of optic gliomas in children with NF1 and found that all symptomatic tumours were diagnosed before six years of age, and only 9% of children had evidence of tumour growth or deteriorating vision after diagnosis (Listernick, Charrow, Greenwald & Mets, 1994).
Bone abnormalities in NF1 NF1 patients may show abnormal bone development such as bone overgrowth. Overgrowth occurs when the upper or lower leg bones become thicker and longer on one side of the body, producing an inequality in leg lengths. Another orthopaedic problem seen in children with NF1 is congenital bowing of a long bone, most commonly the tibia. This bowing can be problematic, as fractures in this area tend to result in pseudoarthrosis (a new, false joint arising at the site of an ununited fracture) and fail to heal.
Scoliosis occurs in approximately 25% of children with NF1. The majority of cases of scoliosis in NF1 have a long C-shaped curve involving a significant portion of the spine (up to 10 segments), which is the type of scoliosis often seen in the general population. A more severe type of scoliosis is seen specifically in NF1 and involves a smaller portion of the spine (less than five vertebrae) causing a sharp, angular curve. This latter form may be associated with a localised area of vertebral dysplasia, possibly secondary to a paravertebral neurofibroma.
Macrocephaly and short stature and are frequent manifestations of NF1. Approximately 40-50% of children with NF1 have head sizes that are well above average for their age and height (absolute head circumference >98th percentile). Head growth tends to follow a curve parallel but greater than normal growth rate. In most cases there are no associated neurological problems, and the increased head circumference is due to increased brain volume rather than ventricular dilation or abnormalities of the bony calvarium. This increased brain volume has been shown to be associated specifically with lateral volume expansion of the cerebral hemispheres (DiMario, Ramsby, & Burleson, 1999), an increase in gray- matter (Moore, Slopis, Jackson, De Winter and Leeds, 2000), as well as increases in white-matter volume (Said, Yeh, Greenwood, Whitt, Tupler & Krishnan, 1996).
Short stature (<10th percentile) is common in patients with NF1. One study found that 25.5% of prepubescent children had short stature and there was a significant gradual reduction of their relative height for age (standard scores) during puberty (Carmi, Shohat, Metzker and Dickerman, 1999). In addition, short stature was also more common among patients with familial NF1 particularly if their father was affected and amongst those with CNS pathology (Carmi et al., 1999).
Central nervous system involvement in NF1 Headache is a common complication of NF1 and usually occurs in the absence of intracranial lesions or raised intracranial pressure. Since there is an increased risk of development of CNS tumours in patients with NF1, many patients with headaches require neuroimaging, although the risks for such problems are low.
Seizures are present in approximately 5% of patients with NF1. The types of seizures are variable and there is no one type of seizure which is typical in NF1 patients (Kulkantrakorn & Geller, 1998). Vivarelli and colleagues found that 7% of their patients had epilepsy, with the majority of their patients having partial rather than generalised seizures. Over half of their patients had seizures secondary to brain lesions. In most patients the seizures were able to be controlled, but around 29% were drug resistant. All patients with uncontrolled seizures had severe mental retardation (Vivarelli, Grosso, Calabrese, Faretani, Di Bartolo, Morgese & Balestri, 2003).
Other brain abnormalities have been identified, particularly on magnetic resonance imaging (MRI). The most common lesions, often referred to as T2-hyperintensities, are seen on T2 weighted MRI images as areas of hyperintensity (prolongation of T2). These lesions are usually isointense on T1 weighted images, they exert no mass effect, there is no surrounding oedema, and do not enhance with contrast (Sevick, Barkovich, Edwards, Koch, Berg & Lempert, 1992). They are not associated with focal neurological deficits or the presence of macrocephaly. The T2-hyperintensities are seen in 60-70% of children with NF1 (North 1997), and are also referred to as ‘hamartomas’ or unidentified bright objects (UBOs). They most commonly occur in the basal ganglia, brain stem, thalamus, optic tracts, and cerebellum (Van Es, North, McHugh, & de Silva, 1996). Pathological studies suggest that these hyperintense areas on MRI may represent dysmyelination or increased water content in the brain. Structural brain abnormalities have also been identified including larger brain volumes (Said, Yeh, Greenwood, Whitt, Tupler & Krishnan, 1996), increased area of the corpus callosum (Kayl, Moore, Slopis, Jackson & Leeds, 2000; Moore, Slopis, Jackson, De Winter & Leeds, 2000), and abnormal grey-white- matter ratios (Moore et al., 2000).
Cognitive dysfunction in NF1 Cognitive deficits represent the most common complication in children with NF1, affecting up to 80% of children (Hyman et al., 2005). School performance is often a major concern of parents as it can cause significant morbidity in terms of educational opportunities, career choice and self-esteem. There does not however appear to be a unique profile of learning disabilities as both nonverbal and verbal learning problems are both common (Ozonoff, 1999). Children with NF1 are often easily distractible, poorly organised, and have difficulties with visual perception (Eldridge, Denckla, Bien, Myers, Kiaser-Kupfer, Pikus, Schlesinger, Parry, Dambrosia, Zasloff & Mulvihill, 1989; North, Joy, Yuille, Cocks & Hutchins, 1995). Language problems as well as problems with motor coordination are also quite common (Mazzocco, Turner, Denckla, Hofman, Scanlon & Vellutino, 1995). Mental retardation (Full Scale IQ < 70) is only slightly more common in patients with NF1 than in the general population (North, 1999). More details...
Emotional and psychosocial problems Children with NF1 have more problems with anxiety, depression and internalising behaviours, as well as having poorer social skills than their siblings (Dilts, Carey, Kircher, Hofman, Creel, Ward, Clark & Leonard, 1996). Johnson and colleagues also found a higher risk of suicide in patients with NF1, with 16% of children with NF1 having thoughts of suicide compared to 6% of unaffected siblings and 3% of unrelated controls (Johnson, Saal, Lovell, & Schorry, 1997). Samuelsson and Riccardi (1989) reported that 33% of adults with NF1 had been diagnosed with a mental illness, with the majority being diagnosed with anxiety and depression.
