| Radiologic findings of the head and spine in neurofibromatosis 1 (NF1) in Northern Finland | ||
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NF1 is a progressive hamartomatous neurocutaneous disorder, which is limited to more or less cosmetic lesions in most patients, but which causes significant developmental or medical problems in about one third of the patients (Pöyhönen 2000a, Sippel et al. 2001). Learning and behavioural disturbances are common in children, and the psychological problems associated with skin manifestations may be severe. Malignant brain tumours, malignant peripheral nerve sheath tumours (MPNST) and childhood leukemia are the main causes of increased mortality in NF1 (Sorensen et al. 1986, Rasmussen et al. 2001).
The presence and nature of the main diagnostic signs – café-au-lait macules, freckles, neurofibromas and Lisch nodules – in several population or clinical studies from different countries were recently evaluated by Pöyhönen (2000a).
Café-au-lait macules. – Practically all NF1 patients have presented with multiple café-au-lait macules by the age of 5 years. The macules are not seen in newborns, but increase both in number and in size with age. In the Northern Finnish study (Pöyhönen 2000a), macules were seen in all patients under 30 years of age, but in only 75% of those aged over 60 years. The café-au-lait macules do not cause symptoms and have not been reported to predispose to malignant change.
Freckles. – Light brown freckles usually occur in the axillae and groins, but may also appear over larger areas of the body. They have not been reported in the newborn, but appear later in 70% to 87% of the patients. In a Welsh study of 135 NF1 patients, axillary freckling was seen in 67% and inguinal freckling in 44% of the patients (Huson et al. 1994). In Northern Finland, about half of the children under 6 years of age showed freckles, and 87% of all patients (n = 164) had them.
Neurofibromas. – Neurofibromas are benign tumours that may appear as either small, soft cutaneous nodules or, less frequently, as subcutaneous denser lumps along any nerve. They may also be pedunculated or diffuse. They usually involve the skin, but may occur in deep peripheral nerves, in viscera and blood vessels innervated by the autonomic nervous system and in spinal nerves (Riccardi 1981). Neurofibromas are rarely seen in young children – they were seen in only 4% of children aged under 6 years, but in more than 50% of children between 6 and 16 years of age in Northern Finland – but practically all patients are affected in later age. Neurofibromas may cause symptoms, depending on their location.
Lisch nodules. – Lisch nodules are melanocytic iris hamartomas derived from neural crest tissue, and they have been shown to be almost pathognomonic to NF1 (Lewis & Riccardi 1981, Huson et al. 1987). Iris hamartomas were first described in connection with neurofibromatosis in 1918 by Waardenburg (Ragge et al. 1993) and later in 1937 by Karl Lisch (Lisch 1937). They are small, multiple nodules and are usually seen in both irises, but may also appear unilaterally. Lisch nodules begin to develop in early childhood – they were seen in 20% of children aged under 6 years and in 65% of those aged under 11 years in the Northern Finnish series. The usefulness of Lisch nodules in the diagnosis of NF1 is well known, and if they are large enough, they are visible to the naked eye, but in young children the nodules are not yet present or are small, and are best seen with a slit lamp.
Plexiform neurofibromas are tumours that grow along nerves and infiltrate into surrounding tissues. They are usually congenital and highly vascularised and may grow superficially or in deep structures. They may lead to localised or segmental hypertrophy of the bone and limb. Plexiform neurofibromas that reach the midline of the body have been suggested to indicate aggressivity of the tumour or involvement of the spinal cord ( Riccardi 1980). Cutaneous hyper-pigmentation or hypertrichosis may be associated with pfexiform neurofibromas. Plexiform neurofibromas are almost exclusively associated with NF1 (Klatte et al. 1976, Riccardi 1981, Listernick & Charrow 1990, Peltonen & Jaakkola 1991, Pöyhönen 2000a). They have been reported in 15% to 40% of patients in different studies and were found in 20% of the Northern Finnish patients (Pöyhönen 2000a).
There is an increased risk of both primary and secondary malignancies in NF1 (Jensen et al. 1998). Sorensen et al. (1986) reported a relative risk of 4.0 of developing a malignant neoplasm or a benign central nervous system tumour in probands with NF1 relative to the general population. In addition, about one fifth of the NF1 patients with a primary malignancy developed a secondary malignancy. The following malignancies are especially associated with NF1: malignant peripheral nervous sheath tumours, astrocytomas, rhabdomyosarcomas, pheochromocytomas, carcinoid tumours and childhood leukemia. Hemispheric, brainstem and cerebellar astocytomas are also more common in NF1 patients than in the normal population. Faravelli et al. (1999) reported a family with brain tumours in seven members, and discussed different hypotheses to explain this unusual recurrence, such as the nature of the mutation or cosegregation of other predisposing genes. Airewele et al. (2001), in their study of 173 NF1 patients, found females to be at a much higher risk for cancer than males. No elevated cancer risk was detected in unaffected first-degree relatives, regardless of whether or not the proband had cancer, suggesting that the malignancy in the proband is not a result of a modifying gene that has a significant impact on the overall cancer risk.
Malignant transformation occurs in about 5% of plexiform neurofibromas. They show a tendency to develop into malignant peripheral nerve sheath tumours (MPNST), the most common of them being neurofibrosarcoma (Rubenstein 1986). Of the 164 NF1 patients from Northern Finland, 11 (7%) had malignant tumours, the most common one being MPNST, which was seen in 5 patients (Pöyhönen et al. 1997b). Hope and Mulvihill (1981) pointed out that neurofibrosarcomas may occur wherever neurofibromas develop, and it has been shown that they arise from established neurofibromas, most often from ones of the large plexiform variety.
Griffiths et al. (1983) presented three patients with NF1, duodenal carcinoid tumour and pheochromocytoma (one bilateral case) and three patients with NF1 and a duodenal carcinoid tumour. Although pheochromocytoma is rare in NF1, it has been thought to occur in about 1% of the patients (Fuller & Williams 1991). The authors also mentioned that the NF1 patients with duodenal carcinoid have a greater risk to develop pheochromocytoma. Wilms´ tumour has also been reported in connection with NF1 (Walden et al. 1977, Stay & Vawter 1997).
Bader and Miller (1978) found the risk of childhood leukemia (juvenile chronic myeloid leukemia) to be increased in NF1. An association between NF1, juvenile xanthogranuloma and leukemia has been described (Crepin et al. 1995).
Multiple malignancies (neurofibrosarcoma, pheochromocytoma, breast carcinoma, astrocytoma, adenocarcinoma of the stomach) in a family with NF 1 have been described (Landsmeer-Beker et al. 1993).
Dysplastic vascular tumours have been detected in patients with NF1. Mansat et al. (1995) presented five patients with "acute" vascular tumours appearing within one day in four patients and within several weeks in one patient. An underlying neurofibroma was found in three cases, and an intramuscular injection had preceded the tumour in one case. All tumours were operated on because of suspected malignancy. Histologic examination revealed vascular dysplasia of capillary vessels in four cases and hematoma in one case. The patients were followed up for 4 to 5 years, without recurrence. The pathogenesis of these tumours remained unknown.
Other cutaneous lesions observed in NF1 include both local and generalized hyperpigmentation, presence of hypopigmented macules, pseudoatrophic macules, skin angiomas and juvenile xanthogranulomas.
Short stature is common in NF1 and was recorded in 18% of the Northern Finnish patients. A markedly asymmetric face was seen in 13/164 patients and other dysmorphic features in 7/164. Macrocephaly is also common in NF1 and will be described in more detail later.
NF1 is often associated with skeletal lesions, such as scoliosis, congenital bowing and thinning of the long bones, pseudoarthrosis and vertebral anomalies, which will be described in more detail later.
Precocious puberty is usually caused by a hypothalamic lesion (Saxena et al. 1970). Guillamo et al. (2002) reported precocious puberty as a main clinical finding in 5 (10%) out of 48 patients with optic glioma. Retardation of growth combined with retarded sexual development and anorexia nervosa has also been found in association with NF1.
Pulmonary manifestations occur in 5 to 10% of NF1 patients. (Fraser et al. 1994). The lesions consist of diffuse interstitial fibrosis (pathologically fibrosing alveolitis) and bullae, either alone or in combination. Thoracic neoplasms, usually neurogenic in origin, may arise in the intercostal nerves, in the mediastinum or in the lungs themselves.
Aortic, celiac, mesenteric and renal arterial stenosis and aneurysms of multiple vessels, including intracranial, have been found in neurofibromatosis (Tomsic et al. 1976).
The association of Noonan‘s sydrome with neurofibromatosis has been discussed (Allanson et al. 1985, Meinecke 1987). Both inherited cases and new mutations of NF associated with the Noonan phenotype have been described. It has been suggested that this combination could be a variant of NF1 (Meinecke 1987). Five patients of the Northern Finnish patients had features characteristic of Noonan’s syndrome (Pöyhönen 2000a). Weaver sydrome (van Asperen et al. 1993), Poland anomaly (Stoll et al. 1993) and gastroschisis (Segre et al. 1993) in combination with NF1 have been reported as coincidental findings.
Psychomotor retardation, learning difficulties and even mental retardation are known to be associated with NF1 (Ozonoff 1999). In the Northern Finnish study (Pöyhönen 2000a), learning difficulties and developmental delay were observed in 28% of the patients and fine motor co-ordination problems in 39%. Intellectual handicap was identified in 22 patients (13%), and 8 (5%) were mentally retarded (with IQ under 70). A psychiatric disorder, mostly chronic psychosis or depression, had been diagnosed in 19% of the patients. Only 55% of the adults had passed the school matriculation examination, and 46% of the adults were employed.
In total, 65% of the NF1 patients suffered from one or more symptoms related to NF1 and needed either medical intervention, rehabilitation or follow-up. In only 38% of the cases had the patient´s medical problems been treated before NF1 was diagnosed.