NEUROFIBROMATOSIS TYPE 1 (NF1) (VON RECKLINGHAUSEN DISEASE, PERIPHERAL NF)
NF1 is the most common form of NF, with a prevalence of about 1 per 3,000 persons. Inheritance is autosomal dominant with variable expression, but approximately 50 % of cases represent new mutations. Characteristic clinical features are listed in Table 1 Conventional diagnostic criteria require two or more of the following features: (1) six or more café-au-lait lesions (more than 5 mm greatest diameter in children and more than 15 mm greatest diameter in adults); (2) two or more neurofibromas or one plexiform neurofibroma; (3) axillary or inguinal freckling; (4) two or more Lisch nodules; (5) optic glioma; (6) characteristic osseous lesion (sphenoid dysplasia or cortical thinning of long bone, with or without pseudoarthrosis); and (7) a first-degree relative (parent, sibling, or child) with NF1 according to the above criteria.
Table 1 Clinical features of NF1
|Renal artery stenosis|
|NS Neoplasia: Optic glioma, astrocytoma and glioma, neurilemomas, neurofibrosarcoma or malignant schwannomas|
|Endocrine Neoplasia: Phaeochromocytoma, carcinoid|
|Other Neoplasia: Wilms’ Tumours, Rhabdomyosarcoma, Leukemia, Neuroblastoma|
Table 2 Clinical features of NF2
|Clinical features||Frequency (%)|
|Optic sheath meningioma||4|
Adapted from Evans et al. (1992)
The approximate frequencies of disabling nonneoplastic complications of NF1 were estimated by Huson et al. (1989) to be 33 % for intellectual handicap (3 % moderate-severe retardation, 30 % minimal retardation or learning difficulties), 5 % for scoliosis requiring surgery, 4 % for epilepsy, 2 % for severe pseudoarthrosis, and 2 % for renal artery stenosis. Café-au-lait spots occur in more than 99 % of patients with NF1 but are not specific and may fade in older patients (de Raed et al 2003).
The diagnosis of NF1 among at-risk relatives can usually be made early: Huson et al. (1989) found that all gene carriers have developed six or more café-au-lait spots by the age of 5 years, and 90 % of affected subjects have Lisch nodules by this age. Lisch nodules were reported to be present in 93– 100 % of adults (aged over 20 years) with NF1 (Huson et al. 1989; Lubs et al. 1991; De Raed et al. 2003). Unlike café-au-lait spots and neurofibromas, multiple Lisch nodules are specific for NF1 and have only been reported rarely in NF2. In addition, Lisch nodules frequently develop before neurofibromas (Lubs et al. 1991), which, in the absence of molecular genetic testing, is very useful in the differentiation between minimally affected and unaffected individuals. In children with possible NF1 and no Lisch nodules, the ophthalmological assessment should be repeated periodically. Slit-lamp examination allows Lisch nodules to be distinguished from common iris nevi.
Individuals with NF1 are at increased risk of a variety of neoplastic lesions, including optic glioma, neurofibrosarcoma, brain gliomas, pheochromocytoma, and leukemia. Estimates of the increased risk of neoplasia are variable because of differences in the methods of ascertainment, and some older studies have not distinguished between NF1 and NF2.
Sorensen et al. (1986) reported that the common perception of NF as a severe disorder with a greatly increased risk of cancer is incorrect. Although probands in a hospital-based study had a fourfold increase in the incidence of malignant neoplasms or benign CNS Tumours, the relative risk among affected relatives was only 1.5 (0.9 in males, 1.9 in females). There was a significant excess of glioma, and although the relative risk of pheochromocytoma was greatly increased (because it is rare in the general population), the absolute risk was small. In a population-based study, Huson et al. (1989) estimated the overall risk of malignant or CNS Tumours to be approximately 5 % (0.7 % for optic glioma, 0.7–1.5 % for other CNS Tumours, 1.5 % for rhabdomyosarcoma, and 1.5 % for peripheral nerve malignancy). Endocrine Tumours (pheochromocytomas, pancreatic apudomas) may occur in 3.1 %, and spinal and visceral neurofibromas each occur in about 2.1 % of patients. Stiller et al. (1994) reported a relative risk of chronic myelomonocytic leukemia of 221 in NF1, whereas the relative risks for acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma were 5.4 and 10, respectively. There is a small increase in the risk of breast cancer in women with NF1, and targeted early breast cancer screening has recently been suggested for these women (Evans 2012).
Fig. 2 Neurofibromatosis type 1. Dermal neurofibromata