Neurofibromatosis type 1
(Code 636)
A clinically heterogeneous neurocutaneous genetic disorder characterized by café-au-lait spots, Lisch nodules in the iris, axillary and inguinal freckles, and multiple neurofibromas.
Summary
Epidemiology
The prevalence is 1 in 3,000 live births. The disease has been reported in all ethnic groups and affects both males and females equally.
Clinical
The clinical manifestations are highly variable, even within the same family. Multiple café-au-lait spots are observed in almost all patients (some at birth and most before the first year of life). Intertriginous freckles develop from the age of 5 years. Multiple cutaneous and subcutaneous neurofibromas develop in adults. In older patients, they continue to increase in number and size. Cutaneous neurofibromas do not become malignant. Plexiform neurofibromas (which develop along the nerve and its branches) can cause disfigurement, pain, and functional problems; they are usually present at birth and may become malignant later in life. Ocular manifestations include optic pathway gliomas and iris hamartomas (Lisch nodules). Optic pathway gliomas usually develop before the age of 6 and rarely progress thereafter. Osteopenia, osteoporosis, excessive bone growth, short stature, macrocephaly, scoliosis, skeletal dysplasia (sphenoid bone wings, vertebrae), and pseudarthrosis may be present. Other manifestations include hypertension, vasculopathy, intracranial tumors, malignant peripheral nerve sheath tumors, and sometimes seizures or hydrocephalus. Intellectual development is generally not severely affected, but cognitive deficits and learning difficulties are common (50 to 75%). The overall risk of cancer is higher than in the general population (lifetime risk of 10 to 12% for malignant tumors of the peripheral nerve sheaths, mainly between the ages of 20 and 40; increased risk of breast cancer before the age of 50). Familial spinal and segmental forms of NF1 have been reported. Watson syndrome is part of the NF1 spectrum. Neurofibromatosis-Noonan syndrome is a variant of NF1 in 99% of cases.
Etiology
NF1 is caused by mutations in the NF1 tumor suppressor gene (17q11.2) and, in rare cases, by a 17q11 microdeletion (only 5% of cases).
Diagnostic method(s)
Official diagnostic criteria have been established. At least two of the following criteria are diagnostic: more than 5 café-au-lait spots, 2 or more neurofibromas or one plexiform neurofibroma, optic pathway glioma, freckles, 2 or more Lisch nodules, specific bone dysplasias, first-degree relative with the disease. Magnetic resonance imaging can be used to determine the extent of plexiform neurofibromas. Molecular genetic testing may be requested, although it is not usually necessary.
Differential diagnosis
Legius syndrome is often clinically indistinguishable from NF1; it is seen in approximately 2% of individuals who meet the diagnostic criteria for NF1. However, there are a small number of individuals with NF1 who, like patients with Legius syndrome, do not develop non-pigmented manifestations. Constitutional mismatch repair deficiency syndrome should be considered. Other differential diagnoses include McCune-Albright syndrome, Noonan syndrome with multiple lentigines, and Proteus syndrome. Most cases of multiple non-ossifying fibromatosis are cases of NF1.
Prenatal diagnosis
Prenatal and preimplantation genetic screening is possible in high-risk pregnancies.
Genetic counseling
The mode of inheritance is autosomal dominant. Half of cases are due to de novo mutations in NF1. Penetrance is complete, but the manifestations of the disease vary greatly, which complicates genetic counseling.
Management and treatment
Specific cardiovascular, ocular, neurological, and orthopedic manifestations should be treated by the appropriate specialists. Cutaneous or subcutaneous neurofibromas can be removed surgically. Plexiform neurofibromas are much more difficult to treat.
Progn
The overall prognosis is satisfactory, but significant morbidity is frequently observed. The prognosis for malignant tumors of the peripheral nerve sheaths is generally poor. Malignant tumors and vascular diseases are the most common causes of premature death.