six or more café au lait macules of > 5 mm in children and > 15 mm in adults

two or more neurofibromas of any type or one plexiform neurofibroma

freckling in the axillary or inguinal regions

two or more Lisch nodules on the iris

an optic glioma

distinctive osseous changes such as sphenoid dysplasia or thinning of the long bone cortex with or without pseudoarthrosis

a first-degree relative with neurofibromatosis 1

The earliest cutaneous manifestation of NF-1 is the appearance of café-au-lait macules. These well-circumscribed, light brown macules or patches may usually appear within the first year, but may be present at birth and are definitely present by four years of age.

NF-1 may also present at birth with plexiform neurofibromas, which are diffuse, elongated neurofibromas occurring along the course of a nerve with associated skin hypertrophy, hyperpigmentation, or increased hair. These may cause considerable cosmetic disfigurement.

In middle childhood, many patients with NF-1 develop diffuse freckling in the axillae or other body folds, known as Crowe's sign.

Regular peripheral neurofibromas usually start to develop at puberty and increase in number and size in early adult life. Neurofibromas are soft, pink or flesh-colored papules, nodules or tumors that in NF-1 are mainly distributed over the trunk and limbs.

Lisch nodules are melanocytic hamartomas of the iris which develop by the second decade of life in the majority of NF-1 patients.

Optic gliomas are the most common CNS tumor occurring in NF-1. Other CNS tumors in NF-1 may include astrocytomas, schwannomas, and non-neoplastic hamartomas which can occasionally lead to epilepsy in some patients. Malignancies in NF-1 include neurofibrosarcomas, pheochromocytomas, leukemia, Wilms' tumors, and rhabdomyosarcomas.

Pruritus can be a severe symptom and can possibly be associated with numerous mast cells present within these tumors. A mast cell blocker such as ketotifen has been reported to be somewhat beneficial for this.

Assessment

Children with NF-1 should be assessed every 6 months, and adults annually, for progression of the disease. Evaluation must include a full neurologic examination.