Figure 1 . Multple hyperpigmentated macules are evident on the trunk, and a small, slightly raised purplish-brown lesion can be seen on the back (arrow).
An 11 -year-old girl is referred for evaluation of multiple hyperpigmented macules (Figure 1). A few of these macules were present at birth, and many others appeared during early childhood. She has not noticed any new macules for several years, but a small, slightly raised, purplish-brown lesion appeared on the small of her back the previous summer (Figure 1).
The girl has had no other significant health problems and is of average intelligence. The mother reports that the girl's father has two hyperpigmented macules that appear similar to the girl's. One is located on his back, and the other is on his leg. He has no other health problems.
The physical examination is unremarkable except for the finding described above. Breast and pubic hair development are Tanner stage 3. DISCUSSION
The hyperpigmented macules illustrated here are commonly known as café-au-lait spots and are most commonly an indication of neurofibromatosis (NF). These macules are recognized in normal infants as "birth marks." They are of no significance unless six or more are present, in which case they are suggestive of NF, most often type 1 NF (von Recklinghausen disease).
Specific diagnostic criteria for NF-I have been developed (Sidebar); when two or more of these features are present, the diagnosis can be made with confidence. The condition results from mutations in the NFl gene, which encodes the protein neurofibromin, and is inherited as an autosomal dominant with complete penetrance.
The patient presented here also has a dermal neurofibroma, indicated by the arrow in Figure 1. This benign tumor occurs frequently in patients with NF-I , often not appearing until around the age of puberty. The neurofibromas have no relationship to the café-au-lait spots and may be quite numerous (Figure 2). They usually are smaller than 1 cm in diameter and harmless except for their cosmetic significance. They have little or no potential for malignant transformation.
Figure 2. Multiple neurofibromas in an older adult with typical NF-I.
Of particular interest in the patient presented here is the distribution of the café-au-lait macules, which are found only on the right side of the trunk, extending from approximately the iliac crest to the scapula, without extension across the midline. This is indicative of segmental NF (NF-5). The segmental distribution indicates that the mutation in the gene occurred after fertilization, resulting in some cells with the mutation and others without it.
Segmental NF results from a new mutation in a cell at the twocell stage of embryogenesis or later and is never inherited. However, if the germ line in someone with segmental NF carries the mutation, the children of that person may inherit the mutation and have typical NF-I, because all of their cells will have the mutation. Genetic counseling of such patients can be very challenging, as it is often unclear if there are cells in the germ line that carry the mutation.