I get many emails from people around the world asking for my opinion about whether skin pigmentation on a child might be indicative of neurofibromatosis, or perhaps some other medical condition.  I understand the anxiety associated with finding such pigmentary spots and that for some people there may not be ready access to medical experts who can help them decide whether the spots are indicative of a medical condition or not.  Very often these emails are accompanied by photos of the skin spots.  I have tried to answer these as best I can, but there are significant limitations in my ability to provide clear answers.  First, the pictures are rarely of high enough quality to clearly see the skin spots.  Café-au-lait spots can be difficult to photograph, and most of these pictures are taken under less than optimal conditions.  Second, when I do a clinical evaluation of a child with café-au-lait spots I include a comprehensive physical exam, as well as take a medical and family history.  Hence, my clinical impressions are based on much more information than I can obtain from an email exchange.  Finally, and perhaps most importantly, I cannot responsibly provide medical advice for individuals I have not seen clinically.

For these reasons, I’m sorry that I can’t provide a specific answer to your question.  I can, however, offer some general information that may be helpful:

1. People sometimes ask about “typical” or “atypical” café-au-lait spots, in the belief that only “typical” spots occur in NF1. I know that this term has been used in medical literature, but I do not find this to be a helpful distinction.  “Typical” spots are generally taken to be those that are clear and distinct from surrounding skin, easily seen in ordinary room light, and have sharp margins.  “Atypical” spots are more irregularly shaped, less distinctly pigmented, and may have indistinct or irregular margins.  It is true that café-au-lait spots associated with NF1 are usually easily seen and have distinct margins, but in fact the café-au-lait spots in children with NF1 can be highly variable in shape, size, degree of pigmentation, and distinctness of the margins.  As a general statement, if all of the spots are indistinct, faintly pigmented, and irregularly shaped, that is less likely to be associated with NF1.  In a child with NF1, however, it is possible that some of the spots have this “atypical” appearance.
2. The diagnostic criterion for NF1 involving café-au-lait spots that is widely used and accepted is the presence of six or more café-au-lait spots measuring at least 5 mm before puberty and 15 mm after puberty. It is not unusual for a healthy child to have a few café-au-lait spots, and it is not recommended to provide an evaluation for NF1 if the spots are fewer than six in number.  These spots also should be clear and distinct – finding very faint or small skin spots does not count towards the six spots needed for diagnosis.  In children with NF1, the café-au-lait spots are sometimes present at birth, but in other children they gradually appear in the early years of life.  I find that six or more café-au-lait spots are usually visible by around 2 years of age, and new spots do not usually appear after that time, though spots tend to tan upon sun exposure, so may become more distinct with time.
3. We do see occasional healthy children with as many as six café-au-lait spots, though usually these spots are usually relatively indistinct and have irregular margins. Often these children have fair skin and red hair, or have parents of different ancestry, with one having darker skin than the other.  These children tend to be healthy and do not have any underlying medical problem as far as is known.
4. Aside from café-au-lait spots, the other common skin pigmentation seen in association with NF1 is skin-fold freckling. Skin-fold freckles usually appear between 3 and 5 years of age and involve the groin area and under the arms.  There can also be freckles at the base of the neck, around the mouth, and under the breasts in women.  The freckles are usually numerous and appear as a “splash” of freckles on the skin in these regions.  A single freckle or café-au-lait spot under the arm or in the groin is not indicative of skin-fold freckling.
5. Aside from NF1, there are other medical conditions in which multiple café-au-lait spots can appear. Legius syndrome is associated with multiple café-au-lait spots and skin-fold freckling, but none of the tumors that are seen in NF1.  One cannot distinguish Legius syndrome from NF1 by clinical evaluation in a child who has not developed any neurofibromas.  NF1 is much more common than Legius syndrome, so most children with more than six café-au-lait spots and skin-fold freckles will have NF1, and if there is an parent with NF1, the diagnosis of NF1 can be made clinically in the child.  In the absence of family history or other NF1-associated signs, however, only genetic testing can distinguish between these conditions.  Noonan syndrome is a genetic condition where some affected individuals develop café-au-lait spots, usually darker than those seen in NF1.  One expects to see other medical signs in children with Noonan syndrome, including distinctive facial appearance and cardiac problems.  Congenital mismatch repair deficiency is a very rare but serious condition associated with an increased risk of malignancy.  The café-au-lait spots in this condition tend to be similar to those seen in NF1.  NF2 is a condition associated with tumors of the nervous system, especially schwannomas of the hearing nerves and other cranial and spinal nerves, and meningiomas (tumors of the membranes that cover the brain or spinal cord).  Some people with NF2 have six or more café-au-lait spots, but café-au-lait spots are not usually the presenting sign in individuals with NF2.  There are other, generally rare, conditions where one may seen multiple café-au-lait spots, though these usually are associated with other medical problems that inform the diagnosis.
6. Genetic testing is available for diagnosis of NF1 and Legius syndrome and involves testing the NF1 gene and the SPRED1 gene (involved in Legius syndrome) for genetic variants indicative of either condition. I do not recommend testing if a child has fewer than six clearly defined and easily visible café-au-lait spots and no other signs of NF1.  Although both tests are generally reliable, it is not possible to detect every conceivable genetic variant in either of these genes with current technology.  I find that many parents are not as reassured by a negative test as one might imagine.  The NF1 test, for example, is estimated to be at least 95% sensitive, which means that if a person has definite NF1 there is a 95% chance that their mutation will be found.  For very anxious parents, that remaining 5% chance of missing a mutation may be a continuing source of anxiety.  Also, genetic testing sometimes reveals a “variant of unknown significance;” this is a variant for which we don’t have sufficient evidence to determine if it is associated with NF1.  That can also be a source of anxiety for some families.
7. Sometimes the signs of NF1 will be confined to a restricted region of the body, such as an arm or leg, or one side of the trunk. This is referred to as “segmental NF1,” and is due to a phenomenon of somatic mosaicism for an NF1 gene mutation.  This means that the genetic change was not inherited from either parent, but rather arose in the child during early development, resulting in a mixture of cells with or without the mutation (mosaicism).  It is possible for a person with segmental NF1 to develop other signs, such as neurofibromas, and to pass NF1 on to the next generation (if sperm or egg cells have a mutation).  This is hard to predict at an early age, though I find that most children who present with segmental NF1 expressed as café-au-lait spots remain healthy.  I do recommend that a child with segmental NF1 be followed by a health provider who is familiar with the condition.  The parents of a child with segmental NF1 do not face an increased risk of NF1 in a future pregnancy.

I hope you find this information helpful and that you will understand why I cannot answer specific medical questions.  Due to the large number of questions I tend to get, I also cannot commit to answering specific questions about these issues.  If there are frequently asked questions I’ll try to include them in a future NF Blog – please see our web site for access to the blog (https://www.uab.edu/medicine/nfprogram/blog).

Bruce Korf