Diagnostic criteria and interpretation of neurofibromatosis type 1
I have previously written an article on “Milk Coffee Spots in Babies, Is it a “Memory” or a “Disease””, which drew a lot of attention from parents of babies with coffee spots. Although many parents were shocked by the large number of skin photos of neurofibromatosis patients on the internet, they were overly afraid of the fact that milk coffee spots are a “mark” (a certain number of coffee spots that normal people can have) and not a “disease” (a serious genetic disease such as neurofibromatosis). However, I am also glad to see that after reading this article, many parents of children with multiple café-au-lait spots have finally diagnosed neurofibromatosis at an early stage after detailed consultation, proper consultation and targeted examination or genetic testing, so that they can take early countermeasures to avoid serious complications and take prenatal diagnostic measures to avoid the reappearance of similar patients in their families. patients.
Multiple café au lait spots may be the earliest manifestation of neurofibromatosis, so what are the diagnostic criteria for neurofibromatosis? In addition to multiple café au lait spots, what other clinical manifestations of neurofibromatosis may occur? When do these manifestations occur? What tests are needed to confirm or exclude neurofibromatosis? This article will focus on explaining these questions.
There are two subtypes of neurofibromatosis, neurofibromatosis type 1 and neurofibromatosis type 2, in addition to a condition known as neurofibromatosis type 1, called Legius syndrome. All three diseases are inherited and are autosomal dominant, meaning that children of patients with neurofibromatosis usually (note that this is usually, not absolutely) have a 50% chance of inheriting the disease in their offspring. Of these, neurofibromatosis type 1 has the highest incidence, with an incidence of 1 in 2500-3000. What is this concept? On average, roughly 1-2 people we know will have neurofibromatosis (of course you may not know he/she has it), making neurofibromatosis type 1 a relatively common genetic skin disease. Let’s start by introducing it.
I. Diagnostic criteria for type 1 neurofibromatosis.
Six or more milk coffee spots, >5 mm in diameter before puberty and >15 mm after puberty
Two or more neurofibromas or one plexiform neurofibroma
Freckles in the axillary or inguinal region
Two or more iris lissencephalic nodes
Characteristic bone damage (pterygoid wing dysplasia or long bone dysplasia)
Glioma of the optic nerve pathway
History of type 1 neurofibromatosis within first-degree relatives
Only 2 of the 7 diagnostic criteria need to be met, meaning that the presence of 2 of these 7 clinical manifestations is sufficient to confirm the diagnosis of type 1 neurofibromatosis in a patient. It is important to note that the clinical manifestations of these diagnostic criteria do not necessarily occur together in a type 1 diagnosis of neurofibromatosis, especially in cases such as optic nerve glioma and skeletal damage. In addition, the clinical manifestations of type 1 neurofibromatosis are not limited to those mentioned in these 7 diagnostic criteria, but may be complicated by a variety of neurological or visceral tumors. Because neurofibromatosis type 1 is itself a tumor susceptible disease and tumorigenesis depends on many acquired factors (such as diet, environmental pollution, immune status, infection, and other unpredictable factors), the clinical manifestations of neurofibromatosis type 1 (especially in adulthood) tend to vary widely. The overall risk of developing tumors in this disease is much higher than in the general population. I have seen a patient with familial type 1 neurofibromatosis whose father (note that he was male) died in his 50s due to breast cancer.
Time of presentation of common clinical manifestations of type 1 neurofibromatosis
As mentioned above, not all of the clinical manifestations in the diagnostic criteria appear in the same patient with type 1 neurofibromatosis, so it is important to understand which of the clinical manifestations in the criteria are the most common and, as parents (with a non-medical background), when they appear and how we can use them to help determine or rule out a diagnosis of type 1 neurofibromatosis.
Common clinical manifestations of type 1 neurofibromatosis: 1. milk coffee spots; 2. freckles in skin folds; 3. iris lee nodules; and 4. cutaneous neurofibromatosis bodies. These manifestations are seen in almost all patients with typical type 1 neurofibromatosis.
1. Milk café-au-lait spots, most often seen at birth, will appear before the age of 2 years in most cases. A typical milk café au lait spot is a long oval brown patch with regular edges, resembling the color of milk mixed with coffee. At this point, we can measure the longest diameter of the spots with a ruler (e.g. the long axis of the oval shape) and record it. If the longest diameter of the spot is greater than 12.5px (37.5px after puberty), it will be recorded as 1 spot. If the total number is greater than 6, the probability of developing type 1 neurofibromatosis later in life is >95%. Regarding the diagnostic criteria of “6”, I personally believe that if the child is just born and the number of spots is 3-5 (usually less than 3 in normal people), close follow-up is needed; if the child is >2 years old and the coffee spots are less than 6 and smaller in diameter, then the possibility of type 1 neurofibromatosis is greatly reduced. In addition, it has been shown that the coffee spots in type 1 neurofibromatosis are mostly regular oval-shaped, and if they are particularly irregular in shape and small in diameter, they should not be included in the number of 6 coffee spots. There is no effective treatment for typical neurofibromatosis-related café au lait spots. Some people have tried laser treatment, but the results are not satisfactory and the recurrence rate is extremely high. It is recommended not to try. If the spots are on exposed areas, they can be covered up with concealer if necessary. The higher the number of milk café au lait spots, the higher the likelihood of having type 1 neurofibromatosis, but there is no clear relationship between the number of café au lait spots and the severity of the disease, in a patient who has established type 1 neurofibromatosis.
Illustration: Classic milk coffee spot and axillary freckle
2, neurofibromatosis body or plexiform neurofibroma. Neurofibromas are small, soft, intradermal or subcutaneous masses that feel very soft to the touch, even like a hernia sac. Neurofibromas can appear under the skin in all parts of the body, usually accelerating around puberty and increasing suddenly during pregnancy in female patients. Neurofibromas are benign and usually do not require any treatment, and those located in exposed areas can be removed by dermatologic surgery. Plexiform neurofibromas are large, slightly hard tumors that are most often found in the extremities or in a particular nerve stage and can be combined with large café au lait spots or be present alone. These tumors are at some risk of malignancy and require close follow-up and observation.
Figure: Neurofibroma body and plexiform neurofibroma (right)
These freckles do not differ in appearance from the freckles we are familiar with on the face, except that the freckles we are familiar with do not grow in the fossa and groin, which are non-light exposed areas. In addition, these freckles tend to be multiple, usually starting to appear in increasing numbers around the age of 5-8 years. Since they are not located on exposed areas, it is recommended that these freckles can be left untreated.
4. Iris Lee’s nodules, which are a type of melanocyte-derived misshapen tumor, are located above the iris of the eye, which is something we cannot see with the naked eye and requires a slit lamp examination by an ophthalmologist. Iris Lees’ nodules usually appear around the age of 5-10 years. Therefore, if the appropriate test is to be performed, it is best to do so under the age of 5. One is that the child can cooperate now, and the fact that the test is too young to have a Lees’ nodule does not rule out that it will manifest later. Lees’ nodules are benign masses that usually do not become malignant and do not have any effect on vision or visual field and do not require treatment.
The above are the common clinical manifestations of type 1 neurofibromatosis and the time of appearance and examination methods. Of course many parents of babies may be particularly anxious to know if this is the disease when they find multiple coffee spots soon after birth, and the best diagnostic criteria at this time is still to be determined or ruled out by genetic testing. When is genetic testing appropriate, what kind of tissue samples need to be collected for analysis, how to judge the test results, and what is the risk of recurrence in the family. In the next scientific article we will focus on explaining these queries.