Dermatology Online Journal
Piebaldism and neurofibromatosis: State of knowledge
- Author(s): Duarte, Ana
- Mota, Alberto
- Baudrier, Teresa
- Morais, Paulo
- Santos, António
- Cerqueira, Rita
- Tavares, Purificação
- Azevedo, Filomena
- et al.
Piebaldism and neurofibromatosis: State of knowledgeHospital de São João, EPE Porto, Porto, Portugal
Ana Duarte MD, Alberto Mota PhD, Teresa Baudrier, Paulo Morais, António Santos, Rita Cerqueira, Purificação Tavares, Filomena
Dermatology Online Journal 19 (1): 17
Despite progress in understanding the molecular basis, the diagnosis of neurofibromatosis 1 (NF 1) is based on clinical criteria, established by the National Institute of Health (NIH) Consensus Conference in 1987. The association of NF1 and piebaldism has been reported, but some authors disagree with this co-occurrence. In the light of present knowledge, we highlight that both entities might co-exist in the same patient.
In a recent publication in Dermatology Online Journal, Dr. Spritz  refutes the concomitant occurrence of neurofibromatosis type 1 (NF 1) and piebaldism, based on what he named as “minor criteria” of NF 1. After an exhaustive review of the literature, we have not found a diagnostic criteria consensus for that personal description of “minor” criteria. In fact according to the National Institute of Health (NIH) Consensus Conference, the diagnosis of NF 1 is clinical and is based on the presence of two or more of the following findings: a) six or more café-au-lait spots greater than 5 mm diameter in prepubertal individuals and more than 15 mm after puberty, b) two or more neurofibromas or one plexiform neurofibroma, c) freckling in the axilary or inguinal regions, d) optic pathway tumor, e) two or more Lish nodules (iris hamartomas), f) distinctive bone lesions such as sphenoid wing dysplasia, and g) a first degree relative with NF 1 .
Despite progress in understanding the molecular basis of NF 1, these criteria are still the gold standard for the diagnosis. Also the sensitivity of the molecular diagnosis of NF 1 is 95 percent  and 5 to 10 percent of mutations are microdeletions spanning the NFl gene, which escape detection by standard polymerase chain reaction (PCR)-based exon or RNA-based analyses , confirming that the absence of mutation detection does not rule out the diagnosis of NF 1, as we have published in our observation .
Piebaldism is a rare disorder, characterized by localized leukoderma and leukotrichia. We have not found any reports considering axilary or inguinal freckling as a clinical feature of piebaldism, besides those of Dr. Spritz, citing their own “unpublished data” and Dr. Küster personal communication .
Furthermore, Dr. Spritz claims that both entities may coexist, but in that case the NF 1 diagnosis should be based on non-pigmentary criteria, such as neurofibromas . However there is scientific evidence that mutation of the KIT gene, which is present in piebaldism, may be responsible for aborting the progression of neurofibromas, since c-kit activity controls migration, proliferation, and survival of NF1+/- bone marrow-derived mast cells . Also schwann cells and fibroblasts, the two main components of neurofibromas, secrete KIT-ligand in response to different stimuli  and the low levels of mastocytes and c-kit in piebaldism may explain the lack of neurofibromas when NF1 is associated. In addition, the activation of the c-kit receptor seems to be crucial for the initiation and progression of neurofibromas . In the light of this evidence the authors suggest that, in the presence of piebaldism, neurofibromas are not an appropriate clinical feature for the diagnosis of NF 1.
As it was clearly reported, NF 1 can be associated with piebaldism. [7, 8, 9, 10]. Whether the simultaneous occurrence of these two dominantly inherited diseases is significantly higher than by chance remains to be established . Piebaldism is a benign disease without significant morbidity other than cosmetic, but the diagnosis of a possible concomitant NF 1 should never be missed in order to minimize systemic and neurologic complications of the latter. A high index of suspicion is necessary to diagnose NF 1 in an early stage. The authors believe that in a patient with piebaldism with freckling away from the border of the hypopigmentated macules, other features of NF 1 should be ruled out.
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