Cutaneous Neurofibromas (cNF)

Neurofibromatosis Type 1 (NF1) is a rare genetic disease that affects between 1 in 2500-3500 births worldwide.  Males, females, and all races are affected by the disease equally.  While there is considerable variation in the type and severity of symptoms patients with NF1 develop, patients affected by NF1 typically develop abnormal patches of pigmented skin called café au lait spots and numerous benign tumors on or along nerves called neurofibromas.  Other possible symptoms include learning disabilities and ADHD, skeletal abnormalities such as scoliosis, short stature, and macrocephaly, which negatively impact quality of life.

Neurofibromas in the skin called cutaneous neurofibromas (cNF) occur in greater than 95% of patients with NF1, with 88% of patients older than 40 years developing greater than 100 cutaneous neurofibromas.  While rarely malignant or life-threatening, cNFs can result in significant disfigurement, pain, and social anxiety.  The onset of cNF tumors typically occurs around puberty.  cNFs continue to increase in number throughout life. Current treatment options such as surgical excision and CO2 laser do not prevent recurrence and lead to scarring.

NF1 has an autosomal dominant pattern of inheritance meaning patients only need to inherit one mutated gene to be affected by NF1. If one of the parents has a mutated NF1 gene, they have a roughly 50% chance of passing on the gene and having a child affected by NF1.  Additionally, half of NF1 cases arise by chance.  In these cases, sporadic mutations occur, leading to a child being affected by NF1 when neither parent is affected.

In healthy individuals, the NF1 gene encodes a protein, neurofibromin, that acts as a tumor suppressor in many cells including nerve cells, oligodendrocytes, and Schwann cells.  Neurofibromin is responsible for regulating cell growth and proliferation signaling in the Ras/Raf/MEK/ERK pathway. With a mutated NF1 gene, patients produce a nonfunctional neurofibromin protein that no longer suppresses the signaling pathways leading to increased cell growth, cell survival, and cNF formation.

Birthmarks

Epidermal Nevus Syndromes (ENS)

Epidermal Nevus Syndromes (ENS) describe a diverse group of rare disorders believed to be caused by a sporadic mutation that occurs at an early stage of embryonic development.  Mutations can occur in the proto-oncogenes HRAS and KRAS leading to dysregulation of the Ras/Raf/MEK/ERK signaling pathway. While the symptoms and severity of ENS vary extensively, all affected individuals can develop rough overgrown skin lesions in the outermost layer of skin, called epidermal nevi.  ENS are reported to occur in approximately 1-3 per 1000 live births; however, only a small fraction of these individuals will have epidermal nevi. Epidermal nevi can vary in size, shape, texture, quantity, and location on the body.

Nevus Sebaceus (NS)

Nevus Sebaceus (NS) is a congenital skin condition that typically appears on the head or neck region as a yellowish growth.Approximately 0.3% of newborns are affected by NS.The incidence of NS is equal between male and female patients, and it affects all races and ethnicities. The activation of the Ras/Raf/MEK/ERK signaling pathway is increased in NS due to mutations in the HRAS and KRAS genes.NS growths are typically benign; however, a small percentage of NS growths are thought to become malignant.

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