How NF1 Evolves: Symptoms and Progression

Neurofibromatosis Type 1 (NF1) is described by doctors as having variable expressivity ^[1]. This means that while two people may have the exact same genetic mutation—even within the same family—their symptoms, the severity of those symptoms, and when they appear can be very different ^[1][2].

Because NF1 affects the way cells grow throughout the body, it is a multisystem condition, meaning it can impact the skin, bones, brain, and blood vessels ^[3]. Understanding how these symptoms typically evolve over a lifetime can help you and your medical team stay ahead of your or your child’s needs.

Infancy and Early Childhood (Ages 0–5)

In the earliest years, NF1 is primarily identified through skin and bone findings.

• Café-au-lait macules (CALMs): These flat, light-brown birthmarks are often the very first sign of NF1 ^[4]. While some babies are born with them, more usually appear during the first year of life ^[4][5].
• Plexiform neurofibromas (pNFs): These are complex tumors that grow along nerves ^[6]. Unlike other types of neurofibromas, pNFs are often present at birth or develop in early childhood ^[7]. They can sometimes be felt as a soft mass under the skin, or you might notice asymmetric growth, such as one arm or leg appearing thicker or longer than the other ^[7].
• Tibial Dysplasia: A rare but significant early sign is a bowing of the lower leg bone (tibia) ^[8]. If left untreated, this can lead to a “false joint” or pseudarthrosis, where the bone does not heal properly after a fracture ^[8].

School-Age Children (Ages 6–12)

As children enter school, the focus often shifts toward neurological and cognitive development.

• Cognitive and Learning Challenges: Many children with NF1 experience difficulties with executive function, which includes planning, working memory, and staying organized ^[9]. Up to 50% of children with NF1 may have ADHD (Attention-Deficit/Hyperactivity Disorder) ^[10]. Additionally, up to 30-40% may exhibit traits of Autism Spectrum Disorder (ASD), making early screening for both conditions just as important ^[10].
• Optic Pathway Gliomas (OPGs): These are benign (non-cancerous) tumors that grow on the nerves connecting the eyes to the brain ^[2]. Most OPGs are found in children under age 7 and often do not cause symptoms, but they require regular eye exams ^[2][11]. Watch for visual ‘red flags’ between appointments, such as a bulging eye (proptosis), noticeable squinting, or a child complaining about their vision ^[2].
• Skinfold Freckling: Small freckles in the armpits or groin typically begin to appear during these years ^[4].

Adolescence and Adulthood (Ages 13+)

During puberty and into adulthood, new physical changes may occur, and monitoring for rare complications becomes more important.

• Cutaneous Neurofibromas (cNFs): These are small, pea-sized bumps on or just under the surface of the skin ^[6]. They can increase in number during puberty or pregnancy due to hormonal changes ^[12][7]. While they are benign, the development of visible tumors can take a massive emotional and mental health toll, significantly impacting body image and quality of life ^[6].
• Vascular Issues and Hypertension: NF1 can affect the walls of blood vessels (vasculopathy), which may lead to high blood pressure (hypertension) ^[13][3]. In children and teens, a condition called renal artery stenosis (narrowing of the arteries to the kidneys) is a primary cause of severe high blood pressure ^[13]. Regular blood pressure monitoring is vital throughout life.
• Rare Complications:
  • Pheochromocytoma: A very rare, usually benign tumor of the adrenal gland that can cause high blood pressure and headaches, mostly presenting in adulthood ^[14].
  • MPNST: A very small percentage (about 8–13%) of plexiform neurofibromas can transform into a malignant peripheral nerve sheath tumor (MPNST), which is cancerous ^[15][16]. Doctors watch for “red flags” like constant, severe pain or a tumor that suddenly grows rapidly ^[15].