#137: Connecting the Cafe au Lait Dots: Neurofibromatosis Type 1

March 26, 2025 | By Sam Masur

Audio

Summary:

Grab a cafe latte and settle in for a nerve-rackingly good conversation with Dr. Carlos Prada, Pediatric Genetics specialist at Northwestern University’s Lurie Children’s Hospital. Dr. Prada walks us through the most common presentations of NF1, the recently updated diagnostic criteria, and important follow-up screening exams and treatment options. It’s an episode so good, even your nerves will be on edge!

Neurofibromatosis Type 1 (NF1) Clinical Pearls

1. NF1 is a “common rare condition” affecting around 1 in every 2000-2,500 live births.
   
   
2. The most common presenting symptom of NF1 is cafe au lait macules (CALMs) with the second most common symptom being freckling of the axillae or groin region. Many of the clinical features of NF1 are age-dependent. CALMs are typically present at (or shortly following) birth. The presence of one or two CALMs can be a normal variant in children.
   
   
3. Most children do not meet full criteria for NF1 until they are about 5 years old, meaning that observation and close follow-up are important for children with one or two associated symptoms.
   
   
4. It’s recommended that children with suspected or confirmed NF1 receive an annual dilated eye exam until age 10 and at least every 2 years until age 18 to evaluate for development of an optic pathway glioma.
   
   
5. Management of NF1 is typically multidisciplinary with input from various specialties. No routine imaging is required at time of diagnosis, unless there’s an underlying concerning symptom such as vision loss.

NF1 Show Notes 

Pathophysiology of NF1

Neurofibromatosis Type 1 (NF1) is a multisystemic disorder, affecting the skin, brain, bones, and nerves, causing an increased predisposition to developing tumors. 

NF1 is an autosomal dominant inheritance or a spontaneous, de-novo mutation of the NF1 gene located on chromosome 17, which is responsible for the production of a protein called neurofibromin. 

• Under usual conditions, the NF1 gene functions as a tumor suppressor gene, where the production of neurofibromin “turns off” the Ras pathway, leading to well-controlled cell division.
• In patients with NF1, the gene mutation causes loss of function of the neurofibromin protein, enabling the Ras pathway to remain constitutively active, causing uncontrolled cell growth and division, leading to subsequent tumor formation and other symptomatic features of NF1.
• For example, cafe-au-lait macules are caused by the loss of neurofibromin in melanocytes, causing overproduction of melanin and subsequent hyperpigmentation. 

When the spontaneous, de-novo mutation occurs after fertilization (post-zygotic), NF1 can exhibit mosaicism, referred to as Segmental NF1. This would present with NF1 symptoms isolated to a specific area (ie, left arm, right lower extremity).

Epidemiology

According to a meta-analysis by the Orphanet Journal of Rare Diseases, NF1 has an estimated prevalence between 1 and 3,000-4,000 people and an incidence of 1 in 2,000-2,500 live births.  It affects males and females equally and is not known to affect any ethnic or racial background disproportionately. Additionally, NF1 has 100% penetrance, meaning that everyone with an NF1 mutation will develop symptoms or features of the disease (Genetics in Medicine).

Risk Factors

The most important risk factor of developing Neurofibromatosis Type 1 (NF1) is a family history of NF1, specifically a parent with the disease. This is because it is typically transmitted in an autosomal dominant fashion, meaning that each child of an affected parent carries a 50% risk of inheriting the disease, and it does not skip generations! (National Organization for Rare Disorders). 

Presenting Symptoms

(1) Cafe au lait macules (CALMs): The most common presenting symptom and the main reason Dr. Prada receives referrals is the presence of cafe au lait macules (CALMs). These are flat, hyperpigmented skin lesions with well-defined, regular borders that typically appear in the first few months after birth, usually before 2 years of age. These can be biopsied and genetically tested, too! One or two CALMs can be normal for some children, but more than 6 is diagnostic criteria for NF1. It is important to note that the quantity of CALMs is not indicative of disease severity.

Expert opinion: If struggling with diagnosing or identifying skin findings, don’t be afraid to curbside or refer to pediatric Dermatology! NF1 affects all races so identification of these skin findings on different ethnicities is important so it doesn’t go underdiagnosed!

(2) Freckling in the axillae or groin: The second most common reason Dr. Prada receives referrals is skin freckling in the axillae or groin/inguinal region, or other areas not exposed to sunlight. 

Expert opinion: Dr. Prada says this is a time when Pediatricians can request to examine an adult! This would be to see if they have the same or similar skin findings that could have gone undiagnosed.

(3) Changes in vision/Vision loss: although a less common presenting symptom of NF1, there is an association with the development of Optic pathway gliomas. These are brain tumors that occur along the optic nerve. They can be detected on dilated eye exams, and can present with optic disc swelling, visual field defects and double or blurry vision. This would warrant more emergent neuroimaging and workup. Expert opinion: OPG’s are relatively common in NF1. Dr. Prada says that out of every 100 children he sees with NF1, 15-20 will have an OPG.

(4) Neurofibromas: also known as an enlarged nerve, neurofibromas can be spotted on physical exam as a soft, painless bump on or under the skin anywhere over the body. They can affect either superficial or deep nerves. Plexiform neurofibromas are the more severe form of neurofibromas, as they are a more complex tumor involving multiple nerves and its branches. Since neurofibromas typically appear around puberty, they may not be the presenting symptom. Remember: plexiform neurofibromas vary in their location and can encroach on important structures such as the spine or trachea. 

(5) Lisch nodules (Iris hamartomas): These are small, dome-shaped bumps on the iris of individuals with NF1. Typically identified by slit-lamp examination, these are a subtle exam finding and usually appear around 5-10 years old.

(6) Bone abnormalities: such as sphenoid wing dysplasia, tibial dysplasia or bowing, pseudoarthrosis of a long bone, short stature, or even scoliosis.

(7) Nonspecific findings: learning difficulties or disabilities (ie, ADHD), macrocephaly, behavioral abnormalities, hypertension, precocious puberty (if underlying brain tumor), seizures (less common).

Diagnosis

Diagnostic Criteria

In 2021, the American College of Medical Genetics and Genomics (ACMG) published an update to the Neurofibromatosis Type 1 (NF1) diagnostic criteria (Nature). The criteria includes:

(A) If the patient has a parent diagnosed with NF1 and meets at least 1 of the criteria below, the diagnosis of NF1 is made.

(B) If the patient does not have a parent diagnosed with NF1, > 2 of the following must be present: 

1. ≥ 6 café-au-lait macules > 5 mm in greatest diameter in prepubertal patients and > 15 mm in greatest diameter in postpubertal patients
2. Freckling in the axillary or inguinal region
3. ≥ 2 neurofibromas of any type or 1 plexiform neurofibroma
4. Optic pathway glioma
5. ≥ 2 Lisch nodules (iris hamartomas) identified by slit-lamp examination or≥ 2 choroidal abnormalities
6. A distinctive osseous lesion (eg, sphenoid dysplasia, anterolateral bowing of the tibia, pseudarthrosis of a long bone)
7. A heterozygous pathogenic NF1 variant with a 50% variant allele fraction in apparently normal tissue (eg, white blood cells)

Expert opinion: The clinical features of NF1 are so good for the diagnosis that we previously didn’t always do genetic testing on these patients. Dr. Prada says that only about 50% of the cases he sees have a positive family history!

Expert opinion: Most children will not meet diagnostic criteria until they are about 5 years old. It is not unusual for a child to have an isolated CALM or skin freckling – that does not mean that they do not have NF1! They have to be monitored and followed as they age to monitor for any new symptom appearances or progression that would solidify the NF1 diagnosis. The older the child is, the more likely they will meet all of the required clinical criteria on exam!

Differential Diagnosis/NF1 Mimics

There are other conditions that cause cafe-au-lait macules (CALMs) or other NF1-like symptoms! Be on the lookout for them when evaluating patients. 

(1) Legius Syndrome – a rare genetic disorder caused by a mutation of the SPRED1 gene; is very similar to NF1 in that it also causes cafe au lait macules but affected patients do not develop tumors. They may also have macrocephaly and learning difficulties. Expert opinion: Dr. Prada says, “For every 100 patients I diagnose with NF1, I will diagnose at least 1 with Legius Syndrome”.

(2) Noonan Syndrome – a rare genetic disorder caused by a mutation of the PTPN11 gene; Noonan syndrome typically causes pulmonary valve stenosis, proportionate short stature and facial dysmorphism, but has a subtype/variant called “Noonan Syndrome with Multiple Lentigines” that causes CALMs that are often mistaken for NF1.

(3) McCune-Albright Syndrome – a genetic syndrome caused by a mutation of the GNAS1 gene; has similar skin findings that are commonly confused with NF1’s! McCune-Albright Syndrome will cause unilateral cafe au lait macules (CALMs) but they differ in that they have irregular, ragged borders (“Coast of Maine” appearance), whereas in NF1 the cafe au lait macules (CALMs) have regular, defined borders (“Coast of California” appearance). Additionally, MAS also presents with endocrine (such as precocious puberty) and bone involvement.

(4) Tuberous Sclerosis – another neurocutaneous, genetic disorder caused by mutation(s) in the TSC1 and/or TSC2 genes. The skin findings can often be confused with NF1! Tuberous sclerosis presents with Ash leaf spots (hypopigmented macules on the body that resemble an ash-leaf) and other neurologic, cardiac, and renal abnormalities.

(5) Constitutional Mismatch Repair Deficiency (CMMRD) Syndrome – a rare genetic disorder caused by mutations in one or more mismatch repair genes (MLH1, MSH2, MSH6, and PMS2) that increases the risk of developing cancer at a young age (Journal of Medical Genetics). It often presents with CALMs similar to NF1, but also with early-onset cancers of the brain, blood and GI/GU tracts, amongst others.

Genetic Testing

Usually ordered by providers at NF1 center (ie, Genetics), but could be ordered from primary care pediatrician/other pediatrics provider. The genetic testing is done via blood or saliva samples.

• If the concern is a CALM alone, Dr. Prada recommends testing for NF1 and/or Legius Syndrome together. 
• If they have a history of pulmonic stenosis or another atypical feature not exclusive to NF1, they typically send for a RASopathy genetic panel (which includes 15+ genes) or exon testing.

Expert opinion: Always counsel families about incidental or secondary findings that may come from larger or more extensive genetic testing. It may not identify the diagnosis you have in mind, and could even possibly identify a genetic variant that is unique to that patient or that might not be relevant to their symptoms.

Management

NF1 is typically treated with a multidisciplinary approach, in a team of many different specialists.  While typically led by Genetics, the team also often includes Neurology, Ophthalmology, Dermatology, and Oncology. General/Plastic Surgery, Orthopedics, and Developmental-Behavioral Pediatricians also commonly work to assist the patients. Social workers are also valuable assets to the team!

Most of these teams are located in larger cities at NF Clinics (to help find a NF1 provider, visit the Children’s Tumor Foundation: https://www.ctf.org/find-a-doctor/). There is not an NF clinic in every state, making access to care for some patients difficult. 

Expert opinion: If you work in primary care pediatrics and suspect a patient has NF1 but there are barriers to care such as difficulties in travel to a larger city/NF clinic, then important, local referrals would be to Ophthalmology and Neurology – you can even try telemedicine with the NF clinic!

Anticipatory guidance and education is important for all patients and families. Don’t be shy to refer for further guidance!

Important Screening Exams

(1) Yearly dilated eye exams – with a qualified pediatric Ophthalmology provider to evaluate for any ocular manifestations of NF1 (Optic pathway glioma, choroidal abnormalities, Lisch nodules). Even if you suspect NF1 and the child hasn’t quite met diagnostic criteria yet, or NF1 is on your differential diagnosis, the eye findings in NF1 can be very subtle so eye exams are recommended. According to the Journal of Child Neurology, the recommended screening for children with NF1 entails annual eye exams in all children less than ten years of age, and at least every two years until 18 years of age.

Expert opinion: Optic pathway gliomas usually develop and present before age 8, with the risk after age 8 decreasing significantly.

(2) Regular blood pressure monitoring – hypertension occurs more commonly in patients with NF1, with the most common cause being renal artery stenosis. Patients with NF1 also have an increased risk of developing Pheochromocytomas. 

(3) Regular developmental and growth chart monitoring – monitor for any changes in neurologic or motor development as many children with NF1 will require extra assistance at school such as classroom accommodations (if vision problems), an IEP or 504 plan. Additionally, some children with NF1 have short stature.

(4) No routine imaging is typically required – at the time of diagnosis unless clinical concern is present (ie, if vision loss/headaches/seizure, emergent neuroimaging is recommended to evaluate for any underlying pathology such as an optic pathway glioma). 

Expert opinion: While there is no concrete imaging screening protocol, Dr. Prada will typically advocate for a whole-body MRI (if the patient is able to tolerate) to investigate if the patient has an underlying plexiform neurofibroma that is going undiagnosed and has the potential of impeding on critical structures. He anticipates this screening recommendation will become more common practice in the coming years. Part of Dr. Prada’s research involves doing whole body MRI as there is a treatment now that can reduce the size of plexiform tumors before they become symptomatic!

(5) Breast and other Cancer Screenings – Patients with NF1 have an increased risk of developing certain types of cancers as they age (ie, malignant peripheral nerve sheath tumors, brain cancer, leukemias, etc). Dr. Prada mentions that there is a 10-15% risk of malignancy in patients with NF1. Specifically, women with NF1 have an increased risk of breast cancer – especially developing at a younger age – so routine screening is recommended to start around age 30. Anticipatory guidance should be provided while they are in the Pediatrics office!

Treatment and Future Innovations

There have been many advancements in treatment research for NF1! While there is currently no cure, there are multiple avenues for treating specific symptoms. While treatment is usually approached from the “oncology” perspective, chemotherapy has historically not been the best option as these are benign tumors. 

• If the patient has an Optic pathway glioma causing vision loss or other concerning symptoms, treatment is typically chemotherapy guided by Neuro-oncology.
• If the patient has a superficial neurofibroma, there is an option for debulking surgery with General/Plastic surgery. 
• If the patient has a/an symptomatic, inoperable plexiform neurofibroma (and is older than 2 years of age) they may qualify for pharmacologic treatment with Selumetinib, a drug approved by the FDA in 2020. It’s an oral medication that functions as an inhibitor of both the MEK1 and MEK 2 enzyme in the MAPK signaling pathway, leading to reduction of the plexiform neurofibroma size and improved other associated symptoms such as pain or disfigurement. For more information on Selumetinib, see this NEJM Article.
• It’s important to note that Selumetinib can take up to 6 months to 1 year to show improvements, not every child who takes it will respond, and some common adverse side effects are skin rashes, acne, paronychia, and abdominal discomfort. 
• There are currently clinical trials testing other new drug therapies and treatments with the hope of advancing treatment in the future!

Citations

1. Lee TJ, Chopra M, Kim RH, Parkin PC, Barnett-Tapia C. Incidence and prevalence of neurofibromatosis type 1 and 2: a systematic review and meta-analysis. Orphanet J Rare Dis. 2023 Sep 14;18(1):292. doi: 10.1186/s13023-023-02911-2. PMID: 37710322; PMCID: PMC10500831.
2. Jordan, J., Bundra, K., & Zupan, M. Neurofibromatosis 1. NORD. National Organization for Rare Disorders. 2022 April 25. https://rarediseases.org/rare-diseases/neurofibromatosis-type-1-nf1/ 
3. Gross, A.M., Wolters, P.L., Dombi, E., et al. Selumetinib in Children with Inoperable Plexiform Neurofibromas. N. Engl. J. Med. 2020, 382, 1430–1442.
4. Legius, E., Messiaen, L., Wolkenstein, P. et al. Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation. Genet Med 23, 1506–1513 (2021). https://doi.org/10.1038/s41436-021-01170-5.
5. Suerink M, Ripperger T, Messiaen L, Menko FH, Bourdeaut F, Colas C, Jongmans M, Goldberg Y, Nielsen M, Muleris M, van Kouwen M, Slavc I, Kratz C, Vasen HF, Brugiѐres L, Legius E, Wimmer K. Constitutional mismatch repair deficiency as a differential diagnosis of neurofibromatosis type 1: consensus guidelines for testing a child without malignancy. J Med Genet. 2019 Feb;56(2):53-62. doi: 10.1136/jmedgenet-2018-105664. Epub 2018 Nov 10. PMID: 30415209. 
6. Jett, K., Friedman, J. Clinical and genetic aspects of neurofibromatosis 1. Genet Med 12, 1–11 (2010). https://doi.org/10.1097/GIM.0b013e3181bf15e3
7. Campen CJ, Gutmann DH. Optic Pathway Gliomas in Neurofibromatosis Type 1. J Child Neurol. 2018 Jan;33(1):73-81. doi: 10.1177/0883073817739509. PMID: 29246098; PMCID: PMC5739070.\

Goal

Listeners will explain the basic pathophysiology, diagnosis, and management of Neurofibromatosis Type 1 (NF1) in children and adolescents. 

Learning Objectives

After listening to this episode listeners will…  

1. Recall the basic pathophysiology of NF1.
2. Recognize both the most common symptoms, as well as atypical presentations, of NF1. 
3. Identify the diagnostic criteria for NF1 and common differential diagnoses. 
4. Recognize important screening exams and follow-ups required in patients with, or suspected to have, NF1.
5. Describe the principles of treatment for NF1.

Disclosures

Dr. Prada reports consulting for Chiesi, Biomarin, Orchard Therapeutics, and Takeda. He also is a speaker for Sanofi. The Cribsiders report no relevant financial disclosures. 

Citation

Hogue T, Prada C, Holloway R, Berk J, Chiu C, Masur S. “#137: Connecting the Cafe au Lait Dots: Neurofibromatosis Type 1“. The Cribsiders Pediatric Podcast. https:/www.thecribsiders.com/ March 26, 2025.