Neurofibromatosis type 1 (aka von Recklinghausen disease)

Neurofibromatosis is a familial cancer syndrome that results from a mutation in either

the NF1 or NF2 genes. These disorders display autosomal dominant inheritance
patterns. They result in a number of findings that involve structures derived from
ectoderm (ex. skin, nerves, eyes).

Epidemiology

- 1:2600 to 3000/per individual (incidence)

- Median age of death 59 years
- Segmental NF1 has prevalence of 1:36,000 to 1:40,000
o Incidence is unknown

NF1 (B&B)

o Chromosome 17
o Encodes neurofibromin (tumor suppressor protein)
o Restricts RAS function; therefore, mutation results in RAS overactivity and
uncontrolled growth
o Autosomal dominant with 100% penetrance (all gene carriers have
disease)
 Variable expressivity seen in which different phenotypes are seen
from the same genotype
o Neurofibromas
 Benign tumors that develop on nerves (usually cutaneous nerves)
 Can be all over the body, trunk, or face
o Lisch nodules
 Brown spots on the iris
o Café-au-lait spots
 “coffee with milk”
 Light brown macules
o Freckles
 Not random
 Cluster in skin folds (ex. axilla and groin)
 These are unusual places for freckles to be found
o Optic glioma
 Usually develops by 3 years of age
o Bone abnormalities
 Curvature of the long bones
 Facial deformity of the eye socket
 Scoliosis
o Intellectual impairment
o Patients develop HTN
 Renal artery stenosis
  Rarely pheochromocytoma
o Can also develop malignant tumors
 Usually arise from deeper tumors called peripheral nerve sheath
tumors
 Occurs in adolescence or adulthood
 Presents as pain or sudden growth of a neurofibroma

- Diagnostic criteria include:

o 6+ café-au-lait spots
o 2+ neurofibromas
o Freckles in axilla or groin
o Optic glioma
o 2+ lisch nodules
o Bone lesions
o 1st degree relative with NF1

- Presentation would be:

o Birth to 2 years
 Café-au-lait spots
 Bone abnormalities
 Optic glioma
o 2-6
 Lisch nodules
 Developmental delay
o Adolescence
 Cutaneous neurofibromas

Management

- Longitudinal care is aimed at early identification of complications of NF1 and

appropriate treatment
o Approach depends on tumor type, location, etc.
- Annual visits for children with NF1 should include (per AAP)
o Skin exam for new neurofibromas, signs of plexiform neurofibromas
o Check BP for HTN
o Evaluate growth
o Skeletal changes (ex. scoliosis)
o Ophthalmologic exam
o Assess for precocious puberty
o Developmental milestones
- Surveillance for adults should include:
o Monitor for malignant peripheral nerve sheath tumor
 Can arise from plexiform neurofibromas (PN)
 Presents as symptomatic PN (pain, rapidly growing, neurologic
Sxs)
  MRI if suspected
o Breast cancer
 Start mammography at age 30 due to increased breast cancer risk
o Pheochromocytoma
 Patients over 30 or pregnant with HTN, palpitations, diaphoresis, or
headaches should have plasma metanephrines checked
 Screening not recommended for asymptomatic patients
o HTN
 High risk of renovascular HTN
 Assess for abdominal bruits
 Most cases of HTN in adults with NF1 is primary essential, but
screening for renovascular HTN should still be done
o Screen for osteoporosis and scoliosis
o Cognitive and psychiatric
 Depression screening
 ADHD screening
 Cognitive impairment is normal but severe impairment warrants
workup for other etiologies
o Chronic pain
 Fingertip pain or toe pain may indicate glomus tumors
 New onset pain may indicate MPNST
o Genetic counseling
 For risk of transmission to offspring

Treatment

- Cutaneous neurofibromas are generally not removed

- PN treatment is difficult
o Surgical debulking of the tumor is the go-to
o Recently, pharmacologic intervention has been explored with inhibitors of
the MEK pathway (ex. Selumetanib)
- Bone abnormalities/scoliosis
o Orthopedic intervention can be indicated
- MPNST
o If these arise, surgical resection followed by radiation therapy is indicated

References

UpToDate

B&B – Neurocutaneous Disorders

Dombi E, et al. Activity of Selumetinib in Neurofibromatosis Type 1-Related Plexiform

Neurofibromas. New England Journal of Medicine. 2016; 375(26): 2550-2560.
Gross AM, et al. Selumetinib in Children with Inoperable Plexiform Neurofibromas. New
England Journal of Medicine. 2020; 382(15): 1430-1442.