Neurofibromatosis Type 1

axillary/inguinal freckling

"Crowe's sign", 75-85% of NF1 patients, noted around 3-4 years old

Optic nerve glioma

15% of NF1 patients, benign tumor of optic nerve and/or chiasm; usually presents in childhood and largely asymptomatic (much more aggressive than non-NF patients) If it involves optic chiasm, more likely to result in vision loss Chemo - MRI, opthalmology exams, 3-6 months

NF1 diagnostic criteria

2+ following: 1. 6 or more cafe au lait spots (>5 mm prepubescent, >15 mm after puberty) 2. 2 cutaneous neurofibromas or one plexiform neurofibroma 3. Multiple axillary/inguinal freckles 4. A distinctive osseous lesion (sphenoid wing dysplasia, tibial bowing) 5. Optic nerve glioma 6. 2 or more lisch nodules (hamartomas) 7. a first degree relative with NF1

NF1 musculoskeletal findings

30% have some skeletal abnormality 10-25% kyphoscoliosis (vertebral wedging, sharp curve) 5% Tibial dysplasia (congenital/first year of life, anterior lateral bowing, may progress to fracture, pseudoarthrosis) 2-10% Sphenoid wing dysplasia (bulging or recessing globe)

details of plexiform neurofibromas

30% of NF1 patients, usually present before adolescence, may be congenital (facial plexiforms in particular) Those in face and neck appear during first year of life, rapid growth in first 5 years and may grow during puberty May be associated with pain, sensory loss, or underlying hypertrophy Malignant degeneration in 8-13%

NF1 neurologic findings

headaches, migraines 8-10% seizures CNS tumors (ONG, astrocytoma, brainstem glioma) low grade, slow growing gliomas less aggressive than general population 50-60% learning disabilities 25-30% ADHD (inattentive type)

NF1 management

Follow-up 3-6 months (growth/development, blood pressure, skin, pain) annual opthalmology for kids MRI scan of brain and orbits (at some centers) Chest xray every 3 years for thoracic neurofibromas (CCHMC only) consider whole body MRI in future

NF1 malignancies

JMML, astrocytoma, brainstem glioma, pheochromocytoma in adults (suspect in patients with episodic HTN), neuroblastoma, gastrointestinal stromal tumor (GIST) - better prognosis than non-NF

Cutaneous neurofibromas

Majority of adult NF patients, rarely malignant, infrequent before puberty, may increase with puberty/pregnancy, may be cutaneous or subcutaneous, purplish/brown, areolar common in post-pubescent females

T2 hyperintensities

Unidentified bright signals (T2 hyperintense signals) 60-70% of NF1 patients (80% children) Transient differentiation in myelination? Found in: optic tract, basal ganglia, brainstem, cerebellum, or sub-cortical white matter Sometimes hard to differentiate from glioma Disappear with age, uncommon in adults

NF1 elevator speech

1/3,000 in the US; most common neurologic disorder (monogenic); all sexes and races equally, highly penetrant, highly variable

Cafe au lait spots in general population

10-20% have two or less

Lisch nodules

55-70%; elevated, smooth dome-shaped tan macules usually less than 2 mm; benign iris hamartomas 5% by age 3, 33% by age 6, 94% post pubertal

NF1 Prognosis

60-70% have mild/moderate course 30% have serious complications 20% have disfigurement 10% require orthapedic surgeries life expectancy = 55 years

Cafe au lait spots in NF1 patients

95% have them; more than 6 found in 78%; generally present at birth but increase after age 2, may increase in size and number, may tan in summer and fade in winter, can fade in early adulthood

Malignant peripheral nerve sheath tumors

Most occur within a pre-existing plexiform neurofibroma Symptoms: severe pain (morning) and rapid growth Signs: tenderness to touch, lack of typical pattern on MRI, increased uptake (PET scan > 7) Higher incidence in those with whole gene deletions

Cafe au lait spots (differentials)

NF1, McCune-Albright, NF2, LEOPARD syndrome, urticaria pigmentosa

Treatment of MPNST

Poor prognosis for NF patients (36% survival at 2 years, 20% survival at 5 years); longer time of onset to surgery Poor response to chemo/radiation Surgical resection is best chance (do it early); early amputation may be best

NF1 pregnancy

Rapid increase in number and size of neurofibromas Hypertension may become more evident Pelvic or genital neurofibromas may require c-section (overall increase in c-section)

plexiform neurofibromas

arising from large nerve trunks, interdigitate with normal tissue

paraspinal neurofibromas

arising from nerve foots/neural foramina

NF1 molecular biology

autosomal dominant, 50% de novo protein: neurofibromin GTPase-activating protein tumor suppressor inactivates the ras protein (leads to uncontrolled survival, growth, proliferation)

Segmental NF1

cafe au lait spots, neurofibromas, freckling, hemihypertrophy typically doesn't cross midline thought to be due to somatic mutations do germline testing to rule out NF1 familial cases have been reported

NF1

chromosome 17q11.2, autosomal dominant

NF1 diagnosis

clinical >250 pathological mutations 60 exons, 4 alternative spliced transcripts, 350 kb Introns also contain genes (3) $1500, Univ Alabama Greater than 95% sensitivity

cutaneous neurofibromas

dermal

SPRED1

missing complications and much less common; some won't meet NF1 criteria CAL, axillary freckling, macrocephaly, lipomas, learning disability - consider when testing is negative - can test SPRED1 though UAB

benign NF1 tumors

neurofibromas (cutaneous, subcutaneous, paraspinal, plexiform)

subcutaneous neurofibromas

nodular, may involve length of nerve

Other features of NF1

short stature (avg 25th percentile) macrocephaly hypertension (essential vs. renal vascular) renal artery stenosis due to fibromuscular dysplasia pheo (1/223) 10% with intestinal neurofibromas premature or precocious puberty

NF1 Names

vonRecklinghausen disease, vonRecklinghausen Neurofibromatosis, peripheral neurofibromatosis