Neurofibromatosis type 1
(von Recklinghaussen disease)
Autosomal dominant multi-system disorder of neural crest origin
Mutation in NF1 gene on chromosome 17q21
About 50% cases are caused by a new mutation
Encoding for Neurofibromin protein, deficiency of which causes increased RAS activity. This affects cell proliferation, differentiation, and survival, causing lesions in the skin, nervous system and skeleton with high risk of malignancy.
NF1 Diagnostic criteria (Any 2 or more of)
– 6 or more café-au-lait macules (>0.5cm in diameter or >1.5cm in post-pubertal)
– 2 or more neurofibromas or 1 plexiform neurofibroma
– Freckling in the axillary or inguinal region.
– Optic pathway glioma
– 2 or more Lisch nodules on iris (hamartomas on slit lamp)
– Bony dysplasia (sphenoid wing dysplasia, bowing of long bone +/- pseudoarthrosis)
– First degree relative (parent or child) with NF1
Diagnostic confirmation:
Diagnosis needs to be confirmed or rejected at each review when not all signs have developed
All children with 6 café au lait macules aloneneed annual follow-up
Approximately 50% of patients meet the diagnostic criteria by 1y age and 97% by 8y age.
NF1 mutational analysis can help in uncertain cases or prenatal counselling, but is not a requirement
Consider other differential diagnoses of hyperpigmented lesions like McCune-Albright syndrome, Melanosis, Peutz-Jeghers syndrome.
Clinical Presentation:
Main issues apart from skin lesions are bone dysplasia, hypertension, learning difficulties, and an increased risk of malignancy.
– Skin: Café au lait spots, skinfold freckling, cutaneous neurofibroma, subcutaneous neurofibroma, plexiform neurofibroma
– Skeletal: Bowing of long bones, fractures, Pseudoarthrosis, Scoliosis
– Eyes: Optic pathway glioma, Glaucoma, Iris hamartomas
Sphenoidal wing dysplasia causing pulsating exophthalmos / proptosis
– CNS: Macrocephaly, Brainstem and cerebellar gliomas, Abnormal vasculature, Neurofibromas causing aqueduct stenosis and raised ICP, Sensorineural hearing loss, Epilepsy (5-7%)
– Peripheral nerves: Malignant peripheral nerve sheath tumours
Neurofibromas causing peripheral nerve damage or cord compression
– Developmental / Behavioural: learning difficulty, ASD and ADHD, Disordered sleep, Disordered development, Anxiety, Depression, emotional issues due to disfigurement
– Cardiac: Pulmonary stenosis, Coarctation of aorta, Mid-aortic stenosis
– GIT: Carcinoid tumours, Neurofibromas causing GI bleeds and anaemia
– Kidneys: Renal artery stenosis and aneurysm, Phaeochromocytoma
– Puberty/ reproductive issues: Precocious or delayed puberty
Pregnancy with hypertension, obstruction in birth canal, Increased risk in breast cancer in adult life
Management:
– Monitor café-au-lait marks: Approximately 50% of patients meet the diagnostic criteria by 1y age and 97% by 8y age.
– If parent has NF1, newborn baby needs review at 1y, 2y & 5y age
– Confirm diagnosis using above criteria
– Provide adequate information about condition & signpost to support group
– Children should have annual monitoring for complications and appropriate investigation or referrals
– Baseline cardiac and renal investigations & monitor if issues
– Learning support may be required within school
– Genetic counseling for young people after onset of puberty/ by 15y
At each annual review, monitor
– Growth (Height & weight for all; HC in under 3y age)
– Blood pressure
– Developmental surveillance in pre-school children
– Pubertal assessment in older school aged children
– Emotional, behavioural and learning issues including school progress
– Opthalmology review annually until 7y age, then optician every few years until puberty attained
– Examination: Skin lesions including changes, spine for curvature, skeletal changes of pseudoarthrosis & full neurological examination
Referrals may be required to– Opthalmology, Audiology, Orthopaedics, Spinal surgeon, Oncologist, Neurologist, Neurosurgeon, Plastic surgeon, Nephrologist, Clinical Geneticist, Psychologist, Learning support etc