Neurofibromatosis Type 1

Neurofibromatosis type 1 (NF1; von Recklinghausen disease) is an autosomal dominant RASopathy with an incidence of about 1 in 2,500 to 3,000 births and nearly complete penetrance by adulthood. It is caused by loss of function of NF1 (17q11.2), which encodes neurofibromin, a negative regulator of RAS. About 50% of cases are de novo. Mosaic and segmental NF1 occur.

Some genotype phenotype relationships exist: large 1.4 Mb deletions cause severe phenotypes (dysmorphism, developmental delay, numerous neurofibromas, malignant peripheral nerve sheath tumour risk), while 3 base pair in frame deletion c.2970-2972 delAAT lacks cutaneous neurofibromas.

Diagnostic criteria (two or more required):

• Six or more cafe-au-lait macules (above 5 mm in prepubertal children, above 15 mm after puberty)
• Axillary or inguinal freckling (Crowe sign)
• Two or more neurofibromas of any type or one plexiform neurofibroma
• Optic pathway glioma
• Two or more Lisch nodules (iris hamartomas) or two or more choroidal abnormalities
• Distinctive osseous lesion (sphenoid dysplasia, anterolateral bowing of the tibia, pseudarthrosis)
• A heterozygous pathogenic NF1 variant at 50% or more allele fraction in normal tissue

Complications:

• Neurological: learning disabilities (50 to 70%), ADHD, autism spectrum features, macrocephaly, headaches, seizures, hydrocephalus (aqueduct stenosis), and unidentified bright objects on T2 MRI
• Tumours: optic pathway glioma (15 to 20%, mostly asymptomatic; presents before age 6 with proptosis, visual loss, precocious puberty), plexiform neurofibromas (about 30 to 50%; disfigurement, pain, and malignant transformation to malignant peripheral nerve sheath tumour with lifetime risk 8 to 13%), spinal neurofibromas, pheochromocytoma, gastrointestinal stromal tumours, juvenile myelomonocytic leukaemia, rhabdomyosarcoma, breast cancer (increased risk in women under 50), and glomus tumours
• Skeletal: scoliosis (10 to 20%; dystrophic with rapid progression), tibial pseudarthrosis, short stature, osteopenia
• Cardiovascular: hypertension (renal artery stenosis, pheochromocytoma, coarctation), vasculopathy (stenosis, moyamoya), and pulmonary stenosis

• Clinical examination is typically diagnostic from age 4 to 8; genetic testing (NF1 sequencing, deletion/duplication, RNA-based methods, and mosaic testing) confirms the diagnosis in infants with isolated cafe-au-lait macules (6 or more in a child with no family history; 90% develop NF1 within 6 years, when additional features appear) or atypical cases. Annual examination includes growth, blood pressure, skin, spine, development, and ophthalmological assessment (annual until 8 to 10 years, to detect optic pathway glioma). MRI is performed for symptoms or to assess plexiform neurofibromas (whole body MRI to define volume and risk); PET-CT or biopsy for suspected malignant change (rapid growth, severe pain, neurological deficit, hardening).

• Multidisciplinary clinic follow up, annually from diagnosis through adulthood.
• Selumetinib (MEK inhibitor): 25 mg/m2 orally twice daily (capsule) for children aged 2 years and above with symptomatic, inoperable plexiform neurofibromas; shrinks tumours in about 70%; monitor for gastrointestinal toxicity, rash, elevated creatine kinase, decrease in ejection fraction (echocardiogram baseline and periodically), and ocular toxicity (ophthalmological examination). Mirdametinib is another option, including in adults.
• Surgery for symptomatic or growing neurofibromas, with caution regarding bleeding; complete excision of plexiform tumours is often not possible.
• Optic pathway glioma: observation when asymptomatic; chemotherapy (carboplatin with vincristine, or vinblastine) for progressive visual loss; avoid radiotherapy because of the risk of secondary tumours and moyamoya; MEK inhibitors (selumetinib, trametinib) are increasingly used.
• Malignant peripheral nerve sheath tumour: wide surgical resection with multimodal therapy; poor prognosis.
• Scoliosis: bracing or surgery; tibial pseudarthrosis: surgical stabilisation.
• Hypertension: assess for renal artery stenosis and pheochromocytoma.
• Learning and behavioural problems: early educational support, and stimulants for ADHD.
• Women: breast cancer screening (annual mammography and MRI from age 30 to 50).
• Genetic counselling: 50% recurrence risk for an affected parent.