Neurofibromatosis type 1 and type 2 — branching viva

Opening framework

My framework has four layers. First, the diagnosis \u2014 NF1 is a clinical diagnosis built from the NIH criteria, and this child with eight cafe-au-lait macules and axillary freckling already meets two of the seven, so she has NF1. Second, the mechanism \u2014 a loss-of-function variant in NF1 on chromosome 17 that abolishes neurofibromin, the RAS-GAP that switches off active RAS. Third, the surveillance \u2014 annual review of growth, blood pressure, vision, skin and development. Fourth, the family \u2014 cascade testing and counselling on the 50 per cent autosomal-dominant recurrence risk. [1]

Applying the criteria and the 2021 revision

The NIH criteria require two or more of seven features: six or more cafe-au-lait macules of at least 5 mm before puberty or 15 mm after, skinfold freckling, two or more neurofibromas or one plexiform, optic pathway glioma, two or more Lisch nodules, a distinctive osseous lesion, and an affected first-degree relative. This child meets cafe-au-lait macules and freckling, so the clinical diagnosis is secure. The 2021 revision adds a pathogenic NF1 variant or an unequivocal plexiform neurofibroma on MRI as standalone criteria, which helps when the skin phenotype is still emerging. [10] [5]

The molecular basis and recurrence risk

NF1 is on chromosome 17q11.2 and encodes neurofibromin, a GTPase-activating protein that converts active RAS-GTP to inactive RAS-GDP. Without it, the RAS-MAPK cascade runs unchecked and drives proliferation in Schwann cells and melanocytes. It is autosomal dominant with full penetrance and variable expressivity, so an affected parent transmits the variant to half their children, though severity varies within a family. Around half of cases are de novo, so a negative family history never excludes NF1. I would offer cascade testing to the father and counsel the family on reproductive options. [1]

Branch: the painful enlarging thigh lump

A painful, rapidly growing, firm lump in a pre-existing neurofibroma is malignant peripheral nerve sheath tumour until proven otherwise. I would arrange urgent MRI of the lesion, a positron-emission tomography scan to assess metabolic activity and staging, and a biopsy to confirm histology, then refer to the oncology and sarcoma service. Malignant transformation occurs in 8 to 13 per cent of patients over a lifetime and is the most feared complication of NF1. [1] [8]

Branch: the 17-year-old with hearing loss

This is neurofibromatosis type 2, which is a completely different disease. NF2 is caused by variants in NF2 on chromosome 22q12.2 encoding merlin, a cytoskeletal tumour suppressor, not neurofibromin and not the RAS pathway. It presents with vestibular schwannomas, meningiomas and ependymomas, and the skin findings are minimal. I would confirm with gadolinium MRI of the brain and internal auditory canals, audiometry, and NF2 sequencing, and manage in a specialist NF2 clinic with surgery, radiosurgery or bevacizumab. [2]