Neurofibromatosis
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Direct answer
Neurofibromatosis comprises autosomal dominant disorders of nerve sheath tumour formation, the commonest being neurofibromatosis type 1 caused by NF1 mutations on chromosome 17. Diagnosis of NF1 rests on the NIH criteria, which need two or more of seven features, including six or more café-au-lait macules, two or more neurofibromas and two or more Lisch nodules. Neurofibromatosis type 2 instead produces bilateral vestibular schwannomas due to NF2 mutations on chromosome 22.
What you must remember
- NF1 gene: located on chromosome 17q11.2 and encoding neurofibromin, a RAS-GTPase activating protein; about half of cases arise de novo.
- Café-au-lait macules: six or more, over 5 mm before puberty or over 15 mm after puberty; they are the commonest early sign.
- Neurofibromas: dermal neurofibromas are soft, with a buttonhole sign on pressure, while plexiform neurofibromas feel like a bag of worms and carry a risk of malignant change.
- Lisch nodules: iris hamartomas seen on slit lamp examination; two or more count as a diagnostic criterion.
- Axillary and inguinal freckling: also called the Crowe sign, usually appearing in childhood.
- NF2 gene: chromosome 22q12, encoding the tumour suppressor merlin; it causes bilateral vestibular schwannomas, meningiomas and juvenile posterior subcapsular cataracts.
- Malignancy: malignant peripheral nerve sheath tumours, optic pathway glioma and pheochromocytoma are NF1 associations to know.
NF1 and NF2 side by side
The two main types share a name but differ in gene, tumours and skin signs, which is how exam stems separate them. Use the table to match the stem to the correct type.
| Feature | NF1 | NF2 |
|---|---|---|
| Gene and chromosome | NF1, 17q11.2 | NF2, 22q12 |
| Protein | Neurofibromin | Merlin |
| Hallmark skin signs | Café-au-lait macules, neurofibromas | Few skin signs; cutaneous schwannomas |
| Eye feature | Lisch nodules, optic glioma | Posterior subcapsular cataract |
| Typical tumour | Neurofibromas, optic glioma | Bilateral vestibular schwannomas |
| Hearing | Usually normal | Progressive hearing loss |
Multiple café-au-lait macules with Lisch nodules point to NF1, whereas bilateral vestibular schwannomas with cataract point to NF2. Both are autosomal dominant with variable expression, so a family history helps but is not always present.
Where the criteria and tumours mislead
Most mistakes come from counting features wrongly or assigning a tumour to the wrong gene.
- Trap: diagnosing NF1 from a single café-au-lait macule. Correct: six or more macules of the stated size are needed, because a single patch is common in the general population.
- Trap: calling bilateral acoustic neuromas NF1. Correct: bilateral vestibular schwannomas define NF2, which has a different gene and prognosis.
- Trap: treating a plexiform neurofibroma as benign whatever its behaviour. Correct: rapid growth, pain or neurological change should prompt imaging, since malignant transformation can occur.
- Trap: missing Lisch nodules because no ophthalmic examination was done. Correct: slit lamp examination of the iris is part of NF1 assessment.
Frequently asked questions
How many café-au-lait macules suggest NF1?
Six or more café-au-lait macules suggest NF1, measuring over 5 mm in prepubertal children and over 15 mm after puberty. A single patch is common in the general population, so the count and size matter for diagnosis.
What is a Lisch nodule and why does it matter?
Lisch nodules are benign iris hamartomas seen on slit lamp examination and are a common feature of neurofibromatosis type 1. Two or more Lisch nodules count as one of the seven NIH diagnostic criteria for NF1.
Which gene is mutated in neurofibromatosis type 2?
Neurofibromatosis type 2 is caused by mutations in NF2 on chromosome 22q12, which encodes the tumour suppressor merlin. It produces bilateral vestibular schwannomas, meningiomas and juvenile cataracts.
What is a plexiform neurofibroma?
A plexiform neurofibroma is a diffuse, tortuous nerve tumour that feels like a bag of worms and is characteristic of neurofibromatosis type 1. It can cause disfigurement and carries a risk of malignant peripheral nerve sheath tumour.
What is the buttonhole sign?
The buttonhole sign describes a dermal neurofibroma that herniates through a gap in the subcutaneous tissue when pressed, feeling soft and compressible. It is a classic bedside sign in neurofibromatosis type 1.