Neurofibromatosis type 1 and type 2 — formative SAQs

Question 1 (10 marks)

A four-year-old boy is referred because his preschool teacher noticed "lots of brown spots." On examination he has nine cafe-au-lait macules (the largest 8 mm) and freckling in both axillae. His mother has a few cafe-au-lait spots and one small skin lump. (a) State the diagnostic criteria you apply and whether he meets them. (b) Outline the initial assessment and annual surveillance plan. (c) Explain the genetic basis and recurrence risk. [10]

Model answer

(a) The NIH criteria for NF1 require two or more of seven features: six or more cafe-au-lait macules of at least 5 mm before puberty, axillary or inguinal freckling, two or more neurofibromas or one plexiform neurofibroma, optic pathway glioma, two or more Lisch nodules, a distinctive osseous lesion, and an affected first-degree relative. This boy meets two (cafe-au-lait and freckling), so the clinical diagnosis of NF1 is confirmed. [10]

(b) The assessment completes a structured skin, eye, growth and neurological examination, measures blood pressure, plots height and head circumference, screens development and behaviour, and takes a three-generation pedigree while examining both parents. The annual plan reviews growth, blood pressure, skin, spine, puberty and development, and tests visual acuity and colour vision until at least age eight to detect optic pathway glioma. [1]

(c) NF1 is an autosomal-dominant loss-of-function disorder of the NF1 gene on chromosome 17q11.2 encoding neurofibromin, a RAS-GAP. The recurrence risk to each child of an affected parent is 50 per cent, though expressivity varies. Cascade testing of the mother and first-degree relatives is mandatory, and genetic counselling addresses reproductive options. [5]

Question 2 (10 marks)

A 16-year-old girl presents with six months of progressive right-sided hearing loss and tinnitus. Her father had a vestibular schwannoma removed at age 30. (a) What is the most likely diagnosis and why? (b) What investigations confirm it? (c) How does this condition differ genetically and clinically from NF1? [2]

Model answer

(a) The most likely diagnosis is neurofibromatosis type 2. The combination of progressive unilateral hearing loss and tinnitus with a first-degree relative who had a vestibular schwannoma meets the family-history criterion for NF2, and her hearing loss suggests an ipsilateral schwannoma. Bilateral disease is common but unilateral presentation with a family history is sufficient. [2]

(b) Confirmation requires gadolinium-enhanced MRI of the brain and internal auditory canals to define any vestibular schwannoma or meningioma, pure-tone and speech audiometry, ophthalmology assessment for juvenile cataracts, and NF2 gene sequencing and deletion analysis to enable cascade testing. A whole-neuraxis MRI screens for spinal ependymoma. [2]

(c) NF2 is caused by variants in the NF2 gene on chromosome 22q12.2 encoding merlin (schwannomin), a cytoskeletal tumour suppressor, not neurofibromin. The tumour spectrum is vestibular schwannomas, meningiomas and ependymomas rather than cafe-au-lait macules and neurofibromas, the cognitive profile is usually normal, and the management is surgical and rehabilitative. The two conditions share a name and little else. [2]