Can the diagnosis of NF1 be excluded clinically? A lack of pigmentary findings in families with spinal neurofibromatosis demonstrates a limitation of clinical diagnosis

Abstract

Background: Consensus clinical diagnostic criteria for neurofibromatosis type I (NF1) include café-au-lait macules and skinfold freckling. The former are frequently the earliest manifestation of NF1, and as such are of particular significance when assessing young children at risk of the condition. A phenotype of predominantly spinal neurofibromatosis has been identified in a small minority of families with NF1, often in association with a relative or absolute lack of cutaneous manifestations. An association with splicing and missense mutations has previously been reported for spinal neurofibromatosis, but on the basis of molecular results in only a few families.

Method: Patients with spinal NF1 were identified through the Manchester nationally commissioned service for complex NF1.

Results: Five families with spinal NF1 were identified, with a broad spectrum of NF1 mutations, providing further evidence that this phenotype may arise in association with any genre of mutation in this gene. Pigmentary manifestations were absent or very mild in affected individuals. Several further affected individuals, some with extensive spinal root tumours, were ascertained when additional family members were assessed.

Conclusions: Clinical NF1 consensus criteria cannot be used to exclude the diagnosis of spinal NF1, especially in childhood. This emphasises the importance of molecular confirmation in individuals and families with atypical presentations of NF1.

Keywords: Clinical genetics; Dermatology; Genetics; Other neurology.

Figure 1

(A–E) Pedigrees of families 1–5.

Figure 2

(A and B) Coronal short TI inversion recovery (STIR) images of (A) cervical and (B) lumbosacral spine of patient I:1 of family 2. At 30 years of age, multiple lesions are present bilaterally, most marked in the mid and lower cervical levels (A; arrowed) and in the sacrum, particularly of the S1 nerve root (B; arrowed). A mild thoracic kyphoscoliosis is also seen (A), and degenerative change of the L5/S1 intervertebral disc (B). (C) Coronal maximum intensity projection (MIP) 2 cm thick STIR image from the whole body MRI scan of patient II:1 of family 5. At 43 years of age, spinal nerve sheath tumours can be seen bilaterally at nearly every vertebral level: cervical and lumbar lesions are demonstrated. Alongside the extensive nerve root tumours, multiple subcutaneous lesions can be seen in the scalp (arrow) and extremities. (D) Coronal curved plane reformat MIP STIR image from the whole body MRI scan of patient III:1 of family 5. At 20 years of age, similar to his mother's presentation, spinal nerve sheath tumours can be seen bilaterally at nearly every vertebral level. A particularly large lesion, approximately 30 mm in smallest diameter, is seen in the sub-occipital area.