Multiple orbital neurofibromas, painful peripheral nerve tumors, distinctive face and marfanoid habitus: a new syndrome

Abstract

Four unrelated patients having an unusual clinical phenotype, including multiple peripheral nerve sheath tumors, are reported. Their clinical features were not typical of any known familial tumor syndrome. The patients had multiple painful neurofibromas, including bilateral orbital plexiform neurofibromas, and spinal as well as mucosal neurofibromas. In addition, they exhibited a marfanoid habitus, shared similar facial features, and had enlarged corneal nerves as well as neuronal migration defects. Comprehensive NF1, NF2 and SMARCB1 mutation analyses revealed no mutation in blood lymphocytes and in schwann cells cultured from plexiform neurofibromas. Furthermore, no mutations in RET, PRKAR1A, PTEN and other RAS-pathway genes were found in blood leukocytes. Collectively, the clinical and pathological findings in these four cases fit no known syndrome and likely represent a new disorder.

Figure 1

Patient 1. Facial features with mild dysmorphism and facial freckling. Ptosis and eyelids swelling due to bilateral plexiform neurofibromas, coarse facial features, and full lips (a). Thickened corneal nerves (b), MRI brain (c) and computed tomography of orbits (d). Numerous enhancing mass lesions consistent with nerve sheath tumors within the orbits bilaterally (e). Enhancing mass lesions in the anterior parotid glands bilaterally, of the divisions of the fifth cranial nerves as well as the vidian nerves (d). Changes of a migrational anomaly involving the right anterior frontal lobe. This configuration suggests polymicrogyria in association with closed right schizencephaly extending to the right anterior frontal horn of the lateral ventricle (e). Massive enlargement of orbital nerves and multiple orbital tumors intraoperative view (f). Removed plexiform neurofibroma involving the branch of frontal nerve (g).

Figure 2

Patient 1. Plexiform neurofibromas. The right orbital lesion showed some fascicles to be mucin-rich (a). In addition, whorls of schwann cells were a focal conspicuous finding (b). Cross section of one fascicle showed the characteristic, centrally situated residual nerve surrounded by tumor tissue (c). Sublingual tumor (d) revealed similar features; note multiple affected fascicles.

Figure 3

Patient 2. Proptosis due to bilateral orbital tumors, full lips (a), and mucosal neurofibromas (b). MRI of the brain shows migrational anomaly involving the right anterior frontal lobe. The configuration suggests polymicrogyria in association with closed right schizencephaly extending to the right anterior frontal horn of the lateral ventricle (c). MRI spine shows numerous enhancing mass lesions extending through the neural foramina at multiple spinal levels, most prominent at the lower cervical and upper thoracic levels, consistent with nerve sheath tumors (d). Involvement of bilateral brachial (e) and lumbosacral (f) plexi with multiple neurofibromas. MRI of the orbits shows two enhancing mass lesions consistent with nerve sheath tumors within the right orbit (g). Polypoid mass in the right nostril (h).

Figure 4

Patient 2. Neurofibroma, right nostril. Note mild clinically insignificant atypia consisting of mild hypercellularity and hyperchromasia.

Figure 5

Patient 3. Limited MRI imaging was available. MRI brain with mass lesions at the skull base (a). Subcutaneous neurofibroma in the right temporal area (b). Multiple orbital neurofibromas bilaterally (c). Neurofibromas involving multiple thoracic nerve roots (d) and massive bundle of pelvic tumors (note thoracic scoliosis as well) (e).

Figure 6

Patient 3. Plexiform neurofibroma, left orbit. Note varying expansion of three fascicles (a) and relative abundance of mucin (b), showing strong staining for Alcian blue (c).

Figure 7

Patient 4. Asymmetric proptosis due to bilateral orbital tumors and full lips (a). MRI brain and orbits show innumerable neurogenic tumors including bilateral orbital neurofibromas (b–e). Numerous bilateral enhancing mass lesions in the orbits, parotid glands, superficial and deep upper face, masticator region and skull base (limited imaging was available). Marfanoid habitus and multiple keloid scars (f, g).