Peripheral nerve tumors are hallmarks of several well-known familial tumor syndromes, including NF1 and NF2, familial and sporadic schwannomatosis, and MEN2B. Isolated neurofibromas and schwannomas are also encountered in other rare, heritable conditions, such as Carney complex and PHTS. They, of course, also occur sporadically in otherwise healthy individuals.
Herein, we presented four unrelated patients with a strikingly similar clinical phenotype, which included multiple painful neurofibromas of mucosal, cranial and large spinal nerves, bilateral and multiple orbital neurofibromas, enlarged corneal nerves, congenital neuronal migration abnormalities, as well as distinctive facial features and a marfanoid habitus. Clinical findings in our four cases and one similar case from the literature (Meyer and Wobig26
) are presented in . We have included that patient despite the fact that testing in this case was less complete. Except for facial freckling, no other pigmentary skin changes were present; specifically there were no café-au lait spots, intertriginous freckling or Lisch nodules. No cutaneous neurofibromas were present. Unlike NF1, subcutaneous tumors were remarkably painful and had a tendency to rapidly enlarge. The pain associated with the neurofibromas in our patients is intriguing, as pain is not usually observed in the context of sporadic or NF1-associated plexiform neurofibromas. Histological examination of the tumors did not reveal any pathology that would readily explain the pain such as inflammation, thrombosis or acute hemorrhage. The tumors, however, are remarkable in that some of the histological features, specifically the abundance of mucin (myxoid stroma) and prominent schwann cell nodules resemble variants of neurofibromas or lesions with hybrid (schwannoma/neurofibroma) features. Although prominent myxoid change and tumors with hybrid histological features have been associated with schwannomatosis (and therefore often associated with pain), the tumors in schwannomatosis are schwannomas (not neurofibromas), and there is no direct evidence or functional data that links myxoid stroma or hybrid histological features with pain.
Table 1 Clinical findings in affected patients (including one similar case from the literature26)
Thus, the etiology of pain in our patients remains unknown but possibility of pro-inflammatory cytokines or nerve growth factor as a major mediator of painful response can not be excluded.6, 7
All cases appeared to be sporadic in occurrence as there was no reported family history of similar features. Interestingly, all four patients are female, which may be coincidental but could also represent the gender bias in disease expression. Mutational analysis of peripheral blood leukocytes showed no pathogenic mutation in the NF1, NF2, SMARCB1, PTEN, PRKAR1A, PTPN11, RAF1, SOS1, KRAS, NRAS, CBL, and SHOC2 genes. In addition, mutational analysis of tumor-derived schwann cells revealed normal NF1, NF2, and SMARCB1 genes, thus excluding mosaicism for these gene mutations. We also excluded a small deletion or duplication as the cause of the condition by performing array CGH upon blood and tumor tissue.
Although our patients shared some clinical features with MEN2B, particularly mucosal neuromas, full lips, thickened corneal nerves, and a marfanoid habitus, there were deviations from the MEN2 phenotype. They included the presence of bilateral orbital neurofibromas, multiple peripheral nerve tumors, neuropathy and developmental brain abnormalities, features unassociated with MEN2B. In addition, no RET
gene mutation was observed in our probands. In patient 1, analysis of the RET
gene was negative, aside from the presence of a heterozygote p.Gly691Ser polymorphism known to be overrepresented in MTC and a possible modifier of MEN2A expression.8, 9
The same polymorphism was detected in peripheral leukocytes in the patient's unaffected mother. The p.Gly691Ser polymorphism in our patient was likely a familial variant of doubtful clinical significance. In patient 2, the RET
mutation analysis was normal in cultured neurofibroma-derived schwann cells and fibroblasts, as well as in DNA extracted from uncultured neurofibroma tissue. This excluded mosaicism for a RET
mutation as an explanation of the atypical clinical findings. Analysis of RET
gene was not performed in patients 3 and 4; the information for patients 3 and 4 was obtained retrospectively (post mortem), and therefore was somewhat limited. However, similarities in phenotypes and lack of mutations in NF1
gene in all four cases described here suggest that they all have represented the same clinical entity.
There have been several reports in the literature of patients with atypical MEN2B findings, including (a) an incomplete MEN2B phenotype and (b) lack of RET
gene mutations in the presence of MEN2B features. A few patients with multiple neuroma syndrome or MEN2B without MTC or a RET
gene mutation have been described.3, 10
There have been only a few other reports describing patients with MEN2B-like features.11, 12, 13, 14
These cases, termed ‘pure mucosal neuroma syndrome' by Gordon et al14
and by Spyer et al12
, showed neither associated endocrinopathies nor RET
mutations. The cases reported by Gómez et al11
and by Dennehy et al13
were familial, thus excluding mosaicism for MEN2
mutations as a possible explanation. There are more examples of phenotypic overlap suggesting the presence of additional, still undefined subgroups of disorders similar to MEN 2A and 2B. For example, Kane et al15
reported a unique kindred manifesting with MTC and thickened corneal nerves, but without other clinical features of MEN2A or MEN2B and absence of RET
gene mutations. Despite a number of described atypical cases, none included a developmental brain anomaly, non-mucosal nerve neurofibromas, or ‘neurofibromatous' neuropathy. Aside from a single description of a patient with bilateral, localized orbital neurofibromas and Charcot-Marie-Tooth disease, no other instances of a neuropathic process in patients with orbital neurofibromas or with MEN2B-like feature have been reported.16
Orbital neurofibromas are rare and usually sporadic. They are only infrequently (7–10%) associated with NF1.17, 18, 19, 20, 21
Neurofibromas in the area of the eyelids and orbits often result in development of glaucoma,22, 23
as was the case in two of our patients. Bilateral orbital involvement with neurofibromas is extremely unusual. Only a few instances, either as an isolated clinical finding16, 24
or in association with multiple other features of NF1, have been reported.25
Meyer and Wobig26
described a patient presenting with symmetric bilateral orbital neurofibromas and several features of MEN2B, including marfanoid habitus, enlarged corneal nerves, thickened lips and mucosal neuromas, but neither diagnostic testing for RET
mutations had been performed nor was information provided regarding associated features, such as neuropathy or a neuronal migration defect.26
Despite striking clinical similarities between cases reported by Meyer and Wobig26
and those of our patients, lack of additional information obviates the conclusion that they have had the same condition.
We propose that the patients reported herein represent a new syndrome characterized by bilateral orbital neurofibromas, painful peripheral neurofibromas, distinct facial features, marfanoid habitus, enlarged corneal nerves, and a neuronal migration defect. Additional feature of this new syndrome may be propensity for keloid scars and facial skin freckling including lips. We suggest that previously reported patients with ‘pure mucosal neuroma syndrome' have a minor form of this condition. Its genetic basis remains to be determined.