In contrast to Neurofibromatosis type 1 (NF1), a genetic disorder, with gene mutations in chromosomes 17 and multiple cutaneous and CNS neurofibromas and pigmentation, NF2 is a dominantly inherited, tumor prone disorder with pathogenic mutations or mosaicism in the NF2
gene on chromosome 22 characterized by the development of multiple schwannomas, meningiomas, ependymomas, and only infrequently, neurofibromas [13
]. Its prevalence is estimated approximately at 1:60,000 [13
] or less (1:87,410) [14
]. The gold standard for diagnosis is the development of bilateral or unilateral vestibular schwannomas accompanied by hearing loss, tinnitus, and/or imbalance. Other important tumor features are schwannomas of cranial, spinal and peripheral nerves, intracranial and intraspinal meningiomas, ependymomas and gliomas [15
In our case, the laboratory, imaging and clinical examination revealed a single, localized lesion in the middle of the tongue dorsal surface without any signs of systemic amyloidosis. In fact, based on the patient’s medical history of Neurofibromatosis type II (NF2), the nodular lesion was clinically suspicious for a “neurogenic” tumor. Cases of neurofibromas have been described in oral mucosa in NF-1 [17
] and perineuriomas in patients with NF2-gene abnormalities [18
], but so far nothing is known of oral manifestations as part of NF2 disorder, except for a case of a nodular lesion of the tongue but without histological confirmation, as described by Barsley and Cottone [19
] in 1992.
As aforementioned, our patient’s genetic analysis revealed ring-shape chromosome 22 or even its loss (mosaicism) and according to Ruggieri and Huson [20
] this phenomenon may explain the development of ipsilateral (left ear) but not bilateral vestibular schwannomas. Noteworthy, imaging and/or histological investigation of the excised lesion revealed multiple intracranial meningiomas, including an optic nerve meningioma (right) leading to unilateral blindness as well as multiple meningiomas in the thoracic spine. Instead, our patient had not cutaneous nodules resembling neurofibromas of NF-1.
Not only neurofibroma or schwannoma, but also other entities such as fibroma, granular cell tumor, lipoma, leiomyoma, thyroglossal duct cyst, salivary gland neoplasm and median rhomboid glossitis were also included in the clinical differential diagnosis. On microscopic examination of the excised lesion, detection of eosinophilic amorphous material positive for Congo-Red in association with the clinical and laboratory analysis confirmed the diagnosis of localized amyloidosis without systemic involvement.
Amyloidosis represents a rare heterogenous group of conditions characterized by extracellular proteinaceous depositions of amyloid which may cause organ abnormalities [3
]. The mechanism, of amyloid formation, includes amyloid (pro)precursor genes activation, under the influence of cytokines, clonal plasma cells, abnormal proteolysis and the production of several precursor pools of different amyloidogenic molecules, which in turn form fibrils of amyloid after their enrichment with proteoglycans, glycosaminoglycans, inorganic ions and serum amyloid P [3
The incidence of amyloidosis is approximately 5-12 patients per million per year [23
], with a peak age in 50 years and male to female ratio 2:1, without racial bias. Disease severity ranges from asymptomatic to severe, life-threatening [4
]. Beyond the initial symptoms like fatigue and weight loss, organs such as heart [26
], kidney [27
], gastrointestinal, liver, spleen [28
] and nervous system (central and peripheral) [29
] may involved with severe consequences.
Prognosis depends on the severity of the disease at the time of diagnosis and the rate of amyloid accumulation. Median survival, after diagnosis of AL amyloidosis is 1–2 years, whereas 10-year survival rate is seen only in less than 5% of patients. The poor prognosis is associated with cardiac and liver involvement, neuropathy, or lack of control of any possible underlying plasma-cell disease (i.e. multiple myeloma). In contrast, the prognosis of localized amyloidosis is much better, but as in our case a careful follow-up is needed for the possible demonstration of a latent hematological disorder or organ involvement, in the future [4
Oral manifestations of amyloidosis are quite uncommon, and may be presented early in the course of the disease as mucosal papules, nodules or ulcers, macroglossia, petechiae/ecchymoses or even hemorrhagic bullae [12
]. Although the tongue is the most common oral site [6
], cases of amyloid deposition in the palate [11
], maxillary vestibule [35
], gingival [9
] and floor of the mouth [36
] have been mentioned as well. Rarely, minor or major salivary glands infiltration and related hypofuction-xerostomia can be seen [37
]. Noteworthy, oral involvement is extremely rare as the localized solitary manifestation of amyloidosis, but when present the tongue is primarily affected [6
In summary, this case report describes the existence of localized amyloidosis in a patient with NF-2. Although a familial “neuro”-related type of amyloidosis with peripheral neuropathy caused by ATTR amyloid accumulations has been described, so far nothing is known of an association between Amyloidosis and Neurofibromatosis. Thus, the synchronous presence of these two distinctive pathological entities in our patient at this time suggests a random co-existence, rather than a direct relationship.