NF1, also known as von Recklinghausen disease, is an autosomal dominant multisystem disorder that affects approximately 1 in 3500 people . In 1987, seven cardinal diagnostic criteria for NF1 were established . If any two of the following seven criteria are met, a diagnosis of NF1 is made: (a) two or more neurofibromas on or under the skin or one plexiform neurofibroma, (b) freckling of the groin or the axilla (arm pit), (c) six or more café-au-lait spots measuring 5mm in the greatest diameter in prepubescent individuals and over 15mm in the greatest diameter in post-pubescent individuals, (d) skeletal abnormalities such as sphenoid dysplasia or thinning of the cortex of the long bones of the body, (e) two or more Lisch nodules (hamartomas of the iris), (f) optic glioma, or (g) a first-degree relative with NF1. These diagnostic criteria are highly specific to adults with NF1. The patient in this study presented with neurofibromas all over the surface of his body, multiple café-au-lait spots, and axillary freckling. The NF1 gene was discovered in 1990. Mutational analysis is now available in a clinical setting and is useful for diagnostic confirmation of individuals who do not fulfill diagnostic criteria or when a prenatal diagnosis is desired .
Neurofibromatosis is an autosomal dominant disorder, meaning that only one copy of the affected gene is needed for the disorder to develop. Therefore, if only one parent has neurofibromatosis, his or her children have a 50% chance of developing the condition as well. The severity in affected individuals can vary and this variation may be due to variable expressivity. An individual with mild clinical symptoms can have a more severe phenotype and so genetic counseling is important . Approximately half of the known cases are due to de novo mutations and no other affected family members are seen. The patient in this case had no family history of NF1, suggesting that he has a de novo mutation.
PTC is one of the most common types of endocrine cancer. The prevalence of thyroid cancer is rapidly increasing in South Korea, and most cases are PTC. The high rates of incidence of RET/PTC rearrangements or point mutations in RAS and c-MET oncogenes are genetic hallmarks of PTC . The BRAF kinase is a serine-threonine kinase that mediates signal transduction through the MEK-ERK pathway. An activating mutation of the BRAF kinase gene, located on exon 15, was recently found to result in a valine-to-glutamic acid substitution at amino acid 600 (BRAF
mutation) that is an oncogene in human cancer and the most common mutation in PTC . In recent years, the BRAF
mutation has shown a high specificity for PTC, and its prevalence is highly variable, ranging from 30% to more than 80%, depending on the study. In the present study, the BRAF
mutation was identified by multiplex real-time PCR. This method is as sensitive as dual-priming oligonucleotide-based multiplex PCR (Seegene) for detecting BRAFV600E mutations.
The NF1 gene located on chromosome 17q11.2 encodes neurofibromin. The Ras-GAP is a potentially functional domain of neurofibromin . The Ras-GAP-related domain (Ras-GRD) accelerates the conversion of active Ras-GTP to inactive Ras-GDP in various cell types and acts as a negative regulator of the p21ras signaling pathway . Ras GTPases interact with multiple pathways, including the RAF-MEK-ERK mitogen-activated protein kinase pathway. Mutations in the NF1 gene result in abnormal cell growth and in the formation of benign and malignant tumors . Because BRAF
mutation and NF1 gene mutation are both involved in the MEK-ERK pathway, Koksal et al. suggested that the development of PTC in patients with NF1 may be associated with the ras gene but that further evidence is necessary to confirm this association.
PTCs are very rare in NF1. Only three cases have been reported. Nakamura et al. reported a case of NF1 associated with a pheochromocytoma and PTC in a 58-year-old woman. Hashiba et al. reported a case of skull metastasis from PTC in a 74-year-old woman with NF1. Koksal et al. reported neurofibroma adjacent to the thyroid gland and PTC in a patient with NF1. These cases all involved large tumors. The nodule in this study was small and was incidentally diagnosed by thyroid US. US features of malignant nodules include the presence of microcalcifications, hypoechogenicity, and irregular margins and the absence of a halo, predominantly solid composition, and intra-nodular vascularity . The nodule in this case had irregular margins, hypoechogenicity, microcalcifications, and extracapsular extension on US. This nodule was suspected to be associated with PTC, and a US-guided FNAB was performed at the thyroid nodule. The diagnosis based on FNA cytology indicated suspicious PTC. A total thyroidectomy with central compartment neck dissection of the thyroid tumor was performed. The tumor in the left thyroid lobe was diagnosed as PTC, and metastasis of seven central lymph nodes at left level VI was confirmed.