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Birt-Hogg-Dube syndrome presenting as multiple oncocytic parotid tumors
© Lindor et al.; licensee BioMed Central Ltd. 2012
Received: 5 April 2012
Accepted: 10 September 2012
Published: 10 October 2012
Mutations in FLCN cause Birt-Hogg-Dubé syndrome, an autosomal dominant disorder notable for development of cutaneous fibrofolliculomas or trichodiscomas, a variety of renal tumors, and spontaneous pneumothorax due to cystic lung changes. We present a woman referred for genetic evaluation due to bilateral parotid gland tumors, who was subsequently diagnosed with Birt-Hogg-Dubé syndrome.
BHD syndrome is an uncommon genodermatosis characterized by the presence of multiple fibrofolliculomas, trichodiscomas, and acrochordons of the skin. There is significantly increased susceptibility to renal tumors, of which about half are hybrid chromophobe/oncocytic renal cancers; about 5% are oncocytomas. Pulmonary cysts occur in the majority of adults with BHD syndrome, leading to spontaneous pneumothorax in at least a quarter of affected individuals. A longer list of tumors have been reported rarely in BHD ; parotid tumors have been reported several times but have not served as the sentinel lesion bringing a patient to diagnosis.
The family history was notable for maternal grandfather with prostate cancer, maternal grandmother with a bladder cancer diagnosed in her 40s and a lung cancer diagnosed in her 50s (she had smoked). A maternal uncle had a throat cancer and died at 58. The paternal family history was negative for neoplasms. Her three siblings and two children were apparently healthy.
Parotid gland oncocytic lesions include a spectrum of histologic findings including nodular oncocytic hyperplasia, benign oncocytoma, and oncocytic carcinoma, and it may be reasonable to include Warthin tumor somewhere in this spectrum. Nodular oncocytic hyperplasia, if this is the correct description of the case comprises only 0.1% of parotid gland diseases  while 0.7% of 3,500 salivary gland tumors in another series contained benign oncocytic lesions . There are a number of individual case reports suggesting that this disorder appears to be so uncommon as to warrant single case report presentations. Warthin tumors (also called papillary cystadenoma lymphomatosum, adenolymphomas, or cystadenolymphomas) are not so rare, being the second most common tumor of salivary glands (after pleomorphic adenomas), and characteristically affect older males, and are uncommonly bilateral.
A solitary parotid oncocytoma was reported in a 56 year old man with Birt-Hogg-Dubé's syndrome . In 2005, Schmidt et al., reported on 219 individuals with BHD syndrome studied at that National Cancer Institute and parotid tumors were reported in two women (ages 62 and 72) and two men (ages 20 and 39). Three of these were oncocytomas but no information about multiplicity was provided . Palmirotta et al., reported on two new BHD families and one woman had a parotid pleomorphic adenoma at age 43 . In 2008, Toro et al., reported on 51 families (50 were new) with 89 gene mutation carriers and in this series two individuals has parotid gland oncocytomas,at ages 20 and 39 (it is not clear if this overlapped the Schmidt study or if the same ages were coincidental) . Finally, Maffé et al., reported two parotid tumors among 19 patients with suspected Birt–Hogg–Dubé syndrome: a Warthin parotid tumor occurred in a 59 year old male in whom no FLNC mutation was found; and of most relavance to the current report, bilateral parotid tumors not otherwise specified, occurred at ages 32 and 43 years old in one man with a documented FLNC mutation .
Finding an oncocytic tumor in the parotid is of interest as the renal tumors which are characteristic of BHD often contain oncocytic cells. The relevance of this similarity is obscure. Oncocytic neoplasms, in general, are thought to result from cells that accumulate abundant mitochondria in their cytoplasm to form oncocytes via oncocytic metaplasia. They account for less than 1% of salivary gland tumors and can occur in other organs including kidneys, thyroid and parathyroid glands .
Molecular studies of Warthin tumors of the salivary glands indicate a recurrent t(11;19) translocation with associated CRTC1-MAML2 fusion oncogene in a subset of Warthin tumors . We were not able to study this biopsy for this finding. The chromosomal location of FLCN is 17p11.2 so no direct link to this translocated region is evident. Comparative genomic hybridization studies of salivary tumors did show some tumors with deletions involving 17p11.2 region in apparently 6 of 15 Warthin tumors but details in that publication were insufficient to determine if FLCN was deleted or not .
The function of FLCN is still a matter of investigation. Baba et al.,  have studied the protein and stated that “the interaction of FLCN with FNIP1 and AMPK suggests a possible role for FLCN and FNIP1 in the nutrient/energy-sensing pathways involving AMPK and mTOR and may provide a molecular mechanism for the BHD phenotype”. No direct link to mitochondrial dysfunction has been proposed yet for this tumor suppressor gene but the oncocytic nature of the tumors in both kidney and now parotid gland raise this as a possibility.
Around half of BHD families recognized to date have a mutation in hot spot involving deletion (c.1285delC) or duplication (c.1285dupC) of a C nucleotide in the polycytosine tract in exon 11 of FLCN. The mutation found in this patient is not in this area but has been reported previously in six individuals from two families [as IVS7 + 1]  and has not been reported since, per the Leiden Open Variome Database update of 2011 https://grenada.lumc.nl/LOVD2/shared1/variants.php?select_db=FLCN&action=view_unique. The major manifestation in these families generally appeared typical of BHD syndrome with renal tumors in five, lung cysts in six, documented fibrofolliculomas in five. Also reported was an angiofibroma, dermatofibrosarcoma protuberans, cutaneous leiomyosarcoma, and trichodiscoma. No parotid tumors were reported. Combined with the current case report, these families might be perceived as having more diverse dermatological findings than other BHD families, raising the possibility of some genotype-phenotype interaction.
Based upon the DNA diagnosis, the patient was counseled regarding autosomal dominant inheritance of this syndrome and the implications for multiple relatives, and was provided screening recommendations) for typical BHD syndrome with regard to renal and pulmonary complications, and she will remain under closer surveillance for changes in the parotid tumors and for additional dermatologic findings .
Written consent for use of patient photographs were obtained.
We thank Danielle Wright for preparation and submission of this manuscript.
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