Case studies: BHD syndrome associated with pulmonary malformation and with lung neoplasm

  • Matsutani et al. (2016) reported for the first time BHD syndrome accompanied by pulmonary arteriovenous malformation. The patient, a young male with no significant medical history, presented with chest pain. Chest X-ray and CT revealed emphysematous changes in both lungs and a tumour with pleural fluid. A thoracoscopy revealed dark red pleural fluid and multiple cysts in the lung. The tumour lesion was resected and identified as a non-malignant intrapulmonary hematoma caused by a significant haemorrhage in the pulmonary parenchyma, which was diagnosed as intrapulmonary hematoma. Aggregated vascular vessels were found in the area surrounding the haemorrhage and were diagnosed as pulmonary arteriovenous malformation. Family history of the patient included cases of pneumothorax and colon cancer. A medical examination revealed the presence of numerous small papules on the patient’s nose and neck. Chest CT showed multiple pulmonary cysts, indicating the possibility of BHD syndrome. Genetic testing revealed a deletion of exon 11 of the FLCN gene confirming the diagnosis of BHD syndrome. BHD syndrome is known to be associated with multiple pulmonary cysts and spontaneous pneumothorax, however, the causes of pulmonary cysts are not well understood. Pulmonary arteriovenous malformation is a rare disease associated with abnormal connection between pulmonary blood vessels (Mangla et al., 2014). In the present study BHD syndrome was discovered due to an intrapulmonary haemorrhage caused by pulmonary arteriovenous malformation. This was the first report associating pulmonary arteriovenous malformation with BHD syndrome and it is unknown if there is a relationship between the two. Kapoor et al. (2015) hypothesize that mutation of FLCN affects hypoxia-inducible factor 1-alpha (HIF-1α) and is associated with vascular pathogenesis.
  • Gunji-Niitsu et al. (2016) reported for the first time, a patient with BHD syndrome associated with a clear cell “sugar” tumor (CCST) of the lung. A 38-year-old woman presented with two nodules in the left lung and multiple cysts on the basal and medial area of the lungs chest that were found during a preoperative CT for a tonsillectomy. Patient’s past medical history included several episodes of spontaneous pneumothorax and malignant diseases. The family history included cases of spontaneous pneumothorax and renal cancer. Skin examination revealed small papules on the faces and necks of both the patient and her mother. Analysis of the patient’s resected lung nodule showed large polygonal cells with clear cytoplasm proliferating in a solid pattern. Immunohistochemistry revealed that these tumour cells were positive for clear cell “sugar” tumour (CCST) markers. CCST of the lung is a rare benign tumour associated with aberrations on chromosome 16 and at the TSC2 locus resulting in activation of the mTOR pathway (Pan et al., 2008). Genetic testing revealed a germline mutation on exon 12 of the FLCN Direct sequencing of the FLCN exon 12 from dissected CCST cells clearly revealed loss of the wild-type FLCN sequence, which confirmed complete functional loss of the FLCN gene. However, no loss of heterozygosity around TSC2-associated genetic region was demonstrated, supporting the idea that TSC2 and FLCN share the mechanism for their tumorigenesis. No pulmonary neoplasm has been reported to date that was proved to have complete loss-of-function type FLCN mutation, supporting the 2-hit theory. The number of deaths from cancer in the patient’s ancestors was remarkable. In BHD, although FLCN is considered a tumour-suppressor gene, the established propensity for cancer is limited to the renal tumours. Whether BHD syndrome confers the risk of developing other types of cancer remains elusive.

In summary, these studies report for the first time cases of BHD syndrome associated with pulmonary tumour and malformation. Clarification of a possible relationship between BHD syndrome and pulmonary arteriovenous malformation and CCST is still needed with accumulation of more BHD syndrome cases and basic research studies.

  • Matsutani, N., Dejima, H., Takahashi, Y., Uehara, H., Iinuma, H., Tanaka, F., & Kawamura, M. (2016). Birt-Hogg-Dube syndrome accompanied by pulmonary arteriovenous malformation Journal of Thoracic Disease, 8 (10) DOI: 10.21037/jtd.2016.09.68
  • Gunji-Niitsu, Y., Kumasaka, T., Kitamura, S., Hoshika, Y., Hayashi, T., Tokuda, H., Morita, R., Kobayashi, E., Mitani, K., Kikkawa, M., Takahashi, K., & Seyama, K. (2016). Benign clear cell “sugar” tumor of the lung in a patient with Birt-Hogg-Dubé syndrome: a case report BMC Medical Genetics, 17 (1) DOI: 10.1186/s12881-016-0350-y

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