Novel folliculin gene mutation and an elevated serum vascular endothelial growth factor-D level in the context of cystic lung disease

Abstract

Birt-Hogg-Dubé syndrome (BHD) is a rare autosomal dominant genetic disorder characterized by the development of benign cutaneous neoplasms, renal tumors, and pulmonary cysts. Caused by mutations in the folliculin (FLCN) gene on chromosome 17, the pulmonary manifestations observed in BHD include multiple subpleural cysts that are frequently associated with pneumothorax. Diffuse cystic lung disease is also commonly encountered in lymphangioleiomyomatosis (LAM), either in isolation or in the context of tuberous sclerosis complex (TS). The diagnosis of BHD is confirmed by identifying pathogenic FLCN germline mutations. Modern evidence, however, supports using serum vascular endothelial growth factor-D (VEGF-D) levels in differentiating LAM from other cystic lung diseases, including BHD, with high specificity. This case report describes the unique finding of an elevated VEGF-D serum level (1290 pg/ml) in a patient with cystic lung disease, bilateral pneumothorax and a novel disease-causing mutation (E280X) in the FLCN gene.

RÉSUMÉ

Le syndrome de Birt-Hogg-Dubé (BHD) est une maladie génétique autosomique dominante rare caractérisée par le développement de néoplasmes cutanés bénins, de tumeurs rénales et de kystes pulmonaires. Causées par des mutations du gène de la folliculine (FLCN) sur le chromosome 17, les manifestations pulmonaires observées dans le BHD comprennent de multiples kystes sous-pleuraux qui sont fréquemment associés à un pneumothorax. La maladie pulmonaire kystique diffuse est également fréquemment rencontrée dans la lymphangioleiomyomatose (LAM), soit isolément, soit dans le contexte du complexe de sclérose tubéreuse (ST). Le diagnostic de BHD est confirmé par la détection de mutations germinales FLCN pathogènes. Toutefois, les données probantes modernes soutiennent l'utilisation des taux de facteur de croissance de l’endothélium vasculaire D (VEGF-D) dans le sérum pour différencier la LAM d'autres maladies pulmonaires kystiques, y compris la BHD, avec une grande spécificité. Ce rapport de cas décrit la découverte unique d'un taux sérique élevé de VEGF-D (1290 pg/ml) chez un patient atteint de maladie pulmonaire kystique, de pneumothorax bilatéral et d'une nouvelle mutation pathogène (E280X) dans le gène FLCN.

Keywords:

• Birt-Hogg-Dubé syndrome
• lymphangioleiomyomatosis
• vascular endothelial growth factor-D
• cystic lung disease

Acknowledgment

We would like to thank Dr. Francis X. McCormack of the University of Cincinnati College of Medicine and the Cincinnati Children’s Hospital Translational Core Laboratories for the measurement of VEGF-D, and Dr. Chantal Morel of the University Health Network in Toronto for carrying out the genetic testing for BHD.

Financial/nonfinancial disclosures

The authors have no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Declaration of interest statement

The authors have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Dr. Nathan Hambly has received honoraria from Actelion, Bayer, Boehringer-Ingelheim, Janssen and Roche. He has also received research grants from Actelion, Bayer, Boehringer-Ingelheim, Janssen and Roche.