History of present illness
The patient had developed recurrent spontaneous pneumothorax more than four times during the past 8 mo, but had no fever, chest pain, or hemoptysis. The patient occasionally experienced cough, mild panting, and suffocation. In January 2018, the patient experienced mild panting and developed dyspnoea for the first time. Chest X-ray showed left pneumothorax, after which left closed thoracic drainage was performed. In May 2018, the patient presented with mild panting and suffocation. Chest X-ray showed left pulmonary pneumothora and mild left lower lung atelectasis. Pulmonary bulla resection was performed under thoracoscopy and general anaesthesia. After surgery, the pathological findings showed blood stasis of the lung tissues, alveolar ectasia and fusion, bullous formation, proliferation of fibrous tissue of the blister wall, and chronic inflammatory cell infiltration. In July and August 2018, the patient suffered from pneumothorax in the left lung.
The patient’s lung computed tomography (CT) examination showed low-density cystic changes in the right lung, left lung, and interlobular fissure (Figure 1). After admission, the patient suffered from left pneumothorax again without a clear reason. The bedside chest radiograph indicated that the left lung tissue was compressed by 30% (Figure 2). Abdominal ultrasound and abdominal and pelvic enhanced CT showed no renal tumour but a high-density shadow on the right liver (the right abdomen) (Figure 3).
Figure 1 Patient’s axial computed tomography image showing multiple thin-walled cysts with clear margins and diverse sizes.
A: Small thin-walled cyst located in the apical segment of the right upper lobe; B and C: Irregular morphology cysts located in the apical posterior segment; D: Lower chest showing subpleural cysts at both lung bases.
Figure 2 X-ray showing pneumothorax.
Patient’s chest X-ray showing pneumothorax in the left lung; the lung tissue was compressed to about 30%. The orange arrow represents the pneumothorax line.
Figure 3 Abdominal computed tomography
. A: Dotted high-density shadow (orange arrow) on the right liver; B: No abnormal occupation was captured in the kidneys.
Further diagnostic work-up
The patient underwent pulmonary bulla resection under video-assisted thoracoscopic surgery and pleurodesis under the guidance of general anaesthesia. The postoperative pathological reports displayed pulmonary emphysema-like changes with pulmonary bullae formation and small interlobular septa in the partially enlarged cystic cavity. Normal lung tissue had partial interstitial congestion (Figure 4).
Figure 4 Postoperative pathological reports.
The postoperative pathological reports displayed the formation of multiple cysts (thin arrow). The inner surface of the pulmonary cyst was covered with alveolar epithelium (thick arrow).
In addition, the patient had a family history of spontaneous pneumothorax. The patient’s mother and her second maternal aunt had suffered from recurrent spontaneous pneumothorax in the past. The mother had the worst condition, which manifested as lung-free marking and pleural line shadow in the right lung, the right lung being compressed into the hilar region by about 70%, compression into a strip-like solid shadow of the right lung, multiple thin-walled cavities of varied sizes in the whole lung (with the maximal length of about 79 mm at diameter), and a small amount of effusion in the right pleural cavity (Figure 5).
Figure 5 Axial computed tomography images.
A: The patient’s mother showed multiple thin-walled cysts in the apical segment of the right upper lobe; B: Irregular morphology cysts located in the upper-lung of both sides; C: Bilateral multiple lung cysts located at the level of the upper mediastinum; D: Right-sided pneumothorax and bilateral lung cysts located at both lung bases.
Her second maternal aunt developed right pneumothorax at the age of 40. To review the common features, the patient, her mother, and her second maternal aunt underwent chest CT. The results revealed pulmonary alveolar or cystic changes in all of the subjects. In addition, the chest and abdominal CT of her first maternal aunt indicated a saccular shadow of the right lower lobe and a possible left renal hamartoma. Her uncle (mother’s brother) had no pulmonary bulla or cystic changes or lesions in the kidney.
Multiple white dome-shaped papules with a diameter of < 0.5 mm were found on the anterior and posterior neck and the posterior side of the ears of the patient (Figure 6). Meanwhile, multiple white dome-shaped papules were found on the mother’s and her second maternal aunt’s necks, cheeks, and posterior ears (Figure 7). The dermatologist considered that the patient’s papules conformed to the appearance of fibrofolliculomas but required pathological confirmation. Mild infiltration of lymphocytes around the vessels in the superficial dermis with melanophage showed dominant findings in the pathological specimens of the patient’s skin (Figure 8).
Figure 6 Multiple white dome-shaped papules visible in the neck of the patient that were consistent with the featured lesions of Birt-Hogg-Dubé syndrome.
Figure 7 Multiple white dome-shaped papules were seen on the skin of her mother’s neck and back.
Figure 8 Pathological findings of skin biopsy showing lymphocytic infiltration around the superficial vasculature of the dermis with melanocytes.
Due to the patient’s history of recurrent spontaneous pneumothorax, multiple skin papules, cystic lesions in the lungs, and a family history of pneumothorax, we suspected a congenital disease, particularly BHD. The family tree is shown in Figure 9.
Figure 9 Seven of the patient’s family members were genetically analysed.
Seven of the patient’s family members were genetically analysed (I-1 was deceased), and the germline mutations in the folliculin gene mutation of the patients’ were derived from her mother. The source of her mother’s gene mutation could not be tracked due to the failure of the gene test in I-1. The patient, her mother, and her second maternal aunt had a similar genetic mutation, and the performance of their clinically affected organs was identical.
After obtaining written informed consent from the patient and her family, we accomplished the family genetic test for BHD. Seven of the family members underwent genetic analysis, which included extracting the genomic DNA from peripheral blood leukocytes. The results showed that the patient’s FLCN gene was located on chromosome 17. The nomenclature of the variant was c.1285dup. The heterozygous nucleotide variation of c.1285_1286insC (interpolation of C at 1285_1286 nucleotides of the coding region) was found in the FLCN gene of the subject. This mutation occurred due to a change in amino acid synthesis starting from amino acid His, No. 429, and terminating at 27th amino acid after the change p. (His429Profs*27) as a frameshift variant, which we believe affected the protein function. The American College of Medical Genetics and Genomics rating suggested PVS1 and PM2 by taking into consideration the suspected diseases (Figure 10). The genetic test of the patient’s mother also showed mutations in this site, considering that the variation of the patient’s FLCN gene was derived from her mother. The pathogenicity of this mutation has been reported in the literature and is associated with BHD syndrome.
Figure 10 The American College of Medical Genetics and Genomics rating considered suggested the presence of PVS1 and PM2 by taking into consideration the suspected diseases.
A: Genetic test revealed a heterozygous nucleotide variation (red arrow) of c.1285_1286insC in germline mutations in the folliculin gene of the patient; B: The patient’s mother; C: The patient’s second maternal aunt; D: No genetic variation (red arrow) was detected in her elder aunt; E: Her elder uncle; F: Her second uncle; G: Her grandmother.