The case is a 34-year-old woman, with the chief complaint of tightness of breath. Dyspnea had begun gradually 3 years before, was progressive in nature, and was not concomitant with cough, sputum, hemoptysis, pleuritic chest pain, wheeze, or weight loss. The patient had no history of smoking and her occupation did not expose her to environmental pollution or toxins. The patient was exposed to tuberculosis (TB) by her mother, who had inactive old TB. The patient had been previously referred to several other clinicians and, with diagnosis of asthma, was under treatment with multiple sprays. In spite of regular use of the sprays, her symptoms had not relieved. We asked for prior medical histories and patient claimed that she had history of epileptic attacks and was under treatment for her condition with valproate. In physical examination, lungs had generalized reduced respiratory sounds and were hyperresonant in percussion. Patient had hypomelanotic facial macules with fibrous facial plaques. Spirometry test conducted at our visit showed moderate obstructive ventilatory impairment (FEV1/FVC = 84%, FEV1 = 62% of the predicted values). The obstruction showed no significant response to bronchodilators (change in FEV1 after bronchodilator = 9% of the FEV1). Patient had no new brain magnetic resonance imaging (MRI) and the etiology of attacks was not clear. We recommended a brain MRI, which revealed multiple low-signal subependymal lesions less than 1 cm in size, beneath both right and left lateral ventricles along with multiple bilateral supratentorial subcortical flair hyperintense signal lesions (Figure 1). Electroencephalography was also obtained and no epileptic discharges were seen at the time. Also considering the history of TB exposure and her resistant dyspnea, a high-resolution computerized tomography (HRCT) of the chest was recommended; as a result, diffuse atelectasis of bronchioles in both lungs was seen along with multiple thin-walled cystic lesions distributed equally in all pulmonary zones (Figure 3). Our differential diagnoses for this finding were lymphangioleiomyomatosis, Birt-Hogg-Dube syndrome, pulmonary Langerhans' histiocytosis, lymphoid interstitial pneumonia, amyloidosis, follicular bronchiolitis, and pulmonary adenocarcinoma. In abdominal cuts of a chest CT some very suspicious lesions were also seen in the liver and kidneys, which had the Hounsfield values of the subdermal fat tissue (Figure 2). Ultrasonography of the kidneys and liver reported significantly increased heterogenous echogenicity of the renal parenchyma (without any distinct lesions) and multiple echogenic lesions in the right and left lobes of the liver with maximum diameter of 40 mm in the right lobe. Although other differential diagnoses were also possible, LAM-TSC was the most probable of them because of the pattern of the findings from chest HRCT, brain MRI, dermatological findings, and lesions in the liver and kidneys.
According to European Respiratory Society guidelines for the diagnosis and management of LAM, the diagnosis can be made clinically with the combination of findings from high-resolution CT and patient's history (angiomyolipoma, lymphangiomyolipoma, chylothorax or abdominal chylous effusion, definite or probable TSC) and/or by pathological diagnosis made by tissue biopsy. There is no obligation to redo a biopsy if the other criteria are met. Because none of the lesions were previously confirmed to be TSC associated, we asked the patient to give consent for an ultrasonography-guided kidney biopsy. However, she rejected to give consent after understanding the method of the procedure. Later, we recommended a genetic test to confirm this diagnosis and rule out Birt-Hogg-Dube syndrome. TSC1 and TSC2 gene mutation analysis was performed and, as a result, a novel variant mutation was detected in TSC2 gene as follows: c.3599G>C; p.Arg1200Pro; Het. The method for this analysis included using a Nimblegen chip capturing TSC1 and TSC2 genes followed by Next Generation Sequencing. Definite diagnosis of LAM-TSC was made. To the best of our knowledge, this mutation has not been reported in the literature, and its impact on pattern of disease presentation and response to treatment is not clear yet. A transthoracic echocardiography was taken to rule out the cardiac burden of the disease. Normal function and anatomy of the heart were seen, and no rhabdomyomas were detected in the heart. At this time, we decided to put the patient on sirolimus (1 milligram twice daily) as the main medication for her systemic and pulmonary symptoms. Tests before starting the treatment showed border line level of alanine transferase (ALT) 32 U/L (upper limit of normal for women <31 U/L). The patient was strongly recommended to avoid pregnancy. More than one year after starting sirolimus, patient's liver function tests are nearly left intact (last test results: ALT 45 U/L, aspartate aminotransferase (AST) 34 U/L (ULN for women 31 U/L), alkaline phosphatase 309 U/L (ULN for women <306 U/L), total bilirubin 1.02 mg/dl, urea 34 mg/dl, creatinine 0.83 mg/dl). Patient has not developed hyperlipidemia or any hematologic disorders. In follow-up visits, a body plethysmography was ordered and results are as follows: FEV1/FVC = 59.4%, FEV1 = 64.4%, TLC = 75.8%, RV = 50.6% of the predicted values. It appears that pulmonary function has remained stable. No events of pneumothorax or epileptic attacks have occurred during this period. In the latest ultrasonography, shrinkage of the tuberous lesions in the liver is seen. Largest echogenic lesion in the right lobe of the liver (as mentioned above) has shrunk to diameter of 34 mm. Unfortunately, the size and echogenicity of the renal parenchyma has not changed significantly. Facial lesions have diminished, and patient no longer visits dermatologist for cosmetic purposes.