Lymphangioleiomyomatosis of Tuberous Sclerosis.

Tuberous sclerosis complex is an autosomal dominant neuorcutaneous disorder characterized by the presence of hamartomatous lesions in multiple organs [1]. Approximately two-thirds of the cases are sporadic. Tuberous sclerosis classically demonstrates the clinical triad of mental retardation, epilepsy and facial angiofibromas (Vogt triad) [1, 2]. Tuberous sclerosis is considered to be caused by mutation of two genes kwon as TSC1 and TSC2. TSC1 is located on long arm of chromosome 9 and encodes for protein hamartin, TSC2 is located on short arm chromosome 16 and encodes for protein tuberin. TSC1 and TSC2 are tumor suppressor genes are responsible for regulate the cell function and growth. When they are altered by mutation it disturbs the regulation of cell growth which results in formation of tumors involving multiple organs. TSC2 gene is found continuous with PKD gene and thought to be why sometimes multiple renal cysts are found in tuberous sclerosis [2]. The recent criteria for diagnosing tuberous sclerosis consist of both major and minor features [2]. Pulmonary manifestations of tuberous sclerosis are rare and occur in about 1% to 2.3% of tuberous sclerosis patients. Common pulmonary manifestations are Lymphangioleiomyomatosis (LAM) and multifocal micronodular pneumocyte hyperplasia (MMPH). MMPH is a rare disorder that is described in few literature reports. Other rare thoracic involvements are Lymphangioleiomyomatosis of mediastinum or thoracic duct and aneurysms of thoracic aorta or pulmonary artery [2]. Histologically LAM is characterized by multiple parenchymal cysts. The walls of cysts contain abnormal proliferation of smooth muscle fibers. The proliferation of smooth muscle causes several clinical manifestations depending on its location. Around the air ways it leads to obstruction, air trapping with cyst formation and pneumothorax. When the proliferation is around pulmonary venules it leads to venular congestion and dilatation resulting in hemoptysis and hemosiderin- laden macrophages which cause pulmonary hypertension and cor pulmonale. Hyperplasia around lymphatics leads to obstruction and chylothorax [3]. LAM occurs almost exclusively in women and usually presents with spontaneous pneumothorax, hemoptysis with chest pain or exertional dyspnea. Patients with pulmonary disease presents at a younger age group and have normal intelligence compared to the patients with more extrapulmonary disease [2]. Major complications of LAM are pneumothorax and chylous pleural effusion. Pneumothorax is found in 39%-53% and chylothorax is found 0%-14% at the time of presentation of patients with pulmonary LAM [2]. Multifocal micronodular lymphocytic hyperplasia (MMPH) is a very rare pulmonary lesion that is associated with tuberous sclerosis. They are characterize by multicentric, well demarcated nodular proliferation of type 2 pneumocytes along the alveolar septa [2,4]. MMPH needs to be differentiated from Atypical adenomatous hyperplasia (AAH) which coexist with or considered as a precursor of well differentiated adenocarcinoma and bronchoalveolar cell carcinoma [5]. MMPH can occur in tuberous sclerosis with or without LAM and they occur predominantly in female patients. Clinically they may present with cough, dyspnea and mild to moderate hypoxemia [2]. Common features in chest radiograph of tuberous sclerosis are mottling, reticular shadows and honeycombing. Other main differential diagnoses for these appearances are Histiocytosis X and Scleroderma [6]. High resolution CT scan demonstrates the characteristic features and obviates the need of lung biopsy. The typical CT findings in LAM are round thin walled cysts of variable contour and sizes, which usually symmetric and distributed uniformly throughout the lung. Communication of cyst with the air way is demonstrated by the decrease of cyst dimensions on expiratory CT images [2]. On thin section CT, MMPH demonstrate multiple tiny nodules varying in size from 1-8mm, diffusely scattered and randomly distributed throughout the lungs. Differentiation from miliary metastasis or granulomatous disease is difficult on CT. Unlike with LAM, treatment is not recommended for MMPH as it does not appear to be fatal or progressive [2]. MRI imaging can be helpful in detecting chylous pleural effusion or ascites [2].