Tuberous Sclerosis Complex: State-of-the-Art Review with a Focus on Pulmonary Involvement

Abstract

Tuberous sclerosis complex (TSC) is an autosomal-dominant neurocutaneous disease with high phenotypic variability. The incidence is approximately one in 5000-10,000 births. TSC is characterized by widespread hamartomas and benign or rarely malignant neoplasms affecting various organs, most commonly the brain, skin, retinas, kidneys, heart, and lungs. The wide range of organs affected reflects the roles of TSC1 and TSC2 genes in the regulation of cell proliferation and differentiation. Clinical diagnostic criteria are important because genetic testing does not identify the mutation in up to 25% of patients. Imaging is pivotal, as it allows a presumptive diagnosis of TSC and definition of the extent of the disease. Common manifestations of TSC include cortical tubers, subependymal nodules, white matter abnormalities, retinal abnormalities, cardiac rhabdomyoma, lymphangioleiomyomatosis (LAM), renal angiomyolipoma, and skin lesions. Pulmonary involvement consists of LAM and, less commonly, multifocal micronodular pneumocyte hyperplasia (MMPH), which causes cystic and nodular diseases, respectively. Recent reports indicate that pulmonary LAM is found by computed tomography in up to 35% of the female patients with TSC. MMPH is rare and may be associated with LAM or, less frequently, occurs as an isolated pulmonary manifestation in women with TSC. Dyspnea and pneumothorax are common clinical presentations of LAM, whereas MMPH is usually asymptomatic. The aim of this review is to describe the main clinical, imaging, and pathological aspects of TSC, with a focus on pulmonary involvement.

Hamartomas from head to toe: an imaging overview

“…[27][28][29] Multifocal micronodular pneumocyte hyperplasia Multifocal micronodular pneumocyte hyperplasia (MMPH) is the second most common pulmonary manifestation in patients with TSC and is characterized by multifocal nodular proliferation of Type II pneumocytes along the alveolar septa. 30 The prevalence of MMPH in patients with TSC is similar in males and females (59% and 57%, respectively). 31 MMPH may also be seen in females with sporadic lymphangioleiomyomatosis (LAM).…”

“…31 MMPH may also be seen in females with sporadic lymphangioleiomyomatosis (LAM). 30 It is a non-progressive and asymptomatic condition. On CT, MMPH is characterized by multiple discrete, welldemarcated solid or ground-glass nodules, varying between 2 mm and 10 mm in size ( Figure 7).…”

“…64 The classic clinical triad is that of facial adenoma sebaceum, epilepsy and mental retardation. 30 The disorder has an approximate birth rate of 1/ 6000. The mode of inheritance is autosomal dominant, with a penetrance of 95% and variable clinical manifestations.…”

“…65 Mutations in the TSC 1 and TSC 2 genes lead to abnormal control of cell growth, resulting in tumour formation. 30 Most commonly, tumours are seen in the skin, brain, kidneys, lungs and heart. These can lead to extensive parenchymal replacement Figure 13.…”

“…Pulmonary hamartomas and foci of MMPH are relatively frequent manifestations of disease ( Figure 7). 30,64 Renal AMLs are the most common intra-abdominal manifestations of TSC, found in 70-90% of patients ( Figure 12). Spontaneous or trauma-related bleeding of these tumours represents the leading cause of death in patients with TSC.…”