Women with TSC: Relationship between Clinical, Lung Function and Radiological Features in a Genotyped Population Investigated for Lymphangioleiomyomatosis

Abstract

The advent of pharmacological therapies for lymphangioleiomyomatosis (LAM) has made early diagnosis important in women with tuberous sclerosis complex (TSC), although the lifelong cumulative radiation exposure caused by chest computer tomography (CT) should not be underestimated. We retrospectively investigated, in a cohort of TSC outpatients of San Paolo Hospital (Milan, Italy) 1) the role of pulmonary function tests (PFTs) for LAM diagnosis, 2) the association between LAM and other features of TSC (e.g. demography, extrapulmonary manifestations, genetic mutations, etc.), and 3) the characteristics of patients with multifocal micronodular pneumocyte hyperplasia (MMPH). Eighty-six women underwent chest CT scan; pulmonary involvement was found in 66 patients (77%; 49% LAM with or without MMPH, and 28% MMPH alone). LAM patients were older, with a higher rate of pneumothorax, presented more frequently with renal and hepatic angiomyolipomas, and tended to have a TSC2 mutation profile. PFTs, assessed in 64% of women unaffected by cognitive impairments, revealed a lower lung diffusion capacity in LAM patients. In multivariate analysis, age, but not PFTs, resulted independently associated with LAM diagnosis. Patients with MMPH alone did not show specific clinical, functional or genetic features. A mild respiratory impairment was most common in LAM-TSC patients: In conclusions, PFTs, even if indicated to assess impairment in lung function, are feasible in a limited number of patients, and are not significantly useful for LAM diagnosis in women with TSC.

Healthcare transition from childhood to adulthood in Tuberous Sclerosis Complex

“…Pulmonary manifestations of TSC include: lymphangioleiomyomatosis (LAM), found in about 75% of women with TSC, and characterized by proliferation of bundles of smooth muscle cells, resultant in cystic changes in the lung parenchyma; multifocal micronodular pneumocytic hyperplasia (MMPH), caused by the growth of proliferating epithelial cells into the alveolar walls, present with or without LAM in up to 60% of patients with TSC; and rarely clear cell lung tumor. Clinically, LAM can manifest with exertional dyspnea, recurrent pneumothoraces, thoracic lymphadenopathy, and hemoptysis (Johnson et al, ), while the presence of MMPH is not associated with a specific clinical or functional profile (Di Marco et al, ). Even if in some cases LAM is the reason for diagnosis of TSC during infancy (Hancock, Tomkins, Sampson, & Osborne, ), usually the pulmonary manifestations of TSC are typically only seen in adult women, since “age” has been found to be the only independent condition associated with the development of LAM (Di Marco et al, ).…”

“…Clinically, LAM can manifest with exertional dyspnea, recurrent pneumothoraces, thoracic lymphadenopathy, and hemoptysis (Johnson et al, ), while the presence of MMPH is not associated with a specific clinical or functional profile (Di Marco et al, ). Even if in some cases LAM is the reason for diagnosis of TSC during infancy (Hancock, Tomkins, Sampson, & Osborne, ), usually the pulmonary manifestations of TSC are typically only seen in adult women, since “age” has been found to be the only independent condition associated with the development of LAM (Di Marco et al, ). In most cases, the diagnosis results from proactive screening, as CT scans are recommended for women with TSC at ages between 18 and 30 years, even if asymptomatic (Krueger & Northrup, ).…”

Multifocal micronodular pneumocyte hyperplasia (MMPH) in a patient with tuberous sclerosis-evidence for long term stability

“…TSC is a rare autosomal dominant neurocutaneous disorder characterized by the presence of skin lesions (hypopigmented macules, Shagreen patches, angiofibromas and subungal fibromas) along with benign hamartomas & tumors in multiple organ systems (most commonly brain, lung, kidney and liver) [1], [2], [3]. TSC is diagnosed using the Gomez criteria with the classic Vogt's triad (mental retardation, seizures and facial angiofibromas) being seen in less than 1/3rd of TSC cases [2].…”

“…TSC is diagnosed using the Gomez criteria with the classic Vogt's triad (mental retardation, seizures and facial angiofibromas) being seen in less than 1/3rd of TSC cases [2]. Lung involvement in the form of LAM & MMPH can occur in up to 50% of TSC cases and its prevalence increases with age [1], [3].…”

“…It can co-exist with LAM or be the sole pulmonary abnormality in patients with TSC [3], [9]. The natural history of MMPH is not entirely clear, but it does not appear to progress towards malignancy in most cases [2].…”