Background: Multifocal micronodular pneumocyte hyperplasia (MMPH) is a rare pulmonary manifestation of tuberous sclerosis complex (TSC). Because of its rarity, no previous study has described the detailed clinical course of this disease. Objectives: This study aimed to clarify the longitudinal clinical characteristics of subjects with MMPH. Methods: Nine patients with MMPH diagnosed at Hokkaido University Hospital were retrospectively analyzed. Changes in computed tomography findings and pulmonary function were compared during the follow-up period. Serum levels of KL-6, surfactant protein (SP)-A, and SP-D were measured to clarify their potentials as blood biomarkers of the disease. Fourteen cases of lymphangiomyomatosis (LAM) were also included to compare their clinical characteristics with those of subjects with MMPH. Results: Of the 9 patients, 7 were female and 2 were male. The median age at diagnosis was 43 years (range, 19–56), and all cases were diagnosed following incidental abnormal radiographic findings. During the follow-up, 1 patient died of lung cancer, but others were radiographically stable and had stable pulmonary function. Serum levels of SP-A in 5 patients (mean, 146.4 ng/mL) and SP-D in 6 patients (mean, 337.3 ng/mL) were elevated in subjects with MMPH, whereas KL-6 levels were within the reference range (mean, 230 U/mL) in all patients. Levels of SP-A and SP-D were significantly higher in subjects with MMPH than those with LAM (p < 0.05). Conclusions: Radiographic findings and pulmonary function were stable in all cases of MMPH. Serum SP-A and SP-D, but not KL-6, may be useful markers for suspicion of the presence of MMPH in patients with TSC.

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Multifocal micronodular pneumocyte hyperplasia (MMPH) is a rare pulmonary disease, generally manifesting as a tuberous sclerosis complex (TSC), characterised by multiple, small ground-glass nodular shadows on chest computed tomography (CT). Histological examination typically reveals multicentric, well-demarcated, nodular type II pneumocystic growth. Herein, we describe three cases of this rare pulmonary disease occurring within one family. Using reverse transcription polymerase chain reaction (RT-PCR) and direct DNA sequencing, we identified a novel germline mutation, a point mutation in TSC1 intron 5, which yielded a splice variant and loss of function of TSC1 . Furthermore, immunohistochemical staining indicated the expression of phospho-p70S6K and phospho-4E-BP1, suggesting that TSC1 function was impaired by the novel gene mutation in MMPH cells.

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