Familial multifocal micronodular pneumocyte hyperplasia with a novel splicing mutation in TSC1: Three cases in one family

Abstract

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.

Genotype and Phenotype Landscape of 283 Japanese Patients with Tuberous Sclerosis Complex

“…In fact, of the 17 patients with liver AML, 15 had renal AML, and eight had a score of 3 for severe renal AML ( Supplementary Table S1 ). Although there are few reports on MMPH, we previously reported that LOH occurs in lesions [ 38 ].…”

Resolution of multifocal micronodular pneumocyte hyperplasia with everolimus in a patient with tuberous sclerosis complex

“…It is well known that hamartomas associated with TSC, such as lymphangioleiomyomatosis (LAM), AML, and subependymal giant cell astrocytomas, are caused by mTOR activation with decreased or absent expression of TSC1/2 genes [ 7 , 8 ] and can be treated with mTOR inhibitors [ [9] , [10] , [11] ]. Loss of heterozygosity for TSC1/2 genes and high expression of phospho-p70S6K and phospho-4E-BP1 proteins observed in MMPH lesions suggest the activation of mTOR pathway and plausibility of a response to mTOR inhibitors [ 2 , 12 ]. In addition, mTOR inhibitors improve seizures in TSC, as observed in this case [ 13 ].…”

Multifocal micronodular pneumocyte hyperplasia with a novel mutation in TSC1: a case report

“…It is characterized by multiple solid nodules or nodular ground-glass opacities (GGOs) observed on CT, randomly distributed throughout the lungs ( 9 ). Histologically, MMPH refers to multicentric and well-demarcated nodular growth of type II pneumocytes ( 10 ). Therefore, the differential diagnosis should consider atypical adenomatous hyperplasia, adenocarcinoma, pulmonary metastases, tuberculosis, sarcoidosis, and histiocytosis X.…”