Tuberous sclerosis complex associated lymphangioleiomyomatosis caused by de novo mutation of TSC2 gene in Vietnam: A case report

Abstract

Lymphangioleiomyomatosis (LAM) represents a rare, insidiously progressive disease of the pulmonary system, marked by cystic degradation of lung tissues leading to respiratory compromise. Pulmonary LAM has been identified as being associated with tuberous sclerosis complex (TSC) in its pulmonary manifestation (TSC-LAM), a multisystem genetic disorder resulting from mutations in either the TSC1 or TSC2 genes. Herein, we describe an early 20s female admitted to the hospital with dyspnea, chest pain, hypopigmented macules, and facial fibroadenomas. She has a medical history of renal angiomyolipomas (ALMs) and pneumothoraces. Diagnosis with LAM was confirmed through high-resolution computed tomography (HRCT) scan and histopathology of lung biopsy. Whole exome sequencing analysis identified a frameshift mutation c.4504del (p.L1502Cfs*74) in the patient's TSC2 gene. This variant was de novo due to its absence in the patient's parents. This is the first report on the clinical and genetic etiology of TSC-LAM in Vietnam.

Keywords: TSC2 gene; TSC‐LAM; pathogenic variants.

FIGURE 1

Patient dermal manifestation (A) facial angiofibroma, and (B) two hypomelanotic macules of tuberous sclerosis complex. Chest computed tomography (CT) image of the patient's lungs at different levels and planar (C) axial and (D) coronal. These cysts are seen replacing most of the lung parenchyma (yellow arrow). High‐grade pneumothorax in the left lung due to advanced cystic lung disease (red arrow). (E), (F): Abdomen CT shows multiple enhancing right renal masses, some of which contain macroscopic fat grossly unchanged consistent with angiomyolipomas (green arrow). A portion of the right kidney was surgically resected, resulting in the formation of a fluid‐filled cystic lesion (indicated by the blue arrow). (G) The proliferation of LAM cell nodules with characteristic spindle‐shaped cells (white arrows) in the center and epithelial cells (black arrows) at the periphery (Haematoxylin and Eosin stain at 200x magnification). (H) The diseased lung specimen of the patient was removed in lung transplant surgery.

FIGURE 2

(A) The schematics of TSC2‐human protein (#P49815) with Rap‐GAP domain (pink box) were illustrated. Wild‐type (WT) TSC2 and mutant with frameshift p.L1502Cfs*74 alternate reading frame ends and code TSC2‐tuberin protein with a truncated Rap‐GAP domain. (B) Sanger chromatogram of p.L1502Cfs*74 mutation (red arrow) presented by heterozygous peaks in proband and absent from family member.