Fetal cardiac rhabdomyoma due to paternal mosaicism of TSC2: A case report

Abstract

Rationale: Rhabdomyoma is the most common type of fetal heart tumors and 50% to 60% of cardiac rhabdomyomas are associated with tuberous sclerosis complex (TSC). TSC is characterized by hamartomas in multiple organ systems including the brain, heart, skin, lungs, and kidneys, resulting in complications such as learning difficulties, epilepsy, behavioral problems, and renal failure. The etiological diagnosis of Rhabdomyoma is very important.

Patient concerns: A 22-year-old G2P0 woman chose to terminate the pregnancy at 24 + 4 weeks of gestation because of the presence of a cardiac space-occupying lesion in the fetus.

Diagnoses: The pathological diagnosis of cardiac neoplasm tissue was cardiac rhabdomyoma, but the etiology was unknown.

Interventions: Targeted exome capture, next-generation sequencing (NGS) and sanger sequencing were performed on peripheral blood lymphocytes and paternal sperm.

Outcomes: Targeted exome capture sequencing revealed a novel heterozygous variant (NM_000548, c.2294delC) in the tuberous sclerosis 2 (TSC2) gene. Sanger sequencing of maternal blood samples showed no mutation at this locus, however, suspected low level mosaicism was observed in paternal blood samples. Deep NGS analysis showed that about 7% paternal alleles from peripheral blood leucocytes and 20% paternal alleles from sperm carried the mutation consistent with somatic and germinal mosaicism.

Lessons: For fetuses suspected of TSC, when pathogenic mutations are detected in the tuberous sclerosis 1 (TSC1) or TSC2 gene, it is recommended that the parents should be screened by deep NGS and their germ cells are screened as well if necessary, which would help to predict the risk of TSC recurrence in the next pregnancy.

Figure 1

Space-occupying lesion in the fetal heart. The image revealed that a slightly stronger echo (1.1x1.3 cm, no pedicle) was found near the apex of the anterior wall of the right ventricle. The motion of the space occupying lesion was synchronous with ventricular systolic and diastolic.

Figure 2

Angiofibroma and café-au-lait spots at face.

Figure 3

The pedigree of the present family. Open symbols represent healthy individuals. Squares indicate males, circles indicate females, black triangles indicate affected fetuses. The proband is indicated by an arrow.

Figure 4

The results of genomic DNA sample sequencing of the family members. Sanger sequencing analysis of the tuberous sclerosis 2 gene revealed no mutationin pregnant woman (A), heterozygous mutation in fetus (B), suspected low level mosaicism in paternal blood samples (C), and mosaicism in paternal sperm samples (D). Deep next-generation sequencing analysis showed that about 49% of the fetal alleles from muscle tissues (E), 7% of the paternal alleles from peripheral blood leucocytes (F), and 20% of the paternal alleles from sperm (G) carried the mutation. Arrows indicate the positions of c.2294. NGS = next-generation sequencing, TSC2 = tuberous sclerosis 2.