Prenatal diagnosis of hemimegalencephaly revealing tuberous sclerosis complex.

Abstract

Tuberous sclerosis complex (TSC) is a rare multisystem autosomal dominant disorder, with lesions observed most frequently in the brain, kidneys and heart1. The lesions consist of hamartomas, benign tumors and, more rarely, malignant neoplasms. The four neuropathological hallmarks of TSC are subependymal nodules, cortical tubers, subependymal giant cell astrocytomas and white-matter abnormalities. The diagnostic criteria for TSC have been updated by Northrup and Krueger2 and classified as major and minor features. Hemimegalencephaly (HME) is not included in these criteria. We report the case of a fetus diagnosed prenatally with HME associated with TSC. A woman was referred at 23 weeks of gestation due to fetal brain anomaly. Ultrasound examination revealed macrocephaly (biparietal diameter of 63.1 mm (97th percentile) and head circumference of 239.2 mm (> 97th percentile)), asymmetrical head shape, enlarged unilateral left cerebral hemisphere and abnormal operculization of the Sylvian fissure consistent with HME3 (Figure 1a). A single 10-mm cardiac septal hyperechogenic mass resembling a rhabdomyoma was identified (Figure 1b). Magnetic resonance imaging performed at 25 weeks of gestation confirmed on T2-weighted sequences enlargement of the left cerebral hemisphere, poor delineation of the cortical mantle from the intermediate zone and displacement of the midline structures toward the right hemisphere. The left lateral ventricle was dysmorphic (Figure 1c). No sign of cortical tuber or subependymal nodule was identified. The cardiac mass associated with HME led to suspicion of TSC, and next-generation sequencing identified a de-novo deleterious heterozygous variant in exon 9 of the TSC2 gene: c.935_936delTC (p.Leu312GlnfsX25). Considering the severity of the brain malformation, the parents opted for termination of pregnancy. Macroscopy and histology of all viscera revealed no malformation except the cardiac rhabdomyoma. The brain weighed 348 g (> 95th percentile). No primary sulci were observed on the left hemisphere. Histologically, both hemispheres were affected. Multiple foci of gemistocytic-like balloon cells were observed in the right cortical plate and intermediate zone. The lesions were diffuse in the left hemisphere. The cortical plate was replaced entirely by balloon cells which were also found within the thickened meninges (Figure 1d), passing through gaps of the glia limitans (Figure 1e). The intermediate zone was also massively invaded by balloon cells. Close to the left ganglionic eminence, subependymal nodules were identified (Figure 1f). HME belongs to the spectrum of disorders related to hyperactivation of the mTORC1 pathway4, which is responsible for unilateral brain and spinal cord overgrowth. HME may result from somatic mutations in the PIK3CA or AKT3 genes, or may be a part of neurocutaneous syndromes, but very infrequently TSC (Appendix S1, Table S1). TSC is caused by loss-of-function germline mutations in TSC1 or TSC2, whose products play essential roles in the control of proliferation, growth and differentiation. Activation of both products is known to be driven by upstream signals of the PIK3/AKT pathway and it could be therefore hypothesized that loss of function of TSC1 or TSC2 could induce an imbalance in PIK3/AKT pathway functioning5. We report for the first time fetal association of HME and TSC, suggesting that prenatally diagnosed HME should prompt careful examination for fetal signs of TSC, and that HME should be considered as a rare but significant prenatal criterion for TSC. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.