Brain morphological analysis in PTEN hamartoma tumor syndrome

Abstract

PTEN hamartoma tumor syndrome (PHTS) is a spectrum of hereditary cancer syndromes caused by germline mutations in PTEN. PHTS is of high interest, because of its high rate of neurological comorbidities including macrocephaly, autism spectrum disorder, and intellectual dysfunction. Since detailed brain morphology and connectivity of PHTS remain unclear, we quantitatively evaluated brain magnetic resonance imaging (MRI) in PHTS. Sixteen structural T1-weighted and 9 diffusion-weighted MR images from 12 PHTS patients and neurotypical controls were used for structural and high-angular resolution diffusion MRI (HARDI) tractography analyses. Megacorpus callosum was observed in 75%, polymicrogyria in 33%, periventricular white matter lesions in 83%, and heterotopia in 17% of the PHTS participants. While gyrification index and hemispheric cortical thickness showed no significant differences between the two groups, significantly increased global and regional brain volumes, and regionally thicker cortices in PHTS participants were observed. HARDI tractography showed increased volume and length of callosal pathways, increased volume of the arcuate fasciculi (AF), and increased length of the bilateral inferior longitudinal fasciculi (ILF), bilateral inferior fronto-occipital fasciculi (IFOF), and bilateral uncinate fasciculus. A decrease in fractional anisotropy and an increased in apparent diffusion coefficient values of the AF, left ILF, and left IFOF in PHTS. K E Y W O R D SHARDI, mega corpus callosum, megalencephaly, PTEN hamartoma tumor syndrome, structural brain MRI

Polymicrogyria is Associated With Pathogenic Variants in PTEN

“…16 Rates of PMG reported in patients with PTHS have varied widely ranging from 0 to 33%. 5,6,17 In our study, we find a high rate with just over half of our PTEN cohort showing MRI evidence of PMG (54.5%). Although ascertainment bias can be a concern due to identification of individuals through a radiology database, we note that the individuals found via this radiology search who had normal PTEN status despite clinically suspected PTHS did not have cortical malformations.…”

“…Consistent with this concept, the prior study, which reported a rate of PMG of 33%, used only 3 T MRI images. 6 In our institution, patients with macrocephaly and developmental delay are generally scanned at 3 T with a high-density multichannel head coil (32 or 64-channel), high resolution imaging technique, and at least one isotropic sequence. However, several of the patients in our cohort were imaged for other reasons or had lower resolution outside imaging, which was not repeated.…”

“…5 A more recent study used quantitative evaluation of brain MRI in individuals with PTHS to demonstrate the frequent finding of megacorpus callosum, present in 9 of 12 patients (75%) and the malformation of cortical development polymicrogyria (PMG) in 4 of 12 patients (33%). 6 Malformations, such as PMG, have clinical implications, such as epilepsy, that have not been explored specifically in the context of PTEN germline variants.…”

Quantitative analyses of high‐angular resolution diffusion imaging (HARDI)‐derived long association fibers in children with sensorineural hearing loss

“…We did not use an FA threshold to terminate tractography (e.g., Takahashi et al, 2012) [Fx]) in both hemispheres were identified and visualized using TrackVis (http;//trackvis. org), as in previous analyses (Cohen et al, 2016;Shiohama et al, 2019bShiohama et al, , 2020Takahashi et al, 2012;Xu et al, 2014).…”

Cerebral MRI and Clinical Findings in Children with PTEN Hamartoma Tumor Syndrome: Can Cerebral MRI Scan Help to Establish an Earlier Diagnosis of PHTS in Children?

“…In the current literature, different neuroimaging features associated with PTEN mutations have been reported, including cerebellar dysplastic gangliocytoma (Lhermitte-Duclos disease (LDD)), meningioma, vascular malformations [12], localized malformations such as focal cortical dysplasia, white matter abnormalities [13], dilated Virchow-Robin spaces [14] and polymicrogyria [15]. Since our institution hosts a rare disease center for familiar tumor syndromes, we have the opportunity to supervise a relatively large pediatric cohort of patients with PHTS.…”