Broad spectrum of neuropsychiatric phenotypes associated with white matter disease in PTEN hamartoma tumor syndrome

Abstract

White matter lesions have been described in patients with PTEN hamartoma tumor syndrome (PHTS). How these lesions correlate with the neurocognitive features associated with PTEN mutations, such as autism spectrum disorder (ASD) or developmental delay, has not been well established. We report nine patients with PTEN mutations and white matter changes on brain magnetic resonance imaging (MRI), eight of whom were referred for reasons other than developmental delay or ASD. Their clinical presentations ranged from asymptomatic macrocephaly with normal development/intellect, to obsessive compulsive disorder, and debilitating neurological disease. To our knowledge, this report constitutes the first detailed description of PTEN-related white matter changes in adult patients and in children with normal development and intelligence. We present a detailed assessment of the neuropsychological phenotype of our patients and discuss the relationship between the wide array of neuropsychiatric features and observed white matter findings in the context of these individuals.

Brain morphological analysis in PTEN hamartoma tumor syndrome

“…In addition to high periventricular T2 signal intensity and megalencephaly (increased brain size) as previously noted (Balci et al, ; Lok et al, ; Vanderver et al, ), our qualitative observation in MR images of patients with PHTS showed a more frequent occurrence of mega CC, perisylvian polymicrogyria, and periventricular heterotopia. The observation of the mega CC in PHTS was in agreement with our quantitative HARDI tractography findings in which CP of the PHTS patients were significantly increased in volume and length.…”

“…PTEN hamartoma tumor syndrome (PHTS) is a spectrum of disorders caused by germline mutations in the PTEN gene. It is clinically divided into several syndromes including Cowden syndrome (OMIM 158350), Bannayan–Riley–Ruvalcaba syndrome (OMIM 153480), Macrocephaly/autism syndrome (OMIM 605309), and adult Lhermitte–Duclos syndrome (OMIM 158350) (Balci et al, ). PHTS syndromes are sometimes inaccurately classified during childhood mostly because clinical manifestations of these syndromes overlap, and cancers, which are essential for the correct clinical diagnosis of Cowden syndrome or Bannayan–Riley–Ruvalcaba syndrome usually occur after the later part of the third decade of life.…”

“…Although PHTS is recognized mainly as a hereditary cancer syndrome, numerous clinical case reports indicate a high rate of comorbidities such as macrocephaly (measured with head circumference) (43–100%) (Hansen‐Kiss et al, ; Kato et al, ; Kurata et al, ), autism spectrum disorder (ASD) (14–50%) (Balci et al, ; Hansen‐Kiss et al, ; Kato et al, ; Kurata et al, ), and intellectual dysfunction/developmental delay (31–67%) (Hansen‐Kiss et al, ; Kato et al, ; Kurata et al, ).…”

“…While studies of brain morphology in PHTS are few and limited in qualitative analysis, typical findings such as posterior periventricular lesions with T2‐weighted hyperintensities have been reported (Balci et al, ; Lok et al, ; Vanderver et al, ). However, to our knowledge, quantitative analysis of brain structure or fiber pathways using structural/diffusion‐weighted MRI or diffusion MRI tractography have not yet been reported.…”

Polymicrogyria is Associated With Pathogenic Variants in PTEN

“…Interestingly, it has separately been found that individuals with PTEN variants and white matter abnormalities may still have normal intelligence, thus clouding the picture of whether the neurodevelopmental phenotype of PTEN is related primarily to dysfunction of the white matter. 18 The radiographic findings in our PTEN cohort are important for both diagnosis and patient counseling. Developmental delay and macrocephaly are common indications for brain MRIs in children.…”