Characteristic brain magnetic resonance imaging pattern in patients with macrocephaly and <i>PTEN</i> mutations

Vanderver, Adeline; Tonduti, Davide; Kahn, Ilana; Schmidt, Johanna; Medne, Līvija; Vento, Jodie M.; Chapman, Kimberly A.; Lanpher, Brendan C.; Pearl, Phillip L.; Gropman, Andrea; Lourenço, Charles Marques; Bamforth, John Steven; Sharpe, Cynthia; Pineda, Mercédes; Schallner, Jens; Bodamer, Olaf A.; Orcesi, Simona; Oberstein, Saskia A J Lesnik; Sistermans, Erik A.; Yntema, Helger G.; Bönnemann, C.; Waldman, Amy; Knaap, Marjo S. van der

doi:10.1002/ajmg.a.36309

Cited by 68 publications

(55 citation statements)

References 32 publications

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“…Three of the children (PC0010, PC0015 and PC0017) had periventricular grey matter heterotopias (figure 1). Five children demonstrated periventricular hypomyelination (PC0015, PC0017, PC0035, PC0042 and PC0043) similar to that reported previously by Vanderver et al 34 and Frazier et al 32 (see online supplementary table 1). Repeat MRI on PC0015 4 years later at age 6.5 years no longer demonstrated any hypomyelination, suggesting it could have represented a delay in maturation.…”

Section: Resultssupporting

confidence: 84%

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A retrospective chart review of the features of PTEN hamartoma tumour syndrome in children

et al. 2017

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This is the largest survey of clinical features in children with pathogenic mutations to date. It confirms earlier reports of increased rates of neurodevelopmental disorders. Dermatological, GI and thyroid abnormalities are age dependent and may not be present at the time of diagnosis, requiring regular monitoring and medical surveillance. Early paediatric diagnosis is important for institution of medical and developmental surveillance as well as for testing other at- risk family members.

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Section: Resultssupporting

confidence: 84%

“…In a retrospective review of individuals with disorders of CNS white matter, Vanderver et al noted a specific ‘MRI phenotype’ in 23 individuals with PTEN mutations, macrocephaly, and DD and/or ASD 34. They all demonstrated enlarged perivascular spaces and periventricular white matter changes on MRI.…”

Section: Resultsmentioning

confidence: 99%

A retrospective chart review of the features of PTEN hamartoma tumour syndrome in children

et al. 2017

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Section: Connecting Phenotype and Genotype Across The Lifespanmentioning

confidence: 99%

“…Two independent studies report structural magnetic resonance imaging (MRI) phenotypes in patients with PTEN-ASD [26,27]. The multinational cohort described by Vanderver et al [27] was retrospectively selected based known white matter pathology (n = 23), and included patients with and without ASD. The study by Frazier et al [26] was designed to identify phenotypic characteristics of PTEN-ASD compared with PTEN mutation-negative ASD patients with and without macrocephaly, as well as healthy controls.…”

Section: Connecting Phenotype and Genotype Across The Lifespanmentioning

confidence: 99%

“…The study by Frazier et al [26] was designed to identify phenotypic characteristics of PTEN-ASD compared with PTEN mutation-negative ASD patients with and without macrocephaly, as well as healthy controls. The former study focused on the periventricular white matter and perivascular spaces, finding that all patients had macrocephaly and multifocal white matter abnormalities, enlarged periventricular spaces, or both [27]. As a prospective study, we were able to measure volumes for total grey and white matter, multiple brain structures including the corpus callosum, as well as cortical thickness and white matter hypointensities [26].…”

Section: Connecting Phenotype and Genotype Across The Lifespanmentioning

confidence: 99%

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Balancing Proliferation and Connectivity in PTEN-associated Autism Spectrum Disorder

2015

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Germline mutations in PTEN, which encodes a widely expressed phosphatase, was mapped to 10q23 and identified as the susceptibility gene for Cowden syndrome, characterized by macrocephaly and high risks of breast, thyroid, and other cancers. The phenotypic spectrum of PTEN mutations expanded to include autism with macrocephaly only 10 years ago. Neurological studies of patients with PTENassociated autism spectrum disorder (ASD) show increases in cortical white matter and a distinctive cognitive profile, including delayed language development with poor working memory and processing speed. Once a germline PTEN mutation is found, and a diagnosis of phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome made, the clinical outlook broadens to include higher lifetime risks for multiple cancers, beginning in childhood with thyroid cancer. First described as a tumor suppressor, PTEN is a major negative regulator of the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (mTOR) signaling pathway-controlling growth, protein synthesis, and proliferation. This canonical function combines with less well-understood mechanisms to influence synaptic plasticity and neuronal cytoarchitecture. Several excellent mouse models of Pten loss or dysfunction link these neural functions to autism-like behavioral abnormalities, such as altered sociability, repetitive behaviors, and phenotypes like anxiety that are often associated with ASD in humans. These models also show the promise of mTOR inhibitors as therapeutic agents capable of reversing phenotypes ranging from overgrowth to low social behavior. Based on these findings, therapeutic options for patients with PTEN hamartoma tumor syndrome and ASD are coming into view, even as new discoveries in PTEN biology add complexity to our understanding of this master regulator.

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Exploring the neurological features of individuals with germline PTEN variants: A multicenter study

Dhawan,

Baitamouni,

Liu

et al. 2024

Ann Clin Transl Neurol

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ObjectivePTEN, a known tumor suppressor gene, is a mediator of neurodevelopment. Individuals with germline pathogenic variants in the PTEN gene, molecularly defined as PTEN hamartoma tumor syndrome (PHTS), experience a variety of neurological and neuropsychiatric challenges during childhood, including autism spectrum disorder (ASD). However, the frequency and nature of seizures and the utilization of allied health services have not been described.MethodsYoung patients with PHTS and sibling controls were recruited across five centers in the United States and followed every 6–12 months for a mean of 2.1 years. In addition to the history obtained from caregivers, neurodevelopmental evaluations and structured dysmorphology examinations were conducted, and brain MRI findings, received therapies, and epilepsy characteristics were reported.ResultsOne hundred and seven patients with PHTS (median age 8.7 years; range 3–21 years) and 38 controls were enrolled. ASD and epilepsy were frequent among patients with PHTS (51% and 15%, respectively), with generalized epilepsy strongly associated with ASD. Patients with epilepsy often required two antiseizure medications. Neuroimaging revealed prominent perivascular spaces and decreased peritrigonal myelination in individuals with PHTS‐ASD. Allied therapy use was frequent and involved physical, occupational, speech, and social skills therapies, with 89% of all patients with PHTS, regardless of ASD diagnosis, utilizing at least one service.InterpretationThis prospective, longitudinal study highlights the wide neurological spectrum seen in young individuals with PHTS. ASD is common in PHTS, comorbid with epilepsy, and allied health services are used universally. Our findings inform care discussions with families about neurological outcomes in PHTS.

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Characteristic brain magnetic resonance imaging pattern in patients with macrocephaly and PTEN mutations

Cited by 68 publications

References 32 publications

A retrospective chart review of the features of PTEN hamartoma tumour syndrome in children

A retrospective chart review of the features of PTEN hamartoma tumour syndrome in children

Balancing Proliferation and Connectivity in PTEN-associated Autism Spectrum Disorder

Exploring the neurological features of individuals with germline PTEN variants: A multicenter study

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