Neuroimaging abnormalities in patients with Cowden syndrome

Dhamija, Radhika; Weindling, Steven M.; Porter, Alyx; Hu, Leland; Wood, Christopher P.; Hoxworth, Joseph M.

doi:10.1212/cpj.0000000000000463

Cited by 27 publications

(38 citation statements)

References 35 publications

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“…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.…”

Section: Discussionsupporting

confidence: 44%

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Polymicrogyria is Associated With Pathogenic Variants in PTEN

Shao

Achkar

Lai

et al. 2020

Annals of Neurology

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Objective: Congenital structural brain malformations have been described in patients with pathogenic phosphatase and tensin homologue (PTEN) variants, but the frequency of cortical malformations in patients with PTEN variants and their impact on clinical phenotype are not well understood. Our goal was to systematically characterize brain malformations in patients with PTEN variants and assess the relevance of their brain malformations to clinical presentation. Methods: We systematically searched a local radiology database for patients with PTEN variants who had available brain magnetic resonance imaging (MRI). The MRI scans were reviewed systematically for cortical abnormalities. We reviewed electroencephalogram (EEG) data and evaluated the electronic medical record for evidence of epilepsy and developmental delay. Results: In total, we identified 22 patients with PTEN pathogenic variants for which brain MRIs were available (age range 0.4-17 years). Twelve among these 22 patients (54%) had polymicrogyria (PMG). Variants associated with PMG or atypical gyration encoded regions of the phosphatase or C2 domains of PTEN. Interestingly, epilepsy was present in only 2 of the 12 patients with PMG. We found a trend toward higher rates of global developmental delay (GDD), intellectual disability (ID), and motor delay in individuals with cortical abnormalities, although cohort size limited statistical significance. Interpretation: Malformations of cortical development, PMG in particular, represent an under-recognized phenotype associated with PTEN pathogenic variants and may have an association with cognitive and motor delays. Epilepsy was infrequent compared to the previously reported high risk of epilepsy in patients with PMG.

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Section: Discussionsupporting

confidence: 44%

“…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%).…”

Section: Discussionmentioning

confidence: 42%

Polymicrogyria is Associated With Pathogenic Variants in PTEN

Shao

Achkar

Lai

et al. 2020

Annals of Neurology

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“…While we are unable to address the presence of PIK3CA mutations in DVA not associated with CCM, it is worth noting that DVAs have been associated with other PI3Krelated disorders [36][37][38][39][40][41][42] including some cancers and neurological malformations, suggesting that DVA may have a role, possibly even as a genetic primer, in these other diseases.…”

Section: Discussionmentioning

confidence: 85%

Developmental Venous Anomalies are a Genetic Primer for Cerebral Cavernous Malformations

Snellings

Girard

Lightle

et al. 2021

Preprint

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Cerebral cavernous malformations (CCM) are a neurovascular anomaly that may occur sporadically in otherwise healthy individuals, or be inherited by autosomal dominant mutations in the genes that encode the proteins of the CCM signaling complex (KRIT1, CCM2, or PDCD10). CCMs have long been known to follow a genetic two-hit model where lesion formation is initiated by somatic mutations resulting in biallelic loss of a CCM complex gene. Recent studies have shown that somatic mutations in MAP3K3 and PIK3CA also contribute to CCM pathogenesis; however, it remains unclear how these mutations contribute to sporadic versus familial cases. Here we show that somatic mutations in MAP3K3 are mutually exclusive with mutations in CCM complex genes and that mutations in MAP3K3 contribute to sporadic, but not familial CCM. Using single-nucleus DNA sequencing, we show that co-occurring MAP3K3 and PIK3CA mutations are present within the same clonal population of cells. Furthermore, we identify PIK3CA mutations in CCM-associated developmental venous anomalies (DVA). It has long been known that sporadic CCM often develop in the vicinity of a DVA. However, the underlying cause of this association is unknown. In this first report of the molecular pathology of CCM-associated DVA, we find that the identical PIKC3A mutation is found in both the DVA and its associated CCM, but that an activating MAP3K3 mutation appears only in the CCM. These results support a mechanism where DVA develop as the result of a PIK3CA mutation, creating a region of the brain vasculature that functions as a genetic primer for CCM development following acquisition of an additional somatic mutation.

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“… 55 Moreover, cerebral venous anomaly and cavernous malformations are observed in the Cowden syndrome. 60 , 61 The PTEN gene has a role in normal post-natal angiogenesis and in inhibition of vascular sprouting: a mutation will result in abnormal angiogenesis, explaining the high vascular malformation incidence. 62 As mentioned by Walcott et al .…”

Section: Discussionmentioning

confidence: 99%

Paediatric intracranial dural arteriovenous shunts: types, clinical presentation and therapeutic management

Smajda

Söderman

Dorfmüller

et al. 2022

Brain Communications

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Paediatric intracranial dural arterio-venous shunts have clinical presentations and evolutions, with angiographic characteristics that differ from those described in adults. We report our experience concerning their therapeutic management, emphasizing the relevance of early diagnosis and appropriate treatment for satisfactory neurocognitive development. Using a prospective database, we reviewed the clinical and radiological data of all children with dural arteriovenous shunts managed between 2002 and 2020. Dural shunts were categorized into three types: dural sinus malformations with arteriovenous shunts; infantile dural arteriovenous shunts; adult-type dural arteriovenous shunts. Therapeutic strategies and outcomes were analyzed depending on lesional subtypes. Modified Rankin Scale for the paediatric population was assessed pre-treatment and at last follow-up. Twenty-eight patients (16 girls [57.1%]; 12 boys [42.9%]) were included: 17 dural sinus malformation (10 boys [58.8%]; seven girls [41.2%]), three infantile shunts (three girls [100%]), eight adult-type shunts (four girls [50%]; four boys [50%]), with a mean age of 19.2±36.6 months at presentation. Twelve (42.9%) had a modified Rankin Scale score of 0-2, four (14.3%) a score of 3, three (10.7%) a score of 4 and eight (28.6%) a score of 5. Embolization was performed in 22 children (78.6%; 12 girls [54.5%]; 10 boys [45.5%]). Fifteen patients could be cured (68.2%): 11 dural sinus malformations (73.3%), four adult-type lesions (100%), but no infantile shunt. Mean post-treatment follow-up was 39.5 months (max. 139 months): 14 patients (63.6%) presented a modified Rankin Scale score 0-2 and eight (36.4%) a score ≥3. In the dural sinus malformation group, the modified Rankin Scale score was improved in 11 patients (73.3%) and unchanged in three (20%). Only one patient with infantile subtype (33.3%) improved clinically. In the adult-subtype group, all children (100%) improved. Of six untreated patients (four girls [66.7%]; two boys [33.3%]), four with adult-subtype shunts showed uneventful evolutions, one with dural sinus malformation died, and therapeutic abortion was conducted in an antenatally diagnosed dural sinus malformation. Pediatric dural fistulas comprise different subtypes with variable clinical courses. Proper diagnosis is mandatory for optimal therapeutic strategies within appropriate therapeutic windows.

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Neuroimaging abnormalities in patients with Cowden syndrome

Cited by 27 publications

References 35 publications

Polymicrogyria is Associated With Pathogenic Variants in PTEN

Polymicrogyria is Associated With Pathogenic Variants in PTEN

Developmental Venous Anomalies are a Genetic Primer for Cerebral Cavernous Malformations

Paediatric intracranial dural arteriovenous shunts: types, clinical presentation and therapeutic management

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