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Background: Inactivating mutations in PTEN are among the most common causes of megalencephaly. Activating mutations in other nodes of the PI3K/AKT/MTOR signaling pathway are recognized as a frequent cause of cortical brain malformations. Only recently has PTEN been associated with cortical malformations, and analyses of their prognostic significance have been limited., Methods: Retrospective neuroimaging analysis and detailed chart review were conducted on 20 participants identified with pathogenic or likely pathogenic mutations in PTEN and a cortical brain malformation present on brain magnetic resonance imaging., Results: Neuroimaging analysis revealed four main cerebral phenotypes-hemimegalencephaly, focal cortical dysplasia, polymicrogyria (PMG), and a less severe category, termed "macrocephaly with complicated gyral pattern" (MCG). Although a high proportion of participants (90%) had neurodevelopmental findings on presentation, outcomes varied and were favorable in over half of participants. Consistent with prior work, 39% of participants had autism spectrum disorder and 19% of participants with either pure-PMG or pure-MCG phenotypes had epilepsy. Megalencephaly and systemic overgrowth were common, but other systemic features of PTEN-hamartoma tumor syndrome were absent in over one-third of participants., Conclusions: A spectrum of cortical dysplasias is present in individuals with inactivating mutations in PTEN. Future studies are needed to clarify the prognostic significance of each cerebral phenotype, but overall, we conclude that despite a high burden of neurodevelopmental disease, long-term outcomes may be favorable. Germline testing for PTEN mutations should be considered in cases of megalencephaly and cortical brain malformations even in the absence of other findings, including cognitive impairment., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare leukodystrophy characterized by early-onset macrocephaly and progressive white matter vacuolation. The MLC1 protein plays a role in astrocyte activation during neuroinflammation and regulates volume decrease following astrocyte osmotic swelling. Loss of MLC1 function activates interleukin (IL)-1β-induced inflammatory signals. Theoretically, IL-1 antagonists (such as anakinra and canakinumab) can slow the progression of MLC. Herein, we present two boys from different families who had MLC due to biallelic MLC1 gene mutations and were treated with the anti-IL-1 drug anakinra., Methods: Two boys from different families presented with megalencephaly and psychomotor retardation. Brain magnetic resonance imaging findings in both patients were compatible with the diagnosis of MLC. The diagnosis of MLC was confirmed via Sanger analysis of the MLC1 gene. Anakinra was administered to both patients. Volumetric brain studies and psychometric evaluations were performed before and after anakinra treatment., Results: After anakinra therapy, brain volume in both patients decreased significantly and cognitive functions and social interactions improved. No adverse effects were observed during anakinra therapy., Conclusions: Anakinra or other IL-1 antagonists can be used to suppress disease activity in patients with MLC; however, the present findings need to be confirmed via additional research., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Macrocephaly is frequently encountered in pediatrics and often leads to imaging. There are no recommendations from the American Academy of Pediatrics or the American College of Radiology providing imaging guidelines for macrocephaly. The goal of this study is to identify risk factors for pathologic macrocephaly and to aid the clinician in identifying patients that would benefit from imaging., Methods: We conducted a medical record review throughout a multistate health care system, Sanford Health, from January 1, 2012 to December 31, 2016. Patients with macrocephaly were identified by problem list in children aged less than 36 months. Data collection included basic demographics, imaging modality, developmental delay, prematurity, seizures, focal neurological symptoms, family history of macrocephaly, sedation used, and sedation complications., Results: A total of 169 patients were included in the analysis. Imaging modalities included 39 magnetic resonance imagings (23.1%), 47 cranial computed tomographies (27.8%), and 83 head ultrasounds (49.1%). Imaging results demonstrated 13 abnormal studies with five of those studies being abnormal with high clinical yield. Patients with abnormal studies were more likely to have developmental delay (P = 0.04) or neurological symptoms (P = 0.015). Positive family history of macrocephaly was predictive of normal imaging (P = 0.004). There were no sedation complications., Conclusions: Intracranial imaging does not appear to be necessary in children with no risk factors and or a positive family history of macrocephaly. Risk factors such as developmental delay or neurological symptoms could identify children at risk for imaging abnormalities that require further management., (Copyright © 2018 Elsevier Inc. All rights reserved.)