Diagnostic Approach to Macrocephaly in Children

Abstract

Macrocephaly affects up to 5% of the pediatric population and is defined as an abnormally large head with an occipitofrontal circumference (OFC) >2 standard deviations (SD) above the mean for a given age and sex. Taking into account that about 2–3% of the healthy population has an OFC between 2 and 3 SD, macrocephaly is considered as “clinically relevant” when OFC is above 3 SD. This implies the urgent need for a diagnostic workflow to use in the clinical setting to dissect the several causes of increased OFC, from the benign form of familial macrocephaly and the Benign enlargement of subarachnoid spaces (BESS) to many pathological conditions, including genetic disorders. Moreover, macrocephaly should be differentiated by megalencephaly (MEG), which refers exclusively to brain overgrowth, exceeding twice the SD (3SD—“clinically relevant” megalencephaly). While macrocephaly can be isolated and benign or may be the first indication of an underlying congenital, genetic, or acquired disorder, megalencephaly is most likely due to a genetic cause. Apart from the head size evaluation, a detailed family and personal history, neuroimaging, and a careful clinical evaluation are crucial to reach the correct diagnosis. In this review, we seek to underline the clinical aspects of macrocephaly and megalencephaly, emphasizing the main differential diagnosis with a major focus on common genetic disorders. We thus provide a clinico-radiological algorithm to guide pediatricians in the assessment of children with macrocephaly.

Refining the Phenotypic Spectrum of KMT5B-Associated Developmental Delay

“…The differential diagnosis of GDD/ID accompanied by macrocephaly is diverse and includes numerous inherited disorders, such as PTEN hamartoma syndromes, Fragile X and Canavan disease, among others ( 21 ). Interestingly, macrocephaly (or relative macrocephaly) has been previously described as a common feature of additional neurodevelopmental disorders associated with variants in other genes of the lysine methyltransferase family, such as KMT2E ( 22 ).…”

Complex Autism Spectrum Disorder with Epilepsy, Strabismus and Self-Injurious Behaviors in a Patient with a De Novo Heterozygous POLR2A Variant

“…Both her parents were macrocephalic (> 98th percentile). This was felt to represent familial benign macrocephaly in the overall context of the investigations below [ 30 ]. She had no obvious dysmorphisms aside from a slight right-sided facial prominence ( Figure 1 ).…”

Research models of neurodevelopmental disorders: The right model in the right place

“…Macrocephaly is defined as head circumference with ≥2 SD for a given age and gender ( Accogli et al, 2022 ), originating from a higher proliferation rate of progenitors as well as defects in growth factor signaling ( Sun and Hevner, 2014 ). Heterozygous loss-of-function mutations in PTEN were identified in patients with macrocephaly and associated with ASD, concurrently ( Butler et al, 2005 ).…”