Macrocephaly in children: A comprehensive review of etiologies, MRI features, clinical, biochemical, genetic correlates, and prognostic implications

Background: Macrocephaly, defined as a head circumference >+2 SD for age and sex, is a common pediatric finding with a wide differential diagnosis. While often benign, it can signal underlying genetic syndromes, metabolic disorders, neurodevelopmental conditions, or structural brain abnormalities. This review synthesizes 25 years of literature to delineate the etiological, clinical, biochemical, hormonal, and radiological spectrum of pediatric macrocephaly.

Objectives: To classify the etiologies of macrocephaly in children; describe the associated MRI patterns; correlate neuroimaging with clinical, endocrine, and growth parameters; evaluate the prognostic value of MRI findings, and establish genotype-phenotype relationships across syndromes.

Methods: A systematic literature review (1999–2024) was conducted using PubMed, Scopus, Embase, and Google Scholar. Inclusion criteria focused on pediatric studies (0–18 years) with macrocephaly, reporting clinical, hormonal, genetic, or MRI data. Data were extracted on etiology, MRI findings, hormonal/metabolic abnormalities, genetic mutations, growth patterns, skeletal features, and developmental outcomes. A severity scoring system (1–4) was used across domains. Visual figures (MRI maps, heatmaps, radar charts, and Foster plots) were generated to integrate findings. No meta-analysis was performed due to heterogeneity.

Results: Etiologies ranged from benign familial macrocephaly to rare syndromes like Canavan disease and 3-M syndrome. MRI revealed syndrome-specific patterns: Sotos and PTEN-ASD showed frontal overgrowth; leukodystrophies (e.g., Canavan, Alexander) showed diffuse white matter degeneration; M-CM exhibited polymicrogyria and cerebellar tonsillar herniation. Endocrine disruptions were common in overgrowth syndromes (elevated IGF-1 in Sotos, M-CM), whereas GH resistance characterized growth-restricted syndromes (e.g., 3-M, MPS). Genetic analysis linked NSD1, PIK3CA, PTEN, GFAP, and ASPA mutations with distinct MRI phenotypes. Prognosis was most favorable in familial, ASD-related, and 3-M macrocephaly; poorest in leukodystrophies and MPS. MRI severity strongly correlated with clinical outcomes and biochemical burden.

Conclusion: Macrocephaly is a heterogeneous entity involving multiple systems. MRI remains central to diagnosis, revealing patterns that align with hormonal, genetic, and clinical profiles. Endocrine markers (e.g., GH/IGF-1) and skeletal findings provide additional diagnostic value. Genetic testing guided by neuroimaging is crucial for precision diagnosis. Prognosis is tightly linked to MRI abnormalities, underscoring imaging's prognostic role.