What is the differential diagnosis for a child or young adult presenting with macrocephaly and frontal bossing?

Differential Diagnosis of Macrocephaly with Frontal Bossing

The differential diagnosis for macrocephaly with frontal bossing includes benign familial macrocephaly, skeletal dysplasias (particularly achondroplasia), overgrowth syndromes (especially Sotos syndrome), hydrocephalus, megalencephaly with cortical malformations, and metabolic disorders. 1

Primary Diagnostic Categories

Benign Familial Macrocephaly

• Most common cause in typically developing children with mild megalencephaly (2-3 SD above mean) and structurally normal brain on imaging 1
• Autosomal dominant inheritance pattern with frontal bossing, dolichocephaly, and square-shaped face 2
• Normal neurological examination and developmental milestones distinguish this from pathologic causes 2

Skeletal Dysplasias

Achondroplasia is the most common skeletal dysplasia presenting with macrocephaly and frontal bossing:

• Caused by activating mutations in FGFR3 gene 3
• Additional features include disproportionate short stature, trident hands, and exaggerated lumbar lordosis 3
• Associated complications include foramen magnum stenosis, hydrocephalus, and upper airway obstruction 3

Overgrowth Syndromes

Sotos syndrome presents with characteristic macrocephaly and frontal bossing:

• Caused by NSD1 gene mutations or deletions 4
• Pre- and postnatal overgrowth with typical facial gestalt including hypertelorism, antimongoloid slant, prominent jaw, and high narrow palate 4
• Associated with brain anomalies, cardiovascular defects, and increased risk of malignancy 4

Trisomy 1q41-qter syndrome should be considered when frontal bossing occurs with:

• Triangular facies, wide fontanelle, thick eyebrows, down-slanting palpebral fissures 5
• Ventricular dilatation, psychomotor delay, and mental retardation 5

Hydrocephalus and Increased CSF Spaces

• Macrocephaly has multiple causes beyond megalencephaly, including hydrocephalus, ventriculomegaly, and increased skull thickness 1
• Benign enlargement of subarachnoid spaces must be distinguished from subdural collections in trauma cases 6
• Hydrocephalus secondary to aqueductal stenosis, hemorrhage, or neoplasm requires urgent evaluation 6

Megalencephaly with Cortical Malformations

Dysplastic megalencephaly represents a spectrum of brain overgrowth disorders:

• Can be bilateral or unilateral (hemimegalencephaly), with or without cortical malformations 1
• Associated with focal cortical dysplasia type II in some cases 1
• Presents with neurodevelopmental delays and often seizures 1

Diagnostic Approach

Imaging Strategy

• Brain MRI is the gold standard for distinguishing between structural causes of macrocephaly 6
• US is useful in infants with open fontanelles for initial screening 6
• CT should be reserved for emergency situations due to radiation exposure 6

Key Imaging Findings to Identify

• Ventricular size and configuration to assess for hydrocephalus 6
• Cortical architecture to detect malformations of cortical development 1
• Extra-axial fluid spaces to distinguish benign enlargement from pathologic collections 6
• White matter signal abnormalities suggesting metabolic or dysplastic processes 1

Clinical Features to Assess

• Growth parameters: distinguish pre- versus postnatal onset of macrocephaly 4
• Developmental milestones: normal development suggests benign familial macrocephaly 2
• Skeletal proportions: disproportionate short stature points to skeletal dysplasia 3
• Family history: autosomal dominant pattern in benign familial macrocephaly 2
• Associated dysmorphic features: facial gestalt helps identify specific syndromes 4, 5

Critical Pitfalls to Avoid

• Do not assume benign familial macrocephaly without neuroimaging, as serious structural abnormalities can be missed 1
• Distinguish between macrocephaly (large head) and megalencephaly (large brain), as causes differ significantly 1
• Recognize that frontal bossing with macrocephaly warrants genetic evaluation when accompanied by developmental delay or dysmorphic features 4, 5
• Monitor for foramen magnum stenosis in achondroplasia, as this can cause sudden death in infancy 3
• Consider metabolic megalencephaly when white matter signal abnormalities are present on MRI 1