Macrocephaly

Etiology

Macrocephaly describes an enlarged head size without specifying an underlying cause. Before the closure of the fontanelles and sutures in children, any increase in the volume of intracranial contents leads to an increase in head size. Etiologies include increased brain parenchyma (also termed megalencephaly) or increased cerebrospinal fluid (CSF). Additional causes include increased intracranial blood volume, thickened cranial bone, or elevated intracranial pressure from other mechanisms.

Megalencephaly

Megalencephaly may be anatomic or metabolic. Anatomic megalencephaly involves an increase in the size or number of brain cells without an associated metabolic disease, and most often follows a familial and benign pattern. Affected patients frequently present at birth with a large head and a normal-sized body, followed by rapid head growth during the first 6 months of life, with head circumference increasing by 0.6 to 1 cm per week rather than the average 0.4 cm per week. Familial megalencephaly typically results in mild macrocephaly, measuring 2 to 4 cm above the 90th percentile, with a growth curve that remains above but parallel to the 98th percentile. Family members commonly share larger-than-average head sizes.[3]

Other causes of anatomic megalencephaly vary widely and often involve genetic factors.[4] Neurocutaneous disorders, including tuberous sclerosis, neurofibromatosis, and hypomelanosis of Ito, may present with megalencephaly. Patients with autism spectrum disorder may demonstrate macrocephaly or megalencephaly, and achondroplasia may present with megalencephaly or hydrocephalus. Sotos syndrome, also referred to as cerebral gigantism, represents another cause of megalencephaly. Associated features include frontal bossing, a high forehead, a high-arched palate, intellectual disability or developmental delay, hypertelorism, and a prominent jaw or pointed chin. Most cases arise from sporadic mutations of the NSD1 gene. 

Metabolic megalencephaly involves enlargement of the brain parenchyma due to the accumulation of metabolic products within neural tissue. Conditions include leukodystrophies, eg, Alexander disease, lysosomal storage disorders, eg, Tay-Sachs disease, and organic acid disorders. Affected patients often present with a normal head circumference at birth followed by growth that exceeds the expected trajectory.[5]

Genetic Etiologies

Fragile X syndrome commonly presents with macrocephaly, intellectual disability, prominent ears and jaw, and macroorchidism, with many features becoming more apparent after puberty. The condition most frequently results from a CGG trinucleotide repeat expansion in the FMR1 gene located on the X chromosome. Nevoid basal cell carcinoma syndrome, also known as Gorlin syndrome, confers a predisposition to basal cell carcinomas and commonly presents with macrocephaly and coarse facial features. Mutations in the PTCH1 gene cause this autosomal dominant disorder.

Cowden syndrome also predisposes affected individuals to certain malignancies, including thyroid and breast cancers, and may present with macrocephaly. Mutations in the PTEN gene underlie this autosomal dominant condition. Many patients with macrocephaly harbor pathogenic genetic mutations, including those in the PPP2R5D gene.[6] Genetic disorders often demonstrate variable penetrance and expressivity, resulting in a broad spectrum of clinical manifestations.

Metabolic megalencephaly involves enlargement of the brain parenchyma due to the accumulation of metabolic products within neural tissue. Conditions include leukodystrophies, eg, Alexander disease, lysosomal storage disorders, eg, Tay-Sachs disease, and organic acid disorders. Affected patients often present with a normal head circumference at birth followed by growth that exceeds the expected trajectory.[5]

Increased Intracranial Fluid

Macrocephaly may also result from increased cerebrospinal fluid (CSF) volume. In hydrocephalus, the ventricular system contains excessive CSF, leading to ventricular dilatation and elevated intracranial pressure. Mechanisms include increased CSF production, impaired absorption, or obstruction of CSF flow. Clinical manifestations of elevated intracranial pressure include lethargy, irritability, developmental delay, nausea or vomiting, and restricted upgaze. Head enlargement may occur while cranial sutures and fontanelles remain open; loss of this compensatory capacity often necessitates surgical intervention, including placement of a ventriculoperitoneal shunt.

Elevated intracranial pressure may also result from space-occupying lesions within the cranial vault. Benign enlargement of the subarachnoid spaces represents another common CSF-related cause of macrocephaly, typically presenting within the first 6 months of life and occurring more frequently in boys than in girls. Neuroimaging demonstrates enlargement of the anterior subarachnoid spaces, distinguishing this entity from the symmetric anterior-to-posterior fluid collections associated with cerebral atrophy. Infants with this condition, particularly those born at term, typically show normal development and normal neurologic examination findings. Despite this, an increased risk of subdural hemorrhage exists even after minimal or absent trauma. Similar neuroimaging findings in infants with histories of complicated neonatal intensive care unit courses or early extracorporeal membrane oxygenation may represent a distinct subgroup associated with poorer neurologic and developmental outcomes.

Increased intracranial blood volume also contributes to enlarged head size and may result from hemorrhage or arteriovenous malformations. Hemorrhage may arise from nonaccidental trauma, prompting evaluation of social history and environmental factors. Physical examination findings may include additional injuries or retinal hemorrhages. Presentations involving intracranial hemorrhage related to nonaccidental trauma commonly include seizures, nausea or vomiting, lethargy, or irritability.

Bone Thickening

An increase in skull volume represents another cause of macrocephaly. Bone thickening may result from bone marrow expansion, as seen in thalassemia major, or from skeletal or cranial dysplasias.[7]

Epidemiology

By definition, macrocephaly is found in about 2% to 3% of the population. Large registries have reported a prevalence at birth of 18.1 per 10,000 births.[8] Although fetal growth curves are not sex-specific, in studies, male fetuses have been found to have larger head circumferences on average than females, differing by 0.3 to 0.5 standard deviations. Therefore, differing growth patterns may potentially affect the classification of microcephaly or macrocephaly, leading to underdiagnosis or overdiagnosis depending on gender.[9][1] The specifics of epidemiology, including geographic distribution, depend on the particular underlying cause. 

Pathophysiology

The pathogenesis of macrocephaly is etiology-specific, as it can result from overgrowth of the skull bones or an increase in the volume of intracranial structures, eg, CSF, blood, or brain parenchyma. Please refer to the Etiology section for more information on causes associated with macrocephaly.

History and Physical

Identification of macrocephaly requires the use of a standardized head measurement technique. Measurement involves wrapping a flexible tape around the head, positioning the tape just above the eyebrows anteriorly and over the most prominent portion of the occiput posteriorly. This measurement, known as the OFC, is plotted on the 2006 WHO international growth charts for children younger than 24 months, by age and sex, to determine the percentile rank. A head circumference at or above the 97th percentile meets criteria for macrocephaly.[10]

Evaluation of macrocephaly requires a detailed clinical history focused on birth measurements, head growth trajectory, associated medical conditions, developmental progress, and family history of macrocephaly. Particular attention should focus on prior central nervous system trauma or infection. A history of neonatal meningitis or intraventricular hemorrhage raises concern for secondary hydrocephalus and warrants close longitudinal follow-up.[11]

Physical examination, in addition to head circumference measurement and fontanelle palpation, should include assessment of overall appearance, facial features, skin findings, and a comprehensive neurologic examination to identify features suggestive of an underlying etiology or genetic syndrome. Ophthalmologic evaluation remains important, as elevated intracranial pressure may cause papilledema, although this finding may be absent in infants with open fontanelles. Additional focused examination techniques include transillumination of the calvaria, evaluation for skeletal dysplasia, and auscultation for a cranial bruit.

Evaluation

Clinical history, physical examination, and selective use of neuroimaging and genetic testing each contribute to the comprehensive evaluation of patients with macrocephaly.[2] When a patient demonstrates age-appropriate development, a neurologic examination with normal findings, no dysmorphic features suggestive of a genetic syndrome, and no family history of developmental or neurologic disorders, assessment with Weaver curves using parental head circumferences may guide interpretation. Findings within the normal range, when plotted on these curves, provide reassurance without the need for further diagnostic evaluation.[12]

Additional assessment becomes appropriate when head circumference measurements exceed the 97th percentile on standardized growth charts. Further evaluation is also warranted when serial measurements cross 1 or more major percentile lines, indicating head growth that exceeds expected velocity, or when patients younger than 6 months experience an increase in head circumference of greater than 2 cm within 1 month.

Neuroimaging plays an important role in identifying the underlying causes of macrocephaly and should follow a systematic diagnostic approach.[13] An open anterior fontanelle allows head ultrasound to serve as a simple and cost-effective initial modality for detecting intracranial abnormalities. Computed tomography offers rapid assessment but exposes infants to ionizing radiation, limiting use to situations requiring urgent information. Magnetic resonance imaging provides superior structural detail without radiation exposure, though its higher cost and the need for sedation often restrict its use.[14][15] Neuroimaging findings in benign macrocephaly commonly include dilatation of the subarachnoid spaces, with possible mild ventricular enlargement or prominence of the basilar cisterns.[16]

Treatment / Management

Management of macrocephaly depends on the underlying etiology. Presence of hydrocephalus warrants referral to neurosurgery for consideration of surgical intervention. Children with hydrocephalus accompanied by symptoms of increased ICP may require urgent neurosurgical treatment, which can prove lifesaving. Prenatal diagnosis of hydrocephalus or macrocephaly occurs in many cases.[13] Reduction of CSF volume and associated intracranial pressure may be achieved through placement of an extraventricular drain or a ventriculoperitoneal shunt.(A1)

Cases without hydrocephalus may require referral to genetics, developmental pediatrics, or pediatric neurology for further evaluation and management. Macrocephalic children with epilepsy often require treatment with antiepileptic medications. Benign familial macrocephaly generally requires no intervention beyond serial head circumference monitoring and caregiver reassurance.

Differential Diagnosis

Evaluation of an infant with macrocephaly requires careful differentiation between isolated macrocephaly and other abnormal head shapes. Plagiocephaly describes flattening of 1 region of the skull and commonly occurs in infants with a history of prolonged head positioning in a single orientation.

Craniosynostosis arises from premature fusion of cranial sutures and leads to characteristic abnormalities in skull shape. Brachycephaly results from early closure of the coronal suture and presents with a widened skull and recessed forehead. Trigonocephaly develops from the premature fusion of the metopic suture, producing a triangular-shaped forehead. Scaphocephaly occurs following early closure of the sagittal suture and presents with anterior–posterior elongation of the skull, accompanied by bitemporal narrowing.

Additional congenital skull deformities may result from traumatic forces or mechanical constraints affecting the head during intrauterine development. Such forces include multiple gestation, abnormal fetal positioning, and oligohydramnios.

Prognosis

The prognosis for macrocephaly depends on the underlying cause. When presented with an infant with otherwise normal growth and development and a normal neurologic exam, macrocephaly, by itself, is often benign, and neurodevelopmental outcomes are good.[17][18] In these cases, enlargement of the subarachnoid space may be seen on imaging. This may still be present during long-term follow-up, but no intervention is needed.[19]

Complications

Benign familial macrocephaly is not associated with any complications. However, macrocephaly due to hydrocephalus can have serious complications, including death, if not promptly treated. Other complications associated with macrocephaly are seizures, developmental disabilities, and neurologic deficits.