Macrocephaly

Occipitofrontal head circumference above the 97th percentile (or > +2 SD) for age and sex. Distinguish megalencephaly (true brain overgrowth) from macrocephaly caused by something else inside the skull (hydrocephalus, subdural collection, large CSF spaces) or by the bones themselves (thick skull, fontanelles delayed in closing). A growth trajectory crossing percentiles is more concerning than a stable head one or two lines above the curve in a child of macrocephalic parents.

The first split is mechanism inside the head:

1. Brain itself is too big (megalencephaly) → think syndromic and overgrowth disorders, PTEN / PI3K-AKT pathway, leukoencephalopathy, lysosomal storage.
2. CSF or blood is taking up space → hydrocephalus, communicating vs obstructive, posthemorrhagic, syndrome-associated (e.g. L1CAM).
3. Skull bones are thick → osteopetrosis, craniometaphyseal dysplasia (rare).

Then layer on family history: a normal-development child of a parent with a large head is often benign familial macrocephaly, and benign external hydrocephalus is the most common cause overall in infants. But "the dad has a big head" doesn't excuse you from imaging if the trajectory or development is off.

Benign / familial

• Benign familial macrocephaly: the most common cause overall. Normal development, normal exam, head circumference parallels the curve above the 97th percentile, parent with large head. No imaging needed if exam and development are normal.
• Benign enlargement of subarachnoid spaces (BESS) / benign external hydrocephalus: infants with rapidly crossing percentiles in the first year; MRI shows enlarged extra-axial CSF. Almost always resolves by age 2.

Overgrowth syndromes (megalencephaly + somatic overgrowth)

• Sotos syndrome (NSD1): macrocephaly + advanced bone age + dolichocephalic face + learning differences. The classic childhood overgrowth syndrome.
• Weaver syndrome (EZH2): macrocephaly + tall stature + camptodactyly. The closest cousin to Sotos; hypertonia and camptodactyly are the bedside differentiators.
• Beckwith-Wiedemann syndrome (11p15.5 imprinting): macroglossia + omphalocele + hemihypertrophy + neonatal hypoglycemia; macrocephaly is part of the picture.
• Simpson-Golabi-Behmel syndrome (GPC3, X-linked): coarse facies + organomegaly + macrocephaly + Wilms risk.
• Bannayan-Riley-Ruvalcaba syndrome (PTEN): macrocephaly + lipomas + hamartomas + penile pigmented macules.

PTEN / PI3K-AKT-mTOR pathway (megalencephaly +/- somatic overgrowth)

• PTEN hamartoma tumor syndrome: macrocephaly is the most consistent feature. Adult-onset cancer risk (breast, thyroid, endometrium); pediatric features include autism spectrum and macrocephaly. Any child with macrocephaly + autism deserves PTEN testing.
• Megalencephaly-capillary malformation (MCAP) and megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH): mosaic PIK3CA / AKT3 / PIK3R2.

Neurocutaneous

• Neurofibromatosis type 1 (NF1): macrocephaly + café-au-lait spots + axillary/inguinal freckling. Look for the cluster.
• Tuberous sclerosis (TSC1, TSC2): less commonly causes macrocephaly but can.

Leukodystrophies (white matter expansion)

• Canavan disease (ASPA): infantile leukodystrophy, macrocephaly, spongy degeneration on MRI.
• Alexander disease (GFAP): macrocephaly + frontal white matter changes.
• Megalencephalic leukoencephalopathy with subcortical cysts (MLC) (MLC1): macrocephaly + temporal subcortical cysts.

Lysosomal storage (slow brain enlargement)

• Hurler (MPS I), Hunter (MPS II), Sanfilippo (MPS III): macrocephaly is part of the dysostosis multiplex package; coarse facies + organomegaly should be obvious.
• GM1 gangliosidosis, Niemann-Pick A: infantile forms can present with macrocephaly + dysmorphism.

Hydrocephalus (CSF, not parenchyma)

• Posthemorrhagic (former preemie).
• Obstructive: aqueductal stenosis (L1CAM, X-linked: hydrocephalus + adducted thumbs + spastic paraplegia).
• Communicating: post-meningitis, post-hemorrhage.
• Chiari, Dandy-Walker.

Skeletal (thick skull bones)

• Osteopetrosis.
• Craniometaphyseal dysplasia.

1. Plot the trajectory. A macrocephaly that has tracked along its own curve from birth in a child with a macrocephalic parent and normal development gets no imaging.
2. Examine the parents. Measure both. Benign familial macrocephaly is a diagnosis of pattern recognition.
3. MRI brain (preferred over CT, no radiation) if any of: crossing percentiles, abnormal development, abnormal exam, signs of raised ICP. Imaging distinguishes megalencephaly from hydrocephalus from external CSF collections.
4. Genetic testing is targeted by the clinical pattern: PTEN if autism / lipomas / pediatric thyroid; NSD1 if Sotos features; methylation if BWS suspected; chromosomal microarray as a broad first-line. Exome / panel sequencing for the overgrowth spectrum.
5. NF1 evaluation if café-au-lait or other neurocutaneous features.