What Causes Macrocephaly?

Patient Presentation
A 4-month-old male came to clinic for his health maintenance visit. His parents had no concerns. He was smiling, rolling over, cooing and interacting with people. He was exclusively breastfed. The past medical history showed a full-term infant born without complications around the 50% for weight and length but larger for head circumference (= 36 cm, 85%). The family history was positive for a 3 year old sister with a larger head but no records were available.

The pertinent physical exam showed a happy infant with weight 7.795 kg (75-90%), length 64.5 cm (75%) and head circumference was 44.5 cm (>90%) using World Health Organization growth charts. At 2 months his head circumference had been 40.5 cm (75-90%) for a growth velocity of 2 cm/month for the previous 2 months. His anterior fontanel was 1 cm and flat, and he had no plagiocephaly. Cranial nerves were normal with good tone and strength. He had no head lag. Deep tendon reflexes were +2/+2. The rest of his physical examination was normal.

The diagnosis of a healthy infant with an enlarging head but normal physical examination and development was made. His father’s head circumference was 60 cm (>90%) and his mother’s was 58 cm (>90%). The diagnosis of presumed familial megalencephaly was made with this information. The family was given tape measures and shown how to measure the infant’s head. They did this weekly over the next 6 weeks and the growth velocity was ~0.25 cm/week. Re-evaluation at 6 months of age again showed a healthy male infant with normal development and a head circumference of 46.5 cm (90%). At 9 months of age his head circumference was 47.5 (again 90%) and he continued to be physically and developmentally normal.

“Macrocephaly is defined as [an occipitofrontal circumference or head circumference, OFC ] of > 2 standard deviations above the mean or above the 97th percentage for a given age, and gender, or when serial measurement shows progressive enlargement, crossing of one or more major percentiles, or when there is an increase in OFC > 2 cm/month in the first 6 months of life.” Megalencephaly is enlargement of the brain parenchyma. The OFC should be measured using a non-elastic tape which surrounds the head along the line of the glabella and posterior occipital protrusion.

There are ethnic differences for head circumferences so the growth chart that best matches the child’s family heritage should be used. A review of the best growth charts can be found here.

General averages for OFC increase are:

  • Average at birth = ~35 cm
  • 0-3 months = 2 cm/month (average 3 month old is ~ 41 cm)
  • 0-1 year = 1 cm/month (average 1 year old is ~ 47 cm)
  • > 1 year = only another 8 cm total (average adult is ~ 55 cm)

A review of the other growth parameters can be found here.

Patients should be evaluated for developmental delay, signs of intracranial infection or trauma, syndromic features, and family history of cutaneous or neurological abnormalities. Children with non-full fontanels, normal mentation and no signs of developmental delay are more likely to have familial, isolated or benign enlargement of the subarachnoid space. Changes in mentation, developmental delay and full fontanels are more likely to have a serious cause of hydrocephalus.

More evaluation may be necessary if abnormalities are found on history and physical exam and should guide that evaluation such as cranial ultrasound or other imaging depending on age and circumstances, bone radiographs, or metabolic evaluation (e.g. Vitamin D level).

Learning Point
The differential diagnosis of macrocephaly includes:

  • Brain parenchyma enlargement
    • Familial/genetic – parents/family also with macrocephaly in an otherwise normal child (63.3%)
    • Isolated – parents and family without macrocephaly in an otherwise normal child (20%)
    • Genetic
      • Autism spectrum disorder (1.1%)
      • Bone dysplasia – achrondroplasia (1.1%), hypochrondroplasia(1.1%)
      • Fragile X – OFC may be enlarged but may not be > 2 standard deviations
      • Neurocutaneous disorders – neurofibromatosis, tuberous sclerosis
      • Overgrowth disorders
    • Metabolic diseases
      • Gangiosidosis
      • Leukodystrophies
      • Rickets (1.1%)
  • Increased cerebrospinal fluid
    • Benign enlargement of the subarachnoid space (BESS or benign external hydrocephalus) (2.2%)
    • Choroid plexus cyst (1.1%)
    • Hydrocephalus – obstructive or communicating (8.9%)
  • Increased blood
    • Subdural hematoma
    • Arteriovenous malformation
  • Increased intracranial pressure
    • Pseudotumor cerebri
    • Infection
    • Inflammation
    • Vitamin A deficiency or excess
  • Bone enlargement
    • Thalassemia
    • Bone dysplasia
  • Masses
    • Brain tumor
    • Arteriovenous malformation

Note: Number in parentheses is from a 2018 study of 90 Turkish children in a well child clinic. Many other studies are from referral clinics such as neurology, neurosurgery or developmental disabilities which will cite different numbers that correspond to their referral population.

Questions for Further Discussion
1. What are the causes of microcephaly? A review can be found here.

2. What are causes of a bulging anterior fontanel? A review can be found here.

3. When do the fontanels normally close? here A review can be found here.

Related Cases

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at SearchingPediatrics.com and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for this topic: Brain Malformations

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

To view videos related to this topic check YouTube Videos.

Tucker J, Choudhary AK, Piatt J. Macrocephaly in infancy: benign enlargement of the subarachnoid spaces and subdural collections. J Neurosurg Pediatr. 2016 Jul;18(1):16-20.

Kurata H, Shirai K, Saito Y, Okazaki T, Ohno K, Oguri M, Adachi K, Nanba E, Maegaki Y. Neurodevelopmental disorders in children with macrocephaly: A prevalence study and PTEN gene analysis. Brain Dev. 2018 Jan;40(1):36-41.

Yilmazbas P, Gokcay G, Eren T, Karapınar E, Kural B. Macrocephaly diagnosed during well child visits. Pediatr Int. 2018 May;60(5):474-477.

Boom JA. Macrocephaly in infants and children: Etiology and evaluation. UpToDate. (rev. 12/8/2017, cited 2/4/2019).

Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa