What Causes Microcephaly?

Patient Presentation
A 5-month-old male came to clinic for his health supervision visit and followup from his neonatal intensive care stay. He was born prematurely at 28 weeks gestation and his stay was complicated by a right sided Grade III intraventricular hemorrhage, a left-sided Grade IV intraventricular hemorrhage, neonatal seizures, respiratory distress and bronchopulmonary dysplasia, retinopathy of prematurity, acute kidney injury that had resolved, possible necrotizing enterocolitis incidents x 2, and herpes simplex encephalitis. He was on home oxygen, a nasogastric feeding tube because of aspiration risk and multiple medications. He was taken care of by his mother, maternal grandmother and home nursing. He was to start home physical therapy, and had multiple followup appointments for specialty care already arranged.

The pertinent physical exam showed a small infant with a nasal canula and feeding tube in place. Weight (= 4.116 kg) and height (=54 cm) were at the 3th percentile and tracking. Head circumference was < 3% and was 36 week gestation (=33 cm). Premature infant standard growth charts were used. He had a small head and was not responsive to the examiner but was to the mother's voice. Extraoccular movements and pupillary reflexes were intact. He was hypotonic but when he became agitated would have increased tone and rigidity. He had several beats of clonus.

The diagnosis of a former premature infant with multiple significant medical problems was made including microcephaly. The physician reviewed the overall care plan with the mother including addressing needs for transportation, medical supplies and respite care. The infant’s next health supervision visit for vaccines including influenza was coordinated with a specialty appointment.

Microcephaly is usually defined as an occipitofrontal head circumference (OFC) more than 2 standard deviations (SD) below the mean for sex, age and ethnicity. Severe microcephaly is used for OFC < 3 standard deviations. Rates of microcephaly range from 0.5-12 patients/10,000 live births.

The OFC should be measured at every well child visit and at other opportunities and plotted on standard growth charts. The OFC is measured using a nonelastic tape measure around the largest part of the head with the tape measure held above the eyebrows and ears. It is a highly reproducible measurement. There are several different international standard growth charts that can be used and those used should reflect the population the patient is drawn from the best. For example, the World Health Organization has growth charts taken from the children in the countries of Brazil, Ghana, India, Oman and the USA (www.who.int/childgrowth/en). In industrialized countries the OFC is larger and may not be as accurately reflected using the WHO chart. Some researchers prefer the Centers for Disease Control growth charts as an industrialized country standard (www.cdc.gov/growthcharts/)

While the OFC reflects the skull size and growth over time, the main determinant of normal growth of the skull is the brain and therefore, the OFC is considered a marker of brain growth. However, the extent of the microcephaly does not significantly correlate with the degree of developmental delay.

There are different categorizations of microcephaly, but the authors of the largest study of microcephaly recommend using primary or secondary (i.e. noted at birth or after birth respectively) as this helps with timing of microcephaly onset and therefore possible underlying causes. Proportional (i.e. weight and height are also 2 SD below their means) vs disproportional (i.e. weight and height are 2 SD or more above their means) also helps with diagnostic reasoning and evaluation.

The phenotype of patients with microcephaly is variable and often reflects the underlying diagnosis and concomitant organ systems that are affected. Intellectual delay or disability is the most common problem associated with microcephaly but other problems do occur.

Learning Point
The differential diagnosis of microcephaly is heterogeneous and many causes are not identified. In the largest study of microcephaly (N=680), where causes could be identified, 38% were primary and 62% were secondary. More patients were male and the majority of children were identified with microcephaly by 7-8 months of age.

  • Known cause = 59%
    • Genetic 28.5%
    • Perinatal brain injury 26.7%
    • Craniosynostosis 2.1%
    • Post natal brain injury 1.9%
  • Unknown cause = 40.7

In Brazil in March 2015, Zika virus became identified as a likely cause of primary microcephaly and an emerging, urgent public health concern, although the virus was identified in 1947.

The differential diagnosis of microcephaly includes:

  • Craniosynostosis
  • Genetic
    • Chromosomal problems
      • Trisomy 13, 18, 21
      • Williams syndrome
    • Monogenetic problems (including named and unnamed syndromes/mutations)
      • Autosomal dominant microcephaly
      • Autosomal recessive microcephaly
      • X-chromosomal microcephaly
      • Aicardi-Goutrieres syndrome
      • Ataxia-telangectasis
      • Borgeson-Forssman-Lahman syndrome
      • Cockayne syndrome
      • Cohen syndrome
      • Cornelia de Lange syndrome
      • Ligase IV syndrome
      • Marden syndrome
      • Mowat-Wilson syndrome
      • Feingold Syndrome
      • Rett Syndrome
      • Rubeinstein-Taybi syndrome
      • Smith-Lemli-Opitz syndrome
      • Seckel syndrome
      • Various other gene mutations
    • Imprinting disorders
      • Angleman syndrome
  • Infections (intrauterine, peri- or post-natal)
    • Encephalitis
    • Meningitis
    • Cytomegalovirus
    • Herpes simplex
    • HIV
    • Rubella
    • Syphilis
    • Toxoplasmosis
    • Varicella
    • Zika virus
  • Intrauterine event or problem
    • Death of twin
    • Placental insufficiency – extreme
    • Vascular incident such as stroke
  • Maternal disease
    • Anorexia nervosa
    • Hyperphenylalanenaemia
  • Metabolic causes
    • Cobalamin metabolism diorders
    • Galactosemia
    • Glycine encephalopathy
    • Glycose transporter defect
    • Glycosylation syndome
    • Leukodystrophies
    • Lysosomal storage disorders
    • Menkes disease
    • Mitochrondrial disorders
      • Pyruvate dehydraogenase deficiency
    • Molybdenum cofactor deficiency and sulphite oxidase deficiency
    • Neuronal ceroid-lipofuscinosis
    • Organic aciduria
    • Peroxisomal disorders
    • Phenylkeonuria
    • Purine and pyramidiaine metabolism disorders
    • Serine biosynthesis disorder
    • Sterol biosynthesis disorder
    • Urea cycle defects
  • Perinatal brain damage
    • Hypoxic-ischemic encephalopathy
    • Vascular event – hemorrhage or thrombosis
  • Structural brain abnormalities
    • Anencephaly
    • Holoprosencephaly
  • Teratogens
    • Alcohol
    • Antiepileptic drugs
    • Cocaine
    • Lead
    • Mercury
    • Radiation
    • Uremia
  • Trauma
    • Accident
    • Child maltreatment
    • Psychosocial deprivation
  • Other
    • Malnutrition
      • B12 deficiency
    • Systemic disorders
      • Congenital heart disease
      • Hypothyroidism
      • Hypopituitarism

Note that many of other disorders may have a genetic cause

Questions for Further Discussion
1. What are potential treatments to help children with microcephaly?
2. What are indications for radiographic imaging for microcephaly and which modalities are best used?

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, the National Guideline Clearinghouse and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for these topics: Brain Malformations, Zika Virus, and Developmental Disabilities.

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.

von der Hagen M, Pivarcsi M, Liebe J, et.al. Diagnostic approach to microcephaly in childhood: a two-center study and review of the literature. Dev Med Child Neurol. 2014 Aug;56(8):732-41.

Harris SR. Measuring head circumference: Update on infant microcephaly. Can Fam Physician. 2015 Aug;61(8):680-4.

White MK, Wollebo HS, David Beckham J, Tyler KL, Khalili K. Zika virus: An emergent neuropathological agent. Ann Neurol. 2016 Oct;80(4):479-89.

Hansen M, Armstrong PK, Bower C, Baynam GS. Prevalence of microcephaly in an Australian population-based birth defects register, 1980-2015. Med J Aust. 2017 May 1;206(8):351-356.

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