The prevalence of all forms of microcephaly from birth ranges from 1 in 30,000 to 1 in 250,000 newborns worldwide. The exact prevalence of MCPH is unknown. In Caucasian populations, it is estimated to occur in 1 per 1,000,000 people in the general population. The condition is more common in several specific regions, such as northern Pakistan, where it affects an estimated 1 in 10,000 newborns.

MCPH can result from mutations in at least twelve genes. Mutations in the ASPM gene are the most common cause. The genes associated play an important role in early brain development, especially in determining the size of the brain. Studies suggest that proteins produced from many of these genes help regulate cell division in the developing brain. As a result of the mutations, affected infants have fewer nerve cells (neurons) than normal and are born with an unusually small brain. The reduced brain size underlies the small head size, developmental delays, and intellectual disability seen in many affected individuals.

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell need to have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the altered gene, but do not show signs and symptoms of the condition. Each parent must pass on the altered copy of the gene to their child for the disorder to appear. If only one parent passes on the altered gene, the child would be a carrier for MCPH but not suffer from the disease.

Affected individuals have a reduction in head circumference at birth at least 2 standard deviations below the average size. MCPH can be observed by week 32 of pregnancy. As the affected individual ages, the head grows very slowly. The head circumference may be 3 standard deviations below the average before 6 months of age, and  4 to 12 standard deviations below the average as adults. Mild to moderate, non-progressive intellectual impairment is present if there is no significant neurological disorder.

Seizures may be present in certain individuals, specifically those with a mutation in the ASPM gene. Many affected individuals have hyperactive behavior, problems with keeping attention, delays in early motor milestones (e.g. sitting, standing, walking) and delays in the development of speech.

Most children with MCPH are of normal height and weight. However, some children with specific genetic mutations may be much shorter than average (short stature).

Diagnosis is based on clinical signs. The most common diagnostic criteria is reduced occipitofrontal (head) circumference, mild to moderate intellectual disability, lack of other malformations or differences in body structure, and a normal to mild shortened height. The condition can be diagnosed on prenatal ultrasound (imaging technique that uses high-frequency sound waves to produce images of a fetus in the uterus). However, the absence of microcephaly in the ultrasound does not mean that the infant does not have microcephaly.

Prenatal (before birth) testing is available for families with known gene mutations. Magnetic resonance imaging (MRI) may demonstrate a proportionately small-sized brain without other structural abnormalities, but normal findings do not exclude the diagnosis.

A diagnosis can be confirmed through molecular genetic testing, which can identify a mutation in one of the genes that cause autosomal recessive primary microcephaly.

There is no treatment for autosomal recessive primary microcephaly, but rather treatment for each specific symptom. Therapy is supportive, and involves special education programs tailored to the affected individual’s needs. This can include speech and language therapy, occupational therapy, and behavioral therapy as needed. There are also community services that provide support for families. Seizures are usually responsive to monotherapy (treatment of a disease with a single drug) with standard antiepileptic drugs (AEDs). Individuals with mild growth retardation may consider growth hormones.

Genetic counseling is recommended for families with a child with autosomal recessive primary microcephaly.

Prognosis depends on severity and related manifestations. Generally, with appropriate support, many affected individuals live somewhat near normal lives. Anecdotal reports document survival (without obvious complications) in person older than age 50 years.

Autosomal Recessive Primary Microcephaly. Genetic Home Reference website. http://ghr.nlm.nih.gov/condition/autosomal-recessive-primary-microcephaly. 

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Faheem M, Naseer MI, Rasool M, et al. Molecular genetics of human primary microcephaly: an overview. BMC Med Genomics. 2015;8 Suppl 1:S4.

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