Nicole J. Ullrich
APPROACH AND DIFFERENTIAL DIAGNOSIS
Normal head growth is affected by the growth and alteration of structures within the cranium (brain, blood, cerebrospinal fluid, and bone) and the timing of these changes in relation to closure of the fontanels. Standards have been determined for head growth in healthy children up to 18 years of age, and the Centers for Disease Control and Prevention has constructed revised standard head circumference for age, based on national survey data from the general US population.1 In addition, special adjusted growth curves have been developed for children with specific underlying medical conditions, such as neurofibromatosis type 1.2
Deviations from normal head growth may be the first indication of an underlying congenital, genetic, or acquired problem. Because of the rapid pace of neuronal and glial cell proliferation and the relative restriction in time during development, it is understandable that an appropriately timed insult could result in profound effects on the number of neurons that result.3 For example, insults that are sustained before embryonic day 40, when the number of neurons is increasing exponentially, would be expected to have a larger impact than those that occur after day 40, when post-mitotic neurons have already been formed. A number of disorders exist that presumably represent excessive or deficient production of neurons and glia.
Macrocephaly typically refers to a head circumference that is greater than two standard deviations above the mean and can be caused by an increase in size of any of the intracranial contents (brain, cerebrospinal fluid, blood or bone). Megalencephaly refers to an abnormally large and heavy brain. Macrocephaly can be classified as anatomic or metabolic, distinguishing increases in head size resulting from an increase in the size or number of brain cells from increases in head size that result from the deposition and subsequent accumulation of metabolic products, without a concomitant increase in the number of cells. A large brain that results from cerebral edema or neoplasia is not classified as megalencephaly.
Familial macrocephaly is the most common type of anatomic macrocephaly, and refers to an autosomal dominantly inherited increased head size associated with normal somatic size, development, and neurologic examination.4,5The next most common etiology for anatomic macrocephaly is increased intracranial pressure with hydrocephalus (see Chapter 553). Macrocephaly may also be associated with a variety of cutaneous or systemic anomalies, such as neurofibromatosis, tuberous sclerosis, linear sebaceous nevus syndrome, and hypomelanosis of Ito.6,7 Lastly, macrocephaly may also be associated with abnormalities of somatic size, such as cerebral gigantism (Sotos syndrome)8,9and Beckwith-Wiedemann syndrome.10
Although most metabolic disorders result in decreased head size, several metabolic disorders are characterized by progressive macrocephaly.11 Examples include aminoaciduria and leukodystrophies, such as Alexander disease,12Canavan disease,13 and lysosomal storage disorders (Tay-Sachs, mucopolysaccharidosis and gangliosidosis).14
Microcephaly, by contrast, refers to a head circumference that is greater than two standard deviations below the mean for age and gender-based norms.15 Except in cases of craniosynostosis, microcephaly always implies microencephaly, or an abnormally small brain. The microcephalic brain may be small but otherwise well formed architecturally; in other cases, malformations or destructive lesions may be present with symmetrically or asymmetrically dilated ventricles.16 Microcephaly is classified as “primary” when resulting from a developmental aberration or insult early in neurogenesis and/or neuronal migration, resulting in an overall decrease in the number or size of proliferative units. Figure 550-1 illustrates lissencephaly in a young child who had microcephaly and seizures. “Secondary” microcephaly results from injury or insult to a previously normal brain. The presence of microcephaly alone does not provide a specific clue as to the underlying etiology.
Autosomal recessive, X-linked recessive, and autosomal dominant patterns of inheritance have been described in primary microcephaly, including several familial patterns associated with ocular disorders; however, there is often no identifiable pattern of inheritance.17 The autosomal dominant type of microcephaly is thought to be less severe, with relatively normal intelligence or mild mental retardation. By contrast, children with autosomal recessive forms may have moderate to severe mental retardation. Primary microcephaly is also a feature of some chromosomal disorders (trisomies, deletions, and translocations), neurocutaneous disorders (incontinentia pigmenti), neural tube defects, and disorders of cerebral cleavage and migration.
FIGURE 550-1. Head CT of a 12-year-old boy with a history of lissencephaly, characterized by the absence of normal sulcation in the cerebral cortex and accompanying microcephaly. Symptoms may include abnormal facies, failure to thrive, seizures, and severe developmental delay. Lissencephaly can be observed in association with other genetic diseases or in isolation.
FIGURE 550-2. World Health Organization Growth Charts for Head Circumference for head circumference and Z-scores in (A) girls and (B) boys. These and additional charts showing head circumference growth by percentiles, and in more detail for growth from birth to 13 weeks are available at: http://www.who.int/childgrowth/standards/chts_hcfa_girls_z/en/index.html (accessed Sept. 19, 2010). United States Center for Disease Control head circumference growth charts are available at: http://www.cdc.gov/growthcharts/cdc_charts.htm (accessed Sept. 19, 2010)
Secondary microcephaly typically results from an insult that occurs during the last part of the third trimester or during the perinatal or early postnatal period. Several environmental factors have been implicated, including irradiation, congenital/intrauterine infections,18 in utero toxin exposures (alcohol, substance use,19 anticonvulsant medications,20 organic substances), hypoxic-ischemic insults, placental insufficiency, intraventricular hemorrhage or stroke,21 untreated maternal phenylketonuria,22 or systemic disease. The degree of mental retardation is thought to correlate directly with the severity of microcephaly.23
EVALUATION AND WORKUP OF ABNORMAL HEAD SIZE
The evaluation for abnormal head size should be prompted by one head circumference measurement that is two standard deviations above or below the norm for age and gender, or when serial measurements reveal progressive changes on standard charts. A detailed medical history is important, including birth, prenatal, and developmental history, as this may elicit predisposing factors, such as maternal infection, substance use, maternal medical history and medication use, and perinatal complications. This may also help determine the time of onset. In addition, family history may reveal the occurrence of underlying neurocutaneous disorders or metabolic abnormalities. Physical examination includes measurement of head circumference and comparison to prior measurements, evaluation of the anterior fontanel, evaluation for hypo- or hyperpigmented lesions (aided by the use of a Wood’s lamp), evaluation for dysmorphic features, organomegaly (indicative of storage disease), and cataracts or retinal abnormalities. Neurologic evaluation is important to evaluate for accompanying developmental, neuromuscular, or accompanying reflex abnormalities. The head circumference should be plotted on a standard curve and compared to prior measurements to help distinguish acute onset from a more insidious development (Fig. 550-2). CDC head circumference growth charts for boys and girls are available at: http://www.cdc. gov/growthcharts/charts.htm (accessed Sept. 19, 2010). WHO head circumference growth tables are available at: http://www.cdc.gov/growthcharts/who_charts.htm. The standard scores for the child and parents should be plotted to determine any genetic contribution to the macrocephaly, such as benign familial macrocephaly. It is important to recognize this syndrome in order to avoid potential costly and unnecessary evaluations.
Diagnostic testing should be considered if abnormal development is noted or with plateau or loss of developmental milestones. Imaging studies may include ultrasound or magnetic resonance imaging of the brain to delineate structural or migrational abnormalities.24,25 Additional vascular studies or plain radiographs may be indicated to evaluate possible skeletal disturbance or growth abnormalities. Laboratory and metabolic investigations should be guided by the history and physical examination. For example, children with loss of developmental milestones may require metabolic evaluation, chromosomal studies, or an electroencephalogram. Evaluation of urine or blood samples for amino- and organic acidurias and/or evaluation for congenital infection may be indicated. Subsequent therapy for macrocephaly or microcephaly depends on the underlying etiology.