Key Points
Microcephaly is characterized by a smaller than normal head circumference. A head circumference measurement of 3 SD below the mean gives a clinically meaningful definition because it has been associated with mental retardation.
Microcephaly has been associated with a number of genetic, infectious, and environmental exposures.
Detailed ultrasound examination to exclude other anomalies is necessary.
A careful history is needed when this diagnosis is suspected. Likewise, the head circumferences of the parents should be measured.
Little information is known about the antenatal natural history of microcephaly, especially during the first and second trimesters.
The diagnosis of microcephaly should not alter obstetric management.
Newborns with microcephaly require an extensive work-up to determine the etiology of the condition.
The long-term prognosis and recurrence risk for microcephaly is related to its underlying cause.
Microcephaly is characterized by a smaller-than-normal head circumference (Figures 20-1 and 20-2). The clinical significance of microcephaly is its association with a small brain— microencephaly. A difference of opinion exists as to whether the lower limit of a normal head circumference should be defined as 2 or 3 SD below the mean (Avery et al., 1972). When a head circumference of 2 SD below the mean is used to define microcephaly, the association with mental retardation is inconsistent. Using such a definition, 2.5% of the general population would be considered microcephalic, and therefore a large number of infants with normal intellectual function would be included (Martin, 1970; Sells, 1977). A head circumference measurement of 3 SD below the mean gives a more clinically meaningful definition of microcephaly, as the correlation of this measurement with mental retardation is stronger (Davies and Kirman, 1962; Warkany et al., 1981).
The most affected part of the brain in microcephaly is the forebrain, and there is frequently associated macrogyria, pachygyria, and basal ganglia atrophy (Davies and Kirman, 1962).
Microcephaly is caused by diverse genetic and environmental factors that disturb brain growth in prenatal and early postnatal life (Warkany et al., 1981). The proportion of cases of microcephaly due to genetic causes has been estimated at 20% to 33% (Van den Bosch, 1959; Cowie, 1987). However, much of the data on which such estimates are based relate to patients born before recent advances in syndrome diagnosis and genetics.
The classification of microcephaly has generally reflected a distinction between genetic and acquired causes (Table 20-1). The term primary, or true, microcephaly has been used when the condition is isolated and is due to an arrest of brain development. The term secondary microcephaly has been applied to acquired insults to the brain. Microcephaly may also be classified based on the presence or absence of associated malformations.
| Microcephaly with Associated Malformations | Microcephaly Without Associated Malformations | |
| Genetic | Genetic | |
| Chromosomal abnormalities | Primary microcephaly | |
| Trisomy 21 | Alpers syndrome | |
| Trisomy 13 | Paine syndrome | |
| Trisomy 18 | Inborn errors of metabolism | |
| Trisomy 22 | Disorders of folic acid metabolism | |
| 4p– | Hyperlysinemia | |
| 5p– | Methylmalonic acidemia | |
| 18p– | Phenylketonuria | |
| 18q– | ||
| Single gene defects | Mode of inheritance | |
| Angelman syndrome | Deletion 15q | |
| Bloom syndrome | Autosomal recessive | |
| Borjeson–Forssman–Lehmann syndrome | Sex–linked recessive | |
| Cockayne syndrome | Autosomal recessive | |
| Coffin–Siris syndrome | Autosomal recessive | |
| DeLange syndrome | Autosomal dominant | |
| DeSanctis–Cacchione syndrome | Autosomal recessive | |
| Dubowitz syndrome | Autosomal recessive | |
| Fanconi pancytopenia | Autosomal recessive | |
| Focal dermal hypoplasia | X–linked dominant | |
| Incontinentia pigmenti | X–linked dominant | |
| Johanson–Blizzard syndrome | Autosomal recessive | |
| Langer–Giedion syndrome | Deletion 8q | |
| Lissencephaly syndrome | Autosomal recessive | |
| Meckel–Gruber syndrome | Autosomal recessive | |
| Menkes syndrome | Sex–linked recessive | |
| Roberts syndrome | Autosomal recessive | |
| Rubinstein–Taybi syndrome | Autosomal dominant/new mutation | |
| Seckel bird–headed dwarfism | Autosomal recessive | |
| Smith–Lemli–Opitz syndrome | Autosomal recessive | |
| Williams syndrome | Elastin mutation | |
| Environmental | Environmental | |
| Prenatal exposure to infections | Prenatal exposure to radiation | |
| Rubella syndrome | Fetal malnutrition | |
| Cytomegalovirus disease | Perinatal trauma or hypoxia | |
| Herpes virus | Postnatal infections | |
| Toxoplasmosis | ||
| Varicella zoster | ||
| Prenatal exposure to drugs or chemicals | ||
| Fetal alcohol syndrome | ||
| Fetal hydantoin syndrome | ||
| Vitamin A or vitamin A analog | ||
| Aminopterin syndrome | ||
| Cocaine exposure | ||
| Methylmercury exposure | ||
| Solvent exposure: toluene, gasoline | ||
| Carbon monoxide poisoning | ||
| Irradiation | ||
| Maternal phenylketonuria |
Determination of the precise cause of microcephaly is difficult. The diagnosis of isolated developmental microcephaly is usually one of exclusion, with other causes of microcephaly having been ruled out (Hunter, 1993).
The overall incidence of microcephaly was 1.6 in 1000 livebirths in the U.S. Collaborative Perinatal Project, in which infants were observed throughout the first year of life. The incidence in whites was found to be 1.3 in 1000 livebirths and in blacks, 1.9 in 1000 livebirths (Myrianthopoulos and Chung, 1974). Estimates of the frequency of developmental microcephaly vary, depending on the population studied, ranging from 1 in 25,000 to 1 in 250,000 (Book et al., 1953; Van Den Bosch, 1959). The frequency of microcephaly from all causes in the Netherlands was estimated to be 1 in 93,000 (Van den Bosch, 1959). The variation in quoted incidence rates probably reflects different levels of ascertainment in different populations, as many studies do not include stillbirths or spontaneous losses.
The diagnosis of microcephaly should be considered when the fetal head circumference is 3 SD below the mean for gestational age. A detailed fetal sonographic evaluation for associated anomalies should be performed in all cases of suspected microcephaly.
The use of head circumference rather than biparietal diameter (BPD) is more appropriate in the diagnosis of microcephaly. The BPD can be inaccurate if the fetus is breech and in conditions that cause intrauterine molding, such as oligohydramnios and multiple gestation. By contrast, the fetal head circumference should not be affected by molding. One series found that a BPD smaller than 3 SD below the mean was associated with a normal outcome in 44% of cases (Chervenak et al., 1984). This high incidence of falsely abnormal results was probably due to the inclusion of fetuses with simple intrauterine molding. In a later series of 24 fetuses with BPD values of more than 3 SD below the mean, only 4 proved to be microcephalic after birth, and 3 of these 4 fetuses had additional major malformations (Chervenak et al., 1987).
Microcephaly may also be diagnosed based on an abnormal ratio of head circumference to femur length or of head circumference to abdominal circumference. Normograms for these ratios have been published (Romero et al., 1988). A diagnosis of microcephaly should be made with caution when using such normograms, because some causes of microcephaly may be associated with intrauterine growth restriction or abnormal long bone growth.
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