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1999-07-27-18 Microcephaly © Pilu http://www.thefetus.net/
Microcephaly

Gianluigi Pilu and Philippe Jeanty

Bologna, Italy

Synonyms: microencephaly

Definition

Microcephaly is a syndrome including different pathological entities that share in common a small head. It is associated with neurologic abnormalities and mental retardation. The diagnosis has been based on measurement of the head circumference at the level of the base of the skull. Different thresholds have been proposed.  Some authors have used a head circumference 2 SD below the mean[1]as a diagnostic criterion, whereas others require 3 SD [2],[3],[4],[5],[6]. The prevalence of the condition is different according to the chosen threshold.  If 2 SD below the mean is used, 2.5 percent of the general population is considered microcephalic.  A significant number of intellectually normal infants would be included in this group. If 3 SD below is employed, the incidence of the condition is 0.1 percent, a figure more in keeping with the epidemiological observations and the intention of the definition-to identify infants at risk for mental retardation.  Although the head circumference in a normally shaped head correlates with brain weight (volume), this may not be true in cases of true microcephaly, since the cranial deficit is mostly above the base of the skull.[7]This problem may explain the difficulties and pitfalls in diagnosing microcephaly purely on the basis of a head circumference.

Incidence

The incidence is estimated to be 1.6 per 1000 single birth deliveries.  Only 14 percent of all microcephalic infants diagnosed by the first year of age had been detected at birth.[8]

Etiology and Associated Malformations

Microcephaly can result from primary cerebral malformations or exposure to teratogens, it is a part of a wide variety of syndromes and it can also be transmitted with Mendelian inheritance, most frequently as an autosomal recessive trait. Microcephaly can be classified into two categories: (1) microcephaly without associated anomalies and (2) microcephaly with associated malformations.  Table 1 presents a classification of microcephaly and associated entities.

Table 1. Classification of microcephaly

Microcephaly with associated malformations

Microcephaly without associated malformations

Genetic

1.             Chromosomal aberrations

Down syndrome

Trisomy 13 syndrome

Trisomy 18 syndrome

Trisomy 22 syndrome

4p-          syndrome

Cat cry (5p-) syndrome

18p- syndrome

18q- syndrome

2.             Single gene defects

Bloom syndrome (AR)

Borjeson-Forssman-Lehmann syndrome (XLR)

Cockayne syndrome (AR)

DeSanctis-Cacchione syndrome (AR)

Dubowitz syndrome (AR)

Fanconi pancytopenia (AR)

Focal dermal hypoplasia (XLD)

Incontinentia pigmenti (XLD)

Lissencephaly syndrome (AR)

Meckel-Gruber syndrome (AR)

Menkes syndrome (XLR)

Roberts syndrome (AR)

Seckel bird-headed dwarfism (AR)

Smith-Lemli-Opitz syndrome (AR)

 

Genetic

1.             Primary microcephaly (AR)

2.             Paine syndrome (XLR)

3.             Alpers disease (AR)

4.             Inborn errors of metabolism

Disorders of folic acid metabolism (AR)

Hyperlysinemia (AR)

Methylmalonic acidemia (AR)

Phenylketonuria (AR)

Environmental

1.             Prenatal infections

Rubella syndrome

Cytomegalovirus disease

Herpesvirus hominis

Toxoplasmosis

2.             Prenatal exposure to drugs or chemicals

Fetal alcohol syndrome

Fetal hydantoin syndrome

Aminopterin syndrome

3.             Maternal phenylketonuria

Environmental

1.             Prenatal exposure to radiation

2.             Fetal malnutrition

3.             Perinatal trauma or hypoxia

4.             Postnatal infections

 

Unknown etiology

1.             Recognized syndromes

Coffin-Sins syndrome

DeLange syndrome

Johanson-Blizzard syndrome

Langer-Giedion syndrome

Rubenstein-Taybi syndrome

Williams syndrome

2. Undefined combinations

Unknown etiology

Happy puppet syndrome

Adapted from Ross, Frias: In: Vinken, Bruyn (eds.): Handbook of Clinical Neurology. Amsterdam, Elsevier "North Holland Biomedical Press, 1977, Vol 30, pp 507-524.

 

Pathology

When microcephaly is present, the most affected part is usually the forebrain.  Cerebral maldevelopment is frequent and include asymmetries, macrogyria, pachygyria, and atrophy of the basal ganglia. The lateral ventricles and subarachnoid space are enlarged due to the atrophy of the cortex. The basal ganglia appear disproportionately large. A decrease in dendritic arborization has also been described. [9]

Diagnosis

Obstetric sonographers are not infrequently faced with the problem of diagnosing fetal microcephaly, usually in one of two situations: either examining a patient at increased risk because of a genetic predisposition or exposure to teratogens, or when a small fetal head is serendipitously encountered during a routine examination. Unfortunately, the experience thus far indicates that the diagnostic value of antenatal sonography is limited, with high rates of both false positives and false negatives.[10],[11],[12]

The diagnosis should be suspected if the head perimeter is 2 SD below the mean for gestational age (Table 2). Although other authors have proposed the use of the biparietal diameter as a diagnostic parameter, intrauterine molding can modify this measurement, whereas the head perimeter is not.  Interpretation of the head perimeter assumes a precise knowledge of the gestational age.  Because this information is not always available, an alternative is to use noncephalic biometric parameters instead of gestational age such as the head to femur and abdominal circumference to head circumference ratio (Table 3 and 4).[13]

 

 
 

Table 2: Head perimeter (mm) throughout gestation

 

weeks

mean

mean-2SD

mean-3SD

mean-4SD

mean-5SD

16

126

96

82

67

52

17

138

109

94

80

65

18

151

121

107

92

77

19

163

133

119

104

89

20

175

145

131

116

101

21

187

157

143

128

113

22

198

169

154

140

125

23

210

180

166

151

136

24

221

191

177

162

147

25

232

202

188

173

158

26

242

213

198

183

169

27

252

223

208

194

179

   
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