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Articles » Central nervous system » Microcephaly
2000-08-08-15 Microcephaly © Goncalves

 Lu?s F. Gonçalves, MD - Maria Verônica Mu?oz Rojas, MD

Florianopolis, Brazil

Clinical syndrome characterized by head circumference more than three standard deviations below the mean for gestational age, generally associated with abnormal neurological findings and mental retardation.

Estimated as 1/250.000 in isolated forms.1

The diagnosis is suspected when the head circumference is below 3 standard deviations below the mean for the estimated gestational age.1 Therefore, it is imperative for a precise diagnosis to ascertain gestational age early in pregnancy. When this information is unavailable or unreliable, the alternative is to use nomograms that compare the head circumference with the length of skeletal structures (e.g., femur length), assuming that, in the majority of the cases, bone growth is not compromised. Additional signs may aid in the diagnosis:

  • a sloping forehead in the fetal profile view;
  • hydrocephaly (Figure 1).

Associated anomalies
Depending upon the cause of microcephaly, a myriad of malformations may be associated.


Microcephaly is classified in two main categories: 1) with associated anomalies; and 2) without associated anomalies. The table below lists the main diseases and conditions associated with microcephaly (Table I).


Microcephaly with associated malformations

Microcephaly without associated malformations


·        Down syndrome

·        trisomy 13

·        trisomy 18

·        trisomy 22

·        4p- syndrome

·        5p- syndrome

·        18p- syndrome

·        18q- syndrome


·        Primary microcephaly (AR)

·        Primary microcephaly (AD)

·        Pain syndrome (RLX)

·        Alpers disease (AR)

·        Unborn errors of metabolism

·        Acid folic metabolism disturbance (AR)

·        Hyperlisenemia (AR)

·        Methylmalonic acidemia (AR)

·        Phenylketonuria (AR)

Genic disorders

·        Bloom syndrome (AR)

·        Borjeson-Forssmann-Lehmann syndrome (RLX)

·        Cockayne syndrome (AR)

·        DeSantics-Cacchione syndrome (AR)

·        Dubowitz syndrome (AR)

·        Fanconi pancitopenia(AR)

·        Focal dermal hypoplasia (DLX)

·        Incontinentia pigmenti (DLX)

·        Lisencephaly (AR)

·        Meckel-Gruber syndrome (AR)

·        Menckes syndrome (RLX)

·        Roberts syndrome (AR)

·        Seckel dwarfism (“bird-headed”) (AR)

·        Smith-Lemli-Opitz syndrome (AR)




·        Prenatal exposure to radiation

·        Fetal starvation

·        Hypoxia or perinatal trauma

·        Postnatal infections

Congenital infections

·        rubella

·        cytomegalovirus

·        herpes

·        toxoplasmosis


Exposure to drugs or chemical agents

·        fetal alcoholic syndrome

·        fetal hydantoin syndrome

·        aminopterin syndrome


Maternal phenylketonuria


Unknown etiology

Unknown etiology

·        “Happy puppet syndrome”

Recognized syndromes

·        Coffin-Siris syndrome

·        DeLange syndrome

·        Johanson-Bizzard syndrome

·        Langer-Giedion syndrome

·        Rubenstein-Taybi syndrome

·        Williams syndrome


Undefined combinations






Dependent upon the underlying disorder. When the head circumference is more than 4 standard deviations below the mean, the prognosis is poor.


Genetic counseling and recurrence risk
The recurrence risk for microcephaly depends on the underlying cause. Both autosomal dominant and autosomal recessive patterns of inheritance for isolated microcephaly have been described. In the first case there is a recurrence risk of 1:2 or 50% if one of the parents is affected and in the second case the recurrence risk is 1:4 or 25%. If the microcephaly is due to an aneuploidy, such as trisomy 21, the recurrence risk is approximately 1% in addition to the maternal-age-related risk. If the microcephaly is due to a deletion or rearrangement in the chromosomes, parental karyotyping should be performed to rule out a balanced translocation, which would increase the recurrence risk. If microcephaly is secondary to drug exposure or infection, the recurrence risk is expected to be minimal in a subsequent pregnancy.
Estimates of the recurrence risk for microcephaly with mental retardation are shown in the Table below. The recurrence risks for microcephaly associated to mental retardation are highly variable among different studies, possibly due to different population groups studied and ascertainment bias. Nevertheless, these studies provide a useful source of information for prenatal diagnosis and counseling parents with a diagnosis of fetal microcephaly.


Table 1: Recurrence Risks for Microcephaly with Mental Retardation


Recurrence Risk in Siblings (%)

Brandon et al. 1959


Bundey and Carter 1974


Bundey and Griffiths 1977


Opitz et al. 1978


Bartley and Hall 1978


Herbst and Baird 1982


Tolmie et al. 1987



There is no available treatment for microcephaly.


Microcephaly mini-information sheet - NINDS
Online microcephaly support group


1. Romero R, Pilu G, Jeanty P, Ghidini A, Hobbins JC. Prenatal Diagnosis of Congenital Anomalies. Norwalk: Appleton & Lange; 1988.
2. Shapiro K. Microcephaly. In: Buyse ML. Birth Defects Encyclopedia. Cambridge: Blackwell Science; 1990:1139.
3. Brandon, MWG, Kirman, BH, William CE. Microcephaly. J Ment Sci 1959;105:721-747.
4. Bundey S, Carter CO. Recurrence risk in severe undiagnosed mental deficiency. J Ment Defic Res 1974:18:115-134.
5. Bundey S, Griffiths MI. Recurrence risks in families of children with symmetrical spasticity. Dev Med Child Neurol 1977:19:179-191.
6. Opitz KM, Kaveggia EG, Durkin-Stamm MV, et al. Diagnostic/genetic studies in severe mental retardation. Birth Defects 1978;14:1-38.
7. Bartley JA, Hall BD. Mental retardation and multiple congenital anomalies of unknown etiology: frequency of occurence in similarly affected sibs of the proband. Birth Defects 1978:14:127-137.
8. Herbst DS, Baird BA. Sib risks for non-specific mental retardation in British Columbia. Am J Med Genet 1982;13:197-208
9. Tolmie JL, Mc Nay M, Stephenson JBP. Microcephaly: genetic counseling and antenatal diagnosis after the birth of an affected child. Am J Med Genet 1987;27:583-594.

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