Microcephaly

Microcephaly indicates the association of abnormal neurologic development and a small head. The smaller the head dimensions the greater the probability of microcephaly. However, there is not an absolute quantitative cut-off. A head circumference more than 2 standard deviations at birth below the mean is suspicious, but most infants with such measurement (about 2.5% of the general population) will have a normal intelligence.¹ Defining microcephaly antenatally is even more difficult, because affected fetuses have usually normal cranial measurements in early gestation, that only decline in late gestation or after birth.^{2, 3}

microencephaly

ICD-10: Q02

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

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) primary microcephaly without associated anomalies and (2) microcephaly with associated malformations. Table 1 presents a classification of microcephaly and associated entities.

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.5 Fetuses with primary microcephaly (or microcefalia vera) usually have a morphological normal or almost normal brain.

Microcephaly is a progressive condition and prenatal diagnosis is impossible in most cases. About 80% of affected infants have a normal head circumference at birth⁴ and about 90% of those diagnosed at birth have normal cranial measurements in the second trimester.^{2, 3, 6} Cases diagnosed in utero represent the exception, fetuses with extreme reduction of head dimensions, usually with multiple anomalies. In some cases microcephaly is the result of an insult affecting the brain during the critical time of brain proliferation. In one series that reports only on cases that were diagnosed during pregnancy, the time of diagnosis was on average 28 weeks and associated anomalies were present in 83.3% of the patients.⁷

Obstetric sonographers are faced with the dilemma of diagnosing microcephaly 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. In both cases, a definitive diagnosis is frequently impossible. In familial microcephaly the head measurements tend to be in the normal range during gestation.⁸ Microcephaly should be suspected if the head perimeter is 2 SD below the mean for gestational age, but only when the measurement is 5 or more SD below the mean, or there is a striking disproportion between the head and the trunk or limbs the diagnosis is certain.⁹ Charts of the head dimensions are presented in Tables 2-4. The use of appropriated charts should be stressed since the variability between them can be very significant.

In those cases in which the head measurements is in the intermediate zone, a detailed neurosonographic examination and/or cerebral MRI may of help as two thirds of microcephalic infants have abnormal cerebral anatomy, including mostly holoprosencephaly, anomalies of the corpus callosum and cortical malformations.^{10, 11}

Additional sonographic findings that increase the likelihood of fetal microcephaly have been reported from time to time, but the experience is scanty and their significance remains uncertain. The list includes enlarged subarachnoid space,¹² sloping forehead,¹² small frontal lobe,¹³ abnormalities of cerebral circulation¹². It has been reported that in severe microcephaly the intracranial contents may not be visible sonographically,¹⁴ but this occurs only when the head is extremely small.

Craniosynostosis may results in a restriction of the fetal head that may affect the measurement of the head circumference. The most important clue is the evaluation of the shape of the head, that is constantly altered with craniosynostosis, while it tends to be normal but for a sloping forehead with microcephaly. Severe placental insufficiency may be associated with small cranial measurements. Usually in these cases, other abnormal findings are present such as oligohydramnios and abnormal Doppler findings of the utero-placental and fetal circulation. It needs to be stressed that infants with microcephaly have frequently growth restriction and therefore the comparison with other biometric parameters is of limited significance.

The available experience suggests that even expert ultrasound in pregnancies at risk will fail to diagnose fetal microcephaly in many cases. As most microcephalic infants have different types of cerebral maldevelopment, attention should be focused not only on the cranial measurements but on the cerebral anatomy as well. Multiplanar brain imaging is a useful adjunct to biometric evaluation.¹²

The fetal head circumference should always be measured in sonographic examination performed in the second or third trimester. If the value is small (less than minus 2 standard deviations from the mean) and/or there is a disproportion with the size of the trunk or limbs the possibility of microcephaly should be considered and a targeted examination is recommended.

The prognosis is different for infants with or without associated anomalies. For the latter group, the outlook is related to the severity of the associated anomalies. Trisomy 13, trisomy 18, Meckel syndrome, and alobar holoprosencephaly are all fatal conditions. For infants without associated malformations, the prognosis is dependent on head size. The available literature suggests that the risk of mental retardation with an head circumference between – 2 and – 3 SDs is in the range of 10-30%, rising to 50-60% for measurements below – 3 SDs.^{15, 16} These data derive from clinical series that include children with associated malformations. Prenatal data are limited. In the largest available series, none of 20 infants that were found in utero to have a head circumference between – 2 and – 3 SD had mental retardation or neurocognitive problems at long term follow-up.¹⁷

A detailed ultrasound evaluation of entire fetal anatomy and amniocentesis for fetal karyotype are recommended in fetuses with a head circumference less than -2 SDs from the mean, particularly in early gestation. In the absence of associated anomalies, patients are counseled only on the basis of the head perimeter. If this is between 2 SD and 3 SD below the mean for gestational age, there is a very good chance that the infant will be normal, although intrauterine evolution can not be predicted. Below -3 SD, the prognosis is guarded. If the diagnosis is made before viability, the option of termination of pregnancy should be considered.

Microcephaly with associated malformations

A. 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)

B. 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

C. Unknown etiology

1. Recognized syndromes

Coffin-Sins syndrome

DeLange syndrome

Johanson-Blizzard syndrome

Langer-Giedion syndrome

Rubenstein-Taybi syndrome

Williams syndrome

2. Undefined combinations

II.Microcephaly without associated malformations

A. 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)

B. Environmental

1. Prenatal exposure to radiation

2. Fetal malnutrition

3. Perinatal trauma or hypoxia

4. Postnatal infections

C. 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.

Reproduced from Romero R, Pilu G, Jeanty P, Ghidini A, Hobbins JC: Prenatal Diagnosis of Congenital Anomalies. Appleton and Lange, Norwalk, 1988

Reproduced from Romero R, Pilu G, Jeanty P, Ghidini A, Hobbins JC: Prenatal Diagnosis of Congenital Anomalies. Appleton and Lange, Norwalk, 1988

Reproduced from Romero R, Pilu G, Jeanty P, Ghidini A, Hobbins JC: Prenatal Diagnosis of Congenital Anomalies. Appleton and Lange, Norwalk, 1988

1. Sells CJ. Microcephaly in a normal school population. Pediatrics. 1977;59(2):262-5. Epub 1977/02/01.

2. Bromley B, Benacerraf BR. Difficulties in the prenatal diagnosis of microcephaly. Journal of ultrasound in medicine : official journal of the American Institute of Ultrasound in Medicine. 1995;14(4):303-6. Epub 1995/04/01.

3. Reece EB, Goldstein I. Three-level view of fetal brain imaging in the prenatal diagnosis of congenital anomalies. The Journal of maternal-fetal medicine. 1999;8(6):249-52. Epub 1999/12/03.

4. Myrianthopoulos NC, Chung CS. Congenital malformations in singletons: epidemiologic survey. Report from the Collaborative Perinatal project. Birth defects original article series. 1974;10(11):1-58. Epub 1974/01/01.

5. Davies H, Kirman BH. Microcephaly. Arch Dis Child. 1962;37:623-7. Epub 1962/12/01.

6. Dahlgren L, Wilson RD. Prenatally diagnosed microcephaly: a review of etiologies. Fetal diagnosis and therapy. 2001;16(6):323-6. Epub 2001/11/06.

7. den Hollander NS, Wessels MW, Los FJ, Ursem NT, Niermeijer MF, Wladimiroff JW. Congenital microcephaly detected by prenatal ultrasound: genetic aspects and clinical significance. Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology. 2000;15(4):282-7. Epub 2000/07/15.

8. Jaffe M, Tirosh E, Oren S. The dilemma in prenatal diagnosis of idiopathic microcephaly. Developmental medicine and child neurology. 1987;29(2):187-9. Epub 1987/04/01. Malinger G, Lev D, Lerman-Sagie T. Assessment of fetal intracranial pathologies first demonstrated late in pregnancy: cell proliferation disorders. Reprod Biol Endocrinol. 2003 Nov 14;1:110.

9. Chervenak FA, Rosenberg J, Brightman RC, Chitkara U, Jeanty P. A prospective study of the accuracy of ultrasound in predicting fetal microcephaly. Obstetrics and gynecology. 1987;69(6):908-10. Epub 1987/06/01.

10. Jaworski M, Hersh JH, Donat J, Shearer LT, Weisskopf B. Computed tomography of the head in the evaluation of microcephaly. Pediatrics. 1986;78(6):1064-9. Epub 1986/12/01.

11. Steinlin M, Zurrer M, Martin E, Boesch C, Largo RH, Boltshauser E. Contribution of magnetic resonance imaging in the evaluation of microcephaly. Neuropediatrics. 1991;22(4):184-9. Epub 1991/11/01.

12. Pilu G, Falco P, Milano V, Perolo A, Bovicelli L. Prenatal diagnosis of microcephaly assisted by vaginal sonography and power Doppler. Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology. 1998;11(5):357-60. Epub 1998/06/30.

13. Goldstein I, Reece EA, Pilu G, O'Connor TZ, Lockwood CJ, Hobbins JC. Sonographic assessment of the fetal frontal lobe: a potential tool for prenatal diagnosis of microcephaly. American journal of obstetrics and gynecology. 1988;158(5):1057-62. Epub 1988/05/01.

14. Kurtz AB, Wapner RJ, Rubin CS, Cole-Beuglet C, Ross RD, Goldberg BB. Ultrasound criteria for in utero diagnosis of microcephaly. Journal of clinical ultrasound : JCU. 1980;8(1):11-6. Epub 1980/02/01.

15. Avery GB, Meneses L, Lodge A. The clinical significance of "measurement microcephaly". Am J Dis Child. 1972;123(3):214-7. Epub 1972/03/01.

16. Dolk H. The predictive value of microcephaly during the first year of life for mental retardation at seven years. Developmental medicine and child neurology. 1991;33(11):974-83. Epub 1991/11/01.

17. Stoler-Poria S, Lev D, Schweiger A, Lerman-Sagie T, Malinger G. Developmental outcome of isolated fetal microcephaly. Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology. 2010;36(2):154-8. Epub 2010/01/14.

Pilu G, Malinger G: Microcephaly. Visual Encyclopedia of Ultrasound in Obstetrics and Gynecology. www.isuog.org, 24 June 2013.

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