Diagnostic approach to microcephaly in childhood: a two‐center study and review of the literature

Abstract

ABBREVIATIONS cMRICranial magnetic resonance imaging CGH Comparative genomic hybridization OFC Occipitofrontal head circumference AIM The aim of this study was to assess the diagnostic approach to microcephaly in childhood and to identify the prevalence of the various underlying causes/disease entities.METHOD We conducted a retrospective study on a cohort of 680 children with microcephaly (399 males, 281 females; mean age at presentation 7-8mo, range 1mo-5y) from patients presenting to Charit e -University Medicine Berlin (n=474) and University Hospital Dresden (n=206). Patient discharge letters were searched electronically to identify cases of microcephaly, and then the medical records of these patients were used to analyze parameters for distribution. RESULTSThe putative aetiology for microcephaly was ascertained in 59% of all patients, leaving 41% without a definite diagnosis. In the cohort of pathogenetically defined microcephaly, genetic causes were identified in about half of the patients, perinatal brain damage accounted for 45%, and postnatal brain damage for 3% of the cases. Microcephaly was associated with intellectual impairment in 65% of participants, epilepsy was diagnosed in 43%, and ophthalmological disorders were found in 30%. Brain magnetic resonance imaging revealed abnormalities in 76% of participants.INTERPRETATION Microcephaly remains a poorly defined condition, and a uniform diagnostic approach is urgently needed. A definite aetiological diagnosis is important in order to predict the prognosis and offer genetic counselling. Identifying gene mutations as causes of microcephaly increases our knowledge of brain development and the clinical spectrum of microcephaly. We therefore propose a standardized initial diagnostic approach to microcephaly.Microcephaly is defined as an occipitofrontal head circumference (OFC) below the third centile or more than 2 standard deviations (SD) below the mean for sex, age, and ethnicity. 1,2 The term 'severe' microcephaly is applied to an OFC more than 3SD below the mean. Microcephaly is associated with a reduction in brain volume and often intellectual and/or motor disabilities. The pathogenesis of microcephaly is heterogeneous, ranging from genetic causes to environmental factors that can have an impact on developmental processes that influence brain size.3-5 Any condition that affects important processes of brain growth, such as progenitor cell proliferation, cell differentiation, and cell death, can thus induce microcephaly. Anomalies leading to microcephaly may exclusively affect cerebral development (non-syndromal microcephaly) or may be associated with extracranial malformations and/or facial dysmorphism (syndromal microcephaly).Microcephaly may be evident at birth (primary microcephaly) or postnatally (secondary microcephaly). The child with secondary microcephaly has a normal OFC at birth and then subsequently the relative OFC drops to a value more than 2SD below the mean. These terms do not imply distinct aetiologies. Both primary and secondary microce...

Emerging Role of Zika Virus in Adverse Fetal and Neonatal Outcomes

“…The prognosis is therefore worse in children in whom microcephaly is part of a syndrome or resulting from a congenital infection (30). In the same cohort of 680 cases of microcephaly described above, 65% presented with either intellectual disability (21). These results are congruent with findings of another study in which only half of the children with microcephaly had a normal intelligence quotient (IQ) (31).…”

“…OFC measurements are considered to correlate to brain size and reflect brain development. Distinction should be made between primary microcephaly, in which abnormal OFC is observed at birth, and secondary microcephaly, which develops later (21).…”

“…The most common etiologies of microcephaly are listed in Table 1. In a study evaluating 680 children with microcephaly, the prevalence rates of different etiologies were as follows: 28.5% genetic (including inborn errors of metabolism), 26.7% perinatal brain injury (such as maternal disease [3.8%], birth injury [17.3%], and exposure to teratogenic substances [4.4%]), 13% cryptogenic (suspected genetic cause but no diagnosis identified), 2.1% craniosynostosis, 1.9% postnatal brain injury (such as encephalitis, child abuse, concussion, and infarct), and the remaining 40.7% with no specific etiology found (21). It is important to emphasize that although congenital infections have been identified as a cause of microcephaly, genetic anomalies are more frequently the cause.…”

“…The number of genetic anomalies associated with microcephaly has increased recently due to significant improvements in genetic testing (29). Additional genetic anomalies associated with microcephaly might be identified through the generalization of next-generation sequencing techniques (21). Therefore, a genetic cause should be ruled out for each case of proven microcephaly as part of the differential diagnosis for suspected cases of congenital ZIKV infection (12).…”

“…Clinical management requires the participation of neurologists, geneticists, obstetricians, and pediatricians and should take into account recommendations for management of microcephaly (reviewed in reference 21). At the first clinical evaluation, signs of dysmorphism, congenital infections, and inborn errors of metabolism should be actively evaluated (21,260,274). The newborn and placenta should be tested for ZIKV as described above, and maternal status for ZIKV infection should be confirmed (255,260,274).…”