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...

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