Definition of a paradigm shift6/11/2023 It should be noted that the mean OFC of children from industrial countries is larger than that shown by the WHO standard values ( accessed on 13 February 2023). , for most of the non-European patients, the SD of OFC is often calculated with reference to values taken from studies performed on Nellhaus (Caucasian children) or Prader (Swiss children), irrespective of the ethnicity of the patients. As already highlighted by van der Hagen et al. The reference values being used to calculate the deviation also vary considerably. However, multiple studies followed −3 SD as a baseline. For instance, the American Academy of Neurology and the Practice Committee of the Child Neurology Society have recommended a cutoff of <−2 SD OFC at the time of birth, while <−3 SD would indicate a severe degree of microcephaly. However, different cutoff values are used to define microcephaly. Adopting these definitions is often difficult and has therefore not been handled uniformly.Ĭlinically, the first step towards the diagnosis of CM is measuring the OFC for a significant reduction. The term microcephaly primary hereditary (MCPH) refers to the genetic forms of CM. CM is the currently favored nomenclature and is broadly divided into three categories: (1) isolated microcephaly, that is, without any further clinical (cerebral or extra-cerebral) abnormalities, including no developmental disability or intellectual disability (2) non-syndromic microcephaly with neurological or psychiatric features, but without cerebral malformations or extra-cerebral abnormalities and (3) syndromic microcephaly with malformations of the cerebrum and/or extra-cerebral morphologic or functional anomalies. “Primary” microcephaly means an abnormal OFC at birth and is also known as “congenital microcephaly” (CM). It underlies the reduced volume of the cerebral cortex, and thus the brain. Microcephaly is defined as a reduction in the occipital–frontal head circumference (OFC) of at least 2 SD below the mean of age, gender, and ethnicity-matched populations. Microcephaly opens an aperture to glimpse into the evolution of the human brain, thus uncovering the veils of its architectural orchestration and immense adaptability. The Definition of Congenital (Primary) Microcephaly and Its Subtypes This review thus attempts to expand our understanding of the phenotypic and etiological variability in CM and invites the development of more comprehensive guidelines.ġ. We also highlight the role of genetic modifiers and de novo variants in the multi-organ phenotype of CM and emphasize their consideration in molecular characterization. We argue that brain-specific splicing events and organ-restricted protein expression may contribute in part to disparate clinical manifestations. It also presents possible arguments on long-standing questions of the brain-specific nature of CM caused by a dysfunction of the ubiquitously expressed proteins. This review article highlights the critical factors considered while defining CM subtypes. Moreover, the mechanism of the paradigm shift from a brain-restricted to a multi-organ phenotype is only vaguely understood. However, the recent bloom of disease–gene discoveries has revealed more overlaps than differences in the underlying genetic architecture for these clinical sub-categories, complicating the differential diagnosis. Congenital microcephaly (CM) exhibits broad clinical and genetic heterogeneity and is thus categorized into several subtypes.
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