Chapter 13 - Microcephaly
Introduction
Microcephaly is defined as an occipitofrontal head circumference (OFC) ≤ − 2 standard deviations (SD) below the mean for sex, age, and ethnicity. The term “true” or “severe” microcephaly is used for an OFC ≤ – 3 SD. The term microencephaly refers to a brain weight 2 SD below the mean. The incidence of true primary microcephaly worldwide varies from 1.3 to 150 per 100 000 live births.
Several developmental processes that are under control of genetic and environmental factors play a role in sculpting the brain size. Any condition that affects important processes of brain growth such as progenitor cell proliferation, cell differentiation, and cell death can thus induce microcephaly (Barkovich et al., 2005). Microcephaly may be evident at birth (primary microcephaly) or postnatally (secondary microcephaly). Anomalies leading to microcephaly may exclusively affect the cerebral development (non-syndromic microcephaly) or are associated with visceral, and/or skeletal malformations, and/or facial dysmorphism (syndromal microcephaly). These terms do not imply distinct etiologies and both syndromal and non-syndromal forms may coexist with some etiologies (as in Fanconi anemia). Microcephaly can be acquired (i.e., caused by environmental factors) (Abuelo, 2007) or genetic.
Section snippets
Acquired congenital microcephalies
Acquired congenital microcephaly can occur after various injuries to the developing brain such as intrauterine infection, irradiation, exposure to drugs/toxins including maternal alcohol consumption (fetal alcohol syndrome), fetal irradiation, maternal hyperphenylalaninemia, placental insufficiency, and/or severe maternal illness (Table 13.1). Prenatal brain damage is believed to be a multifactorial, multihit process that varies in severity between individuals, affects infants of different
Primary microcephalies
Primary microcephalies reflect an imbalance between progenitor cell production and cell death (Francis et al., 2006). Disruption of neural progenitor proliferation (defects in mitotic division or cell cycle regulation of progenitors) or of DNA damage response can lead to a reduced number of neuronal and glial cells within the brain.
Metabolic microcephalies
Two specific forms, commonly associated with primary microcephaly, deserve specific special comments.
Serine deficiency disorders are a group of neurometabolic diseases caused by defects in the biosynthesis of L-serine, a precursor of metabolites such as nucleotides, phospholipids, and the neurotransmitters glycine and D-serine. Clinical manifestations include congenital microcephaly, seizures, severe pyramidal syndrome, and severe psychomotor retardation. The diagnosis of serine deficiency is
Secondary microcephalies
Microcephaly that occurs postnatally within the first years of life (normal OFC at birth) often implies ongoing neurodegeneration and/or death of other cells. Most forms of secondary microcephaly such as those occurring in patients with Rett syndrome, Aicardi-Goutières disease, infantile neuronal ceroid lipofuscinoses, or other metabolic diseases are addressed in other chapters. Patients with secondary microcephaly often show progressive motor and cognitive deterioration and seizures, but their
Syndromic microcephalies
A large number of syndromes are associated with microcephaly, which can either be a major handle for suggesting or confirming the diagnosis, or a secondary, nonmandatory feature (Abuelo, 2007). More than 700 clinical syndromes are recorded with microcephaly in the London Dysmorphology Database and OMIM. Typically, most autosomal chromosomal anomalies are associated with small head size, as in classical 4p16 deletion (Wolff − Hirshhorn syndrome), but also in more recently delineated entities such
Management of microcephaly
Proper evaluation of a microcephalic child should be done by a pediatric neurologist and a dysmorphologist. A comprehensive anamnesis, including prenatal history, postnatal medical and developmental steps, and familial history with three-generational pedigree should be collected. Growth charts for height and OFC and a detailed physical examination should be recorded in all cases. They will sometimes suggest a specific diagnosis or deliver handles for further testings. Genetic etiologies have
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