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Microcephaly in infants and children: Etiology and evaluation

Microcephaly in infants and children: Etiology and evaluation
Literature review current through: Jan 2024.
This topic last updated: Jul 15, 2022.

INTRODUCTION — The measurement of head circumference (also called occipitofrontal circumference [OFC]), a direct reflection of head growth, is an important step in the evaluation of childhood growth and development. Deviations from normal head growth may be the first indication of an underlying congenital, genetic, or acquired problem (eg, congenital infection, genetic syndrome) [1-4]. Many genetic conditions are associated with an abnormal pattern of head growth; the earlier these conditions are detected, the earlier appropriate treatment, services, and genetic counseling can be provided [5].

The etiology and evaluation of microcephaly in infants and children will be reviewed here. The etiology and evaluation of macrocephaly and the clinical genetics approach to microcephaly are discussed separately. (See "Microcephaly: A clinical genetics approach" and "Macrocephaly in infants and children: Etiology and evaluation", section on 'Etiology'.)

MONITORING HEAD GROWTH — Occipitofrontal circumference (OFC) should be measured at health maintenance visits between birth and three years of age and in any child with neurologic symptoms or developmental complaints. The technique for measuring head circumference (picture 1) is discussed separately. (See "The pediatric physical examination: General principles and standard measurements", section on 'Head circumference'.)

OFC measurements are most informative when plotted over time [6]. Normal head growth in infants and children and reference standards for monitoring head growth in healthy children are discussed separately. In the United States, the Centers for Disease Control and Prevention (CDC) recommend that the World Health Organization growth standards ( (figure 1A-B) and (calculator 1)) be used for children age zero to two years and the CDC growth charts ( (figure 2A-B) and (calculator 2)) be used for children age two to three years [7]. Head circumference charts for older children and adults are provided separately. (See "Normal growth patterns in infants and prepubertal children", section on 'Head growth' and "The pediatric physical examination: General principles and standard measurements", section on 'Head circumference'.)

DEFINITIONS

Microcephaly — Given that microcephaly is a sign rather than a diagnosis, we define microcephaly with qualifying terms:

Borderline microcephaly – Occipitofrontal circumference (OFC) between 2 and 3 standard deviations (SD) below the mean for age, sex, and gestation

Moderate microcephaly – OFC between 3 and 5 SD below the mean for age, sex, and gestation

Severe microcephaly – OFC ≥5 SD below the mean for age, sex, and gestation

However, the definition of microcephaly is somewhat controversial [8-11]. Some authors define microcephaly as an OFC more than 2 SD below the mean (ie, <3rd percentile) [5,6,12]. Some require that the measurement be adjusted as necessary for prematurity or parental head circumference [10,13]. Other authors define microcephaly as an OFC more than 3 SD below the mean [14-17]. Still others introduce qualifying terms: mild microcephaly or borderline microcephaly (between 2 and 3 SD below the mean), and severe microcephaly (more than 3 SD below the mean) [18]. The American Academy of Neurology practice parameter defines microcephaly as OFC >2 SD below the mean [11]. These distinctions are somewhat related to prognosis, as described below [14,19-21]. (See 'Associated neurologic impairment' below.)

The definition of microcephaly in the evaluation of infants for congenital Zika virus infection is discussed separately. (See "Congenital Zika virus infection: Clinical features, evaluation, and management of the neonate", section on 'Assessment for microcephaly'.)

Using the definition of more than 2 SD below the mean, approximately 2 percent of the general population would be considered microcephalic even though many of these individuals are simply at the low end of the population distribution [8,22].

Microencephaly — Microencephaly (micrencephaly) is an abnormally small brain. Microencephaly is a neuroimaging or neuropathologic diagnosis [23]. However, because head growth is driven by brain growth, microcephaly usually implies microencephaly (except in cases of generalized craniosynostosis in which skull growth is restricted) [9,12,16,18,23]. (See "Overview of craniosynostosis".)

Although microcephaly always implies microencephaly [5], the reverse is not true. Microencephaly may be present in children with normal OFC [23].

CLASSIFICATION — Microcephaly can be classified in a number of ways [8-10,15,24]:

By time of onset – Congenital microcephaly is present at birth or by 36 weeks gestation. It is sometimes called "primary microcephaly," but "primary microcephaly" also refers to a particular microcephaly phenotype, so "congenital microcephaly" is preferred. (See "Microcephaly: A clinical genetics approach", section on 'Terminology'.)

Postnatal microcephaly refers to failure of normal growth in a brain that was of normal size at birth. It is sometimes called "secondary microcephaly." Time of onset is the most commonly used classification system.

By etiology – Genetic or environmental. (See 'Etiology' below.)

By relation to other growth parameters – Symmetric (proportionate) or asymmetric (disproportionate). Microcephaly is considered symmetric (or proportionate) when the OFC is more than 2 to 3 standard deviations (SD) below the mean but proportionate to weight and length (or height), which also are below the mean [9].

By association with other anomalies – Isolated (or pure) microcephaly is not associated with any other anomalies. Syndromal (or complex) microcephaly is associated with one or more additional anomalies (table 1). These categories tend to overlap.

PATHOGENESIS — Microcephaly has two major mechanisms:

Lack of brain development or abnormal brain development related to a developmental insult during the time-specific period of induction and major cellular migration [23]; this type of microcephaly is thought to result from a reduction in the number of neurons generated during neurogenesis [16]; the forebrain is most severely affected (eg, holoprosencephaly) [14]

Injury or insult to a previously normal brain (sometimes called secondary microcephaly); this type of microcephaly is thought to result from a reduction in the number of dendritic processes and synaptic connections [16]

ETIOLOGY — A variety of genetic abnormalities and environmental insults can affect brain development, resulting in microencephaly and/or microcephaly of congenital or postnatal onset (table 2) [23,25].

In a retrospective series of 680 children with microcephaly who presented for pediatric neurology evaluation at two centers in Germany, the etiologic distribution was as follows [26]:

Genetic or presumably genetic (eg, numerical chromosome aberrations, microdeletions/duplications, monogenic disorders, genetic syndromes) – 29 percent

Prenatal and perinatal brain injury (eg, teratogenic exposure, maternal disease, birth complication) – 27 percent

Craniosynostosis – 2 percent

Postnatal brain injury (eg, infarct, encephalitis, nonaccidental trauma) – 2 percent

Unknown etiology – 41 percent (it is likely that many of these patients had a genetic etiology)

The majority of patients in this series had neurologic findings (eg, intellectual disability, epilepsy). The distribution of causes in primary care patients is likely to differ. A smaller, but similar, retrospective review of 197 Australian newborns with microcephaly demonstrated that 98 percent presented with congenital anomalies, 73 percent had abnormal central nervous system (CNS) imaging, and 51 percent had an abnormal chromosomal microarray, with 23 percent having a known genetic cause [27]. Fifteen percent of the children in this cohort died by five years.

Isolated microcephaly — Isolated microcephaly ("microcephaly vera," "primary microcephaly," or "true microcephaly") is present at birth and uncomplicated by anomalies outside the brain. The brain may have normal architecture but is small (more than 3 standard deviations [SD] below the mean) [8]. Isolated microcephaly is discussed separately. (See "Microcephaly: A clinical genetics approach", section on 'Primary genetic microcephaly and its syndromes'.)

Syndromic microcephaly — Numerous syndromes have microcephaly as one of their features [8]. A complete listing or description of such syndromes is beyond the scope of this review. However, Online Mendelian Inheritance in Man is an online database that permits searching according to combinations of clinical features (eg, microcephaly, syndactyly, cataracts). Select microcephaly syndromes that have recognizable phenotypes are described in the table (table 1) [8,15]. Syndromic microcephaly is discussed separately. (See "Microcephaly: A clinical genetics approach", section on 'Microcephaly with dysmorphism'.)

Neuroanatomic abnormalities — Neuroanatomic abnormalities that are associated with microcephaly include neural tube defects, holoprosencephaly, atelencephaly, lissencephaly, schizencephaly, polymicrogyria, macrogyria, and fetal brain disruption sequence [5].

Neural tube defects – Encephalocele (protrusion of a portion of the cerebral hemisphere or meninges through a skull defect) or spinal neural tube defects can be associated with abnormal development of the brain and microcephaly. (See "Primary (congenital) encephalocele".)

Holoprosencephaly – Holoprosencephaly results from incomplete development and septation of the midline CNS structures. It may occur as an isolated abnormality, in association with other brain defects, or as part of a multiple-anomalies syndrome [8]. It is characterized by varying degrees of brain separation, hypotelorism, facial clefts, and nasal malformations (figure 3). The clinical manifestations range from an isolated single maxillary incisor to cebocephaly (eg, small mouth, single nostril, and close-set eyes (picture 2)) or cyclopia. (See "Overview of craniofacial clefts and holoprosencephaly", section on 'Holoprosencephaly' and "Congenital anomalies of the nose", section on 'Holoprosencephaly'.)

Atelencephaly – Atelencephaly (or aprosencephaly) is a rare brain malformation without any telencephalon-derived brain structures (the cerebrum and related structures) [28].

Lissencephaly – In lissencephaly, the six cortical layers do not form normally due to impaired migration of neurons from the germinal matrix lining the ventricles. The surface of the brain appears completely or partially smooth with loss or reduction of sulci (image 1A-B) [9]. Lissencephaly is usually genetic in origin but may also be caused by infection or intrauterine perfusion failure. Microcephaly develops in all patients with lissencephaly by the first year; a minority is microcephalic at birth [9].

Pachygyria – Pachygyria (macrogyria) is a developmental malformation characterized by a reduction in the number of sulci of the cerebrum and is often seen in lissencephaly.

Schizencephaly – Schizencephaly is characterized by asymmetric infolding of cortical gray matter along the primary brain cleft in the perisylvian region (image 2A-C) [9].

Polymicrogyria – Polymicrogyria is a developmental malformation characterized by excessive gyri on the surface of the brain (image 3A-B).

Fetal brain disruption sequence – Fetal brain disruption sequence is characterized by severe microcephaly of prenatal onset (average occipitofrontal circumference [OFC] 5.8 SD below the mean), overlapping cranial sutures, prominence of the occipital bone, and scalp rugae [18,29-33]. It is thought to result from destruction or necrosis of the brain tissue secondary to prenatal insult (eg, vascular disruption, intrauterine infection) some of which may be genetic in origin (eg, mutations in COL4A1/2) [33].

Hydranencephaly – Hydranencephaly is vascular insult to the brain in which fluid-filled cavities replace the cerebral hemispheres; cerebellum, midbrain, thalami, and basal ganglia are usually preserved.

Metabolic disorders — Various metabolic disorders may be associated with microcephaly, but the prevalence of metabolic disorders among children with microcephaly is low (estimated to be 1 to 5 percent) [11]. Metabolic disorders associated with microcephaly include aminoacidurias (eg, phenylketonuria [PKU]), organic acidurias (eg, methylmalonic aciduria), urea cycle disorders (eg, citrullinemia), and certain storage diseases (eg, neuronal ceroid lipofuscinosis) (table 2). With the exception of maternal PKU, phosphoglycerate dehydrogenase deficiency, and Amish lethal microcephaly, metabolic disorders rarely present with microcephaly [11].

Environmental factors — Environmental factors that may result in decreased brain size include [5,18,19,24,34,35]:

Antenatal, perinatal, and postnatal CNS system infections (see "Overview of TORCH infections", section on 'Clinical features of TORCH infections')

In utero drug or toxin exposure – Characteristic features of fetal alcohol exposure include pre- and postnatal growth retardation, short palpebral fissures, flat philtrum, and thin upper lip (see "Fetal alcohol spectrum disorder: Clinical features and diagnosis", section on 'Clinical features')

Hypoxic-ischemic insults (prenatal or postnatal) (see "Etiology and pathogenesis of neonatal encephalopathy" and "Clinical features, diagnosis, and treatment of neonatal encephalopathy")

Intraventricular hemorrhage or stroke resulting in ischemic destruction (see "Germinal matrix and intraventricular hemorrhage (GMH-IVH) in the newborn: Risk factors, clinical features, screening, and diagnosis" and "Stroke in the newborn: Classification, manifestations, and diagnosis")

Severe malnutrition (postnatal) [36]

Systemic disease that is often genetic in origin (eg, polycystic kidneys, biliary atresia, renal failure)

POSTNATAL EVALUATION

Overview of approach — Evaluation for microcephaly should be initiated when a single occipitofrontal circumference (OFC) measurement is more than 2 to 3 standard deviations (SD) below the mean or when serial measurements reveal progressive decrease in head size (ie, crossing of ≥2 major percentile lines [eg, 10th, 25th, 50th, 75th, 90th] between health supervision visits) [14].

The evaluation of microcephaly includes a thorough history and physical examination of the child and parents (in consideration of familial variation in head size) [6,9,11,14,15,26]. (See 'History' below and 'Physical examination' below and 'Parental OFC and Weaver curve' below.)

Ancillary testing, which is directed by clinical findings from the history and examination, may include laboratory studies and imaging (algorithm 1). (See 'Diagnostic testing' below and 'Neuroimaging' below.)

Factors that determine the need for laboratory and radiologic evaluation include:

Age at onset, although the birth OFC measurement often is not available

History of antenatal insult (infection, toxin, drug) (table 2)

Associated features (eg, proportionality, syndromic features)

Family history

The approach outlined below is largely consistent with that outlined in the practice parameter developed by the American Academy of Neurology and the Child Neurology Society [11].

Syndromic features or signs of metabolic disease — If syndromic features (table 1) or symptoms of metabolic disease are present, consultation with, or referral to, a clinical geneticist should be initiated to determine the appropriate diagnostic evaluation. (See 'Diagnostic testing' below and "Microcephaly: A clinical genetics approach", section on 'Initial genetics consultation'.)

No syndromic features and normal development — For children without syndromic features or symptoms of metabolic disease and who have normal development, our evaluation varies with the severity of microcephaly:

OFC more than 3 SD below the mean – If syndromic features are absent and the OFC was more than 3 SD below the mean at birth (ie, congenital microcephaly), evaluation for congenital infection and neuroimaging may be warranted [14,15,37]. If neuroanatomy is normal, additional evaluation for primary microcephaly may be warranted. (See "Microcephaly: A clinical genetics approach", section on 'Primary genetic microcephaly and its syndromes'.)

If syndromic features are absent and the OFC is more than 3 SD below the mean with postnatal onset, neuroimaging may be warranted.

Consultation with, or referral to, a specialist in pediatric infectious diseases, pediatric genetics, pediatric neurology, and/or pediatric radiologist may be helpful in planning the diagnostic evaluation.

OFC 2 to 3 SD below the mean – If syndromic features are absent and the OFC is between 2 and 3 SD below the mean, measurement of the child's height and weight is important to distinguish proportionate growth retardation from microcephaly.

Parental head circumference is helpful in evaluating familial microcephaly [15]. (See 'Parental OFC and Weaver curve' below.)

No syndromic features and abnormal development — Additional evaluation (ie, neuroimaging or diagnostic testing) may be warranted in children with microcephaly, no syndromic features, and abnormal or delayed development that requires intervention. Testing may include genetic studies and evaluation for congenital infection. Consultation with a clinical geneticist, specialist in pediatric infectious diseases, or pediatric neurology is suggested to determine the most appropriate testing strategy.

History — Important aspects of the history in a child with microcephaly include [6,8,11,15,26]:

Prenatal history, particularly with respect to maternal medical problems (eg, diabetes, epilepsy, phenylketonuria [PKU]), medications, infections, tobacco, alcohol, or substance use, radiation exposure; findings of antenatal ultrasonography if it was performed. (See 'Environmental factors' above.)

Birth history (eg, perinatal complications, infections, metabolic issues). (See 'Environmental factors' above and 'Metabolic disorders' above.)

Weight, length, and OFC at birth to establish the onset of microcephaly and to determine if it is proportionate to weight and length. (See 'Classification' above.)

OFC trajectory to determine whether microcephaly is static or progressive (ie, OFC decreases over time from above the second percentile to below it). The pattern of head growth may suggest the etiology. In a retrospective review of 51 children, causes of progressive microcephaly included idiopathic, familial, syndromic, post-pathogenic event, and mixed [38]. Neither the trajectory nor the cause predicted the child's developmental or intellectual outcome.

History of seizures, developmental history (regression of milestones may indicate metabolic disease).

Family history of consanguinity or similarly affected individuals. The family history should include three generations to detect recessive disorders, which may skip a generation.

For children who were born prematurely, abnormal head ultrasonography findings. In a retrospective review of 923 preterm infants (<28 weeks), microcephaly at age two years was more common among those with intraventricular hemorrhage, ventriculomegaly, or an echolucent lesion than among those with normal ultrasonography (15 to 20 versus 6 percent) [39].

Physical examination — Important aspects of the physical examination of the child with microcephaly include [8,15,23,26]:

General appearance – Dysmorphic features may suggest a particular syndrome (table 1). However, facial dysmorphism may be distorted by microcephaly. Congenital microcephaly is usually associated with a sloping forehead and small anterior fontanelle [14].

OFC – The OFC should be measured and compared with previous measurements. The severity of microcephaly should be assessed by determining the number of SD below the mean (ie, the z score). The z scores for children younger than two years can be determined by using the following calculators for the World Health Organization (WHO) OFC chart (calculator 1) and the Centers for Disease Control and Prevention (CDC) growth chart (calculator 2).

Weight and length trajectories – The child's weight and length (or height) should also be measured and plotted on standard curves. The weight and length percentiles should be compared with the OFC percentile. (See "Normal growth patterns in infants and prepubertal children", section on 'CDC growth charts'.)

Several causes of microcephaly may be associated with postnatal growth failure and/or short stature (eg, Seckel syndrome, Rubinstein-Taybi syndrome).

Head – In addition to measuring the OFC, examination of the head should include assessment of the head shape. In infants, assessment of the fontanelles and palpation of the cranial sutures also should be performed.

The anterior fontanelle usually closes between 10 and 24 months. Early closure can be a normal finding but also is associated with microcephaly, craniosynostosis, hyperthyroidism, or hypoparathyroidism. Persistent enlargement of the anterior fontanelle in children with microcephaly may be due to a syndrome (eg, Down syndrome, trisomy 13 or 18, 5p- [cri-du-chat], Rubinstein-Taybi) or toxins.

An abnormal head shape and ridges along the suture lines are suggestive of craniosynostosis. Overriding sutures and a prominent occiput is suggestive of fetal disruption sequence. (See "Overview of craniosynostosis".)

Eyes – Examination of the eyes may provide clues to intrauterine infection (eg, chorioretinitis, cataract) or metabolic disease (cataract). (See "Cataract in children", section on 'Clinical features' and "Overview of TORCH infections", section on 'Clinical features of TORCH infections'.)

Oropharynx – The oropharynx should be examined for single maxillary incisor (characteristic of holoprosencephaly in conjunction with other midline defects of the eyes, nose, and palate [eg, cleft lip or palate, bifid uvula]).

Skin – Examination of the skin may provide clues to intrauterine infection (eg, petechiae and/or jaundice in the newborn) or metabolic disease (eg, eczematous rash in PKU). (See "Overview of phenylketonuria".)

Abdomen – Hepatomegaly or splenomegaly are suggestive of congenital infection.

Neurologic assessment – Neurologic evaluation, including assessment of tone, reflexes, and intellectual/developmental ability. Children with microcephaly are at risk for cerebral palsy and intellectual/developmental disability [11]. Cerebral palsy is common in children with microcephaly, and children with microcephaly are at risk for intellectual/developmental disability. (See "Cerebral palsy: Classification and clinical features", section on 'Classification' and "Intellectual disability (ID) in children: Clinical features, evaluation, and diagnosis", section on 'Clinical evaluation'.)

Parental OFC and Weaver curve — Parents' occipitofrontal circumference (OFC) measurements should be obtained if possible to assess familial variation in head size [9]. This is particularly true if the microcephaly is between 2 and 3 SD below the mean [15].

The genetic contribution to microcephaly can be assessed by using the Weaver curve [8,40].

The Weaver curve helps to determine whether genetic influences contribute to a child's microcephaly [40]. We typically use the Weaver curve in children without syndromic features, with normal development and with OFC >2 SDs and ≤3 SDs below the mean for age and sex and whose parents have normal development without syndromic features.

To use the Weaver curve:

A standard score is calculated for the child and each of the parents using the following formula:

Standard score (SS) = (OFC - mean value)/SD

The mean values and SD for age and sex are listed in the table (table 3). In calculating the parents' SSs, the mean value and SD for an 18-year-old should be used.

The intercept of the average of the parents' SS (horizontal axis) and the child's SS (vertical axis) is plotted on the Weaver curve (figure 4).

Familial microcephaly is suggested if the child's SS is within the range determined by the average parental SS [40].

Familial microcephaly may reflect familial variation (ie, the child's head size is normal relative to that of the parents) or autosomal dominant microcephaly. In either case, if the child's OFC is <3 SDs below the mean for age and sex, additional evaluation may be deferred unless the child develops neurologic findings or the microcephaly worsens.

Familial microcephaly is unlikely if the child's SS is below the range determined by the average parental SS score; additional evaluation may be warranted, particularly if the child's OFC is >3 SDs below the mean for age and sex. (See 'Diagnostic testing' below.)

Diagnostic testing — Diagnostic testing may be warranted in children with microcephaly and abnormal development or associated clinical findings (algorithm 1). Testing may include [6,11,14,15,23,26]:

Genetic studies if the child has dysmorphic features, unless there is an obvious cause of the microcephaly in a child with OFC <3 SD below the mean – Consultation with a clinical geneticist is suggested to determine the most appropriate testing strategy but will usually include a genomic array, unless there is a readily identifiable syndromic diagnosis. (See "Microcephaly: A clinical genetics approach", section on 'Initial genetics consultation'.)

Evaluation for congenital infection – Consultation with a specialist in pediatric infectious diseases is suggested to determine the most appropriate testing strategy. (See "Overview of TORCH infections", section on 'Approach to the infant with suspected intrauterine infection'.)

Evaluation for metabolic disease or storage disorder – This may include testing for amino- and organic acidurias, lactate and/or very-long-chain fatty acids if the infant is hypotonic, or plasma 7-dehydrocholesterol if the infant has features suggestive of Smith-Lemli-Opitz syndrome (table 1). Consultation with a clinical geneticist is suggested to determine the most appropriate testing strategy. (See "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management", section on 'Initial evaluation' and "Inborn errors of metabolism: Identifying the specific disorder", section on 'Laboratory evaluation' and "Organic acidemias: An overview and specific defects".)

Ophthalmology referral – Ophthalmologic examination may provide clues to congenital infection or genetic disease.

Neuroimaging — Neuroimaging studies, which may identify structural causes of microcephaly, are most useful in microcephalic children with abnormal development [5,11]. Most children with symptomatic microcephaly have abnormal neuroimaging [41,42].

Magnetic resonance imaging (MRI) generally is the preferred imaging modality [12,18,23]. However, computed tomography (CT) may be warranted if craniosynostosis, TORCH infection, or Zika virus infection is suspected because CT is better than MRI in identifying microcalcifications and bone structure. Consultation with a pediatric radiologist may be helpful in planning the evaluation. (See "Overview of craniosynostosis", section on 'Computed tomography' and "Overview of TORCH infections" and "Congenital Zika virus infection: Clinical features, evaluation, and management of the neonate", section on 'Neuroimaging'.)

In a retrospective series of 680 children with symptomatic microcephaly who presented for pediatric neurology evaluation at two centers in Germany, 299 underwent cranial MRI [26]. Seventy-six percent had abnormal findings, including anomalies of white matter (eg, periventricular leukomalacia, delayed or disturbed myelination) in 40 percent and gyration defects in 14 percent. In another study of 55 children with symptomatic microcephaly, MRI revealed abnormalities in 68 percent of the children with genetic microcephaly and 100 percent of the children with acquired microcephaly (intrauterine or postnatally acquired) [42]. Migrational abnormalities were the most common findings in children with genetic microcephaly. Hydranencephaly and infarction were the most common findings in children with acquired microcephaly.

PRENATAL EVALUATION — Prenatally, microcephaly is diagnosed by ultrasound examination. We define prenatal microcephaly as head circumference <3 standard deviations (SD) below the mean or below the 2nd percentile for gestational age (image 4) [43-45]; however, the definition is not standardized and some authors use a threshold of <2 SD below the mean. The diagnosis is complicated by limitations in accuracy of head circumference measurements and inconsistency between prenatal and postnatal head circumference growth curves. Although there are reference values for fetal head circumference [46], standards have not been developed for specific populations (eg, based on sex, race/ethnicity) [47].

The approach to evaluation of prenatal microcephaly depends upon the presence of associated ultrasonographic anomalies, appropriateness of other fetal biometric parameters (eg, length of bones, abdominal circumference) in relation to gestational age, historical features (eg, consanguinity, intrauterine infection), and head circumference measurements of parents and siblings. Associated ultrasonographic anomalies may indicate syndromic microcephaly. (See "Prenatal diagnosis of CNS anomalies other than neural tube defects and ventriculomegaly".)

Additional evaluation (eg, genetic testing, fetal brain MRI, intrauterine infection) may be obtained if a specific diagnosis is desired to help with pregnancy management. Indications for these evaluations may include:

Parental consanguinity

Family members with microcephaly and stigmata of autosomal dominant conditions that include microcephaly (table 1)

Other central nervous system (CNS) and non-CNS morphologic abnormalities that suggest a chromosomal disorder

Otherwise unexplained fetal microcephaly (eg, family members with normal head circumference and fetal biometric parameters other than head circumference appropriate for gestational age)

Signs of intrauterine infection (eg, intracranial calcifications or ascites)

The developmental outcome of prenatal microcephaly depends upon the underlying etiology and associated abnormalities [48].

If there has been a previously affected child, prenatal assessment includes a level II (high risk) fetal sonogram at 20 weeks to assess anatomy. In fetuses with microcephaly, fetal MRI may be an adjunct to sonography. Consultation with a specialist in maternal-fetal medicine is recommended. Repeat sonogram can be obtained if repeat head measurements are desired later in pregnancy; the timing and frequency of repeat sonography depend upon the indication. However, severe postnatal microcephaly may not be evident on sonogram during the second trimester and may not be apparent until very late in pregnancy or even postnatally [49].

ASSOCIATED NEUROLOGIC IMPAIRMENT — The risk of associated neurologic impairment in children with microcephaly depends upon the underlying cause. It is usually increased in children whose microcephaly is part of a wider pattern of malformation (eg, trisomy 13, trisomy 18) and for those with intrauterine infection [14,48]. In a retrospective series of 680 children with microcephaly, most of whom had neurologic symptoms, 65 percent had intellectual disability or developmental delay and 43 percent had epilepsy [26].

The severity of cognitive impairment is generally related to the severity of microcephaly [20,21,50], as illustrated below:

In a study of 212 children with microcephaly, median intelligence quotient (IQ) decreased with decreasing occipitofrontal circumference (OFC) (median IQ 35 versus 62 in children with OFC more than 3.9 standard deviations [SD] below the mean and between 2.0 and 2.1 SD below the mean, respectively) [20].

In another study, IQ scores in seven-year-old children with OFC more than 3 SD below the mean were more likely to have IQ scores <70 than children with OFC between 2 and 3 SD below the mean (51 versus 11 percent) [21]. None of the children with OFC more than 3 SD below the mean had IQ scores greater than 100.

However, individuals with autosomal recessive primary microcephaly, Seckel syndrome, and other primary microcephaly syndromes generally fare better intellectually than would be predicted on the basis of their head circumference. (See "Microcephaly: A clinical genetics approach", section on 'Primary genetic microcephaly and its syndromes'.)

Most children with postnatal-onset microcephaly have poor developmental outcome [51,52]. In a longitudinal cohort of 57 children with postnatal-onset microcephaly who were followed for an average of four years, only 23 percent had a normal developmental quotient [51]. Maintenance of postnatal growth (weight and height) was associated with more favorable developmental outcomes, independent of underlying etiology.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Microcephaly".)

SUMMARY AND RECOMMENDATIONS

Monitoring head growth – Head circumference (occipitofrontal circumference [OFC]) should be measured at health maintenance visits between birth and three years of age and in any child with neurologic symptoms. OFC measurements are most informative when plotted over time. (See 'Monitoring head growth' above.)

Definitions – Microcephaly is an OFC greater than 2 standard deviations (SD) below the mean for a given age, sex, and gestation. Microcephaly is borderline when the OFC is between 2 and 3 SD below the mean, moderate when the OFC is between 3 and 5 SD below the mean, and severe when the OFC is ≥5 SD below the mean. Microencephaly is an abnormally small brain. (See 'Microcephaly' above.)

Etiology – A variety of genetic abnormalities and environmental insults can affect brain development, resulting in microencephaly and/or microcephaly (table 2). (See 'Etiology' above.)

Postnatal evaluation – Evaluation for microcephaly should be initiated when a single OFC measurement is more than 2 to 3 SD below the mean (after confirmation that the measurement was accurate) or when serial measurements reveal progressive decrease in head size. (See 'Overview of approach' above.)

The initial evaluation includes a history and physical examination of the child and parents. Factors that determine the urgency and extent of the ancillary evaluation of microcephaly include (algorithm 1) (see 'Overview of approach' above):

Age at onset

History of central nervous system trauma or infection

Associated symptoms

Neurodevelopmental abnormalities

Syndromic features (table 1)

Family history

Consultation with or referral to a clinical geneticist, pediatric neurologist, or specialist in pediatric infectious diseases can be helpful in determining the appropriate studies for the ancillary evaluation. (See 'Diagnostic testing' above and 'Neuroimaging' above and "Microcephaly: A clinical genetics approach", section on 'Initial genetics consultation'.)

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Topic 2839 Version 41.0

References

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