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Macrocephaly in infants and children: Etiology and evaluation

Macrocephaly in infants and children: Etiology and evaluation
Literature review current through: Jan 2024.
This topic last updated: Feb 20, 2023.

INTRODUCTION — The measurement of head circumference (also called occipitofrontal circumference [OFC]) is a direct reflection of head growth and an important step in the evaluation of childhood growth and development.

The etiology and evaluation of macrocephaly in infants and children will be discussed here. The etiology and evaluation of microcephaly are discussed separately. (See "Microcephaly in infants and children: Etiology and evaluation".)

MONITORING HEAD GROWTH — Head growth is affected by growth and alterations in the contents of the cranium (eg, brain, blood, cerebrospinal fluid [CSF], and bone) and the timing of these changes in relation to closure of the fontanelles and sutures. Changes in the volume of any component before the closure of the fontanelles and sutures may alter the occipitofrontal circumference (OFC). In contrast, changes in volume that occur after closure of the fontanelles and sutures bring about compensatory changes in the other components. (See "The pediatric physical examination: HEENT", section on 'Anterior and posterior fontanelles'.)

OFC should be measured in all children at health maintenance visits between birth and three years of age. OFC should also be measured at each visit in children of all ages with neurologic or developmental complaints. Deviations from normal head growth may be the first indication of an underlying congenital, genetic, or acquired problem (eg, congenital infection, genetic syndrome, hydrocephalus, intracranial hemorrhage, storage disease, or neoplasm) [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 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]. (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

Macrocephaly is defined as an occipitofrontal circumference greater than two standard deviations above the mean for a given age, sex, and gestation (ie, ≥97th percentile) [5,8,9].

Megalencephaly (also called macrencephaly) is enlargement of the brain parenchyma [10].

ETIOLOGY — Macrocephaly is caused by an increase in size of any of the components of the cranium (brain, cerebrospinal fluid [CSF], blood, or bone) or can be attributable to increased intracranial pressure (ICP) (table 1) [5,6,11]. The most common causes of macrocephaly vary with age of onset (table 2). Familial megalencephaly appears to be the most common etiology of mild macrocephaly, especially if the child has normal development [12-15].

Increased brain parenchyma — Megalencephaly is classified as anatomic or metabolic [16].

Anatomic megalencephaly — Anatomic megalencephaly is caused by an increase in the size or number of brain cells in the absence of metabolic disease or acute encephalopathy [5,6,16]. Anatomic megalencephaly is usually present at birth [11]. Postnatally, the occipitofrontal circumference (OFC) continues to be increased and to progress along a trajectory parallel to the upper growth curve percentiles.

Familial megalencephaly – The most common type of anatomic megalencephaly is benign familial megalencephaly (also called genetic megalencephaly) [12-15]. Children with familial megalencephaly are born with large heads and normal body size. During infancy, OFC increases to greater than the 90th percentile, typically 2 to 4 cm (0.8 to 1.5 inches) above, but parallel to, the 98th percentile [5,6]. The OFC may increase by 0.6 to 1 cm (0.2 to 0.4 inches) per week (compared with the normal 0.4 cm [0.15 inches] per week) [13,16]. Head growth velocity slows to a normal rate by approximately six months of age [5].

In children with a normal neurologic examination, normal development, no clinical features suggestive of a specific syndrome, and no family history of abnormal neurologic or developmental problems, familial megalencephaly can be confirmed by measuring the patient's parents' head circumferences and by using Weaver curves [5,17]. If the child's OFC falls within the normal ranges as estimated using the Weaver curves, neuroimaging is not necessary. (See 'Assessment of familial macrocephaly' below.)

Other causes of anatomic megalencephaly – Other disorders associated with anatomic megalencephaly include (table 1) [6,8,11]:

Neurocutaneous disorders (eg, neurofibromatosis, tuberous sclerosis complex, linear sebaceous nevus syndrome, and hypomelanosis of Ito) (table 3) – (See "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis" and "Tuberous sclerosis complex: Clinical features".)

Autism spectrum disorder (ASD) – Macrocephaly, accelerated head growth during the first year of life, and megalencephaly may be associated with ASD. Children with ASD have associated impairments in socialization, communication, and behavior. (See "Autism spectrum disorder in children and adolescents: Clinical features", section on 'Macrocephaly'.)

Some children with ASD and macrocephaly may have germline PTEN mutations. (See "PTEN hamartoma tumor syndromes, including Cowden syndrome", section on 'Autism spectrum disorders and macrocephaly'.)

Achondroplasia – Achondroplasia is the most frequent form of short-limbed dwarfism (picture 2A-B). In addition to megalencephaly, children with achondroplasia also may develop hydrocephalus. (See "Achondroplasia".)

Cerebral gigantism (Sotos syndrome) – Cerebral gigantism is an overgrowth syndrome with prenatal onset. In addition to megalencephaly, children with cerebral gigantism also may develop hydrocephalus [18]. (See "The child with tall stature and/or abnormally rapid growth", section on 'Cerebral gigantism'.)

Fragile X syndrome – Fragile X syndrome is the most common form of familial intellectual disability in males. The OFC percentile is usually greater than the weight and height percentiles but may not be more than two standard deviations above the mean. Characteristic features (which typically are mild or absent before puberty) include a long face, large ears, prominent jaw, and macro-orchidism. (See "Fragile X syndrome: Clinical features and diagnosis in children and adolescents".)

Cowden syndrome – Cowden syndrome is an autosomal dominant cancer predisposition syndrome that is caused by mutations in the PTEN gene. Affected individuals have an increased risk for thyroid malignancy, and females have a risk for early breast cancer. (See "PTEN hamartoma tumor syndromes, including Cowden syndrome", section on 'Cowden syndrome'.)

Nevoid basal cell carcinoma syndrome (also called Gorlin syndrome) – Nevoid basal cell carcinoma syndrome is an autosomal dominant syndrome that predisposes to basal cell carcinoma (BCC) during adolescence and young adulthood. Affected individuals have a large OFC, "coarse" facial features (eg, prominent forehead, hypertelorism, widened nasal bridge, and mandibular prognathism), jaw cysts, and palmar/plantar pits. It is caused by mutations in the PTCH1 gene. (See "Nevoid basal cell carcinoma syndrome (Gorlin syndrome)".)

Metabolic megalencephaly — The deposition of metabolic products in the brain tissue causes metabolic megalencephaly [5,16,19]. The OFC of children with metabolic megalencephaly is usually within the normal range at the time of birth but increases during the neonatal period [6,11].

Examples of diseases that cause metabolic megalencephaly include leukodystrophies (Alexander disease, Canavan disease, megalencephalic leukoencephalopathy), lysosomal diseases (Tay-Sachs disease, mucopolysaccharidosis, and gangliosidosis), and organic acid disorders (eg, glutaric aciduria type 1) (table 1) [5,6,10,20].

Increased cerebrospinal fluid

Hydrocephalus — Hydrocephalus is a disorder in which the cerebral ventricular system contains an excessive amount of CSF, resulting in increased pressure and dilatation. Hydrocephalus may be caused by increased production, decreased absorption, or obstruction to CSF flow. Hydrocephalus is discussed separately. (See "Hydrocephalus in children: Physiology, pathogenesis, and etiology" and "Hydrocephalus in children: Clinical features and diagnosis".)

Increased OFC is frequently the presenting sign of hydrocephalus (figure 3). In a retrospective cohort of 298 children <5 years of age who were hospitalized for intracranial expansion, hydrocephalus was the main diagnosis in 173 (58 percent) [21]. Approximately three-fourths of the children with hydrocephalus were referred for increasing OFC; other signs and symptoms included nausea/vomiting, irritability, delayed development, and aberrant head shape [21].

Benign enlargement of the subarachnoid space — Benign enlargement of the subarachnoid space (also called benign extra-axial fluid, idiopathic external hydrocephalus, extraventricular hydrocephalus, and benign subdural effusion) is another cause of macrocephaly [22-25].

Benign enlargement of the subarachnoid space is relatively common, accounting for 16 percent of infants with macrocephaly in one case series [26]. In population-based surveillance in Norway, the incidence of benign enlargement of the subarachnoid space was 0.4 per 1000 live births [27]. It is more common in males than in females and frequently has occurred or occurs in other family members [5,22,27,28]. Macrocephaly may or may not be present at birth; if it is not present at birth, the OFC rapidly increases to greater than the 95th percentile and then tends to parallel the curve [6,22,29,30]. The head growth velocity typically slows to normal by the time the child reaches six months of age [5].

Imaging is necessary to make the diagnosis. Head ultrasonography, magnetic resonance imaging (MRI), or computed tomography (CT) scan demonstrates enlargement of the subarachnoid space in the frontal or frontoparietal areas with a prominent interhemispheric fissure and normal ventricles (image 1) [6,22]. The anterior location of the fluid collection distinguishes benign enlargement of the subarachnoid space from cerebral atrophy, in which the fluid collection is distributed anteriorly and posteriorly [24].

Children who were born at term and have enlargement of the subarachnoid space typically have normal development and normal neurologic examinations, though there are exceptions [22,26,29-36]. These children should be observed closely for developmental or neurologic problems. OFC measurements should be plotted monthly for six months to be certain that head growth slows to a normal rate and begins to parallel the normal curve [5]. Repeat imaging is unnecessary unless head growth deviates from the normal curve, the neurologic examination is abnormal, or the development is delayed [6,36]. (See 'Neuroimaging' below.)

Children with benign enlargement of the subarachnoid space usually do not require surgical intervention [36]. However, they may be at increased risk for subdural hematoma with minimal or no trauma [37,38]. (See "Intracranial subdural hematoma in children: Epidemiology, anatomy, and pathophysiology" and "Intracranial subdural hematoma in children: Clinical features, evaluation, and management".)

"Benign" enlargement of the subarachnoid space should be distinguished from extra-axial fluid collections that occur in survivors of the neonatal intensive care unit and/or extracorporeal membrane oxygenation. Macrocephaly and extra-axial fluid in these children are associated with adverse neurologic and developmental outcomes [39-41]. The relative contributions of the extra-axial fluid, medical problems, and/or complications of therapy to the adverse outcome are not clear.

Increased blood — Increased intracranial blood volume may be caused by hemorrhage (intraventricular, subdural, epidural) or arteriovenous malformation. (See "Intracranial subdural hematoma in children: Epidemiology, anatomy, and pathophysiology" and "Intracranial subdural hematoma in children: Clinical features, evaluation, and management".)

Increased OFC is rarely the sole manifestation of intracranial hemorrhage. In a retrospective cohort of 298 children <5 years of age who were hospitalized for intracranial expansion, intracranial bleeding was the main diagnosis in 35 (12 percent) [21]. Increased OFC was the presenting sign in only two; more common presentations included irritability, seizures, nausea/vomiting, fatigue/drowsiness, and paresis.

Increased bone — Bone thickening, a rare cause of macrocephaly, can occur from bone marrow expansion, as seen in thalassemia major, or primary bone disorders (eg, skeletal and cranial dysplasias) (table 1).

Increased intracranial pressure — Increased ICP may be idiopathic (ie, pseudotumor cerebri) or caused by increased volume of the intracranial contents (eg, brain, CSF, blood, mass lesions), infection, inflammation, and various toxic or metabolic abnormalities (eg, lead poisoning, vitamin A deficiency or excess, galactosemia). (See "Idiopathic intracranial hypertension (pseudotumor cerebri): Clinical features and diagnosis" and "Elevated intracranial pressure (ICP) in children: Clinical manifestations and diagnosis".)

Mass lesions — Intracranial mass lesions include intracranial cysts, tumors, or abscesses [8]. Increased OFC is rarely the sole manifestation of intracranial tumor.

In a retrospective cohort of 298 children <5 years of age who were hospitalized for intracranial expansion, tumor was the main diagnosis in57 (19 percent) [21]. Increased OFC was the presenting sign in only three; more common presentations included nausea/vomiting, unsteadiness, headache, fatigue, torticollis, and irritability.

In the same cohort, intracranial cyst was the main diagnosis in 29 children (10 percent); increased OFC was the most frequent presenting sign (in nine patients); other symptoms included seizures, headache, and nausea/vomiting. (See "Clinical manifestations and diagnosis of central nervous system tumors in children".)

EVALUATION OF POSTNATAL MACROCEPHALY

Overview of approach — Evaluation for macrocephaly should be initiated when [19,29,42]:

A single occipitofrontal circumference (OFC) measurement is abnormal, or

Serial measurements reveal progressive enlargement (ie, crossing of one or more major percentile lines [eg, 10th, 25th, 50th, 75th, 90th] between health supervision visits), or

For infants age <6 months, there is an increase in OFC of >2 cm (0.8 inches) per month

It is important to verify the measurement; isolated deviant measurements often are due to technical error.

The evaluation of macrocephaly includes a thorough history and physical examination of the child and parents (in consideration of familial variation in head size). Additional evaluation, which is directed by clinical findings from the history and examination, may include neuroimaging and other tests (algorithm 1). (See 'Other tests' below and 'Neuroimaging' below.)

Factors that increase the urgency and extent of the imaging and laboratory evaluation include [10,29]:

Whether the fontanelles remain open

History of central nervous system (CNS) trauma or infection

Associated symptoms (eg, headache, ataxia), neurodevelopmental abnormalities, or syndromic features

Family history of neurologic or cutaneous abnormalities

Elevated ICP, CNS trauma, or CNS infection — Urgent evaluation is necessary if there are symptoms or signs of increased intracranial pressure (ICP) (eg, headache, vomiting, altered mental status, bulging fontanelle, papilledema), CNS trauma, or CNS infection (eg, fever, meningismus, lethargy, irritability). (See "Elevated intracranial pressure (ICP) in children: Clinical manifestations and diagnosis".)

Syndromic features — Consultation with, or referral to, a clinical geneticist should be initiated to determine the appropriate diagnostic evaluation if the child has syndromic features (table 3). (See 'Other tests' below.)

Developmental delay — If syndromic features are absent and the child has developmental delay, neuroimaging (usually with MRI or CT) is warranted. Neuroimaging may reveal abnormalities consistent with a particular etiology (eg, hydrocephalus, leukodystrophy, gangliocytoma in PTEN hamartoma syndrome) [10]. (See 'Neuroimaging' below.)

If neuroimaging is normal in a child with delayed development, referral to a developmental pediatrician, clinical geneticist, or pediatric neurologist, and the initiation of diagnostic testing may be indicated. The differential diagnosis includes autism spectrum disorder (ASD), metabolic disorders, microduplication syndromes, and microdeletion syndromes [10]. (See 'Other tests' below.)

Normal development — If syndromic features are absent, the degree of macrocephaly is modest, and development is normal, the OFC of first-degree relatives (parents, siblings) should be measured to assess for familial macrocephaly [10]. Ultrasonography of the head may be undertaken in infants with an open fontanelle. (See 'Assessment of familial macrocephaly' below and 'Neuroimaging' below.)

History and examination

History – Important aspects of the history include [43]:

Birth weight, length, and OFC and growth trajectory (table 2)

Rate of attainment and/or loss of milestones

History of seizures

History of predisposing factors for hydrocephalus (eg, meningitis, prematurity with intraventricular hemorrhage)

Family history of consanguinity, large OFC, neurocutaneous disorders, metabolic disorders, and malignancies (the PTEN syndromes [eg, Bannayan-Riley-Ruvalcaba/Cowden syndrome, Proteus syndrome] are associated with breast and thyroid cancers); the family history should include three generations to detect recessive disorders, which may skip a generation. (See "PTEN hamartoma tumor syndromes, including Cowden syndrome".)

Physical examination – Important aspects of the physical examination of a child with macrocephaly include [8,11,29,43]:

General appearance – Dysmorphic features may suggest a particular syndrome (table 3). A large cranial vault may be associated with a prominent forehead and a long occipitofrontal diameter (dolichocephaly or scaphocephaly) [10]. Increased width at the cranial base may be associated with mild hypertelorism, down-slanting palpebral fissures, and a relatively small facial area (giving the face a triangular appearance).

OFC – The OFC should be measured and plotted on a standard curve. Spurious causes of increased OFC should be excluded (eg, caput succedaneum, cephalohematoma, hair arrangements, abnormal head shape) [8]. (See 'Monitoring head growth' above and "Normal growth patterns in infants and prepubertal children", section on 'Head growth'.)

The OFC should be compared with any previous plotted measurements to help determine the onset and progression of increased OFC (table 2). Children with anatomic megalencephaly often are macrocephalic at birth, whereas children with metabolic megalencephaly usually are normocephalic at birth and become macrocephalic in the neonatal period [6].

Weight and stature trajectories – The child's weight and length (or height) should also be measured and plotted on standard curves. They should be compared with previous plotted points to assess the growth trajectory. Several macrocephaly syndromes are associated with short or tall stature (overgrowth) (table 3) [10,11].

Head – In addition to measuring the OFC, examination of the head should include assessment of the fontanelles and auscultation for intracranial bruits (suggestive of arteriovenous malformation). Transillumination of the skull may be performed in infants younger than one year.

The size and timing of closure of the fontanelles should be noted. Palpation or shining a light tangentially across the anterior fontanelle should reveal a slightly concave contour when the child is relaxed and in the upright position. Increased intracranial pressure (ICP) may manifest as an enlarged, convex fontanelle or separation of the suture lines. The anterior fontanelle usually closes by 24 months. Persistent enlargement of the anterior fontanelle in children with macrocephaly may be associated with a number of conditions, including [29]:

-Hydrocephalus (see "Hydrocephalus in children: Physiology, pathogenesis, and etiology" and "Hydrocephalus in children: Clinical features and diagnosis")

-Achondroplasia (see "Achondroplasia")

-Cleidocranial dysplasia (see "Skeletal dysplasias: Specific disorders" and "Skeletal dysplasias: Specific disorders", section on 'Cleidocranial dysplasia')

-Rickets (see "Overview of rickets in children")

-Osteogenesis imperfecta (see "Osteogenesis imperfecta: An overview")

Transillumination of the skull may be performed in children younger than one year of age but is not commonly used in situations where there is easy access to neuroimaging (eg, ultrasonography of the head). Transillumination of the skull requires a flashlight that has a narrow, opaque, sponge-rubber cuff around the light [42]. An alternative is a "cold" fiberoptic halogen light source. The light is applied to the infant's scalp in a darkened room. Translucency that extends beyond 2 to 2.5 cm (0.8 to 1 inch) in the frontal area and beyond 2 cm (0.8 inches) in the occipital region may be abnormal and indicative of subdural effusion, subdural hematoma, hydrocephalus, hydranencephaly, porencephaly, or increased ICP. Findings on transillumination generally require confirmation with neuroimaging. Transillumination is hampered by cephalohematoma, caput succedaneum, scalp edema, thick black hair, or bony cortex thicker than 1 cm (0.4 inches).

Eyes – The eyes should be examined for papilledema (suggestive of increased ICP, but may be absent in infants), cataracts, and retinal abnormalities (suggestive of metabolic disease and/or syndromic macrocephaly). (See "Cataract in children", section on 'Clinical features'.)

Skin – Examination of the skin for hypopigmented (picture 3) or hyperpigmented macules, angiomas (picture 4), shagreen patches (picture 5), telangiectasia, subcutaneous nodules, lipomas, papillomata (picture 6 and table 3).

Cardiovascular system – Signs of congenital heart disease or heart failure (suggestive of a neuro-cardio-facio-cutaneous syndrome) (table 3).

Abdomen – Hepatosplenomegaly (suggestive of a metabolic or storage disorder).

Musculoskeletal system – Evidence of skeletal dysplasia (eg, short limbs, absent or hypoplastic clavicles) (table 1). (See "Skeletal dysplasias: Specific disorders".)

Neurologic assessment – Abnormal tone or deep tendon reflexes. Hypotonia is a common feature of overgrowth syndromes (table 3); spasticity may be a feature of leukodystrophy (eg, Canavan disease, Alexander disease). (See "Alexander disease".)

Assessment of familial macrocephaly — The parents' OFC measurements should be obtained if possible. These measurements can be used to calculate a standard score for use with the Weaver curves to determine the genetic contribution to macrocephaly [17].

The Weaver curve helps to determine whether genetic influences contribute to a child's macrocephaly [17]. A standard score is calculated for the child and each of the parents using the following formula:

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

The mean values and SD for age and sex are listed in the table (table 4). In calculating the parents' standard scores, the mean value and SD for an 18-year-old should be used.

The average of the parents' SS and the child's SS are plotted on the Weaver curve (figure 4). A genetic contribution to macrocephaly is suggested if the child's SS is within the range determined by the average parental score, thus permitting the evaluation to be tailored appropriately [17].

Neuroimaging — Neuroimaging should be obtained in children in whom an expanding lesion is suspected (eg, rapid increase in OFC, for example >2 cm (0.8 inches)/month in an infant <6 months of age) [42]. Among other children, neuroimaging is most helpful (in terms of determining an etiology) for those who have developmental delay but lack features suggestive of a particular syndrome [43,44]. Among children who have features suggestive of a particular syndrome, other laboratory tests (eg, genetic tests) are more helpful in confirming the diagnosis. (See 'Other tests' below.)

Approach to imaging – Radiologic evaluation of macrocephaly may involve radiographs, ultrasonography, CT, or MRI of the head. The optimal imaging strategy permits the detection of significant intracranial pathology and minimizes the potential hazards of radiation and/or sedation [45].

The approach to imaging in children with macrocephaly depends upon the age of onset and associated symptoms. Normal infants may experience genetic shifting in OFC percentiles. Thus, a slow shift across one or two major percentile lines (eg, 10th, 25th, 50th, 75th, 90th) in a developmentally normal child warrants careful clinical observation. If the child's OFC remains within the predicted ranges based on Weaver curves, imaging is not necessary. However, if a child has a dramatic increase in OFC across several major percentile lines or exhibits worrisome neurologic or developmental symptoms, neuroimaging should be undertaken.

The timing of closure of the anterior fontanelle is an important factor when considering clinical observation versus imaging. Head ultrasonography, which is noninvasive and does not require sedation, can only be performed in infants with an open fontanelle. Once the anterior fontanelle closes, neuroimaging options include head CT or MRI, each of which may require sedation.

Radiographs – Radiographs may provide evidence of primary skeletal dysplasia. Although they have limited utility in the evaluation of increased ICP, radiographs may demonstrate findings associated with increased ICP, including widening of sutures, prominent convolutional markings on the inner table of the skull ("beaten silver skull"), and erosion of the sella turcica [8].

Ultrasonography – Head ultrasonography is a reasonable initial study in infants with macrocephaly, normal neurodevelopmental examination, no evidence of increased ICP, and an open anterior fontanelle [45-47]. It may identify ventricular or subarachnoid space enlargement. If head ultrasonography is normal, the infant's OFC and neurodevelopmental status should be monitored closely. (See 'Management' below.)

MRI and CT – Infants with neurologic abnormalities, progressively enlarging OFC, or increased ICP and a closed anterior fontanelle should be evaluated with MRI or CT. A number of factors affect the choice of neuroimaging study, including the suspected etiology, acuity of symptoms, need for sedation, and availability. MRI generally is preferred to CT because MRI avoids exposure to ionizing radiation. Ultrafast MRI techniques may avoid the need for sedation, which is the major disadvantage of MRI [48]. Consultation with a pediatric neurologist and/or neuroradiologist can be helpful in determining the best study for a particular child.

MRI – MRI can delineate the size and position of the ventricles; determine the width of the subarachnoid space; distinguish communicating from noncommunicating hydrocephalus; and identify white matter changes, mass lesions, vascular malformations, subdural fluid collections, and porencephalic cysts [29,43]. MRI with contrast or angiography may be performed to evaluate vascular abnormalities. Ultrafast brain MRI is radiation free and avoids the use of sedation or general anesthesia [49]. If available, it is an option for the evaluation of ventriculomegaly, macrocephaly, and intracranial cysts [49].

CT – CT is used primarily in the acute setting for the evaluation of obstructive hydrocephalus. CT also may be used to identify intracranial calcification (which may be present in basal cell nevus syndrome, infection, hypoparathyroidism, or parasitic cysts) [29]. In addition, CT can identify tubers in tuberous sclerosis complex or asymmetry of the cerebral hemispheres in children with linear sebaceous nevus syndrome. (See "Tuberous sclerosis complex: Management and prognosis", section on 'Brain imaging'.)

Other tests — Additional diagnostic evaluation is directed by the history and physical examination. Consultation with, or referral to, a clinical geneticist can be helpful in determining the appropriate studies.

Children with syndromic macrocephaly may need evaluation for associated abnormalities (eg, echocardiogram, ophthalmologic examination, abdominal ultrasonography, long bone radiographs) [11].

Children with loss of milestones, degenerative conditions, ASD, or intellectual disability/developmental delay may need metabolic evaluation (eg, urine organic acids and mucopolysaccharidosis screen), genetic studies (eg, for duplications, fragile X syndrome, or PTEN mutation analysis), or electroencephalogram. (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 "PTEN hamartoma tumor syndromes, including Cowden syndrome", section on 'Diagnostic criteria'.)

Children with suspected primary skeletal disturbance may need radiographs of the long bones to evaluate cortical thickness.

A skeletal survey is warranted in young children in whom physical abuse is suspected (eg, those with subdural hematoma). (See "Intracranial subdural hematoma in children: Clinical features, evaluation, and management" and "Orthopedic aspects of child abuse", section on 'Skeletal survey'.)

Referral indications — Indications for referral depend upon clinical features and the results of the initial evaluation.

Referral to a clinical geneticist may be helpful in directing additional evaluation in children with syndromic features or suspected metabolic disease.

Children with seizures or abnormal MRI features should be referred to a pediatric neurologist [43].

Children with hydrocephalus or mass lesions may require referral to a neurosurgeon.

Children with developmental problems may benefit from referral to a child development team.

EVALUATION OF PRENATAL MACROCEPHALY — Prenatally, macrocephaly is diagnosed by ultrasound examination and is defined as head circumference >2 SD above the mean or above the 98th percentile for gestational age (as assessed by last menstrual period or femur length). The diagnosis is complicated by limitations in accuracy of head circumference measurements and inconsistency between prenatal and postnatal head circumference growth curves [50]. Although there are reference values for fetal head circumference [51], standards have not been developed for specific populations (eg, based on sex, race/ethnicity).

The approach to evaluation of prenatal macrocephaly varies according to associated ultrasonographic anomalies, appropriateness of other fetal biometric parameters (eg, length of bones, abdominal circumference) in relation to gestational age, features of the history (eg, consanguinity, familial macrocephaly), and head circumference measurements of parents and siblings [50].

Associated ultrasonographic anomalies (eg, callosal dysgenesis, malformations of cortical development, hypertelorism, enlarged kidneys, polydactyly, hypoplastic long bones) may indicate syndromic macrocephaly (table 3) [50].

Head circumference, abdominal circumference, and long-bone length that are greater than expected for gestational age may indicate an overgrowth syndrome (eg, Sotos syndrome, Weaver syndrome).

Fetal head circumference between 2 and 2.5 SD above the mean for gestational age and family members with macrocephaly but no stigmata of autosomal dominant conditions that include macrocephaly (table 3) may indicate familial macrocephaly, although it is unusual for this to present prenatally. (See 'Anatomic megalencephaly' above.)

Additional evaluation (eg, karyotype, fetal brain MRI) may be obtained if a specific diagnosis is desired to help with pregnancy management. Indications for these evaluations may include [50]:

Parental consanguinity

Family members with macrocephaly and stigmata of autosomal dominant conditions that include macrocephaly (table 3)

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

The developmental outcome of prenatal macrocephaly depends upon the underlying etiology and associated abnormalities [52].

Cesarean delivery is indicated in cases in which the head circumference is increased and vaginal delivery is thought not to be possible. The cut-off for determining when a cesarean delivery is indicated will vary with gestational age at delivery, the absolute and relative head circumference, and the size of the maternal pelvis. When the head circumference exceeds 40 cm (16 inches), abdominal delivery should be considered.

MANAGEMENT — The management of macrocephaly depends upon the etiology.

Children who have asymptomatic familial megalencephaly do not require treatment.

Children who have hydrocephalus may require neurosurgical intervention (eg, placement of a ventriculoperitoneal shunt) to reduce cerebrospinal fluid volume. (See "Hydrocephalus in children: Management and prognosis", section on 'Management'.)

Infants and children who have benign enlargement of the subarachnoid space do not usually require intervention. They should be followed closely for developmental or neurologic problems. Occipitofrontal circumference measurements should be plotted monthly for six months to be certain that the growth is paralleling the normal curve. Repeat imaging is not necessary unless head growth deviates from the curve, the neurologic examination is abnormal, or the development is delayed [6]. (See 'Benign enlargement of the subarachnoid space' above and "Developmental-behavioral surveillance and screening in primary care".)

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: Macrocephaly".)

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. OFC measurements are most informative when plotted over time. (See 'Monitoring head growth' above.)

Definitions – Macrocephaly is an OFC greater than two standard deviations (SD) above the mean for a given age, sex, and gestation (ie, ≥97th percentile). Megalencephaly is enlargement of the brain parenchyma. (See 'Definitions' above.)

Etiology – Macrocephaly is caused by an increase in size of any of the components of the cranium (brain, cerebrospinal fluid, blood, or bone) or increased intracranial pressure (table 1). (See 'Etiology' above.)

Evaluation

Evaluation for macrocephaly should be initiated when (algorithm 1) (see 'Overview of approach' above):

-A single OFC measurement is abnormal (after confirmation that it was accurately measured), or

-Serial measurements reveal progressive enlargement, or

-For infants age <6 months, when there is an increase in OFC of >2 cm/month (0.8 inches/month)

Factors that increase the urgency and extent of the evaluation of the child with macrocephaly include history of central nervous system trauma or infection; associated symptoms, neurodevelopmental abnormalities, or syndromic features (table 3); and family history (algorithm 1). (See 'Overview of approach' above.)

Neuroimaging should be obtained in children suspected of having an expanding lesion. Among other children, neuroimaging is most helpful (in terms of determining an etiology) for those who have developmental delay but lack features suggestive of a particular syndrome. The optimal imaging strategy permits the detection of significant intracranial pathology and minimizes the potential hazards of radiation and/or sedation. (See 'Neuroimaging' above.)

Additional diagnostic evaluation is directed by the history and physical examination. Consultation with, or referral to, a clinical geneticist can be helpful in determining the appropriate studies. (See 'Other tests' above.)

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Topic 2849 Version 41.0

References

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