Macrocephaly

Etiology

Macrocephaly refers to a large head size and does not specify the cause. Prior to the closure of the fontanelles and sutures in children and an increase in the volume of any of the intracranial contents will cause the size of the head to increase. Etiology of the condition can be due to increased brain parenchyma, also known as megalencephaly, or increased cerebrospinal fluid (CSF). There are also instances when macrocephaly can be caused by increased blood, thickened bone, or increased intracranial pressure (ICP) from other causes.

Megalencephaly may be anatomic, which refers to an increase in the size or number of cells in the brain without metabolic disease process, or maybe metabolic. Anatomic megalencephaly is most often familial and benign. In these cases, the patient is often born with a large head and a normal-sized body with a further rapid increase in head size over the first six months of life (head circumference increases by 0.6 to 1 cm rather than average 0.4 cm/week). Familial megalencephaly usually produces mild macrocephaly, typically 2 to 4 cms above the 90th percentile, and the growth curve follows above but parallel to 98th percentile. Family members may also have large heads.[1]

The other causes of anatomic megalencephaly are varied and often genetic.[2] Neurocutaneous disorders such as tuberous sclerosis, neurofibromatosis, and hypomelanosis of Ito may be associated with megalencephaly. Patients with autism spectrum disorder may have macrocephaly/megalencephaly. Achondroplasia may also present with megalencephaly or hydrocephalus.

Sotos syndrome, also known as cerebral gigantism, is another cause of megalencephaly. Other features include frontal bossing, a high forehead, high arched palate, intellectual disability or developmental delay, hypertelorism, and a prominent jaw or pointed chin. Most cases of Sotos syndrome result through sporadic mutations in the NSD1 gene.

Fragile X syndrome's features are macrocephaly, intellectual disability, prominent ears and jaw, and macroorchidism. These features may not be as noticeable prior to puberty. Fragile X syndrome is caused most frequently by a CGG trinucleotide repeat in the FMR1 gene, which is located on the X chromosome.

Nevoid basal cell carcinoma syndrome, also known as Gorlin syndrome, relays a predisposition for basal cell carcinomas to the patient. These patients have macrocephaly and coarse facial features. Gorlin syndrome is caused by mutations in the PTCH1 gene. The inheritance pattern is autosomal dominant.

Cowden syndrome is another syndrome that gives the patient susceptibility to certain cancers. Patients with Cowden syndrome can have macrocephaly and can develop thyroid or breast cancers. Cowden syndrome is caused by mutations in the PTEN gene and is also autosomal dominant.

In cases of metabolic megalencephaly, the brain parenchyma is increased in size due to the deposition of metabolic products within the brain tissue. This can include the leukodystrophies such as Alexander disease, lysosomal storage diseases such as Tay-Sach disease, and organic acid disorders. Patients with these conditions often have a normal head circumference that is normal at birth but increases at a rate that exceeds their expected curve.[3] 

Macrocephaly may also be caused by an increase in cerebrospinal fluid. In hydrocephalus, the ventricular system contains an abnormally high amount of CSF, leading to increased pressure and dilatation of the ventricles. Hydrocephalus can be due to increased production, decreased absorption, or a CSF flow obstruction. The clinical presentation of elevated intracranial pressure from hydrocephalus includes lethargy, irritability, developmental problems, nausea or vomiting, and restricted upgaze. The head may enlarge while cranial sutures and fontanelles are still open, but when there is no longer a compensatory mechanism such as this, then surgical management may need to be pursued. This could include a ventriculoperitoneal shunt. Elevated intracranial pressure can also result from a space-occupying lesion located within the cranial vault. Benign enlargement of subarachnoid space is another relatively common cause of macrocephaly secondary to an increase in CSF that manifests in the first six months of life, seen more in boys than girls.

Neuroimaging reveals enlargement of anterior subarachnoid space and distinguishes it from anterior to posterior symmetric fluid collection associated with cerebral atrophy. Infants with this condition, especially if born at term, are developmentally normal with a normal neurological examination. However, they have a higher risk of subdural hemorrhage in the setting of minimal or no trauma. Similar neuroimaging features in infants with a history of complicated neonatal intensive care unit stay or requirement of early extracorporeal membrane oxygenation (ECMO) may represent a different subset and may be associated with worse developmental and neurologic outcomes. 

Increased blood within the cranium can also result in increased head size. This can be related to hemorrhage or an arteriovenous malformation. In the case of hemorrhage, this may be related to non-accidental trauma, and further workup of the social components of the history would be required. On physical exam, the patient may have other injuries or retinal hemorrhages. Either way, the presentation with intracranial hemorrhage following non-accidental trauma would likely accompany other features, such as seizures, nausea/vomiting, lethargy, or irritability.

One more consideration for increased head size is an increase in the volume of the skull. Bone thickening can result from an expansion of the bone marrow, which can be seen in thalassemia major, or from skeletal/cranial dysplasias.[4]

Epidemiology

By definition, macrocephaly is found in about 2% to 3% of the population. There is not a significant difference between genders. The specifics of epidemiology, including geographic distribution, depending on the particular underlying cause.

Pathophysiology

The pathogenesis of macrocephaly is etiology-specific as it can result from overgrowth of the skull bones or an increase in the volume of the intracranial structures like CSF, blood, or the brain parenchyma. Please review the etiology section for a detailed review of causes associated with macrocephaly.

History and Physical

It is important to identify macrocephaly using a standard head measurement. To obtain this measurement, a measuring tape is wrapped around the head, aligning just above the eyebrows on the anterior aspect and then over the prominent aspect of the posterior portion of the head. This is also known as the occipital frontal circumference (OFC). This measurement is plotted on the 2006 WHO international growth charts for children aged less than 24 months using the patient's sex and age, from which percentiles are determined. To meet the criteria for macrocephaly, the patient's head circumference must lie at or above the 97th percentile.[5]

To determine if the macrocephaly is related to another process or syndrome, a careful history should be taken with attention to birth measurements and growth trajectory, any other associated medical problems, a developmental history, and any family history of macrocephaly. For instance, it would be important to know if the patient has had any history of CNS trauma or infection. If there were meningitis or intraventricular hemorrhage in the neonatal state, hydrocephalus could develop as a result, and these patients should be followed closely.[6]

Physical exam apart from head measurements palpation of the fontanelles should include an examination of general appearance and facial features, skin, and complete neurologic exam to identify any clues to underlying etiology or possible genetic syndrome. The ophthalmologic exam should also be performed as patients with increased intracranial pressure may have papilledema, though this may not be seen in infants with open fontanelles. Some other focussed physical examination for macrocephaly includes transillumination of the calvaria, evaluation for signs of skeletal dysplasia, and auscultation for a cranial bruit.

Evaluation

If the patient is developmentally appropriate for the age and has a normal neurologic exam, there are no abnormal features to suggest a specific genetic syndrome, and there is no family history of any developmental or neurologic problems, then Weaver curves may be utilized using both parents' head circumferences. If the patient is within normal range after plotting on this curve, then no further evaluation is needed.[7]

Otherwise, additional evaluation may be warranted when a measurement is above the 97th percentile on the patient's growth chart. If serial measurements cross one or more major percentile lines (the patient's head is growing significantly faster than expected for his or her growth curve), or if the patient is less than 6 months old and head size increases greater than 2 cm in a month, further testing may be warranted.

Head imaging may be required to evaluate the underlying process causing a patient to have macrocephaly. If the anterior fontanelle is open, a head ultrasound may be the simplest and most cost-effective method for the evaluation of any intracranial abnormalities. A CT scan can be done quickly but does expose the young infant to radiation, which in this age is typically avoided unless deemed medically necessary. An MRI, which would likely require an infant to undergo sedation and is more expensive than ultrasound or CT, can be done without the risk of radiation that a CT carries and would provide more detailed structural information. [8][9]

In the case of benign macrocephaly, dilatation of the subarachnoid spaces can be seen on imaging. Additional findings may include slightly enlarged ventricles and/or prominence of the basilar cisterns.[10]

Treatment / Management

The management of macrocephaly is dependent upon the exact etiology. If hydrocephalus is present, then referral to neurosurgery for surgical intervention may be required. Urgent neurosurgical intervention may be lifesaving in children with hydrocephalus and concurrent symptoms of increased intracranial pressure. Drainage of CSF to reduce the fluid volume and reduce the raised intracranial pressure can be performed by placement of an extraventricular drain (EVD) or a ventriculoperitoneal (VP) shunt. In cases without hydrocephalus, a referral to genetics, developmental pediatrics, or pediatric neurology may be required. Macrocephalic children with epilepsy may require treatment with antiepileptic drugs. If dealing with benign familial macrocephaly, no intervention may be needed at all other than serial monitoring of head circumference and reassurance.

Differential Diagnosis

When dealing with an infant with macrocephaly, it is important to differentiate isolated macrocephaly from other possible head shapes. Plagiocephaly refers to a flattening of one area of the skull and is often seen in children with a history of lying with the head in one position. Craniosynostosis results from the early closure of cranial sutures, resulting in several other types of head shapes. Brachycephaly results from the premature closure of the coronal suture and results in a broad head with a recessed forehead. Trigonocephaly is the result of premature closure of the metopic suture and gives the forehead a triangular appearance. Scaphocephaly comes from the early closure of the sagittal suture, which has a clinical presentation of anterior-posterior elongation with bitemporal narrowing. Other congenital deformities of the skull can be results of trauma or forces applied to the head while in utero due to multiple gestation, abnormal fetal position, or oligohydramnios.

Prognosis

The prognosis of macrocephaly is determined by the underlying cause.

When presented with an infant with otherwise normal growth and development and a normal neurologic exam, macrocephaly by itself is often a benign entity, and neurodevelopmental outcomes are good.[11][12] In these cases, enlargement of the subarachnoid space may be seen on imaging. This may still be present in long-term follow-up, but no intervention needs to be made.[13]

Complications

Benign familial macrocephaly is not associated with any complications. However, macrocephaly due to hydrocephalus can have serious complications, including death, if not promptly treated. Other complications associated with macrocephaly are seizures, developmental disabilities, and neurologic deficits.