The volume of the contents of the calvarium determines the size of the head. The brain and the cerebrospinal fluid (CSF) are the normal contents of the calvarium, and too much of one or the other accounts for most cases of macrocephaly. As is true of microcephaly, many macrocephalic infants are not abnormal in any more than a statistical sense. "Constitutional" macrocephaly is fairly common and tends to be familial; there are no treatment implications, of course. There are a small number of very rare diseases of the brain, such as Alexander’s disease and Canavan’s disease, that cause macrocephaly from proliferation of glial tissue or from deposition of the product of a metabolic disturbance. These conditions are seen in the context of catastrophic developmental regression, and they are untreatable.

Most cases of macrocephaly are attributable to excessive volumes of CSF. The excessive CSF may reside within the brain, in the ventricular cavities, or outside the brain, in the subarachnoid spaces. The former condition is ordinary, "internal" hydrocephalus. It generally requires neurosurgical treatment with a CSF shunt, and because of its familiarity to most readers, it requires no further discussion in this review of disturbances of skull growth. The latter condition has been known by a variety of names including - among others less appropriate - "benign enlargement of the subarachnoid spaces" and "external hydrocephalus." External hydrocephalus may be almost as common as ordinary hydrocephalus, and like constitutional macrocephaly, it is commonly familial with autosomal dominant inheritance. The prominence of the subarachnoid spaces is a transient, developmental phenomenon that usually resolves by school age. The macrocephaly, however, is permanent, although it does not attain grotesque extremes. External hydrocephalus does not require surgical intervention; however, the failure of the brain to fill the cranial cavity in infancy creates an unstable biomechanical situation that parents must understand: Infants with external hydrocephalus have a low threshold for subdural hemorrhage in response to minor impacts to the head. If the disproportion between the volume of the brain and the volume of the cranial cavity is marked, a protective helmet may even be indicated during the early stages of the acquisition of ambulation.

The most menacing element of the differential diagnosis of macrocephaly is chronic subdural hematoma. Blood spilled in the subdural space may be degraded and reabsorbed spontaneously, but in some patients it stimulates the formation of a capsule made up of cellular elements derived from the dura above and, not so vigorously, from the arachnoid membrane below. Blood degradation products in the hematoma cavity have fibrinolytic activity, promoting continuous microscopic hemorrhage from the fragile capillaries in the reactive capsule. Thus if the initial trauma is unrecognized or unreported, chronic subdural hematoma may become a self-propagating, progressive condition that can cause insidious enlargement of the unclosed infant skull with few or no overt symptoms of intracranial pressure. The treatment of chronic subdural hematoma entails irrigation of the hematoma cavity to eliminate the fibrinolytic substances that promote its expansion and drainage of the cavity – either temporary external drainage or permanent internal drainage with a shunt. The prognosis depends on the neurological condition of the infant at the time of treatment: If macrocephaly is the sole presenting complaint, the long-term outlook may be quite good. Infants who come to attention because of macrocephaly and are found to have chronic subdural hematoma must be managed as suspected victims of child abuse.

The imaging investigation of macrocephaly in infancy is problematic. The tendency of many primary practitioners is to request simple, relatively inexpensive tests that, unfortunately, are often inconclusive or misleading. Head ultrasound (US) can demonstrate ventricular enlargement, but unless the cause of the hydrocephalus is known from the clinical context, magnetic resonance (MR) imaging will be required to complete the evaluation. Furthermore, head US is insensitive to the presence of extracerebral fluid collections, as in external hydrocephalus and chronic subdural hematoma, and a negative head US must often be followed by MR imaging. Computed tomography (CT) demonstrates extracerebral fluid reasonably well, but only the very highest quality scans permit confident distinction between external hydrocephalus and chronic subdural hematoma and thereby obviate the requirement for MR imaging. Despite the expense and the requirement for monitored sedation, MR imaging is the modality of choice for investigation of macrocephaly.