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Incidence at birth is in the range of 1/20,000.

The skull deformity is characterized by a short anteroposterior diameter with a compensatory increase in bitemporal width. Supraorbital recession and exorbitism may also be present. Brachycephaly may be associated with facial anomalies (midface hypoplasia, slight hypertelorism and bulging temporal fossae). Increased intracranial pressure (ICP) is frequent and may lead to intellectual deficit if left untreated. In adults, elevated ICP is associated with bony defects in the absence of treatment.

The extent to which nonsyndromic brachycephaly is genetically determined is still uncertain. Although the majority of cases are sporadic, familial forms (accounting for 14% of all cases) have been reported, with dominant inheritance in around 10% of cases. In addition, recurrent (paternally inherited) P250R mutations in fibroblast growth factor receptor 3 (FGFR3; 4p16.3) were identified in 74% of familial cases, as well as in 17% of sporadic cases. Among patients carrying the P250R mutation, females are more severely and more frequently affected than males (female to male ratio of 2:1) and mild hearing impairment is common. Minor radiologic anomalies including brachydactyly or fusion of metacarpal bones may occur in some FGFR3 mutation carriers. A mutation in the TWIST 1 gene (7p21) has been reported recently in a single case of isolated bicoronal synostosis, but a genetic origin has not been confirmed for most remaining cases. Several other determinants might be involved including mechanical constraints during pregnancy and after birth.

Diagnosis is based on clinical examination, radiologic studies, and 3D CT scans and/or MRI of the skull. Since postoperative morphological and functional outcomes appear to be better in non-carriers of the FGFR3 mutation, molecular screening is recommended for all families with nonsyndromic forms of brachycephaly.

Clinical distinction between syndromic and nonsyndromic forms brachycephaly is often difficult owing to phenotypic variability in patients carrying the P250R mutation. Although the cranial appearance of some patients might be reminiscent of the Saethre-Chotzen or Pfeiffer syndromes (see these terms), the absence of obvious hand and/or feet anomalies is a hallmark of nonsyndromic brachycephalic patients. Marked bulging of temporal fossae, seen mainly in female carriers of the FGFR3 mutation, might be instructive for differential diagnosis.

Cranial vault reconstructive surgery is the main treatment to improve skull shape and increase intracranial volume. This usually results in reduced ICP. Early identification of hearing loss allows timely intervention when required.

The intellectual outcome of patients after cranial expansion surgery is usually good. However, patients carrying the FGFR3 mutation are five times more likely to require a second operation and show a poorer post surgical outcome than non-carriers.