Craniosynostosis

Craniosynostosis manifests as abnormal head shape ranging from mild isolated forms to severe multisuture involvement. The clinical spectrum extends from severe prenatal multisuture craniosynostosis with feeding and airway compromise to isolated unicoronal craniosynostosis recognised later in infancy. Untreated premature suture fusion may result in craniofacial deformity, raised intracranial pressure, neurocognitive impairment, and psychosocial sequelae. Cases are clinically subdivided into nonsyndromic forms, in which premature fusion occurs in isolation, and syndromic forms, which are accompanied by characteristic facial features, midface retrusion, and variable involvement of the limbs, central nervous system, and other organ systems. More than 180 syndromes featuring craniosynostosis have been described. Onset is typically prenatal or in early infancy; in some milder syndromic forms, including and syndromes, craniofacial features may evolve over the first one to two years of life rather than being apparent at birth.

The estimated birth prevalence of craniosynostosis is approximately 1 in 1,700–2,500. An identifiable genetic cause is found in approximately 20–30% of affected individuals.

A large number of genes have been associated with craniosynostosis, and submicroscopic deletions and duplications represent an additional important class of genetic causes. Genetic forms are commonly classified as syndromic or nonsyndromic craniosynostosis.

Representative syndromic forms include (FGFR2; multisuture craniosynostosis with syndactyly), (FGFR2; craniosynostosis with midface retrusion and normal extremities), (FGFR3; uni- or bicoronal craniosynostosis with variable hearing loss), and (TWIST1; coronal craniosynostosis with ptosis and variable syndactyly). Representative nonsyndromic forms include isolated coronal craniosynostosis associated with TCF12 and ERF, as well as other genetically heterogeneous forms affecting individual cranial sutures.

The genetic conditions associated with craniosynostosis follow heterogeneous inheritance patterns. Most causative variants follow autosomal dominant inheritance, while X-linked patterns (for example in craniofrontonasal syndrome) and autosomal recessive patterns (for example in Baller-Gerold syndrome) are less common. Many affected individuals have a de novo pathogenic variant and therefore no family history of craniosynostosis.

• Where craniosynostosis is suspected to have a genetic cause, molecular genetic testing can identify the underlying condition and confirm a clinical suspicion. Identification of the underlying pathogenic germline variant enables predictive testing of at-risk family members and provides information relevant to family planning.
• The identified genetic cause can inform condition-specific surveillance, multidisciplinary clinical management, and genetic counselling; specific measures are determined by the treating physicians according to the clinical presentation.

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