Crouzon syndrome

Crouzon syndrome is inherited in an autosomal dominant manner; this applies both to the FGFR2-related form and to the FGFR3-related form with acanthosis nigricans. Each child of an affected individual has a 50% chance of inheriting the pathogenic variant. A substantial proportion of affected individuals have the condition as the result of a de novo pathogenic variant, which is associated with advanced paternal age; in such cases the parents are unaffected and the recurrence risk to future siblings is low, with a small residual risk from parental germline mosaicism.

The diagnosis is established in an individual with the characteristic craniofacial features and is confirmed by identifying a heterozygous pathogenic variant in FGFR2 on molecular genetic testing. Craniosynostosis is assessed by physical examination and cranial imaging (CT, MRI). Prenatal ultrasound and foetal MRI may identify suggestive findings such as cloverleaf skull, abnormal biparietal diameter, or ventriculomegaly.

Main differential diagnoses include:

• Crouzon syndrome with acanthosis nigricans: crouzonoid facial appearance accompanied by acanthosis nigricans of the skin; FGFR3, variant p.Ala391Glu
• : broad, medially deviated thumbs and great toes; FGFR1, FGFR2
• : distinguished by symmetrical syndactyly of hands and feet and more frequent neurodevelopmental impairment; FGFR2
• : low frontal hairline, ptosis, facial asymmetry and occasional cutaneous syndactyly; TWIST1

• Genetic testing supports establishing the diagnosis by identifying the underlying pathogenic variant in FGFR2 (or FGFR3 in the form with acanthosis nigricans), providing a basis for genetic counselling and predictive testing.
• A confirmed result supports condition-specific surveillance and management options, such as monitoring for raised intracranial pressure, hydrocephalus, airway obstruction, ophthalmological complications, hearing loss and cervical-spine anomalies, which the treating physicians decide together with the affected individual.

• Wenger T, Miller D, Evans K. FGFR craniosynostosis syndromes overview. 1998 Oct 20 [updated 2020 Apr 30]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews^® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. PMID: 20301628.
• Nguyen QD, Tran TNA, Nguyen HT. Crouzon syndrome with acanthosis nigricans: a case report and literature review. Dermatol Rep. 2023;15(2):9620. PMID: .
• Mathijssen IMJ; Working Group Guideline Craniosynostosis. Updated guideline on treatment and management of craniosynostosis. J Craniofac Surg. 2021;32(1):371-450. PMID: .