Crouzonodermoskeletal syndrome (CDSS) is a rare condition characterized by premature fusion of the coronal sutures, midface hypoplasia, beaked nasal deformity, mandibular prognathism, and proptosis. A specific mutation in the Fibroblast Growth Factor 3 (FGFR3) gene causes CDSS (Ala391Glu) and thus provides a diagnostic marker for early identification. Beyond the Crouzon syndrome-like craniofacial appearance, the CDSS phenotype includes acanthosis nigricans, choanal stenosis/atresia, hydrocephalus, Chiari malformation, and achondroplasia, although presentations vary substantially throughout the literature. In this article, we consolidate and summarize features of previously reported cases of CDSS, and we report the presentation and management of an infant with CDSS at our center. Prior reports of CDSS were sought using a combination of relevant keywords. Selection was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Publications reporting patient-specific data for at least one case of CDSS were included. We identified 74 cases of CDSS among 32 publications from 1985-2023. Most patients were identified at birth with craniofacial abnormalities. Many developed acanthosis nigricans in early childhood. Patients underwent multiple surgeries, including cranial vault reconstruction, cerebrospinal fluid diversion, airway maintenance, and nutrition management. Our patient presented at 4-months-of-age with hydrocephalus, choanal atresia, tracheostomy dependence, proptosis, Chiari malformation, and multi-suture craniosynostosis. Genetic analysis identified the heterozygous FGFR3 Ala391Glu variant diagnostic for CDSS. Over an eleven-month period, he underwent numerous surgeries to address his head shape and associated comorbidities. There was significant variability in clinical presentations, treatments, and outcomes across cases in our review. Early diagnosis of CDSS is essential to anticipate complex medical needs, develop individualized treatment plans, and ultimately to improve patient outcomes. Our review emphasizes the importance of a collaborative, patient-centered approach between plastic surgery, neurosurgery, ophthalmology, otolaryngology, and pediatric general surgery teams to manage the complexities of patients with CDSS.

Crouzon syndrome (CS) is a rare genetic disorder characterized by the premature fusion of cranial sutures, leading to craniofacial abnormalities and potential neurological complications. CS is caused primarily by gain-of-function mutations in the FGFR2 gene and, less commonly, by mutations in the FGFR3 gene (specifically associated with CS with acanthosis nigricans). Managing CS requires a multidisciplinary approach, combining early and later surgical interventions to prevent intracranial hypertension and correct craniofacial deformities, along with ongoing care to address associated complications. Recent advancements in CS classification on the basis of cranial suture involvement have refined phenotype-genotype correlations, improving personalized therapeutic strategies. This review aims to provide a comprehensive and updated overview of CS, including detailed insights into molecular genetics and biological mechanisms underlying its pathophysiology, and a depiction of the clinical features, diagnosis, and surgical aspects of CS. In addition, we delve into innovative theranostic views, where molecular genetic testing allows the design of personalized noninvasive therapeutic approaches based on innovative biotechnologies, including RNA-interference molecules, pharmacological modulation of FGFR signaling pathways, and recombinant proteins. These advancements underscore the importance of integrating molecular studies into diagnostic and therapeutic protocols to increase the precision and effectiveness of nonsurgical treatments for CS.

Crouzon syndrome with acanthosis nigricans (CAN) is caused by the specific mutation c.1172C>A (p.Ala391Glu) in the fibroblast growth factor receptor 3 gene, and has an estimated prevalence of 1:1,000,000 births. Most cases occur de novo; however, autosomal dominant inheritance may occur. The clinical presentation typically includes craniosynostosis, midface and maxillary hypoplasia, choanal atresia/stenosis, hydrocephalus, and intracranial hypertension. Patients develop acanthosis nigricans, a hyperkeratotic skin disorder. The authors present the first known study to investigate the speech, language, hearing, and feeding of patients with CAN. A retrospective case-note review of patients with a genetically confirmed diagnosis of CAN attending the Oxford Craniofacial Unit during a 36-year period (1987-2023) was undertaken. Participants were 6 patients with genetically-confirmed CAN (5 females, 1 male), all cases arose de novo. All patients had craniosynostosis (n = 5/6 multisuture synostosis, n = 1/6 left unicoronal synostosis). Hydrocephalus was managed through ventriculoperitoneal shunt in 67% (n = 4/6) of patients, and 67% (n = 4/6) had a Chiari 1 malformation. Patients had a complex, multifactorial feeding history complicated by choanal atresia/stenosis (100%; n = 6/6), and significant midface hypoplasia. All patients required airway management through tracheostomy (83%; n = 5/6); and/or continuous positive airway pressure (67%; n = 4/6). All patients underwent adenotonsillectomy (100%; n = 6/6). Initial failure to thrive, low weight, and/or height were seen in 100% (n = 6/6) patients; 80% (n = 4/5) had reflux; 100% (n = 6/6) had nasogastric, or percutaneous endoscopic gastrostomy based feeding during their treatment journey. All patients had hearing loss (100%; n = 6/6). Early communication difficulties were common: receptive language disorder (50%; n = 3/6); expressive language disorder (50%; n = 3/6); and speech sound disorder in 50% (n = 3/6)-necessitating the use of Makaton in 80% of patients (n = 3/5). Patients with CAN experience significant respiratory, neurological, and structural obstacles to hearing, speech, language, and feeding. The authors present a recommended pathway for management to support patients in these domains.

Crouzon syndrome with acanthosis nigricans is an autosomal dominant disease, with typical features of classic Crouzon craniosynostosis, verrucous hyperplasia, and hyperpigmentation of the skin. While several mutations in FGFR2 cause classic Crouzon syndrome, Crouzon syndrome with acanthosis nigricans results from a point mutation in the fibroblast growth factor receptor 3 gene (FGFR3). We report the case of an 8-year-old Vietnamese girl diagnosed with Crouzon syndrome with acanthosis nigricans, showing typical clinical features, including a crouzonoid face and dark plaques on the skin. Genetic testing showed a missense variation in FGFR3, associated with Crouzon syndrome with acanthosis nigricans. Following diagnosis, we treated acanthosis nigricans with 10% urea cream. This case study and literature review discuss the cutaneous manifestations and dermatological treatments while demonstrating the importance of clinical examination and evaluation of the patient's medical history during diagnosis. Our findings contribute to the global pool of data, providing practical insights into the manifestations of Crouzon syndrome.

Foramen magnum(FM) stenosis can be responsible for acute and chronic damage to the cervicomedullary junction in children with achondroplasia. The bony anatomy and patterns of suture fusion of the FM in this context are incompletely understood, yet becoming increasingly important in the light of novel medical therapies for achondroplasia. The objective of this study was to describe and quantify bony anatomy and fusion patterns of FM stenosis in patients with achondroplasia using CT scans, comparing them to age-matched controls and other FGFR3 craniosynostosis patients. Patients with achondroplasia and severe FM stenosis, classified as achondroplasia foramen magnum score(AFMS) grades 3 and 4, were identified from a departmental operative database. All had pre-operative CT scans of the craniocervical junction. Measurements obtained comprised sagittal diameter (SD), transverse diameter (TD), foramen magnum area, and opisthion thickness. Anterior and posterior interoccipital synchondroses (AIOS and PIOS) were graded by the extent of fusion. These measurements were then compared with CT scans from 3 age-matched groups: the normal control group, children with Muenke syndrome, and children with Crouzon syndrome with acanthosis nigricans (CSAN). CT scans were reviewed in 23 cases of patients with achondroplasia, 23 normal controls, 20 Muenke, and 15 CSAN. Children with achondroplasia had significantly smaller sagittal diameter (mean 16.2 ± 2.4 mm) compared to other groups (control 31.7 ± 2.4 mm, p < 0.0001; Muenke 31.7 ± 3.5 mm, p < 0.0001; and CSAN 23.1 ± 3.4 mm, p < 0.0001) and transverse diameters (mean 14.3 ± 1.8 mm) compared with other groups (control 26.5 ± 3.2 mm, p < 0.0001; Muenke 24.1 ± 2.6 mm, p < 0.0001; CSAN 19.1 ± 2.6 mm, p < 0.0001). This translated into a surface area which was 3.4 times smaller in the achondroplasia group compared with the control group. The median grade of the AIOS fusion achondroplasia group was 3.0 (IQR 3.0-5.0), which was significantly higher compared with the control group (1.0, IQR 1.0-1.0, p < 0.0001), Muenke group (1.0, IQR 1.0-1.0, p < 0.0001), and CSAN (2.0, IQR 1.0-2.0, p < 0.0002). Median PIOS fusion grade was also highest in the achondroplasia group (5.0, IQR 4.0-5.0) compared with control (1.0, IQR 1.0-1.0, p < 0.0001), Muenke (2.5, IQR 1.3-3.0, p < 0.0001), and CSAN (4.0, IQR 4.0-4.0, p = 0.2). Distinct bony opisthion spurs projecting into the foramen magnum were seen in achondroplasia patients but not others, resulting in characteristic crescent and cloverleaf shapes. Patients with AFMS stages 3 and 4 have significantly reduced FM diameters, with surface area 3.4 times smaller than age-matched controls. This is associated with premature fusion of the AIOS and PIOS in comparison with controls and other FGFR3-related conditions. The presence of thickened opisthion bony spurs contributes to stenosis in achondroplasia. Understanding and quantifying bony changes at the FM of patients with achondroplasia will be important in the future quantitative evaluation of emerging medical therapies.