Extremely severe scoliosis, heterotopic ossification, and osteoarthritis in a three‐generation family with Crouzon syndrome carrying a mutant c.799T>C FGFR2

Abstract

Background Crouzon syndrome is a rare and complex autosomal dominant craniosynostosis syndrome with a prevalence of approximately 1 in 60,000 births. The typical features are craniosynostosis, proptosis, midfacial hypoplasia, and noncranial manifestations, including deformities in the cervical spine, elbow, and fingers. Crouzon syndrome is usually caused by pathogenic variants in the fibroblast growth factor receptor 2 (FGFR2) gene. Methods We reported a three‐generation family with Crouzon syndrome; the proband showed extremely severe limb abnormalities. The clinical features were obtained by physical examination and radiographic examination. Sanger sequencing of all 18 exons of FGFR2 was conducted to identify the disease‐causing mutation. Results The proband was a 44‐year‐old man who showed characteristics of Crouzon syndrome, including craniofacial dysostosis, shallow orbits, proptosis, midface hypoplasia, beaked nose, strabismus, short superior lip, short stature, and neck injection. In addition to these typical characteristics, radiographic examination showed severe scoliosis, heterotopic ossification of the elbows, knee osteoarthritis, metacarpophalangeal joint valgus, collapse of the articular surface of the thumb metacarpal, knuckle ossification and fusion. Sanger sequencing identified a heterozygous pathogenic variant c.799T>C, p.(Ser267Pro) in exon 7 of FGFR2 in affected individuals. Conclusion Crouzon syndrome in this three‐generation family was caused by c.799T>C FGFR2, and the patient showed a different phenotypic appearance from other Crouzon patients with c.799T>C FGFR2.

Clinical assessment and FGFR2 mutation analysis in a Chinese family with Crouzon syndrome

“…[ 14 ] In the past decades, several studies have performed molecular analysis of FGFR2 mutations in Chinese patients with Crouzon syndrome. [ 11 , 15 – 25 ] Almost all of the FGFR2 mutations detected in Chinese patients with Crouzon syndrome have been previously identified in patient cohorts from Europe and the United States. [ 10 , 25 ]…”

Identification of potential pathogenic genes causing occipitalization of the atlas

“…Meina et al found three generations of a family with Crouzon syndrome carrying a mutation of FGFR2 in 2019, in which extremely severe scoliosis, heterotopic ossi cation, and osteoarthritis had manifested. It has been reported that mutations in TBX2 can cause fusion in vertebral anomalies and variable endocrine and T-cell dysfunction [27]. Yinlin et al demonstrated that TBX2 was important for skeletal development, especially during vertebral segmentation [32].…”

“…This variant has been predicted as a pathogenic mutation using the functional prediction tools MutationTaster, SIFT, and Polyphen-2, with a CADD score of 33 and GERP score of 6.03. FGFR2 was reported to be associated with Pfeiffer and Crouzon syndromes, related mostly to the premature fusion of particular skull bones and cervical spine abnormalities [27][28][29].…”

Novel Gene Mutations Associated with Crouzon Syndrome

“…[16] Early signals by the protein directs immature cells in the developing embryo to become bone cells and form the head, hands, feet, and other tissues. [17] Several isoforms of the FGFR proteins have also been identified in different tissues, whose patterns may change throughout growth and development. [18] The cytogenetic location of FGFR gene is 10q26.13.…”