Association of achondroplasia with sagittal synostosis and scaphocephaly in two patients, an underestimated condition?

Abstract

We report on two patients with an unusual combination of achondroplasia and surgically treated sagittal synostosis and scaphocephaly. The most common achondroplasia mutation, p.Gly380Arg in fibroblast growth factor receptor 3 (FGFR3), was detected in both patients. Molecular genetic testing of FGFR1, FGFR2, FGFR3 and TWIST1 genes failed to detect any additional mutations. There are several reports of achondroplasia with associated craniosynostosis, but no other cases of scaphocephaly in children with achondroplasia have been described. Recently it has been demonstrated that FGFR3 mutations affect not only endochondral ossification but also membranous ossification, providing new explanations for the craniofacial hallmarks in achondroplasia. Our report suggests that the association of isolated scaphocephaly and other craniosynostoses with achondroplasia may be under recognized.

Osteological evidence of short stature and parieto‐squamosal arch craniosynostosis in a non‐adult male from the 13th century Leiria, Portugal

“…For instance, a study by Coco et al () reports an association between craniosynostosis, which resulted in severe cranial deformity, HCH, and growth hormone deficiency. A link between a fibroblastic growth factor receptor 3 (FGFR3) mutation, craniosynostosis, and skeletal dysplasia has been found, demonstrating that this mutation affects both endochondral and membranous ossifications (Accogli et al, ). This recent clinical finding opens the possibility for an association between the craniosynostosis and the pathologically short stature of this individual, as both may be consequences of the same genetic mutations.…”

Rap1b Is an Effector of Axin2 Regulating Crosstalk of Signaling Pathways During Skeletal Development

“…(5) More than 450 different types of skeletal dysplasia have been classified by molecular, biochemical, and radiographic criteria. (6) Craniosynostosis, (7)(8)(9) affecting approximately 1 in 2500, is one of the most common craniofacial deformities. (4,10,11) Patients with craniosynostosis develop abnormal skull shape due to excessive intramembranous ossification, leading to aberrant fusion of the cranial suture, which serves as a growth center for craniofacial skeletogenesis.…”

Unique association of hypochondroplasia with craniosynostosis and cleft palate in a Mexican family

“…This partially explains why among FGFR3 ‐related chondrodysplasias, craniosynostosis is a main feature in patients with Muenke syndrome, Crouzon with acanthosis nigricans (MIM #612247), and thanatophoric dysplasia type 2 (MIM #187601). Therefore, it seems plausible that this same mechanism might be involved in the co‐occurrence of craniosynostosis in our patient and the other molecularly proven HCH patient (Angle et al, ), as well as in the other six ACH patients known to date (Accogli et al, ; Albino et al, ; Bessenyei et al, ; Georgoulis et al, ; Karadimas et al, ).…”

“…The presence of craniosynostosis in our male affected sibling could also be a coincidental finding and although molecular studies of other genes associated with craniosynostosis were not performed (as TCF12 , TWIST1 , or ZIC1 ), considering the previous case of molecularly proven HCH associated with craniosynostosis and current knowledge of the role played by FGFR3 signaling in craniofacial development, it is reasonable to suggest that the defective cranial phenotype be a consequence of disturbed endochondral and membranous ossification, in which the effects of other modifying genetic and/or epigenetic factors, together with possible environmental influences, may play a role in determining the final phenotype (Accogli et al, ; Angle et al, ).…”