Molecular analysis of patients with synostotic frontal plagiocephaly (unilateral coronal synostosis)

• Published in: Plastic and reconstructive surgery (1963) Vol. 113; no. 7; pp. 1899 - 1909
• Main Authors: MULLIKEN, John B, GRIPP, Karen W, STOLLE, Catherine A, STEINBERGER, Daniela, MÜLLER, Ulrich
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 01-06-2004
• Subjects: Adult; Biological and medical sciences; Cephalometry; Child, Preschool; Craniosynostoses - genetics; Craniosynostoses - pathology; DNA Mutational Analysis; Female; Humans; Infant; Male; Medical sciences; Mutation; Nose - pathology; Nuclear Proteins - genetics; Orbit - pathology; Protein-Tyrosine Kinases - genetics; Receptor Protein-Tyrosine Kinases - genetics; Receptor, Fibroblast Growth Factor, Type 2; Receptor, Fibroblast Growth Factor, Type 3; Receptors, Fibroblast Growth Factor - genetics; Skull - abnormalities; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Transcription Factors - genetics; Twist-Related Protein 1; Human; Malformation; Surgery; Diseases of the osteoarticular system; Synostosis; Unilateral; Frontal bone; Molecular biology
• ISSN: 0032-1052; 1529-4242
• DOI: 10.1097/01.PRS.0000122202.26792.bf

Mutations in genes known to be responsible for most of the recognizable syndromes associated with bilateral coronal synostosis can be detected by molecular testing. The genetic alterations that could cause unilateral coronal synostosis are more elusive. It is recognized that FGFR and TWIST mutations can give rise to either bilateral or unilateral coronal synostosis, even in the same family. The authors undertook a prospective study of patients presenting with synostotic frontal plagiocephaly (unilateral coronal synostosis) to Children's Hospital Boston during the period from 1997 to 2000. Mutational analysis was performed on all patients and on selected parents whenever familial transmission was suspected. Intraoperative anthropometry was used in an effort to differentiate those patients in whom a mutation was detected from those in whom it was not. The anthropometric measures included bilateral sagittal orbital-globe distance, inter medial canthal distance, and nasal angulation. Macrocephaly and palpebral angulation were also considered possible determinants. There was a 2:1 female preponderance in 47 patients with synostotic frontal plagiocephaly. Mutations were found in eight of 47 patients: two patients with different single-amino-acid changes in FGFR2, three patients with FGFR3 Pro250Arg, and three patients with TWIST mutations. Another patient had craniofrontonasal syndrome for which a causative locus has been mapped to chromosome X, although molecular testing is not yet available. Two features were strongly associated with a detectable mutation in patients with synostotic frontal plagiocephaly: asymmetrical brachycephaly (retrusion of both supraorbital rims) and orbital hypertelorism. Other abnormalities in the craniofacial region and extremities were clues to a particular mutation in FGFR2, FGFR3, TWIST, or the X-linked mutation. Neither macrocephaly nor degree of nasal angulation nor relative vertical position of the lateral canthi correlated with mutational detection. An additional four patients in this study had either unilateral or bilateral coronal synostosis in an immediate relative and had anthropometric findings that predicted a mutation, and yet no genetic alteration was found. This suggests either that the authors' screening methods were not sufficiently sensitive or that perhaps there are other unknown pathogenic loci. Nevertheless, molecular testing is recommended for infants who have unilateral coronal synostosis, particularly if there are the anthropometric findings highlighted in this study or an otherwise suspicious feature in the child or a parent. Infants with either an identified or a suspected mutation usually need bilateral asymmetric advancement of the bandeau and may be more likely to require frontal revision in childhood.