Genetic Analysis of Syndromic and Nonsyndromic Patients With Craniosynostosis Identifies Novel Mutations in the TWIST1 and EFNB1 Genes.

INTRODUCTION: Craniosynostosis, the premature fusion of cranial sutures, is usually divided into 2 major categories: syndromic and nonsyndromic. Mutations in the FGFR1, FGFR2, FGFR3, TWIST1, and EFNB1 genes cause the common craniosynostosis syndromes Muenke, Crouzon and Crouzon with acanthosis nigricans, Apert, Pfeiffer, Saethre-Chotzen, and Craniofrontonasal. Overlapping features among craniosynostosis syndromes, phenotypic heterogeneity even within the same syndrome, especially in the case of Muenke syndrome, and inadequate clinical evaluation can lead to misdiagnosis, which molecular testing can help clarify. OBJECTIVE: The aim of this study is to investigate the underlying genetic cause in 46 patients with syndromic or nonsyndromic craniosynostosis by direct sequencing and/or microdeletion/microduplication analysis of the FGFR1-3, TWIST1, and EFNB1 genes. RESULTS: Genetic analysis identified 3 novel mutations, c.413T>C - p.(Leu138Pro) [p.(L138P)] in TWIST1, the previously reported c.373G>A - p.(Glu125Lys) [p.(E125K)], and c.717dupA - p.(Leu240IlefsTer79) [p.(L240fs)] mutation in EFNB1 gene as well as 6 previously known mutations and a heterozygous TWIST1 gene deletion. The 2 novel mutations within EFNB1 gene arose de novo, but the novel mutation p.(L138P) within TWIST1 gene was inherited from the patient's father, who was found to be mosaic for the mutation. To our knowledge, this is the first case of mosaicism described for TWIST1 gene. CONCLUSIONS: The contribution of molecular genetic analysis to the diagnosis of patients with syndromic craniosynostosis was useful because some were originally misdiagnosed. Conversely, thorough clinical evaluation can guide molecular testing and result in a correct diagnosis.

A novel de novo mutation within EFNB1 gene in a young girl with craniofrontonasal syndrome.

Craniofrontonasal syndrome is mainly characterized by frontonasal dysplasia, telorbitism, a broad nasal root, and frequently a bifid nose and coronal craniosynostosis. Craniofrontonasal syndrome is an X-linked disorder with an unusual pattern of inheritance because heterozygous females are more severely affected than hemizygous males. The craniofrontonasal syndrome-causing gene is EFNB1, localized in the border region of chromosome Xq12 and Xq13.1, encoding for protein ephrin-B1. Here we aim to investigate the underlying genetic defect of a young girl with craniofrontonasal syndrome. The patient underwent surgical correction of her craniofacial deformities. Genetic analysis was carried out by polymerase chain reaction. Products of exon 2 of the EFNB1 gene were sequenced as well as digested with BpmI enzyme. A novel de novo missense mutation 373G>A was identified within the EFNB1 gene, leading to the replacement of glutamic acid at amino acid position 125 with lysine. The replacement of Glu125 with Lys, which lies within the G-H loop, part of the dimerization ligand-receptor interface, is expected to disrupt the interaction between the Eph receptor and ephrin B1 ligand, thus leading to craniofrontonasal syndrome.

The dorsal reverse adipofascial flap for fingertip reconstruction.

Nine patients who presented with fingertip amputations were treated with the dorsal reverse adipofascial flap. The mean age of the patients was 41.3 years and the mean follow-up was 18 months. The flap described here was used only for amputations at the level of the nail fold, from approximately the lunula to the proximal nail matrix. This flap is based on the dorsal arterial branches that originate from the volar digital arteries just distal to the distal interphalangeal joint. The flap uses only the adipofascial tissue over the middle phalanx of the injured finger; it is turned over to cover the fingertip defect and then covered with a split-thickness skin graft. All flaps survived completely, and the patients continue to use their fingertips as before the amputation injury. This one-step operation is easily performed (even in the emergency department), makes no use of the adjacent digits, and provides a pleasing and stable cover for the fingertips.

The biceps femoris short head muscle flap: an experimental anatomical study.

The vascular communication between the heads of the biceps femoris muscle has been established after 25 cadaveric dissections. Perfusions of dye through the long or the short head consistently showed 1-2 anastomotic bundles. Outflow of dye opposite to the site of the perfused head was remarkable in most cases. Intramuscular dissections disclosed broad and well structured vascular networks in all short heads, but this was not true for all long heads. Our observations suggest that the anastomotic vessels alone might support the short head which, when released from its profunda femoris vessels, is adequate to cover lateral knee defects. Depending on the level of the anastomotic vessels, the proximal or the distal part of the short head should be used. A pedicled flap may be used as well, whereas transsection of the biceps tendon offers additional mobility.