De novo ALX4 variant detected in child with non-syndromic craniosynostosis.

Current understanding of the genetic factors contributing to the etiology of non-syndromic craniosynostosis (NSC) remains scarce. The present work investigated the presence of variants in ALX4, EFNA4, and TWIST1 genes in children with NSC to verify if variants within these genes may contribute to the occurrence of these abnormal phenotypes. A total of 101 children (aged 45.07±40.94 months) with NSC participated in this cross-sectional study. Parents and siblings of the probands were invited to participate. Medical and family history of craniosynostosis were documented. Biological samples were collected to obtain genomic DNA. Coding exons of human TWIST1, ALX4, and EFNA4 genes were amplified by polymerase chain reaction and Sanger sequenced. Five missense variants were identified in ALX4 in children with bilateral coronal, sagittal, and metopic synostosis. A de novo ALX4 variant, c.799G>A: p.Ala267Thr, was identified in a proband with sagittal synostosis. Three missense variants were identified in the EFNA4 gene in children with metopic and sagittal synostosis. A TWIST1 variant occurred in a child with unilateral coronal synostosis. Variants were predicted to be among the 0.1% (TWIST1, c.380C>A: p. Ala127Glu) and 1% (ALX4, c.769C>T: p.Arg257Cys, c.799G>A: p.Ala267Thr, c.929G>A: p.Gly310Asp; EFNA4, c.178C>T: p.His60Tyr, C.283A>G: p.Lys95Glu, c.349C>A: Pro117Thr) most deleterious variants in the human genome. With the exception of ALX4, c.799G>A: p.Ala267Thr, all other variants were present in at least one non-affected family member, suggesting incomplete penetrance. Thus, these variants may contribute to the development of craniosynostosis, and should not be discarded as potential candidate genes in the diagnosis of this condition.

De novo ALX4 variant detected in child with non-syndromic craniosynostosis

Current understanding of the genetic factors contributing to the etiology of non-syndromic craniosynostosis (NSC) remains scarce. The present work investigated the presence of variants in ALX4, EFNA4, and TWIST1 genes in children with NSC to verify if variants within these genes may contribute to the occurrence of these abnormal phenotypes. A total of 101 children (aged 45.07±40.94 months) with NSC participated in this cross-sectional study. Parents and siblings of the probands were invited to participate. Medical and family history of craniosynostosis were documented. Biological samples were collected to obtain genomic DNA. Coding exons of human TWIST1, ALX4, and EFNA4 genes were amplified by polymerase chain reaction and Sanger sequenced. Five missense variants were identified in ALX4 in children with bilateral coronal, sagittal, and metopic synostosis. A de novo ALX4 variant, c.799G>A: p.Ala267Thr, was identified in a proband with sagittal synostosis. Three missense variants were identified in the EFNA4 gene in children with metopic and sagittal synostosis. A TWIST1 variant occurred in a child with unilateral coronal synostosis. Variants were predicted to be among the 0.1% (TWIST1, c.380C>A: p. Ala127Glu) and 1% (ALX4, c.769C>T: p.Arg257Cys, c.799G>A: p.Ala267Thr, c.929G>A: p.Gly310Asp; EFNA4, c.178C>T: p.His60Tyr, C.283A>G: p.Lys95Glu, c.349C>A: Pro117Thr) most deleterious variants in the human genome. With the exception of ALX4, c.799G>A: p.Ala267Thr, all other variants were present in at least one non-affected family member, suggesting incomplete penetrance. Thus, these variants may contribute to the development of craniosynostosis, and should not be discarded as potential candidate genes in the diagnosis of this condition.

The optimal medial osteotomy: a study of nasal bone thickness and fracture patterns.

The use of medial osteotomies as an adjunct in rhinoplasty represents an ongoing challenge to the surgeon. Despite previous descriptions, it remains difficult to obtain a consistent, aesthetically pleasing result. Nasal skin is thin and unforgiving in the region of the medial osteotomy, thus irregularities may be created. Also, bony collapse is possible with overmobilization of the osteotomy segment. The present study was undertaken to understand nasal bone thickness and osteotomy fracture tendencies to provide consistent and aesthetically pleasing results when performing medial osteotomy. Seventeen cadavers with known demographics were studied. Left heminoses were skeletonized to bone; 1-mm drill holes in a 3 x 3-mm grid were made from the midline up to the laterocephalic extent of the bony vault. On right hemi- noses, medial osteotomies were performed at either 0 or 15 degrees from the midline and combined with "low-to-low" lateral osteotomies with digital greenstick infracture. Soft tissue was removed to examine fracture patterns and narrowing. A transition in bone thickness was found both with increasing thickness from caudal to cephalic and lateral to medial, leading to a natural cleavage plane, evident in all 17 cadavers. Zero-degree osteotomies caused contour irregularities with rocker-like deformities in seven of eight noses. Fifteen-degree medial osteotomies produced narrowing without contour deformities in all cases (nine of nine), which was significantly different from the result with 0-degree osteotomies (p = 0.0004). Sharp, thin osteotomes were preferred to perform the osteotomies. The order of the osteotomies (medial, lateral) did not affect resultant narrowing or cause contour deformity. Fifteen-degree medial osteotomies followed the natural cleavage plane formed by bone thickness transition, whereas 0-degree osteotomies cut into much thicker bone, resulting in thick spicules of bone attached to the mobilized segment. When 15-degree medial osteotomies were combined with low-to-low lateral osteotomies with digital greenstick infracture, the resultant narrowing was sufficient and the greenstick reliable and controlled, without any evidence of contour deformity. The smooth contour is readily apparent clinically.

Lateral nasal osteotomies: implications of bony thickness on fracture patterns.

Precise lateral nasal osteotomies combined with digital greenstick infracture can be a key feature in determining the success of a rhinoplasty procedure. This procedure may be difficult to perform consistently because the surgeon relies on tactile cues transmitted through intact soft tissue. In 17 cadavers with known demographics, bone fracture patterns after lateral osteotomy and digital greenstick infracture were studied and compared with measured lateral bone pyramid thicknesses. One side of each nose served to measure lateral wall thicknesses by drilling holes in a grid pattern and taking depth gauge measurements. Contralaterally, lateral osteotomy with digital greenstick infractures were performed. Consistent patterns of bone thickness were found. Bone was thinner near the pyriform aperture with a high fragmentation rate after osteotomy. Cephalocaudal thinning of the lateral bony pyramid near the medial canthus corresponded to the zone of greenstick fracture in 14 of 14 noses. Two major fracture pattern groups were noted. When lateral osteotomy was taken to the level of the medial canthus vertically, the greenstick fracture was consistent and predictable based on the transition in bone thickness from the radix area down across the lateral bony vault in untraumatized white cadavers.

Brainstem enkephalinergic projections to spinal autonomic nuclei.

The present studies in the rat employed a combined retrograde transport-immunocytochemical technique to determine the origin in the brainstem of enkephalin (Enk) projections to spinal sympathetic nuclei, including the intermediolateralis nucleus, pars principalis (ILp). We found that Enk projections to the ILp nucleus are found in such serotonergic-containing areas as the raphe obscurus; raphe pallidus; gigantocellular reticular nucleus, pars alpha; paragigantocellular lateral nucleus; raphe magnus; and the rostral extension of the raphe magnus nucleus. The adrenergic-containing rostroventrolateral reticular nucleus as well as the noradrenergic-containing areas A5, A7, ventral locus coeruleus, subcoeruleus, and fiber pathway linking the locus coeruleus and A5/A7 send Enk projections to ILp. In the pons, a large contralateral Enk projection to spinal sympathetic nuclei was found medial to the facial nerve and medial to the motor nucleus of the trigeminal nerve. These observations show the existence of a large number of Enk brainstem regions that can influence spinal autonomic centers via descending supraspinal projections.