Hemifacial microsomia: progress in understanding the genetic basis of a complex malformation syndrome

Abstract

Hemifacial microsomia (HFM) is a common birth defect involving first and second branchial arch derivatives. The phenotype is extremely variable. In addition to craniofacial anomalies there may be cardiac, vertebral and central nervous system defects. The majority of cases are sporadic, but there is substantial evidence for genetic involvement in this condition, including rare familial cases that exhibit autosomal dominant inheritance. As an approach towards identifying molecular pathways involved in ear and facial development, we have ascertained both familial and sporadic cases of HFM. A genome wide search for linkage in two families with features of HFM was performed to identify the disease loci. In one family data were highly suggestive of linkage to a region of approximately 10.7 cM on chromosome 14q32, with a maximum multipoint lod score of 3.00 between microsatellite markers D14S987 and D14S65. This locus harbours the Goosecoid gene, an excellent candidate for HFM based on mouse expression and phenotype data. Coding region mutations were sought in the familial cases and in 120 sporadic cases, and gross rearrangements of the gene were excluded by Southern blotting. Evidence for genetic heterogeneity is provided by the second family, in which linkage was excluded from this region.

Spatio‐temporal dynamics of gene expression of the Edn1‐Dlx5/6 pathway during development of the lower jaw

“…The phenotypes of FAS are strongly suggestive of a defect of CNCCs, and interestingly, targeted inactivation of genes involved in patterning CNCCs often results in proximal defects of the dentary and/or of the middle and external ear (for a recent review see: Gitton et al, 2010). Based on morphological similarities with mouse mutant models, the involvement of Edn1 and putative targets in FAS has been suggested (Kelberman et al, 2001;Masotti et al, 2008;Singer et al, 1994), but not experimentally proven. Our observation on partial allele losses of the Edn1-Dlx pathway might help explain why human FAS affect proximal, rather than distal, derivatives of PA1.…”

Auriculo-condylar syndrome: mapping of a first locus and evidence for genetic heterogeneity

“…As there is no chromosomal rearrangements associated to ACS, we first proposed to investigate if two large ACS families are linked to any of the loci associated with TCS (TCOF1; 5q31 -32), OAVS (14q32), or TownesBrocks syndrome (SALL1, 16q12). 6 The exclusion of these three candidate regions led us to perform a wide genome search. One of the families is herein described for the first time, while the other one had already been reported.…”

Microsomía hemifacial. Revisión de la literatura

“…Se encontró que el uso de medicación vasoactiva en el primer trimestre, particularmente en combinación con el consumo de cigarrillos, se asociaba con un aumento del riesgo de MHF; también se asociaron otros eventos como gestaciones múltiples, diabetes, sangrado durante el segundo trimestre y fuerte consumo de alcohol. 15 Dentro de las causas genéticas, si bien la mayoría de los casos son esporádicos, en algunos casos se ha observado un componente genético autosómico dominante (asociado al cromosoma 14), 16,17 un componente autosómico recesivo 18 y alteraciones cromosómicas, principalmente en los cromosomas 5 (deleción de 5p), 18 (trisomía) y 22 (deleción de 22q11.2), entre otros. 19,20 Other authors suggest this relationship between lack of migration of cells of the neural crest and HFM because in the absence of these cells there is less vascular endothelial growth factor (VEGF).…”

“…The use of vasoactive medication in the first quarter, particularly in combination with smoking, was found to be associated with an increase in the risk of HFM; other factors were also associated, such as multiple gestations, diabetes, bleeding during the second quarter, and intensive alcohol consumption. 15 Within the genetic causes, even though most cases are sporadic, in some cases there has been an autosomal dominant genetic component (associated with chromosome 14), 16,17 …”