Setleis syndrome (SS), or focal facial dermal dysplasia type III (FFDD3, MIM #227260), is an autosomal recessive condition caused by biallelic loss-of-function variants in TWIST2. It is characterized by bitemporal atrophic skin lesions and distinctive facial features. Individuals with de novo or inherited duplication or triplication of the chromosomal region 1p36.22p36.21 have also been reported to have the SS phenotype with additional neurodevelopmental challenges (rarely seen in individuals with TWIST2 mutations) and variable expressivity and penetrance. Triplication of this region is also associated with more severe manifestations compared to a duplication. We report a 2-year-old female patient with features of SS associated with a de novo 3.603 Mb triplication at 1p36.23p36.22 identified on postnatal microarray analysis. Her triplication shares a 281.263 kb overlap with gains at 1p36.22, reported by previous groups, delineating the shortest region of overlap (SRO) to date. This SRO involves 10 RefSeq and 4 OMIM morbid map genes and highlights the candidate dosage-sensitive element(s) underlying the cardinal features of SS phenotype in individuals with gains at 1p36.

Background: Setleis syndrome (SS) is a focal facial dermal dysplasia presenting with bilateral temporal skin lesions, eyelash abnormalities and absent meibomian glands. SS is a rare autosomal recessive disorder caused by mutations in the TWIST2 gene, which codes for a transcription factor of the bHLH family known to be involved in skin and facial development. Methods: We obtained gene expression profiles by microarray analyses from control and SS patient primary skin fibroblast and lymphoblastoid cell lines. Results: Out of 983 differentially regulated genes in fibroblasts (fold change ≥ 2.0), 479 were down-regulated and 509 were up-regulated, while in lymphoblasts, 1248 genes were down-regulated and 73 up-regulated. RT-PCR reactions confirmed altered expression of selected genes. Conclusions: TWIST2 is described as a repressor, but expression profiling suggests an important role in gene activation as well, as evidenced by the number of genes that are down-regulated, with a much higher proportion of down-regulated genes found in lymphoblastoid cells from an SS patient. As expected, both types of cell types showed dysregulation of cytokine genes. These results identify potential TWIST2 target genes in two important cell types relevant to rare disorders caused by mutations in this bHLH gene.

We present a rare case of focal facial dermal dysplasia type 4 (FFDD4) in an otherwise healthy boy infant, presenting as bilateral preauricular scarlike defects surrounded by a hair collar, resembling membranous aplasia cutis congenita. The presence of a hair collar supports the hypothesis that FFDD is caused by abnormal closure at facial embryonic fusion lines, but unlike midline scalp defects is not associated with neurological compromise. Other types of FFDD occur at different sites and can be associated with cranial dysgraphism. Awareness of this rare condition by dermatologists is imperative to enable prompt recognition and minimize diagnostic delay.

The focal facial dermal dysplasias (FFDDs) are a group of rare inherited developmental disorders characterized by congenital scar-like atrophic lesions in the bitemporal (FFDD1, 2, and 3) or preauricular (FFDD4) areas. FFDD4 is an autosomal-recessive trait characterized by preauricular skin defects without additional dysmorphic findings. Previously, only two CYP26C1 mutations in four unrelated patients with FFDD4 were reported. Here, we report two additional unrelated FFDD4 patients with four CYP26C1 mutations including three novel lesions: a missense mutation, c.230G>C (p.Arg77Pro), and two splice-site mutations, c.1191+1G>T (IVS5(+1)G>T) and c.1191+2insT (IVS5(+2)insT). In silico analyses predicted all three mutations as pathogenic. Compound heterozygosity was validated through parental studies. These results provide further evidence that CYP26C1 mutations are the molecular genetic basis of FFDD4. Identification of additional cases by dermatologists, pediatricians, and medical geneticists will lead to further understanding of the clinical spectrum of FFDD4 and define its molecular genetic heterogeneity.

Surveillance for bovine genetic diseases in Denmark identified a hitherto unreported congenital syndrome occurring among progeny of a Holstein sire used for artificial breeding. A genetic aetiology due to a dominant inheritance with incomplete penetrance or a mosaic germline mutation was suspected as all recorded cases were progeny of the same sire. Detailed investigations were performed to characterize the syndrome and to reveal its cause.
Seven malformed calves were submitted examination. All cases shared a common morphology with the most striking lesions being severe facial dysplasia and complete prolapse of the eyes. Consequently the syndrome was named facial dysplasia syndrome (FDS). Furthermore, extensive brain malformations, including microencephaly, hydrocephalus, lobation of the cerebral hemispheres and compression of the brain were present. Subsequent data analysis of progeny of the sire revealed that around 0.5% of his offspring suffered from FDS. High density single nucleotide polymorphism (SNP) genotyping data of the seven cases and their parents were used to map the defect in the bovine genome. Significant genetic linkage was obtained for three regions, including chromosome 26 where whole genome sequencing of a case-parent trio revealed two de novo variants perfectly associated with the disease: an intronic SNP in the DMBT1 gene and a single non-synonymous variant in the FGFR2 gene. This FGFR2 missense variant (c.927G>T) affects a gene encoding a member of the fibroblast growth factor receptor family, where amino acid sequence is highly conserved between members and across species. It is predicted to change an evolutionary conserved tryptophan into a cysteine residue (p.Trp309Cys). Both variant alleles were proven to result from de novo mutation events in the germline of the sire.
FDS is a novel genetic disorder of Holstein cattle. Mutations in the human FGFR2 gene are associated with various dominant inherited craniofacial dysostosis syndromes. Given the phenotypic similarities in FDS affected calves, the genetic mapping and absence of further high impact variants in the critical genome regions, it is highly likely that the missense mutation in the FGFR2 gene caused the FDS phenotype in a dominant mode of inheritance.

Focal facial dermal dysplasias (FFDDs) are rare genetic/developmental disorders characterised by bilateral \'scar-like\' facial lesions. Four subtypes are classified by the bitemporal (FFDD1-3) or preauricular (FFDD4) lesion location. FFDD1-3 are differentiated by additional facial abnormalities and inheritance patterns. Although the genetic defects causing FFDD1 and FFDD2 remain unknown, recent studies identified defects causing FFDD3 and FFDD4. Here, the clinical phenotypes, genetic defects and inheritance of the four FFDD subtypes are described. In addition, the overlapping facial abnormalities in FFDD3 and two other genetic disorders, Ablepharon macrostomia syndrome and Barber-Say syndrome, are noted. Familiarity with the FFDDs by clinicians will further delineate the phenotypes and genetic/developmental defects of these dermal facial disorders.

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Setleis syndrome, focal facial dermal dysplasia type III (FFDD3, MIM #227260), is characterized by scar-like bitemporal lesions and other ocular and facial dysmorphic features. The syndrome results from recessive mutations in the TWIST2 gene, encoding a basic helix-loop-helix transcription factor or de novo genomic duplication or triplication, which include 1.3 Mb at 1p36.22p36.21, or other yet undefined lesions, emphasizing the syndrome\'s genetic heterogeneity. Recently, three patients were reported with 1p36.22p36.21 duplications/triplication that had the characteristic FFDD3 features and developmental delay or intellectual disabilities. Here, we describe a male with this microduplication, and the typical FFDD3 phenotype, but normal intelligence. Notably, his duplication was inherited from his father who did not have any FFDD3 manifestations, indicating lack of penetrance of the 1p36.22p36.21 microduplication. These findings emphasize phenotypic heterogeneity of the 1p36.22p36.21 copy number variant and the importance of screening the parents of patients with the 1p36.22p36.21 copy number variant to determine whether the duplication/triplication is de novo or inherited, for informed reproductive and genetic counseling.

Focal facial dermal dysplasias (FFDD) are characterized by congenital bitemporal or preauricular atrophic skin lesions, and either autosomal dominant or autosomal recessive inheritance. Setleis syndrome (SS), FFDD type III, is a severe form of FFDD with the ectodermal lesions plus other striking facial features. Autosomal recessive nonsense and frameshift mutations in TWIST2 have been found to cause SS in some but not all individuals. Here, we report on four unrelated individuals, one with an unclassified FFDD and the other three with classic SS. Chromosomal microarray analyses revealed unique copy number variants of 1p36 in two individuals with duplications at 1p36.22p36.21 and one with a triplication at 1p36.22p36.21. The fourth patient had normal chromosomes by microarray analysis. All four patients had normal TWIST2 exonic sequences. We propose that a dosage effect of one or more of the 30 genes in the 1.3 Mb 1p36.22p36.21 region of overlap is responsible for FFDD/SS manifestations in some individuals, and this mechanism would be inherited as an autosomal dominant trait. In patients with no duplication/triplication of the 1p36.22p36.21 region and no mutations in TWIST2, there are mutation(s) in one of the 30 genes in this region or mutations in other as yet unidentified genes at different locations that may affect the expressions of genes in this region or act independently to cause this developmental disease phenotype.

Setleis syndrome is characterized by bitemporal scar-like lesions and other characteristic facial features. It results from recessive mutations that truncate critical functional domains in the basic helix-loop-helix (bHLH) transcription factor, TWIST2, which regulates expression of genes for facial development. To date, only four nonsense or small deletion mutations have been reported. In the current report, the clinical findings in a consanguineous Turkish family were characterized. Three affected siblings had the characteristic features of Setleis syndrome. Homozygosity for the first TWIST2 missense mutation, c.326T>C (p.Leu109Pro), was identified in the patients. In silico analyses predicted that the secondary structure of the mutant protein was sustained, but the empirical force field energy increased to an unfavorable level with the proline substitution (p.Leu109Pro). On a crystallographically generated dimer, p.Leu109 lies near the dimer interface, and the proline substitution is predicted to hinder dimer formation. Therefore, p.Leu109Pro-TWIST2 alters the three dimensional structure and is unable to dimerize, thereby hindering the binding of TWIST2 to its target genes involved in facial development.