De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development

Bosma arhinia microphthalmia syndrome (BAMS) is an extremely rare and striking condition characterized by complete absence of the nose with or without ocular defects. We report here that missense mutations in the epigenetic regulator SMCHD1 mapping to the extended ATPase domain of the encoded protein cause BAMS in all 14 cases studied. All mutations were de novo where parental DNA was available. Biochemical tests and in vivo assays in Xenopus laevis embryos suggest that these mutations may behave as gain-of-function alleles. This finding is in contrast to the loss-of-function mutations in SMCHD1 that have been associated with facioscapulohumeral muscular dystrophy (FSHD) type 2. Our results establish SMCHD1 as a key player in nasal development and provide biochemical insight into its enzymatic function that may be exploited for development of therapeutics for FSHD

A case with pfeiffers syndrome treated by monobloc advancement with rigid external distraction

Kraniyofasiyal dizostozisli hastalarda hem estetik problemler hem de görme bozukluklarını, obstrüktif uyku apnesini ve büyüme sorunlarını içeren fonksiyonel problemler gelişmektedir. Bu problemler değişik yöntemlerle tedavi edilebilmektedir. Rijit Eksternal Distraksiyon ile orta yüz ilerletmesi, tek bir işlemle bu sorunların tamamının düzeltilmesine imkan sağlamaktadır. Bu vaka raporunda, monoblok osteotomi ve Rijit Eksternal Distraksiyon Sistemi (RED-II) kullanılarak distraksiyonu gerçekleştirilmiş Pfeiffers sendromlu, 4 yaşındaki hasta sunulmaktadır. Bu hastada frontofasiyal ilerletme RED-H kullanılarak başarılı bir şekilde elde edilmiş, böylece tek operasyonla eksoftal-mus ve üst hava yolu sorunları düzeltilmiştir.Patients with craniofacial dysostosis develop both aesthetic and functional problems including ocular dysfunction, obstructive sleep apnoeas and failure to thrive. These problems can be treated by a number of different techniques. The monobloc frontofacial advancement has the ability to correct all of these functional problems in one procedure. A case report of a 4-year-old boy with Pfeiffers syndrome treated by monobloc osteotomy and distraction using the rigid external distractor (RED) is reported. Monobloc frontofacial advancement in this patient can be successfully achieved using the RED, thus, treating exophthalmus and upper airway problems at a time in one operation

Mutations In The Interleukin Receptor Il11Ra Cause Autosomal Recessive Crouzon-Like Craniosynostosis

We have characterized a novel autosomal recessive Crouzon-like craniosynostosis syndrome in a 12-affected member family from Antakya, Turkey, the presenting features of which include: multiple suture synostosis, midface hypoplasia, variable degree of exophthalmos, relative prognathism, a beaked nose, and conductive hearing loss. Homozygosity mapping followed by targeted next-generation sequencing identified a c.479+6T>G mutation in the interleukin 11 receptor alpha gene (IL11RA) on chromosome 9p21. This donor splice-site mutation leads to a high percentage of aberrant IL11RA mRNA transcripts in an affected individual and altered mRNA splicing determined by in vitro exon trapping. An extended IL11RA mutation screen was performed in a cohort of 79 patients with an initial clinical diagnosis of Crouzon syndrome, pansynostosis, or unclassified syndromic craniosynostosis. We identified mutations segregating with the disease in five families: a German patient of Turkish origin and a Turkish family with three affected sibs all of whom were homozygous for the previously identified IL11RA c.479+6T>G mutation; a family with pansynostosis with compound heterozygous missense mutations, p.Pro200Thr and p.Arg237Pro; and two further Turkish families with Crouzon-like syndrome carrying the homozygous nonsense mutations p.Tyr232* and p.Arg292*. Using transient coexpression in HEK293T and COS7 cells, we demonstrated dramatically reduced IL11-mediated STAT3 phosphorylation for all mutations. Immunofluorescence analysis of mouse Il11ra demonstrated specific protein expression in cranial mesenchyme which was localized around the coronal suture tips and in the lambdoidal suture. In situ hybridization analysis of adult zebrafish also detected zfil11ra expression in the coronal suture between the overlapping frontal and parietal plates. This study demonstrates that mutations in the IL11RA gene cause an autosomal recessive Crouzon-like craniosynostosis.PubMedScopu

Meta-analysis of 13 genome scans reveals multiple cleft lip/palate genes with novel loci on 9q21 and 2q32-35.

Isolated or nonsyndromic cleft lip with or without cleft palate (CL/P) is a common birth defect with a complex etiology. A 10-cM genome scan of 388 extended multiplex families with CL/P from seven diverse populations (2,551 genotyped individuals) revealed CL/P genes in six chromosomal regions, including a novel region at 9q21 (heterogeneity LOD score [HLOD]=6.6). In addition, meta-analyses with the addition of results from 186 more families (six populations; 1,033 genotyped individuals) showed genomewide significance for 10 more regions, including another novel region at 2q32-35 (P=.0004). These are the first genomewide significant linkage results ever reported for CL/P, and they represent an unprecedented demonstration of the power of linkage analysis to detect multiple genes simultaneously for a complex disorder