The dotted line indicates the position of the basement membrane. epidermis is a highly organized, stratified, self-renewing epithelium that functions as a barrier to protect the organism from dehydration, mechanical trauma, and microbial invasion.1,2During development, the immature ectoderm H3B-6545 Hydrochloride initially consists of a single layer of mitotically active, undifferentiated, cuboidal epithelial cells that progress through a defined series of stratification and differentiation events to produce the mature epidermis that consists of four distinct cellular layers maintained by a constant process of displacement and renewal. Development and subsequent maintenance of the epidermis are therefore critically dependent on the intricate balance between proliferation and differentiation of a mitotically-active basal cell population.1,2Disruption of this balance results in a wide variety of congenital anomalies of epidermal development that have profound effects on H3B-6545 Hydrochloride affected individuals and their families. Pterygium syndromes are complex, congenital disorders that include several different clinical conditions characterized by multiple skin webs affecting the flexural surfaces and associated craniofacial anomalies. To date, Van der Woude syndrome (MIM119300) and popliteal pterygium syndrome (MIM119500) have been demonstrated to result from mutations in the transcription factorIRF6(MIM607199),3whereas mutation of the gene encoding the NF-B pathway component IB kinase- (IKKA[MIM600664]) underlies an autosomal-recessive lethal syndrome termed severe fetal encasement malformation or Cocoon syndrome (MIM613630).4Despite these advances, the molecular basis of other pterygium syndromes remains elusive. Bartsocas-Papas syndrome (MIM263650) is a devastating autosomal-recessive disorder characterized by multiple popliteal pterygia, ankyloblepharon, filiform bands between the jaws, cleft lip and palate, and syndactyly.5Early lethality is common, though survival into childhood and beyond has been reported.5 To determine the molecular basis of Bartsocas-Papas syndrome, we performed exome sequencing on a single individual affected by this condition. The proband was the second child of consanguineous parents; no other significant previous family history was identified. Routine anomaly scanning during pregnancy revealed multiple congenital abnormalities. Further investigation during pregnancy was declined. Fetal bradycardia was noted on monitoring 1 week preterm, and an elective Cesarean section was performed. Birth weight was 2.95 kg and the occipitofrontal circumference was 34 cm. Multiple congenital abnormalities, including alopecia totalis with only sparse scalp hair, partial ankyloblepharon, oral synechia resulting in partial occlusion of the oral cavity, hypertelorism, cloudy corneas, absent thumbs, finger oligosyndactyly, hypoplastic genitalia, extensive popliteal pterygia, toe oligosyndactyly, multiple skin tags, and unusual fibrous tethers between the feet and suprapubic region were noted (Figures 1A and 1B). On the basis of these clinical features a diagnosis of Bartsocas-Papas syndrome was Eptifibatide Acetate made. The patient is alive at 6 years of age and intellectual development appears normal. DNA samples were obtained from three members of the family (Figure 1C) via standard procedures and with informed consent under the relevant institutional review boards and the UK National Research Ethics Service. == Figure 1. == Homozygous Mutations inRIPK4Underlie Bartsocas-Papas Syndrome (A and B) Clinical pictures of the affected child whose DNA was subject to exome sequencing. The alopecia, partial ankyloblepharon, oral synechia resulting in partial occlusion of the oral cavity, oligosyndactyly, popliteal pterygia, and fibrous tethers between feet and suprapubic region are apparent. (C) Partial pedigree of the family. The shaded symbol represents the affected child. (D) Sequence chromatograms showing segregation of the homozygousNM_020639.2:c.1127C>A mutation, which resulted in the nonsense change p.S376X and the affected phenotype. (E) Sequence chromatogram of the homozygousNM_020639.2:c.242T>A mutation, which resulted in the missense change p.Ile81Asn. (F) RIPK4 expression in E18.5 mouse epidermis. Cytoplasmic immunofluorescence (red) is observed in basal and suprabasal layers with the nuclei counterstained with DAPI (blue). The dotted line indicates the position of the basement membrane. The scale bar represents 25 m. Targeted enrichment and sequencing were performed on 3 g of DNA extracted from peripheral blood of the affected child. Enrichment was H3B-6545 Hydrochloride performed with the SureSelect Human All Exon 50 MB Kit (Agilent, Santa Clara, CA, USA) for the ABI SOLiD system following the manufacturer’s protocols..