Distinctive facial features consisting of hypertelorism, telecanthus, blepharophimosis, blepharoptosis, epicanthus inversus, periumbilical defects, and skeletal anomalies are seen in autosomal-recessive Carnevale, Malpuech, Michels, and oculo-skeletal-abdominal (OSA) syndromes. The gene or genes responsible for these syndromes were heretofore unknown. We report on three individuals from two consanguineous Turkish families with findings characteristic of these syndromes, including facial dysmorphism, periumbilical depression, mixed hearing loss, radioulnar synostosis, and coccygeal appendage. Homozygosity mapping yielded an autozygous region on chromosome 3q27 in both families. In one family, whole exome sequencing revealed a missense mutation, MASP1 c.2059G>A (p.G687R), that cosegregated with the phenotype. In the second family, Sanger sequencing of MASP1 revealed a nonsense mutation, MASP1 c.870G>A (p.W290X), that also cosegregated with the phenotype. Neither mutation was found in 192 Turkish controls or 1200 controls of various other ancestries. MASP1 encodes mannan-binding lectin serine protease 1. The two mutations occur in a MASP1 isoform that has been reported to process IGFBP-5, thereby playing a critical role in insulin growth factor availability during craniofacial and muscle development. These results implicate mutations of MASP1 as the cause of a human malformation syndrome and demonstrate the involvement of MASP1 in facial, umbilical, and ear development during the embryonic period.

BACKGROUND Knobloch syndrome is a rare, autosomal recessive, developmental disorder characterized by stereotyped ocular abnormalities with or without occipital skull deformities (encephalocele, bone defects, cutis aplasia). Although there is clear heterogeneity in clinical presentation, central nervous system malformations, aside from the characteristic encephalocele, have not typically been considered a component of the disease phenotype. METHODS Four patients originally presented for genetic evaluation of symptomatic structural brain malformations. Whole-genome genotyping, whole-exome sequencing, and confirmatory Sanger sequencing were performed. Using immunohistochemical analysis, we investigated the protein expression pattern of COL18A1 in the mid-fetal and adult human cerebral cortex and then analyzed the spatial and temporal changes in the expression pattern of COL18A1 during human cortical development using the Human Brain Transcriptome database. RESULTS We identified two novel homozygous deleterious frame-shift mutations in the COL18A1 gene. Upon further investigation of these patients and their families, we found that many exhibited certain characteristics of Knobloch syndrome, including pronounced ocular defects. Our data strongly support an important role for COL18A1 in brain development and this report contributes to an enhanced characterization of the brain malformations that can result from deficiencies of collagen XVIII. CONCLUSIONS This case series highlights the diagnostic power and clinical utility of whole-exome sequencing technology – allowing clinicians and physician scientists to better understand the pathophysiology and presentations of rare diseases. We suggest that patients who are clinically diagnosed with Knobloch syndrome and/or found to have COL18A1 mutations via genetic screening should be investigated for potential structural brain abnormalities even in the absence of encephaloceles.

Topical CsA 0.05% eyedrops were found to be safe and effective in the treatment of patients with VKC. Consistent with these results, topical CsA may efficiently reduce conjunctival inflammation in severe VKC.

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BackgroundCataract surgery is associated with the development of late-onset age-related macular degeneration (AMD). The pathogenic mechanism is still not fully established. The purpose of this study was to evaluate the possible changes in central macula thickness (CMT) and subfoveal choroid thickness (SCT) after uneventful cataract surgery.Material/MethodsA total of 65 eyes of 65 patients who underwent phacoemulsification and intracapsular lens implantation were included in this prospective study. Patients had not undergone previous ocular surgery and had no other ocular abnormality. CMT and SCT were measured at baseline and postoperatively at week 1 and months 1, 3, 6 and 12 via spectral domain optical cohorence tomography (SD-OCT).ResultsCMT was 252.4±27.6 μm (mean ±SD) preoperatively, then 253.5±29.8, 256.1±28.7, 257.4±27.2, 253.18±23.7, and 252.8±21.7 μm at postoperative week 1 and postoperative months 1, 3, 6, and 12, respectively. There were insignificant changes in CMT, and it returned to baseline at six months after surgery (all p>0.05). SCT was 237.4±21.6 μm preoperatively, and 240.5±24.8, 241.2±25.7, 242.7±26.3, 243.1±24.2, and 244.2±21.4 μm at postoperative week 1 and postoperative months 1, 3, 6, and 12, respectively. Although there was an increase in SCT during follow-up, the difference between preoperative and postoperative values was not significant (p>0.05).ConclusionsUncomplicated phacoemulsification induces subclinical changes in CMT, probably due to the inflammatory insult of surgery, and CMT returns to baseline value. There were slight, insignificant increases in choroid thickness during follow-up, and this did not return to baseline during follow-up. Changes in the choroid after cataract surgery may provide clues to the development of late-onset AMD.

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There are significant reductions in the blood flow values of the orbital arteries in patients with BehCet's disease, and they are more evident in those with ocular involvement. This might be the result of occlusive vasculitis, which is frequently seen in the retinal vessels of patients with BehCet's disease.