Purpose: To characterize the ocular features of a severe case of renal coloboma syndrome in a long-term follow-up. Methods: Observational case report over a period of 45 years. Examination under anesthesia at the age of 3 months, repeated ophthalmologic examination (age 7, 14, 25, 45 years), fluorescein and indocyanine green angiography, electroretinography, ocular ultrasound, optical coherence tomography, computed tomography scan orbits, and magnetic resonance imaging of the brain. Results: Presentation with severe bilateral posterior eye defects, optic nerve aplasia and a retrobulbar cyst in the left eye, renal abnormalities, and mental retardation. Over time, a progressive axial myopia in the right eye, band keratopathy in the left eye, and progressive bilateral posterior lens opacities were noted. There was only a minor decrease in visual acuity and visual field of the only functional right eye. The mother of this patient had a mild optic disk hypoplasia, progressive lens opacities, and late-onset renal disease. Both had a confirmed mutation in exon 2 of the PAX2 gene. Conclusion: This first published long-term follow-up of renal coloboma syndrome shows progressive posterior lens opacities, axial myopia, and band keratopathy with only a small decline in visual function over time.

Replicating the human genome efficiently and accurately is a daunting challenge involving the duplication of upward of three billion base pairs. At the core of the complex machinery that achieves this task are three members of the B family of DNA polymerases: DNA polymerases alpha, delta, and epsilon. Collectively these multimeric polymerases ensure DNA replication proceeds at optimal rates approaching 2 x 10(3) nucleotides/min with an error rate of less than one per million nucleotides polymerized. The majority of DNA replication of undamaged DNA is conducted by DNA polymerases delta and epsilon. The DNA polymerase alpha-primase complex performs limited synthesis to initiate the replication process, along with Okazaki-fragment synthesis on the discontinuous lagging strand. An increasing number of human disorders caused by defects in different components of the DNA-replication apparatus have been described to date. These are clinically diverse and involve a wide range of features, including variable combinations of growth delay, immunodeficiency, endocrine insufficiencies, lipodystrophy, and cancer predisposition. Here, by using various complementary approaches, including classical linkage analysis, targeted next-generation sequencing, and whole-exome sequencing, we describe distinct missense and splice-impacting mutations in POLA1 in five unrelated families presenting with an X-linked syndrome involving intellectual disability, proportionate short stature, microcephaly, and hypogonadism. POLA1 encodes the p180 catalytic subunit of DNA polymerase alpha-primase. A range of replicative impairments could be demonstrated in lymphoblastoid cell lines derived from affected individuals. Our findings describe the presentation of pathogenic mutations in a catalytic component of a B family DNA polymerase member, DNA polymerase alpha.

Objectives: Despite congenital heart defects (CHD) are one of the most common birth defects and often life-threatening their etiology is still poorly understood. Here we present a new candidate gene for CHD - CAPZB -, which was identified in a patient with hypoplastic left heart syndrome (HLHS). CAPZB encodes the β subunit of the fast growing-end actin binding protein, which belongs to the F-actin capping protein family. It regulates the assembly and disassembly of actin filaments, modulates the cytoskeleton as well as tethers actin filaments to the Z-line of the sarcomere and is therefore essential for muscle development.

One hundred and one patients with complete or incomplete cleft lip underwent the anatomical subunit approximation technique for repair. The patients were followed up prospectively for 1year. The objective of this study was to determine the outcomes for the nasolabial area through anthropometric measurements and assessment of the Asher-McDade Aesthetic Index and Steffensen’s criteria at 1year after surgery. Six assessors (three cleft surgeons and three non-surgeon medical professionals) examined cropped images; reliability was assessed using Cronbach’s alpha. The difference in lip length between the healthy and operated sides was 0.61mm and the difference in nostril diameter was 0.37mm (differences not significant). The average scar width was 2.78±1.35mm. Hypertrophic scars were observed in 9.9% of cases. The average Asher-McDade Aesthetic Index rating varied between 1.35 and 1.98 for all parameters. Cronbach’s alpha coefficient was 0.83, 0.89, 0.98, and 0.89 for nasal form, nasal symmetry, vermilion border, and nasolabial profile, respectively. Steffensen’s criteria rated appearance as ‘good’ in 69.3% to 91.1% of cases. The anatomical subunit approximation technique can be performed in Sub-Saharan Africans for all types of unilateral cleft lip. It significantly improves the length of the medial and lateral lips, leaving an acceptable scar. A study with a larger sample size and longer follow-up is warranted.

We present a newborn diagnosed with posterior amorphous corneal dystrophy (PACD). PACD is a rare disorder with partial or complete posterior lamellar corneal opacification. Genetic screening showed a deletion of chromosome 12q21.33-q22 containing the identified four small leucine-rich proteoglycans (SLRP's) associated with this particular dystrophy. Neither parents were carrier of the deletion. To our knowledge, this is the first report of a de novo mutation causing PACD.

NUMBER 1 L-ARGININE SUPPLEMENTATION REDUCES FIBROSIS IN A MOUSE MODEL OF CHRONIC ARISTOLOCHIC ACID INDUCED NEPHROPATHY I. Jadot, V. Colombaro, B. Martin, I. Habsch, O. Botton, J. Nortier, A-E Declèves, N. Caron 1Molecular Physiology Research Unit URPHYM, University of Namur (UNamur), Namur, Belgium 2Laboratory of Experimental Nephrology, Faculty of Medicine, Université Libre de Bruxelles (ULB), Brussels, Belgium 3Laboratory of Molecular Biology, Faculty of Medicine and Pharmacy, Research Institute for Health Sciences and Technology, University of Mons (UMONS), Mons, Belgium OBJECTIVE Aristolochic Acid (AA) nephropathy (AAN) is a rapidly progressive tubulointerstitial nephritis from toxic origin characterized by two interconnected phases: an early phase of acute kidney injury (AKI) leading to the later phase of chronic kidney disease (CKD) with progressive interstitial fibrosis. A reduced nitric oxide (NO) production in AAN has been demonstrated, which may contribute to renal function impairment. We previously established that sustaining NO bioavailability using L-Arginine (L-Arg) supplementation improves the outcome of AA-induced AKI. Since AKI contributes to the progression of renal disease towards CKD, we investigated in the present study the potential benefit of L-Arg supplementation in a chronic mouse model of AAN. METHODS To address this point, 8 weeks-old C57BL/6J male mice were subjected to daily i.p. injection of AA (3,5 mg/kg) for 4 days and L-Arg was supplemented in drinking water (5%) 7 days before first day of injection and all along the protocol Mice were euthanized 20 days after the first day of injection. RESULTS At day 20, we observed a significant reduction of NO bioavailability in AA-treated animals as measured by reduced urinary nitrate/nitrite and cGMP excretions. AA-treated mice displayed polyuria, proteinuria as well as increased levels of plasma creatinine and blood urea nitrogen. Histological analyses of AA-treated mice revealed numerous foci of tubular atrophy surrounded by severe interstitial fibrosis. Immunohistochemical staining of α-SMA revealed a significant increase of positive area staining. Moreover, mRNA expression of pro-fibrotic mediators like TGF-, CTGF, Periostin, ColI and ColIII was also increased. L-Arg supplementation in AA-treated mice significantly decreased tubular atrophy as attested by reduced tubular injury score. L-Arg treatment also significantly limited development of interstitial fibrosis as attested by both reduced α-SMA immunohistological staining and collagens mRNA expressions. Finally, L-Arg treatment also decreased TGF-, CTGF and Periostin mRNA expressions. CONCLUSION These results suggest that a preservation of NO bioavailibity may lead to a morpho-functionnal protection in AA-induced CKD. In the present mouse model of chronic AAN, NO seems to act as a key factor in protection of renal function and fibrosis development. In conclusion, restored NO bioavailability by L-Arg supplementation was demonstrated beneficial in improving renal injury in chronic AAN.

Non‐invasive prenatal testing ( NIPT ) for fetal aneuploidy detection is increasingly being offered in the clinical setting. Whereas the majority of tests only report fetal trisomies 21, 18 and 13, genome‐wide analyses have the potential to detect other fetal, as well as maternal, aneuploidies. In this review, we discuss the technical and clinical advantages and challenges associated with genome‐wide cell‐free fetal DNA profiling.