Dorfman-Chanarin Syndrome with Renal Involvement: A Rare Case Report and Literature Review.

Dorfman-Chanarin syndrome (DCS) is a rare autosomal recessive disease. It is a multisystemic disease in which renal involvement is uncommon. We report the case of a woman with nephrotic syndrome associated with DCS. A 36-year-old woman was referred to the nephrology department for edema with known history for DCS. On physical examination, she had ichthyosiform erythroderma with generalized scaly skinand ascites. The ophthalmologic examination revealed a cataract in the right eye. Abdominal ultrasound examination showed hepatomegaly and splenomegaly. Laboratory tests showed normal renal and liver function. The blood cell count showed pancytopenia. Immunologic exams showed the presence of anti-mitochondrial antibodies. Kidney biopsy showed mesangial proliferative glomerulonephritis with extensive lipid vacuoles in the tubular epithelial cells. Immunofluorescence study showed mesangial deposits of IgG, C3, kappa, and lambda. To the best of our knowledge, this is the first case of DCS with renal involvement reported in an adult.

Annexin A1 and its receptor gene polymorphisms in systemic lupus erythematosus in the Tunisian population.

BACKGROUND: An association between ANXA1, FPR1 and FPR2 gene polymorphisms and the patho-physiology of many human diseases was suggested by numerous studies. OBJECTIVE: Our study aimed to evaluate association between common polymorphisms in the 9q21.13 and 19q13.41 and susceptibility to systemic lupus erythematosus (SLE) in the Tunisian population. MATERIALS: We performed a case-control study on 107 Tunisian SLE patients and 122 healthy controls to explore 9 polymorphisms of the three studied genes: rs2811226 and rs3739959 (ANXA1), rs5030880, rs1042229, rs1461765570, rs17849971, rs867228 (FPR1), rs17694990 and rs11666254 (FPR2). RESULTS: Four polymorphisms were found to be linked with SLE susceptibility: rs3739959-ANXA1 > G and GG (p = 0.021, OR = 1.73 and p = 0.014, OR = 2.06 respectively), rs867228-FPR1 > TT (p = 0.014, OR = 4.59), rs11666254-FPR2 > GG (p = 0.019, OR = 8.34) and rs17694990-FPR2 > T (p = 0.05, OR = 1.506). In homogenous groups of SLE patients depending on clinical manifestations and serological results, previous associations were confirmed with a panoply of manifestations of lupus including lupus nephritis, malar rash, mouth ulceration and hypocomplementia. CONCLUSION: Our study showed an association between ANXA1 > rs3739959, FPR1 > rs867228, FPR2 > rs11666254, FPR2 > rs17694990 and SLE susceptibility. Our results also showed a strong association between the two ANXA1 studied SNPs and LN which allowed us to suggest these two SNPs as biomarkers of LN development in SLE. Further research is needed to understand by which mechanism the gene variants affect susceptibility to SLE. Key Points • Lupus erythematosus is an autoimmune disease in which a panoply of factors are implicated • Annexin A1 interaction with its receptors are suggested as a target in therapy of a panoply of human disease in particular cancers • The present results highlighted the implication of Annexin A1 and its receptors gene polymorphisms in the physiopathology of lupus, in particular in the involvement of renal and cutaneous lesions.

Next-generation sequencing in patients with familial FSGS: first report of collagen gene mutations in Tunisian patients.

Focal segmental glomerulosclerosis (FSGS) is a histological lesion with many causes, including inherited genetic defects, with significant proteinuria being the predominant clinical finding at presentation. FSGS is considered as a podocyte disease due to the fact that in the majority of patients with FSGS, the lesion results from defects in the podocyte structure. However, FSGS does not result exclusively from podocyte-associated genes. In this study, we used a genetic approach based on targeted next-generation sequencing (NGS) of 242 genes to identify the genetic cause of FSGS in seven Tunisian families. The sequencing results revealed the presence of eight distinct mutations including seven newly discovered ones: the c.538G>A (p.V180M) in NPHS2, c.5186G>A (p.R1729Q) in PLCE1 and c.232A>C (p.I78L) in PAX2 and five novel mutations in COL4A3 and COL4A4 genes. Four mutations (c.209G>A (p.G70D), c.725G>A (p.G242E), c.2225G>A (p.G742E), and c. 1681_1698del) were detected in COL4A3 gene and one mutation (c.1424G>A (p.G475D)) was found in COL4A4. In summary, NGS of a targeted gene panel is an ideal approach for the genetic testing of FSGS with multiple possible underlying etiologies. We have demonstrated that not only podocyte genes but also COL4A3/4 mutations should be considered in patients with FSGS.

Identification of compound heterozygous patients with primary hyperoxaluria type 1: clinical evaluations and in silico investigations.

BACKGROUND: Primary hyperoxaluria type 1 (PH1) is an autosomal recessive inherited disorder of glyoxylate metabolism in which excessive oxalates are formed by the liver and excreted by the kidneys. Calcium oxalate crystallizes in the urine, leading to urolithiasis, nephrocalcinosis, and consequent renal failure if treatment is not initiated promptly. Mutations in the AGXT gene which encodes the hepatic peroxisomal enzyme alanine:glyoxylate aminotransferase are responsible of PH1. In the present work, we aimed to analyze AGXT gene and in silico investigations performed in four patients with PH1 among two non consanguineous families. METHODS: Exhaustive gene sequencing was performed after PCR amplification of coding exons and introns boundaries. Bioinformatic tools were used to predict the impact of AGXT variants on gene expression as well as on the protein structure and function. RESULTS: Direct sequencing of all exons of AGXT gene revealed the emergence of multiple mutations in compound heterozygous state in the two studied families. Two patients were compound heterozygous for the c.731 T > C, c.32C > T, c.1020A > G and c.33_34insC and presented clinically with recurrent urinary tract infection, multiple urolithiasis and nephrocalcinosis under the age of 1 year and a persistent hyperoxaluria at the age of diagnosis. The two other patients presenting a less severe phenotypes were heterozygous for c.731 T > C and homozygous for the c.32C > T and c.1020A > G or compound heterozygous for c.26C > A and c.65A > G variants. CONCLUSION: In Summary, we provided relevance regarding the compound heterozygous mutations in non consanguineous PH1 families with variable severity.

A double mutation in AGXT gene in families with primary hyperoxaluria type 1.

Primary hyperoxaluria type 1 (PH1) is a severe autosomal recessive inherited disorder of glyoxylate metabolism caused by mutations in the AGXT gene on chromosome 2q37.3 that encodes the hepatic peroxisomal enzyme alanine:glyoxylate aminotransferase. These mutations are found throughout the entire gene and cause a wide spectrum of clinical severity. Rare in Europe, PH1 is responsible for 13% of the end stage renal failure in the Tunisian child. In the present work, we identified the double mutation c.32C>T (Pro11Leu) and c.731T>C (p.Ile244Thr) in AGXT gene in five unrelated Tunisian families with PH1 disease. Our results provide evidence regarding the potential involvement of c.32C>T, originally described as common polymorphism, on the resulting phenotype. We also reported an extreme intrafamilial heterogeneity in clinical presentation of PH1. Despite the same genetic background, the outcome of the affected members differs widely. The significant phenotypic heterogeneity observed within a same family, with a same genotype, suggests the existence of relevant modifier factors.

Congenital factor XIII deficiency caused by two mutations in eight Tunisian families: molecular confirmation of a founder effect.

Inherited factor XIII (FXIII) deficiency is a rare bleeding disorder characterized by an umbilical bleeding during the neonatal period, delayed soft tissue bruising, mucosal bleeding spontaneous intracranial hemorrhage, and soft tissue hemorrhages. Congenital FXIII deficiency is an autosomal recessive disorder, usually attributed to a defect in the FXIIIA and B subunits coding, respectively, by F13A and F13B genes. The aim of this study was to determine the molecular defects responsible for congenital factor XIII deficiency in eight Tunisian families. Molecular analysis was performed by direct DNA sequencing of polymerase chain reaction amplified fragments spanning the coding regions and splice junctions of the FXIIIA subunit gene (F13A) in probands and in families' members and compared with the reported sequence of this gene. In all patients, FXIIIA activity was undetectable and the FXIIIB was within the normal range. Direct sequencing of the F13A gene in all probands showed two mutations: the c.869insC mutation found in eight patients and the c.1226G > A transition found in only one. We also confirmed the presence of a founder effect for the first frequent mutation by using two microsatellite markers, HUMF13A01 and a generated ployAC marker (HUMF13A02). We describe here molecular abnormalities found in nine Tunisian probands diagnosed with FXIIIA deficiency. The identification of the founder mutation and polymorphisms allowed a genetic counseling in relatives of these families, and the antenatal diagnosis is now available.