Phenotypic intrafamilial variability including H syndrome and Rosai-Dorfman disease associated with the same c.1088G > A mutation in the SLC29A3 gene.

BACKGROUND: Mutations in the SLC29A3 gene, which encodes the nucleoside transporter hENT3, have been implicated in syndromic forms of histiocytosis including H syndrome, pigmented hypertrichosis with insulin-dependent diabetes, Faisalabad histiocytosis and Familial Rosai-Dorfman disease (RDD). Herein, we report five new patients from a single family who present with phenotypes that associate features of H syndrome and Familial Rosai-Dorfman disease. METHODS: We investigated the clinical, biochemical, histopathological and molecular findings in five Tunisian family members' diagnosed with Familial RDD and/or H syndrome. The solute carrier family 29 (nucleoside transporters), member 3 (SLC29A3) gene was screened for molecular diagnosis using direct Sanger sequencing. RESULTS: Genetic analysis of all affected individuals revealed a previously reported missense mutation c.1088 G > A [p.Arg363Gln] in exon 6 of the SLC29A3 gene. Four affected members presented with clinical features consistent with the classical H syndrome phenotype. While their cousin's features were in keeping with Familial Rosai-Dorfman disease diagnosis with a previously undescribed cutaneous RDD presenting as erythematous nodular plaques on the face. This report underlines the clinical variability of SLC29A3 disorders even with an identical mutation in the same family. CONCLUSION: We report a rare event of 5 Tunisian family members' found to be homozygous for SLC29A3 gene mutations but showing a different phenotype severity. Our study reveals that despite a single mutation, the clinical expression of the SLC29A3 disorders may be significantly heterogeneous suggesting a poor genotype-phenotype correlation for the disease.

PHACES syndrome associated with carcinoid endobronchial tumor.

PHACES syndrome consists of the constellation of manifestations including posterior fossa anomalies of the brain (most commonly Dandy-Walker malformations), hemangiomas of the face and scalp, arterial abnormalities, cardiac defects, eye anomalies and sternal defects. We present a case with a possible PHACES syndrome including sternal cleft and supraumbilical raphé, precordial skin tag, persistent left superior vena cava and subtle narrowing of the aorta with an endobronchial carcinoid tumor. All these anomalies were discovered on chest multi-detector CT. This is a unique case of PHACES syndrome associated with carcinoid tumor. Review of the literature revealed 3 cases of PHACES syndrome with glial tumor. The authors tried to find the relationship between PHACES syndrome and carcinoid tumors or gliomas, which all derive from the neural crest cells.

Is Tunisia ready for precision medicine? Challenges of medical genomics within a LMIC healthcare system.

As one of the key tools on the precision medicine workbench, high-throughput genetic testing has enormous promise for improving healthcare outcomes. Tunisia has made tremendous progress in acquiring and implementing the technology in the clinical context. However, current utilization does not ensure the whole range of benefits that high-throughput genomic testing provides which impedes the country's ability to move forward into the new era of precision medicine. This issue is primarily related to the current state of Tunisia's healthcare ecosystem and the sociological attributes of its population, creating numerous challenges that must be addressed. In the current review, we aimed to identify and highlight these challenges that may be prevalent in other low and middle-income countries. Essentially, they fall into three main categories that include the socio-economic landscape in Tunisia, which prevents citizens from engaging in precision medicine activities; the current settings of the healthcare system that lack or miss key components for the successful implementation of precision medicine practices; and the inability of the current infrastructure and resources to handle the various challenges related to genomic data and metadata. We also propose five pillar solutions as a framework for addressing all of these challenges, which could strengthen Tunisia's capability for effective precision medicine implementation in today's clinical environment.

The Role of Pericytes in Inner Ear Disorders: A Comprehensive Review.

Inner ear disorders, including sensorineural hearing loss, Meniere's disease, and vestibular neuritis, are prevalent conditions that significantly impact the quality of life. Despite their high incidence, the underlying pathophysiology of these disorders remains elusive, and current treatment options are often inadequate. Emerging evidence suggests that pericytes, a type of vascular mural cell specialized to maintain the integrity and function of the microvasculature, may play a crucial role in the development and progression of inner ear disorders. The pericytes are present in the microvasculature of both the cochlea and the vestibular system, where they regulate blood flow, maintain the blood-labyrinth barrier, facilitate angiogenesis, and provide trophic support to neurons. Understanding their role in inner ear disorders may provide valuable insights into the pathophysiology of these conditions and lead to the development of novel diagnostic and therapeutic strategies, improving the standard of living. This comprehensive review aims to provide a detailed overview of the role of pericytes in inner ear disorders, highlighting the anatomy and physiology in the microvasculature, and analyzing the mechanisms that contribute to the development of the disorders. Furthermore, we explore the potential pericyte-targeted therapies, including antioxidant, anti-inflammatory, and angiogenic approaches, as well as gene therapy strategies.

Molecular and biochemical characterization of Tunisian patients with glycogen storage disease type III.

Glycogen storage disease type III (GSD III) is an autosomal recessive inborn error of metabolism caused by mutations in the glycogen debranching enzyme amylo-1,6-glucosidase gene, which is located on chromosome 1p21.2. GSD III is characterized by the storage of structurally abnormal glycogen, termed limit dextrin, in both skeletal and cardiac muscle and/or liver, with great variability in resultant organ dysfunction. The spectrum of AGL gene mutations in GSD III patients depends on ethnic group. The most prevalent mutations have been reported in the North African Jewish population and in an isolate such as the Faroe Islands. Here, we present the molecular and biochemical analyses of 22 Tunisian GSD III patients. Molecular analysis revealed three novel mutations: nonsense (Tyr1148X) and two deletions (3033_3036del AATT and 3216_3217del GA) and five known mutations: three nonsense (R864X, W1327X and W255X), a missense (R524H) and an acceptor splice-site mutation (IVS32-12A>G). Each mutation is associated to a specific haplotype. This is the first report of screening for mutations of AGL gene in the Tunisian population.

X-linked recessive ichthyosis in 8 Tunisian patients: awareness of misdiagnosis due to the technical trap of the STS pseudogene.

INTRODUCTION: X-linked recessive ichthyosis (XLI) is a genodermatosis, caused by a deficiency of the steroid sulphatase enzyme encoded by the STS gene (OMIM # 300,747). Adopted XLI molecular diagnosis approaches differ from one laboratory to another depending on available technical facilities. Our work aims to figure out a sound diagnostic strategy for XLI. PATIENTS AND METHODS: We collected 8 patients with XLI, all males, from 3 unrelated Tunisian families from central Tunisia. Genetic diagnosis was conducted through a large panel of genetic techniques including: Sanger Sequencing, haplotype analysis of STR markers, MLPA analysis, FISH and array CGH. RESULTS: Direct Sanger sequencing of the STS gene showed the same deletion of 13 base pairs within the exon 4 in all patients resulting in a premature stop codon. However, all patients' mothers were not carriers of this variant and no common haplotype flanking STS gene was shared between affected patients. Sequence alignment with reference human genome revealed an unprocessed pseudogene of the STS gene located on the Y chromosome, on which the 13 bp deletion was actually located. STS MLPA analysis identified a deletion of the entire STS gene on X chromosome for all affected patients. This deletion was confirmed by FISH and delineated by array CGH. CONCLUSION: All our patients shared a deletion of the entire STS gene revealed by MLPA, confirmed by FISH and improved by array CGH. Geneticists must be aware of the presence of pseudogenes that can lead to XLI genetic misdiagnosis.

[Triple negative breast cancer: clinical, pathological and molecular characteristics]. / Cancer du sein triple négatif: particularités anatomo-cliniques et moléculaires.

Triple-negative breast cancer (TNBC) is a very heterogeneous disease and refers to a subgroup of breast cancer. The purpose of this study was to describe the clinical, pathological and molecular features of TNBC. We conducted a retrospective analysis of 56 cases of TNBC diagnosed in the Department of Pathology at the Farhat Hached University Hospital over a period of three years (2018-2020). The incidence of TNBC was 5.62% and the mean age of the patients was 50.36 years. The most frequent reason for consultation was the discovery of breast nodules (98.21%). The diagnosis of TNBC was confirmed in 24 cases (42.86%) based on the analysis of mastectomy specimens. Invasive carcinoma of no special type (NST) was the most common histological type (47 cases; 82.5%). Mean tumor size was 35.5 mm. SBR grading was only specified in 42 cases (73.68%). Grade III was the most predominant type (78.6%, n = 33). The notion of lymph node metastasis was found in 44 reports and lymph node invasion was reported in 19 patients (43.2%). Immunohistochemical study showed that all patients were hormone receptor-negative (RO and RP) with no Her2 overexpression (n = 56; 100). This study results are generally in agreement with literature data. Despite recent molecular classifications, there is no clinically verified diagnostic test allowing for clear therapeutic standardization.

Correlation of SMN2, NAIP, p44, H4F5 and Occludin genes copy number with spinal muscular atrophy phenotype in Tunisian patients.

OBJECTIVES: Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder which is characterized by a high clinical variability with severe, intermediate, mild and adult forms. These forms are caused, in 95% of cases, by a homozygous deletion of exon 7 of SMN1 gene. Our purpose was the determination of a possible genotype-phenotype correlation between the copy number of SMN2, NAIP, p44, H4F5 and occludin genes localized in the same SMN1 region (5q13) and the severity of the disease in SMA Tunisian patients. PATIENTS AND METHODS: Twenty six patients affected by SMA were enrolled in our study. MLPA and QMPSF were used to measure copy numbers of these genes. RESULTS: We found that 31.3% of type I patients carried one copy of SMN2, while all patients of other forms had at least 2 copies. NAIP was absent in 87.5% of type I patients. Furthermore, all SMA type I patients had one copy of H4F5. No correlation was found for p44 and occludin genes. CONCLUSION: There is a close relationship between SMN2, NAIP and H4F5 gene copy number and SMA disease severity, which is compatible with the previous reports.