Current phenotypic and genetic spectrum of syndromic deafness in Tunisia: paving the way for precision auditory health.

Hearing impairment (HI) is a prevalent neurosensory condition globally, impacting 5% of the population, with over 50% of congenital cases attributed to genetic etiologies. In Tunisia, HI underdiagnosis prevails, primarily due to limited access to comprehensive clinical tools, particularly for syndromic deafness (SD), characterized by clinical and genetic heterogeneity. This study aimed to uncover the SD spectrum through a 14-year investigation of a Tunisian cohort encompassing over 700 patients from four referral centers (2007-2021). Employing Sanger sequencing, Targeted Panel Gene Sequencing, and Whole Exome Sequencing, genetic analysis in 30 SD patients identified diagnoses such as Usher syndrome, Waardenburg syndrome, cranio-facial-hand-deafness syndrome, and H syndrome. This latter is a rare genodermatosis characterized by HI, hyperpigmentation, hypertrichosis, and systemic manifestations. A meta-analysis integrating our findings with existing data revealed that nearly 50% of Tunisian SD cases corresponded to rare inherited metabolic disorders. Distinguishing between non-syndromic and syndromic HI poses a challenge, where the age of onset and progression of features significantly impact accurate diagnoses. Despite advancements in local genetic characterization capabilities, certain ultra-rare forms of SD remain underdiagnosed. This research contributes critical insights to inform molecular diagnosis approaches for SD in Tunisia and the broader North-African region, thereby facilitating informed decision-making in clinical practice.

Pallister-Hall syndrome diagnosed in a young man after an acute adrenal crisis.

Pallister-Hall syndrome (PHS) is a very rare genetic disorder. The diagnosis is usually suspected at the young age when a hypothalamic hamartoma is associated with polydactyly. Endocrine manifestations are mostly related to hypothalamic hamartoma and rarely reveal the disease. We report the case of an 18-year-old young man in whom the diagnosis of PHS was delayed until his hospitalization in the endocrinology department for acute adrenal insufficiency.

Alpha-mannosidosis in Tunisian consanguineous families: Potential involvement of variants in GHR and SLC19A3 genes in the variable expressivity of cognitive impairment.

Alpha-Mannosidosis (AM) is an ultra-rare storage disorder caused by a deficiency of lysosomal alpha-mannosidase encoded by the MAN2B1 gene. Clinical presentation of AM includes mental retardation, recurrent infections, hearing loss, dysmorphic features, and motor dysfunctions. AM has never been reported in Tunisia. We report here the clinical and genetic study of six patients from two Tunisian families with AM. The AM diagnosis was confirmed by an enzymatic activity assay. Genetic investigation was conducted by Sanger sequencing of the mutational hotspots for the first family and by ES analysis for the second one. In the first family, a frameshift duplication p.(Ser802GlnfsTer129) was identified in the MAN2B1 gene. For the second family, ES analysis led to the identification of a missense mutation p.(Arg229Trp) in the MAN2B1 gene in four affected family members. The p.(Ser802GlnfsTer129) mutation induces a premature termination codon which may trigger RNA degradation by the NMD system. The decrease in the levels of MAN2B1 synthesis could explain the severe phenotype observed in the index case. According to the literature, the p.(Arg229Trp) missense variant does not have an impact on MAN2B1 maturation and transportation, which correlates with a moderate clinical sub-type. To explain the intra-familial variability of cognitive impairment, exome analysis allowed the identification of two likely pathogenic variants in GHR and SLC19A3 genes potentially associated to cognitive decline. The present study raises awareness about underdiagnosis of AM in the region that deprives patients from accessing adequate care. Indeed, early diagnosis is critical in order to prevent disease progression and to propose enzyme replacement therapy.

Sparse classification of discriminant nystagmus features using combined video-oculography tests and pupil tracking for common vestibular disorder recognition.

Vertigo is a common sign related to a problem with the brain or vestibular system. Detection of ocular nystagmus can be a support indicator to distinguish different vestibular disorders. In order to get reliable and accurate real time measurements from nystagmus response, video-oculography (VOG) plays an important role in the daily clinical examination. However, vestibular diseases present a large diversity in their characteristics that leads to many complications for usual analysis. In this paper, we propose a novel automated approach to achieve both selection and classification of nystagmus parameters using four tests and a pupil tracking procedure in order to give reliable evaluation and standardized indicators of frequent vestibular dysfunction that will assist clinicians in their diagnoses. Indeed, traditional tests (head impulse, caloric, kinetic and saccadic tests) are applied to obtain clinical parameters that highlight the type of vertigo (peripheral or central vertigo). Then, a pupil tracking method is used to extract temporal and frequency nystagmus features in caloric and kinetic sequences. Finally, all extracted features from the tests are reduced according to their high characterization degree by linear discriminant analysis, and classified into three vestibular disorders and normal cases using sparse representation. The proposed methodology is tested on a database containing 90 vertiginous subjects affected by vestibular Neuritis, Meniere's disease and Migraines. The presented technique highly reduces labor-intensive workloads of clinicians by producing the discriminant features for each vestibular disease which will significantly speed up the vertigo diagnosis and provides possibility for fully computerized vestibular disorder evaluation.

Hybrid clustering system using Nystagmus parameters discrimination for vestibular disorder diagnosis.

BACKGROUD AND OBJECTIVE: The control of clinical manifestation of vestibular system relies on an optimal diagnosis. This study aims to develop and test a new automated diagnostic scheme for vestibular disorder recognition. METHODS: In this study we stratify the Ellipse-fitting technique using the Video Nysta Gmographic (VNG) sequence to obtain the segmented pupil region. Furthermore, the proposed methodology enabled us to select the most optimum VNG features to effectively conduct quantitative evaluation of nystagmus signal. The proposed scheme using a multilayer neural network classifier (MNN) was tested using a dataset involving 98 patients affected by VD and 41 normal subjects. RESULTS: The new MNN scheme uses only five temporal and frequency parameters selected out of initial thirteen parameters. The scheme generated results reached 94% of classification accuracy. CONCLUSIONS: The developed expert system is promising in solving the problem of VNG analysis and achieving accurate results of vestibular disorder recognition or diagnosis comparing to other methods or classifiers.

Sudden Death Due to Neck Paraganglioma: A Pediatric Case Report and Review of the Literature.

Neck paragangliomas are relatively rare neuroendocrine nonsecretory tumors. They are mainly observed among adults and are often asymptomatic, causing a frequent delay in diagnosis. In pediatric cases, neck paragangliomas can be associated with adrenergic symptoms that may lead to complications.A report of a sudden death due to a carotid paraganglioma in a young girl is reported. Autopsy revealed a thoracic arotic dissection and a 4-cm jugulocarotidian mass in the absence of traumatic injuries. Histology showed no evidence of underlying aortic disease, including signs of Marfan syndrome, and a paraganglioma. Postmortem biochemistry analysis showed blood metanephrines levels 100 times higher than normal range. The cause of death was an aortic dissection complicating a neck paraganglioma. The manner of death was concluded as natural.Our case highlighted the importance for forensic pathologist to consider the diagnosis of paraganglioma in case of sudden hypertensive complications, especially among young people.

A Tunisian family with a novel mutation in the gene CYP4F22 for lamellar ichthyosis and co-occurrence of hearing loss in a child due to mutation in the SLC26A4 gene.

BACKGROUND: Co-occurrence of two genetic diseases is challenging for accurate diagnosis and genetic counseling. The recent availability of whole exome sequencing (WES) has dramatically improved the molecular diagnosis of rare genetic diseases in particular in consanguineous populations. METHODS: We report here on a consanguineous family from Southern Tunisia including three members affected with congenital ichthyosis. The index case had a hearing loss (HL) and ichthyosis and was primarily suspected as suffering from keratitis-ichthyosis-deafness (KID) syndrome. WES was performed for the index case, and all members of the nuclear family were sequenced (Sanger method). RESULTS: The WES approach allowed the identification of two strong candidate variants in two different genes; a missense mutation c.1334T>G (p.Leu445Trp) in exon 11 of SLC26A4 gene, associated with isolated HL and a novel missense mutation c.728G>T (p.Arg243Leu) in exon 8 of CYP4F22 gene likely responsible for ichthyosis. These two mutations were predicted to be pathogenic by three pathogenicity prediction softwares (Scale-Invariant Feature Transform [SIFT], Polymorphism Phenotyping [PolyPhen], Mutation Taster) to underlie the HL and ichthyosis, respectively. CONCLUSIONS: The present study raises awareness about the importance of familial history for accurate diagnosis of syndromic genetic diseases and differential diagnosis with co-occurrence of two distinct clinical entities. In addition, in countries with limited resources, WES sequencing for a single individual provides a cost effective tool for molecular diagnosis confirmation and genetic counseling.

Ectopic thyroid tissue: unusual differential diagnosis of cervical paraganglioma.

Ectopic thyroid tissue (ETT) lateral to the midline is rare. Its occurrence in the carotid bifurcation is exceptional. We present a 45 years woman who consulted with a slow growing right cervical swelling. Clinical examination Ultrasonography, contrast enhanced CT and cervical MRI concluded to a paraganglioma. Intra-operatively, the tumor didn't have the characteristic aspect of a paraganglioma. Complete excision was performed. Histology concluded to an ectopic micro-vesicular thyroid adenoma.Previous literature was reviewed to summarize clinical and radiologic characteristics of such rare entity. Despite its rarity, ETT must be included in the differential diagnosis of cervical paraganglioma.

Agressive infection following a dental extraction in a diabetic patient :Rhinocerebral mucormycosis.

Mucormycosis is a rare and acute fungal infection which is frequently lethal, usually observed in non-controlled diabetic patients. The infection usually begins in the nose but it can invade the lung, the digestive tract, and the skin. Rhinocerebral mucormycosis accounts for 40 to 49% of mucormycosis cases. We report the case of a 44-year-old diabetic man, presenting with rhinocerebral mucormycosis. Our patient was treated by an association of amphotericin B and surgical debridement.

Malignant transformation of nasal inverted papilloma into sarcomatoid carcinoma.

A 57 year-old, male presented with a chronic unilateral nasal obstruction and epistaxis. Intranasal endoscopy showed multiple polypoid lesions. The computed tomography exam revealed a heterogeneous mass that occupied the right nasal cavity with osteolysis of the middle and lower cone causing fluid retention of the right maxillary sinus. He underwent resection of these lesions. Pathological examination revealed malignant transformation of nasal inverted papilloma into sarcomatoid carcinoma. This case report highlights the importance of considering malignant transformation in the differential diagnosis of polypoid lesions.

Whole exome sequencing identifies mutations in Usher syndrome genes in profoundly deaf Tunisian patients.

Usher syndrome (USH) is an autosomal recessive disorder characterized by combined deafness-blindness. It accounts for about 50% of all hereditary deafness blindness cases. Three clinical subtypes (USH1, USH2, and USH3) are described, of which USH1 is the most severe form, characterized by congenital profound deafness, constant vestibular dysfunction, and a prepubertal onset of retinitis pigmentosa. We performed whole exome sequencing in four unrelated Tunisian patients affected by apparently isolated, congenital profound deafness, with reportedly normal ocular fundus examination. Four biallelic mutations were identified in two USH1 genes: a splice acceptor site mutation, c.2283-1G>T, and a novel missense mutation, c.5434G>A (p.Glu1812Lys), in MYO7A, and two previously unreported mutations in USH1G, i.e. a frameshift mutation, c.1195_1196delAG (p.Leu399Alafs*24), and a nonsense mutation, c.52A>T (p.Lys18*). Another ophthalmological examination including optical coherence tomography actually showed the presence of retinitis pigmentosa in all the patients. Our findings provide evidence that USH is under-diagnosed in Tunisian deaf patients. Yet, early diagnosis of USH is of utmost importance because these patients should undergo cochlear implant surgery in early childhood, in anticipation of the visual loss.