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.

Ludwig's Angina.

Ludwig's angina is a severe diffuse cellulitis that presents an acute onset and spreads rapidly and bilaterally. It can affect the submandibular, sublingual or submental spaces resulting in a state of emergency. Early diagnosis and urgent management could be a life-saving procedure. We report a case of wide spread sialadenitis infection extending to the neck with trismus and elevation of the floor of the mouth that caused an obstruction of the airway and resulted in an inspiratory dyspnea and a stridor. The patient was directed to maintain the airway by elective tracheostomy. An appropriate use of parenteral antibiotics, airway protection techniques, and potential surgical drainage of the infection remain the standard protocol of treatment in advanced cases of Ludwig's angina. The aim of this case report is to emphasize on the importance of early diagnosis and appropriate management of Ludwig's angina.

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.

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.

Whole exome sequencing identifies new causative mutations in Tunisian families with non-syndromic deafness.

Identification of the causative mutations in patients affected by autosomal recessive non syndromic deafness (DFNB forms), is demanding due to genetic heterogeneity. After the exclusion of GJB2 mutations and other mutations previously reported in Tunisian deaf patients, we performed whole exome sequencing in patients affected with severe to profound deafness, from four unrelated consanguineous Tunisian families. Four biallelic non previously reported mutations were identified in three different genes: a nonsense mutation, c.208C>T (p.R70X), in LRTOMT, a missense mutation, c.5417T>C (p.L1806P), in MYO15A and two splice site mutations, c.7395+3G>A, and c.2260+2T>A, in MYO15A and TMC1 respectively. We thereby provide evidence that whole exome sequencing is a powerful, cost-effective screening tool to identify mutations causing recessive deafness in consanguineous families.

[Facial nerve paralysis secondary to acute otitis media]. / Paralysie faciale périphérique suite à une otite moyenne aiguë

OBJECTS: To discuss clinical presentation and therapeutic approaches of facial paralysis in acute otitis media. METHODS: We present five cases of facial palsy in children with acute otitis media managed in our ENT department during a period of 12 years (2001-2012). RESULTS: The mean age was 14.2 years; sex ratio was 0.66. All patients presented with a facial asymmetry, but only 3 of them had otalgia before the onset of facial asymmetry. The facial palsy delay was 3.3 days. The ear examination showed that the tympanic membrane was congestive in 4 patients, associated with a bulging in 2 patients, and a small perforation in one patient. Our patients presented grade III to IV initial facial palsy according to House and Brackmann staging. Computed tomography scan revealed a dehiscence of the bony facial canal in one patient. Antibiotic therapy associated with intravenous corticosteroids was administered in all patients. All patients underwent a facial kinesis therapy. A progressive improvement of facial palsy was observed in 4 patients and complete recovery of facial function in one case. DISCUSSION: Conservative treatment associating intravenous antibiotic and corticosteroids with or without myringotomy is the standard approach.

Compound heterozygosity for dominant and recessive GJB2 mutations in a Tunisian family and association with successful cochlear implant outcome.

OBJECTIVES: Mutations of GJB2 encoding connexin 26 are the most common cause of hearing loss. They are responsible for up to 50% of ARNSHL. The pathogenic mutations in this gene are generally inherited recessively. Dominant mutations in GJB2 also cause hearing loss, either in isolated non-syndromic form or as part of a syndrome associated with various skin disorders. METHODS: We screened a Tunisian child affected by congenital, bilateral, profound, sensorineural hearing loss for mutations in GJB2 gene using PCR and direct sequencing. RESULTS: The proband was found to be compound heterozygous for recessive and dominant GJB2 mutations respectively p.V37I (c.109G > A) and p.R143Q (c.428G > A). Surprisingly the hearing mother is a carrier for this dominant GJB2 mutation. This proband underwent a cochlear implant at four years old. The evaluation using APCEI and IT-MAIS tests at six months post implantation indicates a successful cochlear implant outcome since the deaf child began to acquire language abilities and auditory sensation. CONCLUSIONS: The p.R143Q mutation was described for the first time in Tunisia. We confirm the low penetrance of this mutation since the proband mother is a carrier despite her normal hearing. We show the effectiveness of cochlear implant to restore the communication abilities and auditory sensation for our patient.

A novel frameshift mutation (c.405delC) in the GJB2 gene associated with autosomal recessive hearing loss in two Tunisian families.

OBJECTIVES: Mutations in GJB2 are found to be responsible for 50% of congenital autosomal recessive non-syndromic hearing loss, one of the most important mutations in this gene is the c.35delG, which is responsible for the majority of GJB2 related deafness in the Tunisian population. The aim of this study was to determine the molecular etiology of hearing loss in two Tunisian individuals. METHODS: We screened two Tunisian individuals affected by congenital, bilateral, profound, sensorineural hearing loss for mutations in GJB2 gene using PCR and direct sequencing. RESULTS: We identified a novel frameshift mutation in the GJB2 gene, the c.405delC resulting in a truncated protein (p.Tyr136Thrfs*32). It was found in compound heterozygosity with the c.35delG in two non-consanguineous unrelated families from Tunisia. One patient underwent a cochlear implant at 4 years. Initial evaluations post-implantation indicate a successful cochlear implant outcome since the patient began to acquire language abilities and auditory sensation. CONCLUSIONS: With this novel GJB2 mutation, the mutational spectrum of this gene continues to broaden in our population. The occurrence of biallelic GJB2 mutations for the other deaf girl, despite the neonatal pain and hypotension due to complicated delivery, led us to confirm the importance of GJB2 screening for cochlear implant candidates regardless of the etiology of deafness in populations with a relatively high frequency of GJB2 mutation carriers.

Update of the spectrum of GJB2 gene mutations in Tunisian families with autosomal recessive nonsyndromic hearing loss.

Hearing loss is the most frequent sensory disorder. It affects 3 in 1000 newborns. It is genetically heterogeneous with 60 causally-related genes identified to date. Mutations in GJB2 gene account for half of all cases of non-syndromic deafness. The aim of this study was to determine the relative frequency of GJB2 allele variants in Tunisia. In this study, we screened 138 patients with congenital hearing loss belonging to 131 families originating from different parts of Tunisia for mutations in GJB2 gene. GJB2 mutations were found in 39% of families (51/131). The most common mutation was c.35delG accounting for 35% of all cases (46/131). The second most frequent mutation was p.E47X present in 3.8% of families. Four identified mutations in our cohort have not been reported in Tunisia; p.V37I, c.235delC, p.G130A and the splice site mutation IVS1+1G>A (0.76%). These previously described mutations were detected only in families originating from Northern and not from other geographical regions in Tunisia. In conclusion we have confirmed the high frequency of c.35delG in Tunisia which represents 85.4% of all GJB2 mutant alleles. We have also extended the mutational spectrum of GJB2 gene in Tunisia and revealed a more pronounced allelic heterogeneity in the North compared to the rest of the country.

GJB2 and GJB6 screening in Tunisian patients with autosomal recessive deafness.

UNLABELLED: Autosomal recessive nonsyndromic deafness (ARNSD or DFNB) is a very common genetically heterogenous disorder. Although DFNB1 mutations are known to be the most frequent cause of this disorder, they are largely dependent on ethnic groups. The aims of our study are to specify the prevalence and the spectrum of GJB2 mutations as well as the prevalence of GJB6 large deletion in Tunisian population. PATIENTS AND METHODS: 95 unrelated patients with moderate to severe sensorineural hearing loss have been tested. The GJB2 coding region has been studied by PCR/Sequencing and the del(GJB6-D13S1830) mutation has been screened by fluorescent PCR multiplex. RESULTS: 27.36% of patients present mutations on both alleles of GJB2 gene and no one has the del(GJB6-D13S1830) mutation. The c.35delG mutation represents 86.5% of GJB2 deafness alleles and is found in homozygous state in 22 patients and in heterozygous state in one patient. Four other mutations are detected in four probands: two are compound heterozygous for the p.V37I/p.E47X and the c.35delG/p.R184P mutations, and two are homozygous for the p.E47X and the c.333-334delAA mutations. CONCLUSION: Our results showed that c.35delG is the most common but not the only GJB2 mutation and that the del(GJB6-del D13S1830) is absent in our cohort. Consequently, we propose a systematic sequencing of GJB2 coding region for ARNSD Tunisian patients and we suggest additional studies to specify the real prevalence of del(GJB6-D13S1830) in our population.

[Cystic hygroma : report of 25 cases]. / Les lymphangiomes kystiques : A propos de 25 cas.

BACKGROUND: The cystic hygroma is a benign lymphatic malformation, a rare but potentially serious in its character and its evolutionary trend dissecans. The head and neck region constitutes the favorite seat (75%). If the diagnosis is usually easy, the therapeutic management remains controversial. AIM: To analyze clinical and paraclinical characteristics of cystic hygroma and to discuss the various therapeutic methods. METHODS: We report a retrospective study about 25 cases of head and neck cystic hygroma collected during a period of 11 years (1998- 2008) in the ENT department of the hospital The Rabta Tunis. RESULTS: The average age of our patients was 18 years and 5 months. All patients consulted for a neck mass. It was localized in the submandibular region in 7 cases, 3 cases in parotid region, jugulocarotid artery in 3 cases and affecting the posterior triangle in 12 cases. Cervical ultrasound was performed in 22 cases (88%) evoking the diagnosis of cystic hygroma in 16 cases (72%). CT was performed in 10 cases finding hypodense aspect in 8 cases. MRI was carried out in 9 cases. It showed the aspect hyperintense T2, hypointense T1 in 7 cases. Surgical excision was performed in 22 cases and sclerotherapy in 3 patients. During the evolution, a recurrence was observed for each treatment modality. CONCLUSION: Surgery is treatment of choice of cystic hygroma. Sclerotherapy may be indicated as an alternative to surgery in localized and diffuse macrocystic forms.

[The plunging goiter : about 43 cases]. / Les goîtres plongeants : à propos de 43 cas.

BACKGROUND: The plunging goiter consists in a goiter whose lower limit is not palpable in surgical position. AIM: To study the epidemiologic characteristics, the circumstances of discovery, the clinical signs, and the management of this disease. METHODS: A retrospective study about 43 cases of plunging goiters operated during a period of 14 years in the ENT department of the hospital The Rabta Tunis. RESULTS: The average age of our patients was 59.3 years. On physical examination, goiter was palpable in 41 patients (95.3%). The plunging character of the goiter was noted, at echography, in 26 patients. A cervico-thoracic scanner was performed in 41 patients (95.3%). It helped to confirm the plunging goiter in all patients. These goiters were most frequently pre vascular (73.2%) compared to the innomined venous trunk. The lower limits of the intrathoracic extensions were on the level of the superior vena cava in 4 cases (9.7%), on the level of the left brachio-cephalic venous trunk in 16 cases (39%) and on the level of the aortic arch in 15 cases (36,5%). The cervical incision was sufficient in 39 cases (97.5%) and we used a combined sternotomy in one patient (2.5%). CONCLUSION: The plunging goiter is a thyroid tumour cervical originally descended, then developed, in the mediastinum. A good clinical examination and paraclinical can reach a definite diagnosis and to achieve better surgical.

[Intracranial complications of sinusitis]. / Les complications endocrâniennes des sinusites.

BACKGROUND: Intracranial complications of sinusitis are always a subject of actuality. They present diagnostic and therapeutic problems. AIM: To study the clinical characteristics and treatment modalities for intracranial complications of sinusitis while insisting on their severity. METHODS: Retrospective study concerning 7 patients who had intracranial complications secondary to sinusitis. RESULTS: Our study was about 3 men and 4 women. The mean age of patients was 24 years. Neurologic signs were the most common symptoms. The diagnosis was confirmed by CT scan and lumbar puncture. The different complications were empyema in 5 cases and meningitis in 2 cases. Treatment included parenteral antibiotic therapy and surgery. The neurosurgical management has been achieved in 3 cases. Control was obtained in 4 cases, the mean receding was 18 months. CONCLUSION: Intracranial complications of sinusitis must be evoked, especially in cases of febrile headache or facial oedema. CT scan must be realized in slightest doubt. The treatment must be started precociously allowing a cure without after-effects.