Two novel pathogenic variants in MED13L: one familial and one isolated case.

BACKGROUND: Genetic variants involving the MED13L gene can lead to an autosomal dominant syndrome characterised by intellectual disability/developmental delay and facial dysmorphism. METHODS: We investigated two cases (one familial and one isolated) of intellectual disability with speech delay and dysmorphic facial features by whole-exome sequencing analyses. Further, we performed a literature review about clinical and molecular aspects of MED13L gene and syndrome. RESULTS: Two MED13L variants have been identified [MED13L(NM_015335.5):c.4417C>T and MED13L(NM_015335.5):c.2318delC] and were classified as pathogenic according to the ACMG (American College of Medical Genetics and Genomics) guidelines. One of the variants was present in sibs. CONCLUSIONS: The two pathogenic variants identified have not been previously reported. Importantly, this is the first report of a familial case of MED13L nonsense mutation. Although the parents of the affected children were no longer available for analysis, their apparently normal phenotypes were surmised from familial verbal descriptions corresponding to normal mental behaviour and phenotype. In this situation, the familial component of mutation transmission might be caused by gonadal mosaicism of a MED13L mutation in a gonad from either the father or the mother. The case reports and the literature review presented in this manuscript can be useful for genetic counselling.

Sensorineural hearing loss among sickle cell disease patients from southern Brazil.

PURPOSE: A case-control study was done to confirm the higher prevalence of sensorineural hearing loss (SNHL) among sickle cell patients (HbSS) from southern Brazil. PATIENTS AND METHODS: Twenty-eight patients and 28 matched normal controls were studied. Besides complete anamneses and physical otolaryngological examination, all individuals had audiometric and tympanometric testings to determine the presence of SNHL or middle ear problems. The only significant difference between groups was the presence of a positive history of otologic symptoms (hearing loss, dizziness or tinnitus) and neurological sequelae in the HbSS patients. RESULTS: Six patients (21.4%) presented with SNHL compared with one control (3.6%) (Fisher's one-tailed P = .05; OR, 7.36 (95% CI, 0.82, 65.83). The average age of HbSS diagnosis was higher among the patients with SNHL (10 years +/- 8.3) than those without SNHL (5.43 years +/- 5.65), but this was not significant (analysis of variance P > .05). More patients 25 years and older on the examination date had SNHL than younger patients (Fisher's 2-tailed P < .05). Sixty-seven percent of the patients with SNHL had alterations in the acoustic reflex, and a surprising 27% of the patients without NSHL also presented with some elevation or an absence of acoustic reflex. CONCLUSIONS: These data indicate that patients with HbSS from southern Brazil are more predisposed to the development of sensorineural hearing problems than the general population.

The flexible endaural tympanoplasty: pathology-guided, pathogenesis-oriented surgery for the middle ear.

The flexible approach to tympanoplasty has been found to be adaptable to various forms of pathologic conditions found in the temporal bone, including inflammation and infection, congenital stenosis, benign and malignant tumors, and traumatic injuries. This approach finds its best indication among all pathologic conditions in the temporal bone, in the surgical treatment of otitis media, and its sequelae. A procedure conceived to treat this dynamic process must be adaptable to new circumstances and new findings and be ready to manage unexpected situations. The flexible tympanoplasty is a step-wise approach designed to explore the contents of the middle ear methodically and in the process disclose, confirm, and often treat disease.

Clinical-histopathological correlations of pitfalls in middle ear surgery.

Significant anatomical variations within the middle ear are described as well as atypical histopathological findings in 13 selected human temporal bones. Bones studied included such vascular and bony abnormalities as carotid artery canal dehiscence, a high jugular bulb, persistent stapedial artery and facial nerve canal dehiscences. Bones also included obliterative otosclerosis, malleus head fixation and a variety of chronic inflammatory changes and/or sequelae. Those features considered to render cases prone to complications are detailed.

Temporal bone histopathology in chronically infected ears with intact and perforated tympanic membranes.

Chronic suppurative otitis media has been clinically defined as a chronic discharge from the middle ear in the presence of a perforation of the tympanic membrane. However, irreversible tissue pathology in the middle ear or mastoid can occur behind an intact tympanic membrane. One hundred forty-four human temporal bones with chronic otitis media were divided into two groups: those with perforated (28) and those with nonperforated (116) tympanic membranes. The histopathological findings of their middle ears were compared. Granulation tissue in various degrees was the most prominent pathological feature. It was observed in 96% of temporal bones with perforation of the tympanic membrane, and in 97% of those without perforation. Also found were ossicular bony changes (96% with perforation; 90.5% without), middle ear effusion (93% with perforation; 89% without), cholesterol granuloma (21% with perforation; 12% without), cholesteatoma (36% with perforation; 4% without), and tympanosclerosis (43% with perforation; 20% without). This study shows that the histopathological changes of the middle ear are similar in temporal bones with and without perforation of the tympanic membrane. The clinician should, therefore, be aware that an intact tympanic membrane does not necessarily preclude the presence of gross pathological changes of the middle ear cleft.

Otopathologic correlates of the continuum of otitis media.

It has been our hypothesis that different types of middle ear effusions and the clinical manifestations with which they are associated represent the typical inflammatory response. Employing an animal model under controlled conditions, we present statistical evidence that change in the mucosa of the middle ear in otitis media can occur along a continuum, with early forms regressing to more chronic stages of the disease. We also demonstrate an increase in the thickness and a decrease in the permeability of the round window membrane in a longitudinal study of otitis media in the same animal model. Histopathologic changes in human temporal bones with otitis media with effusion or chronic otitis media are similar to the changes in the animal models. These results support a concept that all categories of otitis media (serous, purulent, mucoid, and chronic) represent different stages in a continuum of events.

Congenital cholesteatomas of the cerebellopontine angle.

Thirty cases of congenital cholesteatomas of the cerebellopontine angle (CPA) treated over a period of 20 years are reviewed with regard to their clinical features, the pathophysiology of their symptoms, and their management. The predominant symptoms were related to cranial nerves VII and VIII and headaches. Signs and symptoms were divided into those caused by local involvement of the cholesteatoma, increased intracranial pressure, or both. Diagnostic procedures from invasive procedures such as ventriculography to more sophisticated noninvasive procedures including computed tomography and magnetic resonance imaging are discussed. The surgical management of 27 congenital cholesteatomas was accomplished via a posterior cranial fossa approach. Total excision of the cholesteatoma was the aim but was carried out in only five (18%) patients because of concern regarding the preservation of nearby neurovascular structures. Partial excision was possible in 22 (82%) patients. To minimize re-formation, the residual cholesteatoma was carefully cauterized with the aid of the operating microscope and bipolar diathermy without damaging surrounding neurovascular structures. Follow-up has ranged from 2 to 15 years, with four (13%) cases of re-formation.

The flexible/intact-bridge tympanomastoidectomy technique.

A combination of otologic techniques has been presented in the step-wise surgical rationale that we call the flexible approach. The sequence of steps involved in the flexible approach allows the surgeon to adjust his or her surgery to the individual patient's needs. Very often, in patients with chronic otitis media, a middle ear reconstructive procedure (ossiculoplasty including lateralization of the malleus, removal of pathological tissue, insertion of an implant of silicone rubber sheets, and use of ventilation tubes with or without tympanic grafts) will obviate mastoidectomy. When a mastoidectomy is indicated, the IBM is a suitable procedure that encompasses the advantages of both closed and open mastoidectomy techniques.