Search for a genetic cause in children with unilateral isolated microtia and congenital aural atresia.

PURPOSE: Microtia describes a spectrum of auricular malformations ranging from mild dysplasia to anotia. A vast majority of microtia patients demonstrate congenital aural atresia (CAA). Isolated microtia has a right ear predominance (58-61%) and is more common in the male sex. Isolated microtia is a multifactorial condition involving genetic and environmental causes. The aim of this study is to describe the phenotype of children with unilateral isolated microtia and CAA, and to search for a common genetic cause trough DNA analysis. METHODS: Phenotyping included a complete clinical examination. Description on the degree of auricular malformation (Weerda classification-Weerda 1988), assessment for hemifacial microsomia and age-appropriate audiometric testing were documented. Computerized tomography of the temporal bone with 3-D rendering provided a histopathological classification (HEAR classification-Declau et al. 1999). Genetic testing was carried out by single nucleotide polymorphism (SNP) microarray. RESULTS: Complete data are available for 44 children (50% was younger than 33 days at presentation; 59.1% boys; 72.7% right ear). Type III microtia was present in 28 patients. Type 2b CAA existed in 32 patients. All patients had a normal hearing at the non-affected side. Genome wide deletion duplication analysis using microarray did not reveal any pathological copy number variant (CNV) that could explain the phenotype. CONCLUSIONS: Type III microtia (peanut-shell type) in combination with a type 2b CAA was the most common phenotype, present in 23 of 44 (52.3%) patients with isolated unilateral microtia. No abnormalities could be found by copy number variant (CNV) analysis. Whole exome sequencing in a larger sample with a similar phenotype may represent a future diagnostic approach.

Auditory neuropathy: a challenge for diagnosis and treatment.

In current terminology, auditory neuropathy spectrum disorder (ANSD) is a disease involving the disruption of the temporal coding of acoustic signals in auditory nerve fibres, resulting in the impairment of auditory perceptions that rely on temporal cues. There is debate about almost every aspect of the disorder, including aetiology, lesion sites, and the terminology used to describe it. ANSD is a heterogeneous disease despite similar audiological findings. The absence of an auditory brainstem response (ABR) and the presence of otoacoustic emissions (OAE) suggest an ANSD profile. However, to determine the exact anatomical site of the disorder, more in-depth audiological and electrophysiological tests must be combined with imaging, genetics and neurological examinations. Greater diagnostic specificity is therefore needed to provide these patients with more adequate treatment.

Case report: "auditory neuropathy" in a newborn caused by a cerebellopontine angle arachnoid cyst.

We present a 6-week-old girl, referred because of failed newborn hearing screening in the right ear. Click-evoked oto-acoustic emissions were present in both ears, auditory brainstem responses (ABR) were present in the left but totally absent in the right ear. A magnetic resonance imaging (MRI) study revealed a large arachnoid cyst in the right cerebellopontine angle (CPA) and a diagnosis of "auditory neuropathy/auditory dyssynchrony" was established. A microsurgical resection of the cyst wall and fenestration was performed by a retro sigmoid approach. This is the first case in the literature of auditory neuropathy (AN) in an infant caused by a cerebellopontine angle arachnoid cyst.

Prekallikrein deficiency in a 15-year-old boy with Ménière's disease: a case report.

Congenital prekallikrein deficiency is a rare disorder in which there is an in vitro clotting defect despite absence of bleeding or thrombotic tendency. In this report, a 15-year-old boy with an unexpected markedly prolonged activated partial thrombin time, a normal prothrombin time, and without personal nor familial history of bleeding or thrombosis is presented. Laboratory investigation revealed a severe prekallikrein deficiency. This case highlights the importance of following a diagnostic algorithm to establish the correct diagnosis. Moreover, by selecting appropriate laboratory tests, unnecessary and repeatedly testing can be avoided.

The facio-audio-symphalangism syndrome in a four generation family with a nonsense mutation in the NOG-gene.

We report a four generation family with features of the facio-audio-symphalangism syndrome. This condition is characterized by proximal symphalangism, conductive hearing loss due to stapes fixation and a distinctive facies. A novel nonsense mutation in the NOG gene on chromosome 17q22 was identified in the patients. The variable expression and progressive nature of the syndrome is well illustrated by this family. The role of Noggin as the causative factor of symphalangism is discussed.

Universal newborn hearing screening.

Hearing loss is one of the most common congenital anomalies, occurring in approximately 1-2 infants per 1000. Left undetected, hearing impairments in infants can negatively impact speech and language acquisition, academic achievement, social and emotional development. These negative impacts can be diminished and even eliminated through early intervention at or before 6 months of age. Reliable screening tests that minimize referral rates and maximize sensitivity and specificity are available. The goal of universal neonatal hearing screening is to maximize linguistic and communicative competence and literacy development for children who are hard of hearing or deaf. Audiologic and medical evaluations should be in progress before 3 months of age. Infants with confirmed hearing loss should receive intervention before 6 months of age from health care and education professionals with expertise in hearing loss and deafness in infants and young children.

Otosclerosis: a genetically heterogeneous disease involving at least three different genes.

Otosclerosis is caused by abnormal bone homeostasis of the otic capsule, resulting in hearing impairment in 0.3%-0.4% of the white population. The etiology of the disease remains unclear and environmental as well as genetic factors have been implicated. We localized the first autosomal-dominant locus to chromosome 15 in 1998 (OTSC1) in an Indian family and, recently, we reported the localization of a second gene for otosclerosis to a 16 cM interval on chromosome 7q (OTSC2). In this study, we recruited and analyzed nine additional families (seven Belgian and two Dutch families with 53 affected and 20 unaffected subjects) to investigate the importance of these loci in autosomal-dominant otosclerosis. We completed linkage analysis with three microsatellite markers of chromosome 15 (D15S652, D15S1004, D15S657) and five microsatellite markers of chromosome 7 (D7S495, D7S2560, D7S684, D7S2513, D7S2426). In two families, results compatible with linkage to OTSC2 were found, but in the seven remaining families OTSC1 and OTSC2 were excluded. Heterogeneity testing provided significant evidence for genetic heterogeneity, with an estimated 25% of families linked to OTSC2. These results indicate that, besides OTSC1 and OTSC2, there must be at least one additional otosclerosis locus.

Prevalence of otosclerosis in an unselected series of temporal bones.

BACKGROUND: Histologic otosclerosis is a disease process without clinical symptoms or manifestations that can be discovered only by sectioning of the temporal bone at autopsy. Clinical otosclerosis is otosclerosis at a site where it causes conductive hearing loss by interfering with the motion of the stapes or of the round window membrane. Various authors have studied the prevalence of histologic otosclerosis on laboratory collections of temporal bones. Some 12% to 15% of temporal bones with histologic otosclerosis have demonstrated stapedial fixation. Using these figures for calculating the prevalence of clinical otosclerosis gives an extrapolated clinical prevalence of 0.99% to 1.2%. This does not correlate well with the clinical data on otosclerotic families, from which a clinical prevalence of 0.3% has been estimated. OBJECTIVE: To study the prevalence of histologic otosclerosis in an unselected series of temporal bones. STUDY DESIGN: During a 1-year period, 118 consecutive pairs of temporal bones of deceased patients at a tertiary care center were collected to determine the prevalence of otosclerosis. Although histology remains the gold standard for evaluation of otosclerosis, the gross observation of temporal bone slices combined with microradiography was used to screen for otosclerotic lesions more rapidly and with a lower cost/benefit ratio. The temporal bones, which were suspected of having otosclerosis with these techniques, were further analyzed by conventional histology. RESULTS: 2.5% of the 236 temporal bones (or 3.4% of patients) studied demonstrated histologic otosclerosis. CONCLUSIONS: Although the prevalence of 2.5% is much lower than previously published figures on histologic otosclerosis, the extrapolated data (extrapolated clinical prevalence = 0.30% to 0.38%) correlate well with clinical studies of otosclerotic families. The previous studies based on laboratory collections were likely biased by hearing loss or other otologic diseases.

Hereditary otovestibular dysfunction and Ménière's disease in a large Belgian family is caused by a missense mutation in the COCH gene.

OBJECTIVE: To report the clinical, auditory, and vestibular characteristics of a nonsyndromic otovestibular dysfunction in a large Belgian family caused by a missense mutation of the DFNA9 gene: COCH. STUDY DESIGN: Retrospective study of the clinical, audiologic, and vestibular data of 60 genetically affected cases. SETTING: Tertiary referral center. PATIENTS: All members of a Belgian kindred who carry the genetic (P51S) defect linked to the inherited hearing and vestibular impairment. INTERVENTIONS: Diagnostic otologic, audiometric, and vestibular analysis and imaging. MAIN OUTCOME MEASURES: Pure tone audiometry, supraliminary audiometry. and vestibular investigation. RESULTS: The autosomal dominant inherited impairment was characterized by peripheral degeneration of the inner ear, leading to total deafness and bilateral vestibular areflexia. CONCLUSIONS: The genetically affected persons of a Belgian family shared a progressive sensorineural hearing loss starting between the third and sixth decade. Vestibular symptoms started at about the same age as the hearing loss. The vestibular symptoms consisted of instability in darkness, a tendency to fall sideways, light-headiness, a drunken feeling, and attacks of vertigo. Most of the patients reported tinnitus, and half of them reported pressure in the ears. Clinically, 9 of the 60 patients met the criteria for definite Ménière's disease, and another 13 and 17 patients met the criteria for probable or possible Ménière's disease, respectively. All 9 were older than the age of 35, but only 1 was older than 55 years, so more than 30% of the patients were between 35 and 55 years old. A specific pattern could be recognized in the evolution of the otovestibular impairment. Under the age of 35 years, almost all the affected family members had normal hearing, whereas above the age of 55 years, the hearing loss was at least moderate, and vestibular hypofunction occurred. In between, there was a transition period of two to three decades, when deterioration of the cochleovestibular function occurred, with a temporary audiometric and vestibular asymmetry.

Dehiscence of the facial canal: developmental aspects.

In a series of human fetuses, the course of the facial canal in the temporal bone was investigated by the use of light and scanning electron microscopy. The normal development of the facial canal was correlated to clinical aspects of facial nerve dehiscences. Our observations demonstrate a more complex way of facial canal development not limited to the 'simple' ossification of the otic capsule. Endochondral ossification of the otic capsule does not virtually change the shape of the primitive facial sulcus. The fibrous layers surrounding the facial nerve seem to be responsible for the final architecture of the facial canal and not the otic capsule ossification by itself. The time sequence of their histological development is equally important and permitted us to distinguish three phases in facial canal development. The role of disturbances in epigenetic control for the initiation of dehiscences is discussed.

Normal growth pattern of the middle ear cleft in the human fetus.

The normal growth pattern of the middle ear cleft was studied on macro- and histological sections of the human fetus. When compared with adult temporal bones, the inclination of the tympanic ring remains unaltered throughout fetal development. Expansion of the middle ear cleft is caused by intrinsic growth and by lateral displacement of its constituent elements: tympanic ring, otic capsule and squamous bone. Not only are the two mutually different modes of growth movement quite dissimilar in magnitude and direction, but so is their resultant vector for each constituent; this dissimilarity in growth movement leads to a characteristic change in shape of the middle ear cleft and to curvature of the tympanic membrane. The intrinsic growth of these elements is simultaneously accompanied by remodelling of their shape; lateral displacement of the squamous bone and tympanic ring is caused by the pressure of the enlarging brain. The consequences of developmental disturbances on the normal growth pattern are discussed.

Early ossification within the human fetal otic capsule: morphological and microanalytical findings.

Besides the use of conventional techniques such as light and polarization microscopy, the present paper proposes the combined use of transmission electron microscopy, secondary and backscattered electron imaging, energy dispersive X-ray analysis and computed tomography for the diagnostic evaluation of ear pathology in the human fetus. These methods were used to revisit the primary calcification front of the fetal otic capsule between 16 and 23 weeks gestational age. Ultramicroscopic evaluation demonstrates similar fetal bone formation to that found in other bones of the human fetus. The formation of the endosteal and periosteal layers is a typical example of early intra-membranous ossification. The enchondral layer is made up of fibrillar bone, laid down around the calcified cartilage remnants. Microchemical analysis indicates a significantly higher Ca/P ratio in the endochondral layer with respect to the endosteum and periosteum. The consequences of a lower Ca/P ratio in the endosteal layer are discussed in view of calcium homeostasis and inner ear function.

Subcutaneous diffuse neurofibroma of the neck: a case report.

A case of a rare and unusual variant of neurofibroma, diffuse neurofibroma (paraneurofibroma), in a young patient is presented. The clinical, radiological and histopathological features of this case are reported. The magnetic resonance imaging (MRI) features of the diffuse neurofibroma are comparable with those described in other neurofibromas.

Prevalence of histologic otosclerosis: an unbiased temporal bone study in Caucasians.

BACKGROUND: 'Histologic otosclerosis' refers to a disease process without clinical symptoms or manifestations that can only be discovered by sectioning of the temporal bone at autopsy. 'Clinical otosclerosis' concerns the presence of otosclerosis at a site where it causes conductive hearing loss by interfering with the motion of the stapes or of the round window membrane. Various authors have studied the prevalence of histologic otosclerosis on laboratory collections of temporal bones. Some 12-15% of the temporal bones with histologic otosclerosis have demonstrated stapedial fixation. Using these figures for calculating the prevalence of clinical otosclerosis gives an extrapolated clinical prevalence of 0.99-1.2%. This does not correlate well with the clinical data on otosclerotic families from which a clinical prevalence of 0.3% has been estimated. OBJECTIVE: To study the prevalence of histologic otosclerosis in an unselected series of temporal bones. STUDY DESIGN: During a 1-year period, 118 consecutive pairs of temporal bones of deceased patients at a tertiary center were collected to determine the prevalence of otosclerosis. Although histology remains the gold standard for evaluation of otosclerosis, the gross observation of temporal bone slices combined with microradiography was used to screen for otosclerotic lesions more rapidly and with a lower cost-benefit ratio. The temporal bones with suspected otosclerosis shown with these techniques were further analyzed by conventional histology. RESULTS: 2.5% of the 236 temporal bones (or 3.4% of patients) studied demonstrated histologic otosclerosis. CONCLUSIONS: Although the prevalence of 2.5% is much lower than previously published figures on histologic otosclerosis, the extrapolated data (extrapolated clinical prevalence = 0.30-0.38%) correlate well with clinical studies of otosclerotic families. The previous studies based on laboratory collections were likely biased by the presence of hearing loss or other otological diseases.

Development of the human external auditory canal.

The embryological and fetal development of the external auditory canal is described and its importance for the migratory properties of the epithelium is discussed.

Morphogenesis of the inner ear. Correlation between CT-findings and macrosections.

The development of the temporal bone has been studied on macerated foetuses. For a comprehensive understanding two dissimilar techniques have been linked: CT scan and anatomical dissection technique on frozen tissue. CT scanning has been proved a good method to compare the different stages of maturity. There is also a good correlation between CT images and the anatomical slices obtained by dissection. Both methods are complementary to each other in the study of the morphogenesis of the inner ear.

The involvement of the cochlear nerve in neurinomas of the eighth cranial nerve.

In view of recent controversies concerning the preservation of hearing in acoustic neurinoma surgery, we examined the courses of the vestibular and cochlear nerve fibers in 12 intact acoustic neurinomas studied in our department. Due to its lack of specificity, the Luxol fast blue stain was found to be inadequate for our study of the nerve fibers. In contrast, Verhoeff's stain proved to be satisfactory when combined with a highly specific immunohistochemical technique. There were macroscopically visible adherences between the tumor and the cochlear nerve in 9 out of the 12 specimens. From those specimens, histological sections were obtained in which both the cochlear nerve and tumor could be clearly identified. In these specimens the cochlear nerve was involved in the tumoral process and there was no clear cleavage plane between the nerve and the tumor. However, all these patients suffered only from minimal losses of hearing as a result of their tumors.

Differentiation of cartilage and bone in human fetal temporal bones with Luxol fast blue stain.

A modified Luxol fast blue technique was used to study the development of the temporal bone. This staining method makes it possible to make a clear distinction between the primitive cartilage present and the new forming bone. Although these tissues both contain a significant amount of collagen, their staining properties with the Luxol dyes are widely dissimilar, due to the different physicochemical properties of the collagen types involved in these tissues. The differentiation of mesenchymatous tissue into ligaments and joints can also be very clearly demonstrated with this technique. In studying the endochondral ossification process of the otic capsule and middle ear, the modified Luxol fast blue stain is a valuable technique that is complementary to more conventional staining methods.