Inner ear abnormalities in Kabuki make-up syndrome: report of three cases

Three patients, a female and two males, 28, 15, and 14 years of age, with Kabuki make-up syndrome (KMS) were studied for middle and inner ear abnormalities by using CT scanning of the petrous bones. All three patients had bilateral dysplasia of the inner ear, i.e., hypodysplasia of the cochlea, vestibule, and semicircular canals (so-called Mondini dysplasia), whereas their middle ears had no abnormalities. Audiometry demonstrated a sharp decrease in hearing of the high tone range, bilateral in one and unilateral in another, while the third patient was noncooperative. In view of these findings, it would be advisable to study each individual with KMS and hearing impairment for possible inner ear abnormalities.     

Familial lateral semicircular canal malformation with external and middle ear abnormalities

We report a family with inner ear lateral semicircular canal (LSC) malformation and external and middle ear abnormalities. The family had no history of known syndromes or toxic exposures. Distinct phenotypic manifestations were found in three family members. A young girl exhibited bilateral LSC malformation with a right-sided preauricular tag, a mildly deformed auricle, a stenotic external auditory canal, and a constricted middle ear cavity. She had moderate conductive hearing loss in the right ear but normal hearing in the left ear. Her younger brother exhibited right-sided LSC malformation, microtia, external auditory canal atresia, a malformed middle ear cavity, and abnormal auditory ossicles. He had severe mixed hearing loss in his right ear. Their mother exhibited left-sided LSC malformation without external and middle ear abnormalities, and the hearing was normal in her left ear. None of the three cases had vestibular symptoms, and their results of balance tests were appropriate for the corresponding ages. In contrast, significantly decreased LSC function was revealed by caloric tests in an ear with LSC malformation. Previously, LSC malformation may have been underdiagnosed in patients presenting with external and middle ear abnormalities and their relatives, since this malformation is frequently associated with normal hearing and balance or conductive hearing loss only. To our knowledge, this condition has not been described previously. This condition supports a genetic basis for the combination of LSC malformation and external and middle ear abnormalities and may represent an autosomal dominant condition with variable expressivity.     

Mice overexpressing genes from the 22q11 region deleted in velo-cardio-facial syndrome/DiGeorge syndrome have middle and inner ear defects.

Velo-cardio-facial syndrome/DiGeorge syndrome (VCFS/DGS) is a congenital anomaly disorder associated with hemizygous 22q11 deletions. We previously showed that bacterial artificial chromosome (BAC) transgenic mice overexpressing four transgenes, PNUTL1, (CDCrel-1), GP1B beta, TBX1 and WDR14, had reduced viability, cardiovascular malformations and thymus gland hypoplasia. Since these are hallmark features of VCFS/DGS, we analyzed the mice for additional anomalies. We found that the mice have important defects in the middle and inner ear that are directly relevant to the disorder. The most striking defect was the presence of chronic otitis media, a common finding in VCFS/DGS patients. In addition, the mice had a hyperactive circling behavior and sensorineural hearing loss. This was associated with middle and inner ear malformations, analogous to Mondini dysplasia in humans reported to occur in VCFS/DGS patients. We propose that overexpression of one or more of the transgenes is responsible for the etiology of the ear defects in the mice. Based upon its pattern of expression in the ear and functional studies of the gene, TbX1 likely plays a central role. Haploinsufficiency of TBX1 may be responsible for ear disorders in VCFS/DGS patients.     

TBX1 is required for inner ear morphogenesis

TBX1 is thought to be a critical gene in the pathogenesis of del22q11/DiGeorge syndrome (DGS). Morphological abnormalities of the external ear and hearing impairment (conductive or sensorineural) affect the majority of patients. Here we show that homozygous mutation of the mouse homolog Tbx1 is associated with severe inner ear defects that prevent the formation of the cochlea and of the vestibulum. Consistent with phenotypic abnormalities, Tbx1 is expressed early in otocyst development in the otic epithelium and in the periotic mesenchyme. Tbx1 loss-of-function blocks inner ear development at early otocyst stage and after neurogenesis. Analysis of chimeras suggests that Tbx1 function is required in the otic epithelium cell autonomously, but abnormalities of the periotic mesenchyme indicate that the pathogenesis of the inner ear phenotype is complex. We propose a model where Tbx1 is required for expansion of a subpopulation of otic epithelial cells, which is required to form the vestibular and auditory organs. Our data suggest that Tbx1 deletion in del22q11 patients may cause not only external and middle ear defects but also sensorineural and vestibular phenotypes observed in these patients.     

蜗神经发育不良患者的影像及听力学表现分析

目的 探讨蜗神经发育不良（CND）患者的影像学表现和听力学表现以及两者的相关性。方法 对北京大学第三医院耳鼻咽喉科拟行单侧人工耳蜗植入,合并蜗神经发育异常的患者共7例（12耳）进行回顾性分析,对患者进行听力学检查,以及颞骨高分辨率CT及内耳道MRI等影像学检查,并在颞骨CT中测量内耳道（IAC）及蜗神经管（BCNC）直径,在内耳道MRI中测量内耳道内神经束数目、蜗神经有无狭窄或缺失等指标,并观察有无内耳畸形。分析不同影像学表现下听力情况的差异。结果 7例患者影像学表现均提示蜗神经发育不良。颞骨CT中,3例（5耳）提示内耳道异常,6例（9耳）提示蜗神经管狭窄或缺失,内耳道MRI所见中;7例（12耳）提示蜗神经狭窄或缺失,其内耳道内神经束数目在0～3根不等。此外,影像学检查发现,4例（8耳）合并不同类型的内耳畸形。7例患者听力学表现均为双耳重度或极重度感音神经性听力下降。CND的不同影像学表现（包括IAC、BCNC、内耳道神经束数目、有无内耳畸形等）下,各组间平均听阈差异不显著（P>0.05）。结论 蜗神经发育异常的影像学特点包括颞骨CT中内耳道及蜗神经管的异常,内耳道MRI中神经束数目及蜗神经的异常等,听力多表现为重度或极重度感音神经性聋,影像学及听力学表现之间未发现明显关联。对该类患者的人工耳蜗植入存在较大的挑战。     

Genetic features of hearing loss associated with ear anomalies: PDS and EYA1 mutation analysis

Mutation analysis of the PDS gene and the EYA1 gene, which are reported to be responsible for hearing loss associated with ear anomalies, was performed in 24 deaf patients with various middle and inner ear anomalies. The present study was done to clarify the spectrum of middle and inner ear malformations covered by these two genes. PDS mutations were found only in patients with enlarged vestibular aqueducts and EYA1 mutations were detected only in patients with ear pits and cervical fistulae, indicating that these two genes are associated with particular forms of middle and inner ear malformation. The genetic approach provides a strong tool for the diagnosis of hearing loss associated with ear anomalies. Received: January 16, 2001 / Accepted: June 12, 2001     

Spectrum and Frequency of SLC26A4 Mutations Among Czech Patients with Early Hearing Loss with and without Enlarged Vestibular Aqueduct (EVA)

Mutations in SLC26A4 cause Pendred syndrome (PS) – hearing loss with goitre – or DFNB4 – non‐syndromic hearing loss (NSHL) with inner ear abnormalities such as Enlarged Vestibular Aqueduct (EVA) or Mondini Dysplasia (MD). We tested 303 unrelated Czech patients with early hearing loss (298 with NSHL and 5 with PS), all GJB2‐negative, for SLC26A4 mutations and evaluated their clinical and radiological phenotype. Among 115 available HRCT/MRI scans we detected three MD (2.6%), three Mondini‐like affections (2.6%), 16 EVA (13 bilateral – 19.2% and 15.6% respectively) and 61 EVA/MD‐negative scans (73.4%). We found mutation(s) in 26 patients (8.6%) and biallelic mutations in eight patients (2.7%) out of 303 tested. In 18 of 26 (69%) patients, no second mutation could be detected even using MLPA. The spectrum of SLC26A4 mutations in Czech patients is broad without any prevalent mutation. We detected 21 different mutations (four novel). The most frequent mutations were p.Val138Phe and p.Leu445Trp (18% and 8.9% of pathogenic alleles respectively). Among 13 patients with bilateral EVA, six patients (50%) carry biallelic mutations. In EVA ‐negative patients no biallelic mutations were found but 4.9% had monoallelic mutations. SLC26A4 mutations are present mostly in patients with EVA/MD and/or progressive HL and those with affected siblings.     

先天性外耳道畸形多层螺旋CT的分析与研究

目的通过分析先天性外耳道畸形的多层螺旋cT表现,为临床提供准确、有效的影像信息。方法回顾性分析56例（64耳）婴儿（45天一6个月）先天性外耳道畸形患者的cT表现。结果56例先天性外耳道畸形患者双侧畸形者8例,单侧畸形者48例;合并中耳或内耳畸形者62耳,仅外耳畸形者2耳;鼓部无或轻度发育不良12耳,鼓部重度发育不良19耳,鼓部未发育33耳。结论多层螺旋cT对先天性外耳道畸形具有重要的诊断价值,是定制临床治疗方案的重要依据。     

Hearing loss in skeletal dysplasia patients

A hearing screening program was performed to determine the prevalence of hearing loss and abnormal tympanometry in individuals with short-stature skeletal dysplasias attending a national meeting. Behavioral audiometry, otoacoustic emission testing, and tympanometry were used to assess hearing. Failed hearing screen was defined as hearing ≥ 35 dB at one or more frequencies or by "fail" on otoacoustic emissions. One hundred ten of 112 subjects completed the screening. 58 (51.8%) were children. Seventy-three (65.2%) had achondroplasia, 34 (30.4%) had one of 11 other diagnoses, and 5(4.4%) were undiagnosed. 25.8% of children failed hearing screening in one or both ears, while 46.3% of adults failed in one or both ears. 55.1% of adults and 25.0% of children with achondroplasia failed screening. Abnormal hearing was also found in the some patients with spondyloepiphyseal dysplasia congenital (SEDC; 75%), diastrophic dysplasia (66%), and Morquio (66%). Hearing was normal in those with hypochondroplasia, pseudoachondroplasia, and microcephalic osteodysplastic primordial dwarfism. Tympanometry was abnormal in at least one ear in 53.3% of children and 38.5% of adults. Abnormal tympanometry in the absence of functioning tympanostomy tubes was associated with 9.5 greater odds of hearing loss in children and 2.8 greater odds of hearing loss in the total cohort. Only 3 (2.7%) respondents reported the use of hearing aids. Hearing loss and middle ear disease are common in both children and adults with skeletal dysplasia. Adults were more likely to fail hearing screening than children. Abnormal tympanometry is associated with hearing loss. Hearing screening with appropriate intervention is recommended for these patients.     

The development of the mammalian outer and middle?ear

The mammalian ear is a complex structure divided into three main parts: the outer; middle; and inner ear. These parts are formed from all three germ layers and neural crest cells, which have to integrate successfully in order to form a fully functioning organ of hearing. Any defect in development of the outer and middle ear leads to conductive hearing loss, while defects in the inner ear can lead to sensorineural hearing loss. This review focuses on the development of the parts of the ear involved with sound transduction into the inner ear, and the parts largely ignored in the world of hearing research: the outer and middle ear. The published data on the embryonic origin, signalling, genetic control, development and timing of the mammalian middle and outer ear are reviewed here along with new data showing the Eustachian tube cartilage is of dual embryonic origin. The embryonic origin of some of these structures has only recently been uncovered (Science, 339, 2013, 1453; Development, 140, 2013, 4386), while the molecular mechanisms controlling the growth, structure and integration of many outer and middle ear components are hardly known. The genetic analysis of outer and middle ear development is rather limited, with a small number of genes often affecting either more than one part of the ear or having only very small effects on development. This review therefore highlights the necessity for further research into the development of outer and middle ear structures, which will be important for the understanding and treatment of conductive hearing loss.     

Multidetector row CT demonstration of inner and middle ear structures

The aim of this study is to evaluate the anatomical details of the inner ear and middle ear, using multidetector row CT. Temporal bone CT scans were obtained using 16-detector row CT scanner (Lightspeed 16, General Electric Medical Systems, Milwaukee, WI) in 30 patients with dizziness, vertigo, or hearing loss. The three-dimensional (3D) images were reconstructed with volume rendering techniques. The 3D images were reviewed by two radiologists and scored by using a three-point quality rating for qualitative assessment of the 23 representative structures of the middle and inner ear. The malleus, incus, and facial nerve canal were identified in all patients. The incudomalleolar joint appeared fused in all patients. The stapes were seen clearly in 27 (90%) of 30 patients except in three patients. Among the three remaining patients, there was one who had effusions in the middle ear cavity. Another patient had left cholesteatoma. The third patient had normal middle ear cavity. The cochlea and the three semicircular canals (anterior, posterior, and lateral) were well demonstrated in 29 (97%) of 30 patients except for one old woman with osteoporosis. Sixteen-detector row CT imaging of temporal bone with advanced 3D reformation yields state-of-the-art anatomical details of the temporal region useful to address anatomical localization issues and ease conceptual structural learning.     

Proximal symphalangism with “coarse” facial appearance,mixed hearing loss,and chronic renal failure: New malformation syndrome?

A 25‐year‐old man is described with short stature, moderate mental retardation, an abnormal facial appearance, a webbed neck, skeletal abnormalities including proximal symphalangism of bilateral second through fifth fingers, mixed hearing loss, and slowly progressive, sclerosing nephropathy. He was large at birth with generalized edema, more pronounced around the jaw, neck and the upper part of the body, but became short with increasing age, and currently measures 143 cm (−4.9 SD). He had intermittent proteinuria and slowly progressive deterioration of the renal function. A biopsy of the left kidney showed global glomerular sclerosis with interstitial fibrosis. He was placed on maintenance peritoneal dialysis at age 17 years, and now on hemodialysis. His skeletal abnormalities included, in addition to proximal symphalangism, stenosis of the cervical canal, scoliosis, brachydactyly of the hands, hypoplastic hip joints, and pes valgus. Other abnormalities noted were a communicating defects of the diaphragm (surgically corrected), bilateral inguinal hernia and cryptorchidism. These clinical manifestations indicate a hitherto undescribed combination of manifestations and nephropathy. © 2001 Wiley‐Liss, Inc.     

Identification of autoantibodies against inner ear antigens in a cohort of children with idiopathic sensorineural hearing loss

Abstract

Immune-mediated pathogenesis has been suggested for idiopathic sensorineural hearing loss. Recent studies have investigated the relationship between idiopathic sensorineural hearing loss and autoantibodies against inner ear antigens. We conducted a prospective, observational study in a series of pediatric patients affected by idiopathic sensorineural hearing loss. Autoantibodies against inner ear (anti-Cogan peptide, anti-connexin 26, anti-DEP1/CD148 and anti-reovirus), previously described in the serum of patients with Cogan’s syndrome, were detected in our population. The characteristics of children whose results were positive were also evaluated to verify if clinical data, disease progression and response to treatment could confirm an immune-mediated pathogenesis. Eleven patients were enrolled and 9 of them were positive for inner ear antibodies. Non-organ specific autoantibodies were present in 5 children out of 9. An immune-mediated condition was diagnosed in 2 cases and minor immune manifestations were found in 2 additional patients. In 5 cases hearing loss remained stable without therapy, while 4 children developed progression. Two subjects were treated with corticosteroids and methotrexate, achieving hearing improvement. Another subject showed stabilization on methotrexate. Inner ear autoantibodies can be positive in children with autoimmune sensorineural hearing loss, and in conjunction with clinical data may assist the clinician in identifying a subset amenable for immune modulation therapy. Large prospective studies are needed to investigate usefulness, diagnostic and prognostic role of these autoantibodies.     

Growth hormone deficiency in a child with branchio‐oto‐renal spectrum disorder: Clinical evidence of EYA1 in pituitary development and a recommendation for pituitary function surveillance

Branchio‐oto‐renal spectrum disorder (BORSD) is a rare autosomal dominant condition characterized by ear abnormalities with hard of hearing/deafness, second branchial arch malformations and renal anomalies. Pathogenic variations in EYA1 gene are found in the majority of clinically diagnosed individuals with BORSD. We describe an infant with BORSD related to a paternally inherited heterozygous pathogenic variation in EYA1 gene presenting with poor growth and hypoglycemia due to growth hormone deficiency. Magnetic resonance imaging revealed a diminutive pituitary gland and morphologically abnormal sella. Upon initiation of growth hormone therapy, the hypoglycemia resolved and catch up growth ensued. Pituitary abnormalities have not been reported previously in patients with BORSD. The zebrafish ortholog of eya1 is important for the development of adenohypophysis, suggesting that this patient's growth hormone deficiency and pituitary abnormality are part of BORSD. Inclusion of screening for pituitary hormone deficiency and pituitary imaging should be considered as a part of surveillance in patients with BORSD.     

Oto‐palato‐digital syndrome,type II: Report of three cases with further delineation of the chondro‐osseous morphology

Oto‐palato‐digital syndrome type II (OPD II) is a lethal X‐linked skeletal dysplasia with pleiotropic manifestations. The basic defect is not known. There has been only one detailed report of the chondro‐osseous abnormalities in this condition describing abnormal periosteal ossification in a single case [1990: Am J Med Genet 36:226–231]. We report on three cases of OPD II emphasizing the chondro‐osseous morphology. Although endochondral ossification was normal, periosteal ossification was defective with islands of cortical bone aplasia and hyperplasia of the periosteum. The trabecular bone was also extremely poorly formed and markedly hypercellular. Both membranous ossification and bone remodeling appear to be defective in OPD II and should account for part of the observed phenotype. The biglycan gene maps to Xq28 and is involved in bone formation, but was excluded as a candidate by direct sequencing of cDNA in one case. Am. J. Med. Genet. 95:193–200, 2000. © 2000 Wiley‐Liss, Inc.     

Craniofrontonasal dysostosis with deafness and axillary pterygia

Craniofrontonasal dysostosis (CFND) is an inherited disorder previously referred to as craniofrontonasal dysplasia. However, there is no evidence of tissue dysplasia and, therefore, the term dysostosis has been substituted. The disorder is characterized by frontonasal dysostosis, coronal craniostenosis, and the variable presence of other skeletal defects, including short webbed neck, sloping shoulders, polydactyly, syndactyly, and broad first toes. Here we report an affected mother and daughter who also have limited hip abduction. In addition, the mother had an axillary pterygia, congenital footplate fixation of the left ear, and right sensorineural hearing loss; these manifestations have not been reported previously in CFND and expand the phenotype of this syndrome. Both patients had marked restriction of shoulder abduction, and the mother had limited forearm pronation; these manifestations have been reported in only one other patient with CFND. Awareness of the possibility of these abnormalities may allow for early intervention by physical therapy and hearing aides in infants and young children with these manifestations as a component of CFND.     

Stapedoplasty in patients with small air-bone gap: why not?

Otosclerosis is a primary osteodystrophy which affects a localized area within the human temporal bone. Hearing loss is the most functional deficit caused by otosclerosis. However, tinnitus and vestibular disorders are frequently reported by otosclerotic patients, especially in those patients with inner ear involvement. The best therapy in achieving a significant improvement is surgery (stapedoplasty). In most patients if the operation is not carried out for pure middle ear type, the hearing impairment can progress to high-degree hearing loss. Recently, guidelines for the treatment of otosclerosis reported the 20 dbHL threshold as the minimum air-bone gap in performing stapedoplasty. We believe that stapedoplasty is an effective procedure for selected patients affected by otosclerosis with an air-bone gap which is smaller than 20 dbHL. An operation in the earlier phases of the disease can arrest the progression of otosclerosis, preserve inner ear structures and provide a complete auditory recovery, with increased satisfaction of the patient.     

Prospective evaluation of hearing impairment as a sequela of acute bacterial meningitis

As part of a prospective study of acute bacterial meningitis in children, we studied for five years the hearing of 185 infants and children who had acute bacterial meningitis when they were more than one month of age. Nineteen (10.3 per cent) of the patients had persistent bilateral or unilateral sensorineural hearing loss. The incidence of hearing loss as determined by electric-response audiometry and conventional tests was 31 per cent with Streptococcus pneumoniae, 10.5 per cent with Neisseria meningitidis, and 6 per cent with Hemophilus influenzae infections. Transient conductive hearing impairment was found in 16 per cent of the sample, but in no case was there apparent improvement in a sensorineural deficit over time. The site of disease resulting in impaired hearing cannot be stated with certainty, but involvement of the inner ear or auditory nerve was suspected. The number of days of illness (symptoms) before hospitalization and institution of antibacterial treatment was not correlated with the development of sensorineural deafness.