Ralf Birkenhäger

Spectrum of hearing disorders and their management in children with CHARGE syndrome.

Objective: The CHARGE syndrome is associated with ear anomalies and deafness in addition to other malformations. Deformations of the ossicles or aplasia of the semicircular canals, cochlear hypoplasia, hypoplasia or aplasia of the VIIIth cranial nerve and abnormal routing of the VIIth cranial nerve, sigmoid sinus, and emissaries are typical findings. The aim of this study is to explore the feasibility and procedure of cochlear implantation in patients with CHARGE syndrome and to assess the outcome. Study Design: Retrospective case review. Setting: Tertiary referral center; cochlear implant program. Patients: Ten patients with CHARGE syndrome and 3 patients with CHARGE-like syndrome treated in our center due to hearing impairment. Eleven patients were congenitally deaf, 1 patient had progressive hearing loss, and 1 patient had mixed hearing loss. Intervention: Computed tomography of temporal bones and magnetic resonance imaging of the brain; bone-anchored hearing aid surgery, cochlear implantation, rehabilitation results. Main Outcome Measures: Surgical suitability and hearing rehabilitation. Results: We illustrate the management of preoperative diagnostics, surgical planning, and hearing rehabilitation. One patient with mixed hearing loss underwent bilateral bone-anchored hearing aid surgery. Because 2 patients had bilateral aplasia of the auditory nerves, we recommended an auditory brainstem implant. The unilateral cochlear implantation was performed in 9 patients and bilateral in 1 patient. In selected cases, it was helpful to plan the operation using a simulator for temporal bone surgery. Complex malformations, such as in CHARGE syndrome, with an increased intraoperative risk for complications should be facilitated by using intraoperative digital volume tomography-assisted navigation and intraoperative digital volume tomography control of electrode position. The results after CI surgery vary due to the differing extent of additional disabilities such as developmental delay, intellectual delay, and visual impairment. Nine of our patients showed improved responsiveness with the cochlear implant. Open speech comprehension could not be observed in 8 patients, whereas the follow-up period was less than 1 year in 4 patients. The relatively high age of our patients at implantation might be an important factor. Conclusion: Careful planning of the treatment of CHARGE syndrome patients with sensorineural hearing loss can, to a limited extent, lead to auditory benefit without increasing surgical complications. Cochlear implantation is therefore indicated after critical assessment.

Autosomal dominant prelingual hearing loss with palmoplantar keratoderma syndrome: Variability in clinical expression from mutations of R75W and R75Q in the GJB2 gene.

About one to three of a 1,000 neonates are afflicted at birth with a serious hearing impairment, with about half of the cases due to genetic causes. Genetic causes of hearing impairment are very heterogeneous. About half of all cases of genetically caused nonsyndromic hearing loss can be ascribed to mutations in the GJB2 gene (connexin 26) and to deletions in the GJB6 gene(connexin 30). Thus far, about 90 different mutations have been identified in the GJB2 gene, of which the majority are autosomal recessive. Ten mutations are autosomal dominant and are in most cases associated with various skin diseases: the keratitis‐ichthyosis‐deafness (KID) syndrome, Vohwinkel syndrome and palmoplantar keratoderma with deafness. To date, the following mutations have been identified which lead to the Palmoplantar Keratoderma syndrome with deafness; Gly59Ala, Gly59Arg, His73Arg, Arg75Trp, and Arg75Gln. We are reporting on four patients with severe hearing impairment. They are members of three unrelated families, who are carriers of mutations Arg75Trp or Arg75Gln, but unlike patients of other publications, do not all present with Palmoplantar Keratoderma syndrome. Our investigations document additional evidence for the correlation between the cited mutations in the GJB2 gene and a syndromic hearing impairment with palmoplantar keratoderma.

A novel dominant and a de novo mutation in the GJB2 gene (connexin-26) cause keratitis-ichthyosis-deafness syndrome: implication for cochlear implantation.

Objective: Keratitis-ichthyosis-deafness (KID) syndrome is a rare congenital disorder, characterized by hyperkeratosis and erythrokeratoderma associated with profound sensorineural hearing loss. Additional concomitant phenomena of the KID syndrome are dystrophic nails, dental abnormalities, scarring alopecia, and vascularizing keratitis. The disorder is caused by mutation in the GJB2 gene (connexin-26), a gap junction protein. The aim of this study was to explore the feasibility and procedure of cochlear implantation in patients with KID syndrome and to assess the genetic causes. Study Design: Retrospective case review. Setting: Tertiary referral center. Cochlear implant program. Patients: We report on 2 cases of KID syndrome with congenital profound hearing loss. A 50-year-old woman with skin necrosis and implant extrusion 5 years after cochlear implantation and a 10-month-old infant girl with bilateral deafness, alopecia, bright light sensitivity, and congenital dermatosis. Intervention: Genetic analysis. Cochlear implantation. Main Outcome Measures: Mutation analysis, surgical suitability, and hearing rehabilitation. Results: We detected a novel heterozygous missense mutation (Ile30Asn) in Patient 1 and a de novo mutation (Asp50Asn) in the GJB2 gene (connexin-26) in Patient 2. To decrease the risk of skin flap necrosis, we describe alternative surgical cochlear implantation techniques with a novel very thin receiver/stimulator (Nucleus CI 513; Cochlear Corp.). The postoperative course of both patients has been without any problems until now. Conclusion: The combination of the cutaneous lesions with visual and auditory impairment demands to diagnose impaired hearing as early as possible. It would be helpful to search for KID syndrome in dealing with patients with deafness, skin lesions of unknown cause, and wound healing problems to choose the right method of surgical treatment and subsequent aftercare.

Novel mutation in the homeobox domain of transcription factor POU3F4 associated with profound sensorineural hearing loss.

Background: Hearing loss affects 1 to 3 in 1,000 newborns, with 50% of these cases because of genetic causes. The majority of these are nonsyndromic (70%), and 2% are X linked. So far, 6 different X-linked loci have been mapped, but the causative gene POU3F4 has been identified only for the Locus DFN3. Clinical features of DFN3 often include a mixed, progressive hearing loss, temporal bone anomalies, and stapes fixation. POU3F4 belongs to a subfamily of transcription factors, which are characterized by 2 conserved deoxyribonucleic acid-binding domains, a POU and a HOX domain, both helix-turn-helix structural deoxyribonucleic acid-binding motifs. Several reports have described mutations of POU3F4 in patients with hearing loss and temporal bone abnormalities. In this study, we describe the clinical features and genetic analysis of a male child from a German family with congenital deafness and a novel POU3F4 mutation. Method: Mutational analysis of the affected individual and first-degree relatives was performed using direct sequencing of the coding exon and intron transitions of POU3F4. Result: The patient (II-1) had profound hearing loss, a severely dysplastic cochlea, and cerebrospinal fluid gusher during cochlear implantation. Sequence analysis of all family members demonstrated a novel missense mutation at nucleotide position 973, thymine to adenine (c.973 T>A), p.W325R in the patient (II-1), the mother (I-2), and sisters (II-2, II-3) heterozygous. The father (I-1) is not a carrier of the mutation. Conservation of the affected amino acid residue was seen across a number of different species. Conclusion: We identified a novel mutation in the third helix of the HOX domain of the POU3F4 transcription factor associated with congenital hearing loss.

Kidney failure in Townes-Brocks syndrome: an under recognized phenomenon?

Though uncommon, kidney malformations are described in several cases of Townes–Brocks syndrome. By contrast, kidney failure has been reported as the presenting feature of Townes–Brocks syndrome on only one occasion. While the SALL1 gene, mutations of which result in the Townes–Brocks phenotype, is expressed in the developing kidney, the absence of other corroborative reports of kidney failure presenting in affected individuals suggests that the solitary observation of kidney failure is as likely due to chance as to causal association. In now reporting a further instance of this association, we review the literature, demonstrating that several other instances of kidney failure are in fact known, despite an incomplete dataset. These findings suggest that kidney failure may be a constituent element of the natural history of Townes–Brocks syndrome and raise the possible benefits of longitudinal survey for progressive kidney impairment in patients with this syndrome.

Prevalence of mutations located at the dfnb1 locus in a population of cochlear implanted children in eastern Romania.

OBJECTIVE Hearing loss is one of the major public health problems, with a genetic etiology in more than 60% of cases. Connexin 26 and connexin 30 mutations are the most prevalent causes of deafness. The aim of this study is to characterize and to establish the prevalence of the GJB2 and GJB6 gene mutations in a population of cochlear implanted recipients from Eastern Romania, this being the first report of this type in our country. METHODS We present a retrospective study that enrolled 45 Caucasian cochlear implanted patients with non-syndromic sensorineural severe to profound, congenital or progressive with early-onset idiopathic hearing loss. We performed sequential analysis of exon 1 and the coding exon 2 of the GJB2 gene including also the splice sites and analysis of the deletions del(GJB6-D13S1830), del(GJB6-D13S1854) and del(chr13:19,837,343-19,968,698). RESULTS The genetic analysis of the GJB2 gene identified connexin 26 mutations in 22 patients out of 45 (12 homozygous for c.35delG, 6 compound heterozygous and 4 with mutations only on one allele). We found 6 different mutations, the most prevalent being c.35delG - found on 32 alleles, followed by p.W24* - found on 2 alleles. We did not identify the deletions del(GJB6-D13S1830), del(GJB6-D13S1854) and del(chr13:19,837,343-19,968,698). CONCLUSIONS Although the most prevalent mutation was c.35delG (80% from all types of mutations), unexpectedly we identified 5 more different mutations. The presence of 6 different mutations on the GJB2 gene has implications in hearing screening programs development in our region and in genetic counseling.

Mondini Malformation Associated With Diastematomyelia and Presenting With Recurrent Meningitis

The authors report the case of 5-year-old girl who presented with 4 episodes of recurrent meningitis. Her initial workup revealed a lumbosacral dermoid sinus associated with diastematomyelia and a tethered cord. Therefore, a surgical repair to correct the anomaly was performed. However, another episode of meningitis occurred after surgery, and a subsequent temporal bone scan revealed the presence of left Mondini dysplasia. To the authors’ knowledge, this is the first report of Mondini dysplasia in association with diastematomyelia.

Head and neck cancer in young adults and nonsmokers: Study of cancer susceptibility by genome-wide high-density SNP microarray mapping

Abstract Conclusion. Our results raise the question as to whether specific patterns of ‘germline loss of heterozygosity (LOH)’ could contribute to the genetic susceptibility for head and neck squamous cell carcinoma (HNSCC). Objectives. HNSCC usually occurs in older individuals with a history of smoking. However, about 5% of HNSCC patients have never used tobacco or develop this disease at an exceptionally young age. Therefore, genetic susceptibility must contribute significantly to HNSCC risk. The objective was to introduce a novel approach that might help to unveil candidate genes contributing to cancer predisposition and to identify individuals at risk for HNSCC, and to present our observations with this method in a specific group of patients. Methods: High-resolution SNP (single-nucleotide polymorphism) microarray mapping for homozygous stretches in germline DNA was performed in 12 patients who appeared particularly susceptible to develop HNSCC, because they were exceptionally young or never users of tobacco. Results: We could identify strings of consecutive homozygous SNPs that were much longer than would be expected to appear by chance alone, indicating regions of DNA deletions that we named germline LOH.

A Novel Homozygous Mutation in the EC1/EC2 Interaction Domain of the Gap Junction Complex Connexon 26 Leads to Profound Hearing Impairment

To date, about 165 genetic loci or genes have been identified which are associated with nonsyndromal hearing impairment. In about half the cases, genetic defects in the GJB2 gene (connexin 26) are the most common cause of inner-ear deafness. The genes GJB2 and GJB6 are localized on chromosome 13q11-12 in tandem orientation. Connexins belong to the group of “gap junction” proteins, which form connexons, each consisting of six connexin molecules. These are responsible for the exchange of ions and smaller molecules between neighboring cells. Mutational analysis in genes GJB2 and GJB6 was brought by direct sequencing of the coding exons including the intron transitions. Here we show in the participating extended family a homozygous mutation c.506G>A, (TGC>TAC) p.Cys169Tyr, in the GJB2 gene, which could be proven for the first time and led to nonsyndromal severe hearing impairment in the afflicted patients. The mutation is located in the EC1/EC2 interaction complex of the gap junction connexon 26 complex and interrupts the K+ circulation and therefore the ion homeostasis in the inner ear. The homozygous mutation p.Cys169Tyr identified here provides a novel insight into the structure-function relationship of the gap junction complex connexin/connexon 26.

LOH-profiling by SNP-mapping in a case of multifocal head and neck cancer

AIM To introduce an approach for the detection of putative genetic host factors that predispose patients to develop head and neck squamous cell carcinomas (HNSCC). METHODS HNSCC most often result from the accumulation of somatic gene alterations found in tumor cells. A cancer-predisposing genetic background must be expected in individuals who develop multiple cancers, starting at an unexpectedly young age or with little carcinogen exposure. Genome-wide loss of heterozygosity (LOH) profiling by single nucleotide polymorphism microarray mapping was performed in a patient with a remarkable history of multifocal HNSCC. RESULTS Regions of genomic deletions in germline DNA were identified on several chromosomes with a remarkable size between 1.6 Mb and 8.1 Mb (mega base-pair). No LOH was detected at the genomic location of the tumor suppressor gene P53. CONCLUSION Specific patterns of germline DNA deletions may be responsible for susceptibility to HNSCC and should be further analyzed.