Keratitis-ichthyosis-deafness Research Articles

A Novel Dominant and a De Novo Mutation in the GJB2 Gene (Connexin-26) Cause Keratitis-Ichthyosis-Deafness Syndrome

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. Retrospective case review. Tertiary referral center. Cochlear implant program. 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. Genetic analysis. Cochlear implantation. Mutation analysis, surgical suitability, and hearing rehabilitation. 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. 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.

Connexin-26 mutations in deafness and skin disease

Gap junctions allow the exchange of ions and small molecules between adjacent cells through intercellular channels formed by connexin proteins, which can also form functional hemichannels in nonjunctional membranes. Mutations in connexin genes cause a variety of human diseases. For example, mutations in GJB2, the gene encoding connexin-26 (Cx26), are not only a major cause of nonsyndromic deafness, but also cause syndromic deafness associated with skin disorders such as palmoplantar keratoderma, keratitis-ichthyosis deafness syndrome, Vohwinkel syndrome, hystrix-ichthyosis deafness syndrome and Bart-Pumphrey syndrome. The most common mutation in the Cx26 gene linked to nonsyndromic deafness is 35DeltaG, a frameshift mutation leading to an early stop codon. The large number of deaf individuals homozygous for 35DeltaG do not develop skin disease. Similarly, there is abundant experimental evidence to suggest that other Cx26 loss-of-function mutations cause deafness, but not skin disease. By contrast, Cx26 mutations that cause both skin diseases and deafness are all single amino acid changes. Since nonsyndromic deafness is predominantly a loss-of-function disorder, it follows that the syndromic mutants must show an alteration, or gain, of function to cause skin disease. Here, we summarise the functional consequences and clinical phenotypes resulting from Cx26 mutations that cause deafness and skin disease.

A rare connexin 26 mutation in a patient with a forme fruste of keratitis–ichthyosis–deafness (KID) syndrome

Keratitis-ichthyosis-deafness (KID) syndrome is a rare ectodermal dysplasia characterized by generalized erythrokeratotic plaques, sensorineural hearing loss, and vascularizing keratitis. Cutaneous changes and hearing loss typically present in early childhood, whereas ocular symptoms present later. Mutations in the connexin (Cx) 26 gene, GJB2, are now established to underlie many of the affected cases, with the majority of patients harboring the p.D50N mutation. A rare patient demonstrating features of incomplete KID syndrome associated with an uncommon Cx26 gene mutation is described. The patient presented late in adolescence with partial features of KID syndrome. There was limited cutaneous involvement and the rare association of cystic acne. Both hearing impairment and ophthalmic involvement were mild in severity. Genetic mutation analysis revealed a previously described, rare mutation in GJB2, resulting in a glycine to arginine change at codon 12 (p.G12R). This report describes a patient exhibiting characteristics suggestive of a late-onset, incomplete form of KID syndrome with the GJB2 mutation (p.G12R). The p.G12R mutation has only been described in one other patient with KID syndrome, whose clinical presentation was not characterized.

Cochlear implantation in children with keratitis-ichthyosis-deafness (KID) syndrome: Outcomes in three cases

Three children with keratitis-ichthyosis-deafness (KID) syndrome received cochlear implants at the Royal Victorian Eye and Ear Hospital. KID syndrome is a rare genodermatosis associated with mutation of the connexin-26 gene with characteristics affecting skin, hair, vision and hearing. Ichthyotic involvement of the ear canal epithelium and associated non-erosive keratosis obturans complicate hearing assessment and aid fitting. The tendency to eczematous dermatitis and otitis media is an additional problem with cochlear implantation. All cases have required additional medical management, however the outcomes show that the cochlear implant can be effective in these patients. Copyright © 2008 John Wiley & Sons, Ltd.

Cochlear implantation in children with keratitis-ichthyosis-deafness (KID) syndrome: outcomes in three cases

Three children with keratitis-ichthyosis-deafness (KID) syndrome received cochlear implants at the Royal Victorian Eye and Ear Hospital. KID syndrome is a rare genodermatosis associated with mutation of the connexin-26 gene with characteristics affecting skin, hair, vision and hearing. Ichthyotic involvement of the ear canal epithelium and associated non-erosive keratosis obturans complicate hearing assessment and aid fitting. The tendency to eczematous dermatitis and otitis media is an additional problem with cochlear implantation. All cases have required additional medical management, however the outcomes show that the cochlear implant can be effective in these patients. Copyright © 2008 John Wiley & Sons, Ltd.

Keratitis-ichthyosis-deafness (KID) syndrome

A 21-year-old man presented with a life-long history of diffusely thickened skin with a grainy-to-ridged surface, verrucous perioral plaques with radial fissures, and diffuse palmoplantar keratoderma with a stippled appearance. These skin findings were accompanied by sensorineural hearing loss and keratoconjunctivitis, a clinical triad diagnostic of keratitis-ichthyosis-deafness (KID) syndrome. The patient also had a history of recurrent infections and cysts on the scalp. This report draws attention to inflammatory nodules (representing ruptured folliculitis), cysts, and recurrent infections on the scalp as manifestations of KID syndrome and reviews the increasingly recognized risk of follicular tumors and squamous-cell carcinomas in patients with this conditions.

Keratitis–ichthyosis–deafness syndrome with unusual hypopigmentation

Keratitis–ichthyosis–deafness syndrome with unusual hypopigmentation

Trichothiodystrophy‐like Hair Abnormalities in a Child with Keratitis Ichthyosis Deafness Syndrome

Keratitis ichthyosis deafness syndrome is a rare congenital ectodermal disorder. It appears to be genetically heterogeneous and may be caused by mutations in the connexin 26 (Cx26) gene (GJB2) or in the connexin 30 gene. It is characterized by the association of ichthyosis-like skin lesions, hearing loss, and vascularizing keratitis. We report the clinical and molecular findings in a 5-year-old girl with keratitis ichthyosis deafness syndrome. DNA sequencing in our patient revealed a p.Ser17Phe mutation in GJB2. Besides the typical clinical features of keratitis ichthyosis deafness syndrome, a peculiar intriguing finding not previously described in the literature in this condition was that polarizing light microscopy of the scalp hair in our patient revealed striking bright and dark bands as seen in trichothiodystrophy. Amino acid analysis of the hair sample also disclosed a reduced cysteine index. We emphasize that it would be of great benefit to examine hair shafts in other patients with keratitis ichthyosis deafness syndrome for trichothiodystrophy-like abnormalities.

Cochlear implantation and connexin expression in the child with keratitis–ichthyosis–deafness syndrome

We report one child with keratitis-ichthyosis-deafness (KID) syndrome. The child showed sparse, short scalp and body hairs, ichthyotic skin, bilateral sensorineural hearing loss, and visual loss. These are associated with a nucleotide substitution, 148G>A, which results in amino acid change in codon 50 of gap junctional protein connexin (Cx) 26. Immunohistochemistry of skins showed up-regulation of Cx26 and down-regulation of Cx43. He has benefited from cochlear implantation for hearing even though low visual function and skin problems with high risk of infections. This is the very rare report about Cx expression in skins and cochlear implantation in KID syndrome.

Connexin 26 mutation in keratitis–ichthyosis–deafness (KID) syndrome in mother and daughter with combined conductive and sensorineural hearing loss

Keratitis-ichthyosis-deafness (KID) syndrome most commonly results from a mutation in the gap-junctional protein connexin 26 (Cx26) gene, GJB2. Most cases are sporadic and are associated with sensorineural hearing loss. We encountered a mother and daughter with KID syndrome, and pursued genetic analysis and an extensive hearing loss evaluation. The analysis of genomic DNA of both affected patients revealed the mutation 148G --> A in GJB2 (D50N). No mutation was found in an unaffected son. Auditory phenotype analysis showed a combined conductive and sensorineural hearing loss in both affected patients. This is the second vertical transmission of the D50N mutation. These are the first two cases with combined sensorineural and conductive hearing loss without any significant history of middle ear disease. This points to the possibility that the Cx26 D50N mutation can cause conductive hearing loss.

Ocular Manifestations and Histologic Characteristics of Keratitis-Ichthyosis-Deafness (KID) Syndrome

Purpose: Keratitis-ichthyosis-deafness (KID) syndrome is a congenital ectodermal disorder presenting the triad of vascularizing keratitis, erythrokeratoderma, and sensorineural deafness. Ocular manifestations such as hyperkeratinization of the eyelids, loss of eyelashes, keratoconjunctivitis sicca, corneal erosions, ulceration, neovascularization, and scarring opacity may be absent or mild, but if present and severe, they can lead to major visual loss. We report a patient with KID syndrome with severe ocular manifestations and the histologic characteristics of a corneal lesion. Case summary: A 5-year-old boy was referred to the Ophthalmology Department for bilateral hyperkeratinization of eyelids, bare eyelashes, and corneal opacity. He showed hyperkeratotic skin lesions and sensorineural hearing loss. Molecular analysis showed a mutation in the GJB2 gene and confirmed the diagnosis of KID syndrome. Initial conservative treatment did not preserve ocular surface integrity, and instead it was maintained by surgical procedures including superficial lamellar keratectomy with amniotic membrane transplantation. The histologic characteristics of corneal lesions are abnormal epithelial differentiation, absence of connexin 26 expression, and partial destruction of the basement membrane.

A familial case of Keratitis-Ichthyosis-Deafness (KID) syndrome with the GJB2 mutation G45E

Keratitis-Ichthyosis-Deafness (KID) syndrome (OMIM 148210) is a congenital ectodermal defect. KID consists of an atypical ichthyosiform erythroderma associated with congenital sensorineural deafness. A rare form of the KID syndrome is a fatal course in the first year of life due to severe skin lesion infections and septicaemia. KID appears to be genetically heterogeneous and may be caused by mutations in connexin 26 or connexin 30 genes. GJB2 mutations in the connexin 26 gene are the main cause of the disease. Most of the cases caused by GJB2 mutations are sporadic, but dominant transmission has also been described. To date, the rare lethal form of the disease has been only observed in two Caucasian sporadic patients with the GJB2 mutation, with the p.Gly45Glu (G45E) arising de novo. We have reported an African family with dizygotic twins suffering from a lethal form of KID. The dizygosity of the twins was confirmed by microsatellite markers. The two patients were heterozygous for the G45E mutation of GJB2, whereas the mutation was not detected in the two parents. The unusual transmission of the disease observed in this family could be explained by the occurrence of a somatic or more probably a germinal mosaic in one of the parents.

Keratitis‐ichthyosis‐deafness (KID) syndrome with squamous cell carcinoma

Keratitis‐ichthyosis‐deafness (KID) syndrome with squamous cell carcinoma

A case of keratitis–ichthyosis–deafness (KID) syndrome

A 26-year-old Japanese woman was referred to our hospital with generalized hyperkeratosis associated with keratitis and a hearing defect. The patient was born from nonconsanguineous parents. Her skin was moderately hyperkeratotic at birth. During childhood, the thickness of the skin increased progressively. Bilateral sensorineural deafness was recognized at the age of 3 years. Visual disturbance was noted in later childhood, and corneal transplantations to the right eye were performed twice at the age of 16 and 25 years, but did not improve her visual acuity. There was no family history of similar disease. On physical examination, the patient showed erythematous, keratotic, scaly plaques on the cheeks, auricles, and perioral area (Fig. 1a). A grainy, spiculated, hyperkeratotic papillomatosis was particularly marked on the palms and the edge of the feet (Fig. 1b,c). The nails were slight hypertrophic, but not dystrophic. Ophthalmologic examination revealed the loss of eyebrows and eyelashes and hyperkeratotic lesions of the eyelids (Fig. 1d). Corneal opacification was observed in the right eye. Conjunctivitis and blepharitis with photophobia were also observed in both eyes (Fig. 1d,e). A skin biopsy specimen from the right lower thigh showed basket-wave hyperkeratosis and papillomatosis of the epidermis. Hyperkeratotic plugs were not observed (Fig. 1f). Laboratory data, including complete blood cell count, sedimentation rate, immunoglobulins and transaminases, urea, cholesterol, and triglycerides were normal. With informed consent, genomic DNA was extracted from blood samples. The complete open reading frame of the GJB2 gene was polymerase chain reaction amplified and sequenced. A transition mutation (148G --> A) was detected, resulting in a putative amino acid change from aspartic acid to asparagine at codon 50 (Fig. 2). The mutation was not present in her parents or two siblings. These clinical, pathologic, and genetic data supported the diagnosis of keratitis-ichthyosis-deafness syndrome.

Keratitis?ichthyosis?deafness syndrome: disease expression and spectrum of connexin 26 (GJB2) mutations in 14 patients

Keratitis-ichthyosis-deafness (KID) syndrome is a rare congenital disorder characterized by the association of skin lesions, hearing loss and vascularizing keratitis. KID syndrome is caused by autosomal dominant mutations in the connexin 26 gene (GJB2). To establish whether there is a correlation between genotype and phenotype in KID syndrome. Clinical examination and molecular analysis of GJB2 were performed in a cohort of 14 patients with KID syndrome originating from 11 families. We also reviewed the 23 cases with molecular analysis previously reported in the literature. The patients displayed the classical signs of KID syndrome with the additional finding of inflammatory nodules in six patients (43%); this clinical finding has not been described previously in the literature. One patient presented at the age of 18 years with a fatal carcinoma of the tongue, an extremely rare reported complication. For seven of the 11 families (64%) the disease was sporadic, whereas it was familial in the remaining four families (36%). Twelve patients (86%) were heterozygous for the p.Asp50Asn mutation and two patients (14%) were heterozygous for the p.Ser17Phe mutation. Surprisingly, a family in which we personally examined the healthy parents had two affected children heterozygous for the p.Asp50Asn mutation, suggesting germinal mosaicism. Compared with patients with the p.Asp50Asn mutation, the two patients with the p.Ser17Phe mutation had more severe skin involvement. One of these two patients experienced a carcinoma of the tongue. Familial cases appear to be more frequent than reported in the literature. The possibility of germinal mosaicism must be taken into account for genetic counselling. This study also suggests that patients with the p.Ser17Phe mutation may have a more severe phenotype and could be at higher risk for tongue carcinoma.

A case of keratitis ichthyosis deafness (KID) syndrome associated with Dandy–Walker

A case of keratitis ichthyosis deafness (KID) syndrome associated with Dandy–Walker

Cochleosaccular Dysplasia Associated With a Connexin 26 Mutation in Keratitis–Ichthyosis–Deafness Syndrome

The objective of this study was to characterize the temporal bone phenotype associated with a mutation of GJB2 (encoding connexin 26). The authors conducted correlative clinical, molecular genetic, and postmortem histopathologic analysis. The study subject was a male infant with keratitis-ichthyosis-deafness (KID) syndrome. We performed a nucleotide sequence analysis of GJB2 and a histopathologic analysis of the temporal bones. The subject was heterozygous for G45E, a previously reported KID syndrome mutation of GJB2. The primary inner ear abnormality was dysplasia of the cochlear and saccular neuroepithelium. GJB2 mutations can cause deafness in KID syndrome, and possibly in other GJB2 mutant phenotypes, by disrupting cochlear differentiation.

Neurotological and Neuroanatomical Changes in the Connexin-26-Related HID/KID Syndrome

The phenotype of the HID (hystrix-like ichthyosis, deafness)/KID (keratitis, ichthyosis, deafness) syndrome is primarily characterized by skin changes. However, the connexin 26 (Cx 26) autosomal dominant mutation underlying this syndrome is of special neurotological interest. In the present paper, the clinical pattern, audiovestibular and neuroimaging findings and the detailed genetic analysis of 4 patients with identical HID/KID-associated mutation D50N of Cx 26 are reported. The audiological test results demonstrated profound sensorineural hearing loss in all of the patients. Neurotological testing revealed inconsistent abnormalities in dynamic posturography (sensory organization test), but the vestibular ocular reflex upon caloric irrigation was normal in all patients. Vestibular-evoked myogenic potential testing for otolith function (saccule) showed a regular response in 1 patient and pathologic responses in 3 patients, while subjective haptic vertical (utricular function) testing was normal in all of the patients. CCT showed an extended (in length), but very thin (in diameter) bony lining between the basal portion of the internal auditory canal and the vestibule in the 3 scanned patients. Our study provides evidence for functionally intact semicircular canals and normal utricular function in subjects with the autosomal dominant D50N mutation of Cx 26, in contrast to saccular function which was generally compromised and hearing loss which was profound.

Paciente con enfermedad corneal severa en el contexto del síndrome KID

A 33-year-old woman with superficial and deep bilateral corneal vascularization and keratoconjunctivitis sicca, keratoerythema and neurosensory deafness, was diagnosed with keratitis-ichthyosis-deafness (KID) syndrome. KID syndrome is a congenital ectodermal dysplasia characterized by the association of vascularizing keratitis, hyperkeratotic skin lesions and sensorineural hearing loss. Recently, limbal stem cell deficiency was recognized as a possible major pathogenetic factor.

Connexin 26 (GJB2) Mutations in Two Swedish Patients with Atypical Vohwinkel (Mutilating Keratoderma plus Deafness) and KID Syndrome Both Extensively Treated with Acitretin

Neuroectodermal syndromes involving the skin and inner ear may be associated with mutations in connexin proteins, which form gap junctions important for intercellular communication. Vohwinkel syndrome (keratodermia mutilans with hearing loss) and keratitis-ichthyosis-deafness (KID) syndrome are rare ectodermal dysplasias associated with dominant mutations in the GJB2 gene encoding connexin 26. We report here two patients, one with KID and one with Vohwinkel syndrome. Both displayed unusual clinical features and responded well to long-term treatment with oral retinoid. Mutation analysis revealed a novel GJB2 mutation p.Gly59Ser in the patient with Vohwinkel syndrome, whereas a recurrent mutation p.Asp50Asn was found in the patient with KID syndrome. The clinical features, particularly a proneness to skin cancer in the patient with Vohwinkel syndrome, are discussed in relation to the identified genotypes.