Dermatology Online Journal

Keratitis-ichthyosis-deafness (KID) syndrome
Mercedes E Gonzalez MD, Brook E Tlougan MD, Harper N Price MD, Rishi Patel MD, Hideko Kamino MD, Julie V Schaffer MD
Dermatology Online Journal 15 (8): 11

Department of Dermatology, New York University

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Abstract

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.

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History

Figure 1	Figure 2

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A 21-year-old man presented to the Genetic Skin Disease Section of the Charles C. Harris Skin and Cancer Pavilion for evaluation of widespread ichthyosis of unknown etiology. His mother reported that she first noticed a darker color and rougher texture of the skin on his face and ears at age six weeks. During infancy and childhood, the skin over most of his body became progressively coarse and thickened, especially on his face, elbows, knees, hands, and feet. Growth of hair on his scalp had been minimal, and he never had eyebrows or eyelashes. At age 19, a cystic nodule developed on the frontal area of the scalp, with subsequent skin breakdown and purulent drainage that improved with antibiotic therapy but has recurred multiple times. Treatment included courses of co-trimoxazole, ciprofloxacin, and doxycycline.

The patient wore hearing aids for bilateral hearing sensorineural hearing loss that was detected at age six years. He has had a history of dry eyes and persistent conjunctival injection since childhood and had been under the care of an ophthalmologist for the past three years for chronic keratoconjunctivitis and decreased visual acuity. He was otherwise healthy, with normal growth and development. His parents and younger brother had normal hearing and no history of skin or eye problems.

Physical Examination

There was generalized, keratotic thickening of the skin, with a coarse, grainy texture and follicular accentuation. Prominent ridges with a rough surface were present on the knees and the dorsal aspects of the hands and feet, and the palms and soles display a diffuse keratoderma with a stippled appearance. Perioral plaques had a verrucous surface and furrows that extended radially from the lips. There were also deep grooves within thickened skin on the forehead. On the superior scalp, a well-circumscribed area of pink skin with overlying yellow scale-crust was bordered by exophytic papules and folds of skin with large follicular orifices. Scattered stubbly dark hairs were evident on the scalp, and eyelashes and eyebrows were absent. The conjunctivae were injected. The toenails were thickened and yellow with longitudinal ridges and splits as well as subungual hyperkeratosis, but the fingernails were normal.

Laboratory data

A metabolic panel, complete blood count with differential analysis, and lipid panel were normal. A fungal culture of a toenail sample was negative. Analysis of the GJB2 gene showed a missense mutation in codon 50 (D50N).

Histopathology

There are dilated follicular infudibula with a preserved granular layer, ortho-and parakeratotic plugs, and preservation of sebaceous glands. There are scattered vellus hair follicles in the dermis. There are also sections of dystrophic nail plate with subungual parakeratosis and collections of serum, lymphocytes, and neutrophils.

Comment

Keratitis-ichthyosis-deafness (KID) syndrome is a rare ectodermal disorder that features the clinical triad of progressive vascularizing keratitis, sensorineural hearing impairment, and skin manifestations (generalized or localized) that are better classified as erythrokeratoderma than as ichthyosis [1]. A patient with this constellation of findings was first described by Burns in 1915, and the KID acronym was coined by Skinner and colleagues in 1981 [2]. To date, approximately 100 cases of KID syndrome have been reported in the literature.

The extent and severity of the cutaneous and extracutaneous features of KID syndrome are variable. Affected individuals may present at birth with a transient erythroderma. Later in infancy and during childhood, most patients develop well-demarcated, keratotic plaques with an erythematous base and a stippled, verrucous, or ridged surface. These plaques favor the extremities, scalp, ears, and face; perioral plaques with radial furrows are a common finding. Diffusely thickened skin with a rough or ridged appearance, deep facial grooves, and follicular keratoses may occur. Palmoplantar keratoderma, which is usually diffuse with a grainy or reticulated texture, is almost invariably present. Angular cheilitis frequently develops, and chronically fissured lips and gingival hyperemia have been described [3]. Sparse hair, hypohidrosis, dystrophic nails, and abnormal dentition represent additional features. Patients with KID syndrome are predisposed to mucocutaneous infections with bacteria, fungi (especially Candida spp.), and viruses. Ocular findings, which may develop by early childhood or have a delayed onset, are progressive and include vascularizing keratitis, dry eyes, blepharitis, and conjunctivitis. Non-progressive, congenital, sensorineural hearing loss is consistently present with variable degrees of compromise. Cerebellar hypoplasia/Dandy-Walker malformations also have been reported in several patients with KID syndrome [4].

Recently, the follicular occlusion triad (dissecting cellulitis of the scalp, cystic acne, and hidradenitis suppurativa), follicular tumors, and squamous-cell carcinomas (SCCs) have been increasingly recognized as manifestations of KID syndrome [5, 6, 7, 8]. Progressive development of numerous pilar cysts as well as benign and malignant proliferating pilar tumors on the scalp and other sites has been described in several patients, at least two of whom also presented with the follicular occlusion triad [7,8]. In the largest series of KID syndrome patients to date, 43 percent (6/14) had inflammatory nodules (most often located on the scalp and representing ruptured folliculitis), 21 percent (3/14) had epidermal cysts, and 29 percent (4/14) developed a SCC [5]. SCCs of the skin or oral mucosa have been observed in >10 percent of KID syndrome patients; these tumors were diagnosed at a mean age of 25 years (range, 6 to 55 years) and often developed in the setting of chronic folliculitis and/or recurrent infection [1, 5]. It has been postulated that the hyperproliferative tendency and abnormal keratinization of the follicular (as well as interfollicular) epidermis in KID syndrome patients leads to plugging of the follicular orifices, cyst formation, and eventual rupture and inflammatory response [6, 8]. The resultant chronic inflammation and superinfections represent risk factors for the development of SCC and adnexal malignant conditions [7, 8]. Although no dysplastic changes were present in biopsy specimens from the chronically inflamed area on our patient's scalp, continued close surveillance will be required.

KID syndrome is an autosomal dominant condition that is caused by mutations in the GJB2 gene, which encodes connexin 26 [5]. Connexin 26 is a gap junction protein that is expressed in ectoderm-derived epithelia of the inner ear and cornea as well as in the epidermis and its appendages, which explains the constellation of findings in KID syndrome. To date, all pathogenic GJB2 changes identified in KID syndrome patients have been heterozygous missense mutations. The most common mutation is substitution of aspartic acid with asparagine in codon 50 (D50N), and this abnormality accounts for ~80 percent of affected individuals [5]. In addition, there has been one report of a patient with a KID syndrome-like phenotype and congenital atrichia who had a mutation in the connexin 30 gene, GJB6 [9]. Of note, GJB2 mutations represent the most common cause of nonsyndromic autosomal recessive hearing loss and underlie several other autosomal dominant genodermatoses, including hystrix-like ichthyosis-deafness (HID) syndrome (which overlaps with KID), classic Vohwinkel syndrome, palmoplantar keratoderma with deafness, and Bart-Pumphrey syndrome.

Management of KID syndrome requires multidisciplinary care by dermatology, ophthalmology, and otolaryngology services. Topical retinoids and keratolytics have limited benefits. There are several reports of substantial improvement in hyperkeratosis with acitretin therapy, and isotretinoin has variable efficacy in treating the follicular occlusion triad in KID patients [6, 7, 10]. Oral antibiotics and antifungal medications are necessary when infections develop, and prolonged courses are occasionally required. Close monitoring of the skin and oral mucosa for the development of malignancy is essential. Lubricating and anti-inflammatory agents have variable success in managing ocular disease, and cochlear implants have restored hearing in several affected individuals.

References

1. Caceres-Rios H, et al. Keratitis, ichthyosis, and deafness (KID syndrome): review of the literature and proposal of a new terminology. Pediatr Dermatol 1996; 13: 105 [PubMed]

2. Skinner BA, et al. The keratitis, ichthyosis, and deafness (KID) syndrome. Arch Dermatol 1981; 117: 285 [PubMed]

3. Lazic T, et al. A report of GJB2 (N14K) connexin 26 mutation in two patients: a new subtype of KID syndrome. Pediatr Dermatol 2008; 25: 535 [PubMed]

4. Zhang XB. A case of keratitis ichthyosis deafness (KID) syndrome associated with Dandy-Walker. J Eur Acad Dermatol Venereol 2007; 21: 681 [PubMed]

5. Mazereeuw-Hautier J, et al. Keratitis-ichthyosis-deafness syndrome: disease expression and spectrum of connexin 26 (GjB2) mutations in 14 patients. Br J Dermatol 2007; 156: 1015 [PubMed]

6. Montgomery JR, et al. A novel connexin 26 gene mutation associated with features of the keratitis-ichthyosis-deafness syndrome and the follicular occlusion triad. J Am Acad Dermatol 2004; 51: 377 [PubMed]

7. Nyquist G, et al. Malignant proliferating pilar tumors arising in KID syndrome: a report of two patients. Am J Med Genet 2007; 143A: 734 [PubMed]

8. Kim KH, et al. Keratitis, ichthyosis and deafness syndrome with development of multiple hair follicle tumours. Br J Dermatol 2002; 147: 139 [PubMed]

9. Jan AY, et al. Genetic heterogeneity of KID syndrome: identification of a Cx30 gene (GJB6) mutation in a patient with KID syndrome and congenital atrichia. J Invest Dermatol 2004; 122: 1108 [PubMed]

10. Zhang X, et al. Severe ichthyosis-related disorders in children: response to acitretin. J Derm Treat 2007; 18: 118 [PubMed]

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