DISEASE CARD

Defintion

KID is a rare autosomal dominant keratinization disorder, mainly due to heterozygous missense mutations in GJB2, encoding connexin 26. Main features are progressive keratitis, erythrokeratoderma and profound, congenital sensorineural deafness.

Clinical Description

The disease manifests at birth or during infancy with transient erythroderma and occasionally mild scaling. Later on, patients develop well-circumscribed erythematous and hyperkeratotic plaques primarily on the face and extremities, often symmetrically distributed. However, lesions can occur on other areas as well, usually less pronounced. The skin is dry and appears thickened with a coarse-grained aspect. Hyperplastic inflammatory nodules / acne conglobata can occur and is together with hidradenitis suppurativa and dissecting cellulitis of the scalp known as follicular occlusion triad. Patients display an increased risk for skin (super-)infections due to bacteria, viruses and fungi and are often stigmatized due to the body malodour. Some patients develop an “elderly” facies with deep grooves and cheilitis. Palmoplantar keratoderma presents with a grainy leather-like surface. Squamous cell carcinoma of the skin and enoral have been reported in several cases and may even develop in older children or during adolescence. Other features include sparse or absent hairs (sometimes due to scarring), eyelashes, and eyebrows that may be related to follicular hyperkratosis and atrophy. Nail dystrophy (with/without leukonychia) and dental malformations as well as heat intolerance can occur.^{1, 2}

Sensorineural hearing loss is present at birth (usually noticeable by infancy) in nearly all patients and mostly bilateral. 

Ocular pathologies are common too. Vascularizing keratitis may appear during infancy and childhood the resulting corneal neovascularization and cicatrization are a frequent cause of disabling visual impairment and blindness, occurring in up to 75% of patients. Recurrent blepharoconjunctivitis, corneal ulcerations and pannus formation may participate in causing progressive and severe decline of visual acuity. Photophobia and tearing are frequent symptoms.

Pathogenesis

KID is caused by missense mutations in the connexin-26 (Cx26) gene (GJB2) in the majority of cases. A common GJB2 recurrent mutation (p.D50N) accounts for more than 80% of reported cases. One case was found to be caused by a mutation in the GBJ6 gene encoding connexin 30 (Cx30). Connexins are universal membrane proteins, forming gap junction channels that allow the diffusional exchange of ions and small metabolites between cells and thus are essential for cell communication. Connexin 26 and 30 are both expressed in the skin and inner ear. Mutations cause functional impairment of the gap junction system. However, the mechanisms whereby GJB2 mutations cause abnormal epidermal differentiation, decreased host defense and increased carcinogenic potential, remain unclear. ^{3, 4}

Diagnosis

The diagnosis of KID syndrome is established by clinical examination. Histological study of skin lesions is not specific. Sequence analysis of the GBJ2 gene shows a p.D50N missense mutation in more than 80 % of cases. A mutation in GJB6 has also been identified (p.V37E). The majority of cases are sporadic. Prenatal testing may be offered to families with known mutation.^{5, 6}

Treatment

Surveillance for development of skin and mucosal malignancy is important. Antiseptic baths, intermittent antibiotic therapy and systemic antifungal agents (oral ketoconazole or fluconazole) are helpful for controlling and treating infections. Systemic retinoids (acitretin, alitretinoin) may improve the keratoderma but also increase the risk of keratitis and corneal neovascularization. Localized skin debridement, excision and grafting of hyperkeratotic plaques have proven effective in some patients. Routine eye and hearing assessments are essential for early identification of complications. Treatment of eye lesions include lubricants, topical antibiotics, steroids and ciclosporin. Corneal transplants for advanced keratitis show frequently no long-term respond due to revascularization. Gas-permeable contact lenses have recently shown efficacy.⁷ Hearing aids, cochlear implants, speech therapy and appropriate educational context will improve outcome of hearing impairments.^{8, 9}

References

^{1. Caceres-Rios H, Tamayo-Sanchez L, Duran-Mckinster C, de la Luz Orozco M, Ruiz-Maldonado R. Keratitis, ichthyosis, and deafness (KID syndrome): review of the literature and proposal of a new terminology.Pediatr Dermatol. 1996;13(2):105-113.}

^{2. Coggshall K, Farsani T, Ruben B, et al. Keratitis, ichthyosis, and deafness syndrome: a review of infectious and neoplastic complications. J Am Acad Dermatol. 2013;69(1):127-134.}

^{3. Richard G, Rouan F, Willoughby CE, et al. Missense mutations in GJB2 encoding connexin-26 cause the ectodermal dysplasia keratitis-ichthyosis-deafness syndrome. Am J Hum Genet. 2002;70(5):1341-1348}

^{4. van Geel M, van Steensel MA, Küster W, et al. HID and KID syndromes are associated with the same connexin 26 mutation.Br J Dermatol 2002;146(6):938-942}

^{5. Mazereeuw-Hautier J, Bitoun E, Chevrant-Breton J, et al. Keratitis-ichthyosis-deafness syndrome: disease expression and spectrum of connexin 26 (GJB2) mutations in 14 patients. Br J Dermatol. 2007;156(5):1015-1019.}

^{6. Jan AY, Amin S, Ratajczak P, Richard G, Sybert VP. 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(5):1108-1113.}

^{7. Strul S, Straughn P. Successfully Improving Visual Acuity in Keratitis-Ichthyosis-Deafness Syndrome Utilizing Gas-Permeable Lenses: A Case Report. Eye Contact Lens. 2018;44 Suppl 1:S330-s332.}

^{8. Smyth CM, Sinnathuray AR, Hughes AE, Toner JG. Cochlear implantation in keratitis-ichthyosis-deafness syndrome: 10-year follow-up of two patients. Cochlear Implants Int. 2012;13(1):54-59.}

^{9. Bettoli V, Forconi R, Pezzini I, et al. KID Syndrome and Hidradenitis Suppurativa: A Rare Association Responding to Surgical Treatment. Skin Appendage Disord. 2021;7(1):21-24.}