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Here’s looking at you, KID

DII small banner By Warren R. Heymann, MD
April 7, 2017

Keratitis, ichthyosis, and deafness
Late skin findings in lethal keratitis-ichthyosis-deafness syndrome. Intertriginous hyperkeratosis and denudation in a patient with GJB2 p.A88V mutation. 
Credit: JAAD

Keratitis, ichthyosis, and deafness (KID) syndrome is a rare genodermatosis associated with mutations in the GJB2 gene, which encodes connexin 26. Abnormalities of this gap junction protein presumably affects epithelial differentiation, resulting in myriad clinical features. Most cases are sporadic; familial cases inherited by autosomal dominant and occasional recessive transmission have been reported. KID syndrome is characterized by the clinical triad; however, the syndrome also displays other cutaneous manifestations and complications, both infectious and neoplastic. Chronic mucocutaneous candidiasis, superinfection of skin lesions, benign neoplasms (notably trichilemmal tumors), and squamous cell carcinoma (SCC) of both mucosa and skin, occurs in approximately 15% of patients (1).

Two recent cases offer some insight into potential pathomechanisms of disease. A 34-year-old man with molecularly-proven KID syndrome, complicated by chronic mucocutaneous candidiasis, was found to have an absence of epidermal Langerhans cells in lesional tissue. Because Langerhans cells are essential for the development of Th17 cells, it is speculated that this may be a predisposing factor for Candidal infections (2). Homeida et al detail the case of a 25-year old man with KID syndrome who developed an oral SCC of the right buccal mucosa. Immunostaining of the tumor was positive for P16, suggesting that the tumor was infected by the oncogenic human papillomavirus (HPV) 16 (3). Perhaps a diminished Langerhans cell population inhibits immunosurveillance allowing for an oncogenic virus to flourish, thereby increasing the risk for SCC.
It is also essential that dermatologists be careful in diagnosing SCCs in patients with KID syndrome. Candidal infection may result in pseudocarcinomatous hyperplasia that may mimic SCC both clinically and histologically. A case of vegetating candidiasis was erroneously diagnosed as SCC — a Gomori methenamine silver stain confirmed the correct diagnosis. The lesion was successfully treated with a combination of itraconazole and acitretin (4). I have seen one such patient with KID with a several exophytic, fungating plaques that I presumed were SCCs; they proved to be (presumed) Candida on biopsy, and responded well to oral fluconazole.
Until gene therapy for KID syndrome unfolds, a multidisciplinary therapeutic approach involving dermatologists, ophthalmologists, oral surgeons, geneticists, etc. will be necessary. Dermatologists need to focus on infectious complications with antibiotics and antifungal agents; the ichthyotic components may be approached with retinoids. Vigilance for the development of SCCs is mandatory.

Finally, clinicians should be aware that there is a new KID on the block — the autosomal recessive Keratoderma-Ichthyosis-Deafness (ARKID) syndrome, manifested by a severe palmoplantar keratoderma associated with ichthyosis and sensorineural deafness. This is caused by VPS33B mutations affecting Rab proteins 11a and 25, involved in trafficking of the collagen-modifying enzyme LH3. This affects the basement membrane zone and lamellar body secretion (5).

In conclusion, dermatologists should be cognizant of the ramifications of two KID syndromes. As the late Jack Paar would say — “I kid you not”.

1. Coggshall K, et al. Keratitis, ichthyosis, and deafness syndrome: A review of infectious and neoplastic complications. J Am Acad Dermatol 2013; 69: 127-34.
2. Rerknimitr P, et al. Diminution of Langerhans cells in keratitis, ichthyosis and deafness (KID) syndrome patient with recalcitrant candidiasis. J Eur Acad Dermatol Venereol 2016; e47-9.
3. Homeida L, et al. Oral squamous cell carcinoma in a patient with keratitis-ichthyosis-deafness syndrome: A rare case. Oral Surg Oral Med Oral Pathol Oral Radiol 2015; 119: e226-32.
4. Calderón-Castrat X, et al. Vegetating candidiasis: A mimicker of squamous cell carcinoma in keratitis ichthyosis deafness syndrome. Pediatr Dermatol 2017; 34: 201-3.
5. Gruber R, et al. Autosomal recessive keratoderma-ichthyosis-deafness (ARKID) syndrome is caused by VPS33B mutations affecting Rab protein interaction and collagen modification. J Invest Dermatol 2017; 137: 845-7.

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