Extraordinary Case Report
Keratitis–ichthyosis–deafness (KID) syndrome is a rare genodermatosis that was first reported in 1915 and classified in 1981.1,2 It typically results from sporadic, de novo mutations of the GJB2 gene or, less commonly, the GJB6 gene, encoding gap junction proteins connexin 26 and connexin 30, respectively. Vertical transmission has also been reported.3,4 Patients present in infancy with transient erythroderma that progresses into a true ichthyosis with verrucous, well-demarcated, hyperkeratotic plaques.5 Although the skin findings in patients with KID syndrome are heterogeneous, half of the patients have chronic skin infections, with Candida and bacteria as the most common culprits.4
A 25-year-old man with medical history of KID syndrome presented with thick, painful plaques on his bilateral feet as well as eruptive papules on his extremities. The thick plaques on the patient's feet caused intractable discomfort and easy bleeding from minimal trauma. The lesions were treated with urea cream, ammonium lactate cream, benzoyl peroxide wash, and bleach baths with no improvement.
He was diagnosed with KID syndrome from a mutation of the GJB2 gene (G12R). He has shown classic triad of longstanding ichthyosis, progressive keratitis with photophobia, and congenital, stable, sensorineural hearing loss. He developed an oral squamous cell carcinoma within the year preceding presentation that was treated by resection and lymph node dissection. The patient also has palmar hypohidrosis, multiple pilar cysts on the scalp, and severe acne. As an infant, the patient developed multiple candidal infections that were treated successfully with oral ketoconazole.
Physical examination revealed hyperkeratotic and verrucous plaques on the dorsum of the feet with a red, fungating plaque on the right medial foot and severe nail dystrophy (Figs. 1A, B). There were hyperkeratotic papules on the flexural neck, occipital scalp, left posterior thigh, groin, and extensor arms and legs.
An incisional biopsy of the most friable area of the plaque on the right dorsal foot revealed papillomatosis, marked acanthosis, a dense mixed inflammatory dermal infiltrate with areas of dense parakeratosis, a loss of granular layer, and abrupt keratinization (Fig. 2A). Numerous pseudohyphae were noted in the stratum corneum (Fig. 2B). Gram stain incidentally revealed yeast forms in the stratum corneum and the dermatophyte culture was negative.
Oral antifungal therapy with fluconazole was initiated. The fluconazole dose was increased from 100 to 150 mg, and he has maintained this dosage for 2 years. Complete blood counts with differential and liver enzymes were periodically checked and have been within normal limits. The patient notes marked clinical improvement (Figs. 1C, D). Within 3 months, the overall skin erythema and pustulosis improved, and the most recalcitrant plaques began to thin. With one year of daily therapy, the feet plaques improved almost to the point of resolution, and he was able to walk without pain.
A 16-year-old patient with KID syndrome presented with odiferous skin lesions on the right arm and groin. She had been treated with oral ciprofloxacin and doxycycline for presumptive pyoderma with no improvement. Physical examination revealed several relatively well-demarcated, hyperkeratotic, and verrucous plaques with focal erosion on the right arm and groin (Fig. 3). Punch biopsy was performed on the lesion of the right arm. The specimen exhibited scale crust, papillomatous epidermal hyperplasia, acantholysis, mild spongiosis with neutrophilic exocytosis, microabscess formation, a dense superficial and deep perivascular and periappendageal lymphoplasmacytic infiltrate with occasional eosinophils, papillary dermal edema, and telangiectasia (Figs. 4A, B). CD1a and S100 stains revealed the presence of Langerhans cells in the epidermis. Grocott methenamine silver (Fig. 4C) and Periodic Acid-Schiff stains show several fungal spores and pseudohyphae in the stratum corneum. The tissue culture returned with Candida albicans/dubliniensis, Aspergillus, and coagulase-negative Staphylococcus. She has been managed by her infectious disease physician and has since been lost to follow-up.
Patients with KID syndrome are at high risk of developing malignancy and chronic infection. Oral and cutaneous squamous cell carcinomas develop in 15% of patients with KID syndrome and fatal outcomes have been reported.3,4 Half of the patients experience chronic skin infections, most commonly due to Candida—such as our 2 patients—or bacteria.4 Although a common immune defect has not yet been discovered in patients with KID syndrome,6 Rerknimitr et al7 suggested that deficiency of Langerhans cells—which support Th17 cell function—may underlie chronic candidiasis in these patients. However, in our patient (case 2), the immunohistochemical staining with CD1a and S100 highlighted presence of Langerhans cells (Fig. 4D).
The differential diagnoses for verrucous and fungating lesions are broad and include neoplasms such as squamous cell carcinoma, verrucous carcinoma and keratoacanthoma, as well as infections such as deep fungal infection, atypical mycobacterial infection, and syphilis. In addition, inflammatory diseases such as hypertrophic lupus erythematosus, pemphigus vegetans, and halogenoderma can present as verrucous lesions. Proper biopsy technique is essential to obtain the right diagnosis. As the pathologic findings leading to the correct diagnosis may lie in the stratum corneum to deep dermis, incisional biopsy is favored over shave biopsy. As a note of caution, Calderon-Castrat et al8 reported a case of cutaneous candidiasis that was misdiagnosed as squamous cell carcinoma from punch biopsy.
In the literature, there have been few cases of chronic candidiasis successfully treated with oral antifungal agents, such as fluconazole, itraconazole, and ketoconazole.8–11 Our patient's impressive results suggest that the pathogenesis of thick, verrucous, hyperkeratotic plaques in patients with KID syndrome may involve keratinocyte hyperreactivity to yeast. In the presence of widespread skin changes, it can be difficult for clinicians to determine which lesions present true concern for cancerous change.8 However, oral fluconazole can “clear the field” by thinning benign, reactive papules and plaques, thereby making malignant changes easily identifiable,9 and reducing unnecessary biopsies. In one report, a patient with KID syndrome was treated with daily oral fluconazole for 8 years without any adverse effects or development of resistance.11
In summary, our 2 cases highlight that patients with KID syndrome can develop hyperkeratotic and verrucous plaques of chronic candidiasis. These patients were successfully diagnosed due to appropriate biopsy technique and evaluation for fungal/yeast infection. For the clinician, an appropriate biopsy that allows for the evaluation of both the epidermis and dermis is essential. For the pathologist, suspicion for fungal infection as well as malignancy should be entertained as causes of the verrucous and fungating lesions in patients with KID syndrome. By identifying the true culprit, appropriate antimicrobial therapy and/or surgical intervention can be instituted, thereby decreasing morbidity and improving the patient's quality of life.
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Keywords:Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
keratitis–ichthyosis–deafness syndrome; KID syndrome; chronic candidiasis