When Rare Meets Risky: Clouston Syndrome with Cutaneous Squamous Cell Carcinoma

Dear Editor, A 20-year-old male presented with disfiguration of all finger nails and toe nails for the past 10 years. There was pain and purulent discharge from his right great toe for the past 3 years. On mucocutaneous examination, nail plate dystrophy and subungual hyperkeratosis were present in all 20 nails. The right great toe also showed partial onycholysis, nail plate discoloration, and purulent discharge admixed with blood. There was also complete hair loss over whole body, diffuse thickening of both palms and soles with yellowish hyperkeratotic plaques on the pressure areas, and hyperpigmented lichenified plaques on the skin overlying the dorsal aspects of joints of both hands and feet [Figures 1a-d and f]. Pearly white tiny papules suggestive of milia were present on the periorbital region of the face. A hyperpigmented macule was present on the medial aspect of both thighs extending to the pubic region. Mucosae and teeth showed no abnormalities. On inquiry, patient gave a similar history in multiple family members, including three out of four siblings, father, grandfather, paternal uncle and two paternal cousins [Figure 2]. The phenotype of alopecia, nail dystrophy and palmoplantar keratoderma was consistent in all affected family members. However, none had recurrent episodes of paronychia. There was no history of any ocular complaints, deafness, or loss of sweating. Routine blood investigations (complete blood count, liver function tests, renal function tests) and audiogram were normal. Culture and senstivity reports of the purulent discharge from right great toe showed growth of Klebsiella pneumoniae susceptible to levofloxacin and cotrimoxazole. Genetic workup was not performed due to financial constraints.Figure 1: (a) Hyperpigmented plaques on knuckles and dystrophic nails. (b) Hyperpigmented lichenified plaques on dorsal aspects of toes and medial as well as lateral borders, along with nail dystrophy and paronychia of right great toe (black arrow). (c) Loss of hair over scalp, eyebrows and beard. (d) Diffuse thickening of both palms with focal yellowish discoloration on pressure bearing areas. (e) Verrucous growth on the right great toe with purulent and hemorrhagic discharge. (f) Brown coloured macule with well-defined borders on medial aspect of both thighsFigure 2: Pedigree chart depicting affected members over three generationsA punch biopsy from the right palm, on histopathologial examination, showed marked epidermal orthokeratosis with thickened granular layer, thickened papillary dermis and thickened collagen bundles in the vertical array. Sweat units were normal in number [Figure 3a]. Based on the clinical and histopathological examination, the patient was diagnosed as a case of Clouston syndrome with acute on chronic paronychia and café au lait macule. The patient was not concerned about the alopecia and palmoplantar keratoderma, hence no treatment was given for the same. He was started on tablet levofloxacin 750 mg once daily (2 weeks) with ointment mupirocin 2% twice daily for paronychia and urea 10% cream twice daily for pigmentation. Since there was only mild symptomatic improvement, repeated pus specimens were sent for culture and susceptibility over a period of 1 year and treatment was given accordingly. However, there was persistent pain and purulent discharge, and the patient subsequently developed swelling with verrucous growth of size 5 cm × 4 cm × 2.5 cm with focal areas of bleeding and purulent discharge on the distolateral part of right great toe [Figure 1e]. An incisional edge biopsy was performed from the verrucous growth, which showed keratin pearl, and dysplastic keratinocytes with nuclear atypia, suggestive of a well-differentiated squamous cell carcinoma (SCC) [Figure 3b and c]. Magnetic resonance imaging of right foot and pelvis showed no involvement of muscle or bone and no inguinal lymphadenopathy. The patient was then referred to surgical oncology, where great toe amputation was performed. Right inguinal lymph node dissection and histopathology were also carried out, which revealed no metastasis.Figure 3: (a) Histopathological image of punch biopsy taken from the right palm showing marked compact orthokeratosis with thickened granular layer in epidermis. (H and E, 4×). (b) Histopathological image of biopsy taken from verrucous growth on the right toe showing multiple keratin pearls (black star) and keratinocytes with nuclear atypia. (H and E, 10×). (c) Histopathological image of verrucous growth showing group of dysplastic keratinocytes with cells at periphery showing nuclear atypia (H and E, 100×)The first report of Clouston syndrome, also known as hidrotic ectodermal dysplasia type 2, was made by Nicolle and Hallipre in 1895. However, it was later extensively documented in Canadian families by Clouston in 1929.[1] It is a rare autosomal dominant disorder caused by heterozygous mutation in the GJB6 (gap junction protein β6) gene on chromosome 13q12, which encodes connexin-30.[2] It comprises a triad of alopecia, palmoplantar keratoderma, and nail dystrophy. Alopecia presents as sparse wiry hairs at birth, which may progress to total alopecia at puberty. Palmoplantar keratoderma, with variable degrees of hyperkeratosis of the palms and soles, is a common but not an universal finding and increases in severity with age. Nail dystrophy can present as thickened, ridged, discolored, hyperconvex nails and may be associated with paronychia. Pigmentation on joints of extremities, deafness, strabismus, conjunctivitis, cataract, and epidermal cysts can also be seen in some patients.[2] Other diseases that present with palmoplantar keratoderma and alopecia include keratitis-ichthyosis-deafness (KID) syndrome, palmoplantar keratoderma, and congenital alopecia (PPKCA), and pachyonychia congenita. The typical features of KID syndrome include keratitis, ichthyosis, deafness, none of which were present in our patient or his affected family members. PPKCA is of two types: type 1 and 2, both of which present with severe hyperkeratosis and congenital alopecia. In PPKCA-1, unlike Clouston syndrome, nail changes occur only rarely. PPKCA-2 however is autosomal recessive and is characterized by sclerodactyly, or even pseudo ainhum, that is not seen in Clouston syndrome.[3] The characteristic features of pachyonychia congenita, i.e., subungual hyperkeratosis and very thick nails with a characteristic inverted U or V shape, oral leukokeratosis, severe plantar pain are all lacking in Clouston syndrome. In Clouston syndrome, defective nutrition in dystrophic nails is a predisposing factor for recurrent paronychia, which in turn acts as a risk factor for development of SCC. In some instances, SCC of nail bed itself mimics paronychia due to its non-specific symptoms.[1,4] SCC has been reported to occur on areas of abnormal keratinization in a few syndromes with hereditary palmoplantar keratoderma such as Huriez, Unna-Thost, Olmsted and Jakac-Wolf.[5] Also, there is a case report of SCC of trachea associated with hypohidrotic ectodermal dysplasia[6] and few reports of Clouston syndrome with eccrine syringofibroadenoma, syringofibrocarcinoma and metastatic melanoma.[7,8] However, to the best of our knowledge, this is the first case of Clouston syndrome presenting with cutaneous SCC. This highlights the need for regular follow-up in order to keep a vigil for the development of SCC in a case of chronic and recurrent paronychia not responding to conventional treatment in patients with Clouston syndrome. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that his name and initials will not be published and due efforts will be made to conceal his identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest. Use of artificial intelligence (AI) The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.

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