Pachyonychia Congenita: Sporadic Onset with Mutation Analysis

Dear Editor,

Pachyonychia congenita (PC) is a rare, debilitating disease affecting skin and nails, manifesting as palmoplantar keratoderma (PPK) with painful blisters, nail dystrophy, and subungual hyperkeratosis. Up to 30% of cases occur due to sporadic mutations.[1] A 15-year-old boy, born of non-consanguineous marriage, presented with painful nodulopustules of the scalp with alopecia and inflammatory acne for a year and painful blistering of soles and progressive nail dystrophy since birth. His siblings were unaffected. He was treated repeatedly with systemic doxycycline and isotretinoin, topical tacrolimus 0.1% ointment, topical keratolytics, and topical tazarotene for varying intervals of time, with varying improvement, but not to complete satisfaction. Examination revealed erythematous papules, pustules, broken hairs, and soft, non-tender nodules in the occipital area with surrounding non-scarring alopecia [Figure 1a]. Comedones, pustules, erythematous nodules, cysts, and a few pitted scars on the face and neck [Figure 1b and c], discrete keratotic papules and pitted, atrophic scars on extensors of arms [Figure 1d] and dorsa of hands were present. A hyperkeratotic plaque was seen on the right sole. Hoof-like nails with onycholysis and profuse keratotic debris were present [Figure 2a, b and c]. Lips, teeth, and oral mucosae were normal. Skin biopsy was refused by the parents. The patient was advised care of hands and feet and started on doxycycline 100 mg daily, salicylic acid and urea-containing cream for soles, and tazarotene gel for nails. With a provisional diagnosis of PC, genetic testing was done via PC foundation, which revealed a mutation in the keratin 17 gene, K17p.Leu95Pro in the 1A (HIM) domain which causes the type PC-K17, due to leucine being changed to proline at point 95 of the gene. The mutation responsible for alopecia could not be detected, and we assume alopecia to be secondary to inflammation.

Figure 1.

(a) Posterior scalp showing patchy alopecia, broken hairs, papulopustules, and nodules (b) acneiform papules, cysts, nodules, comedones, and scars on face (c) papules and cystic lesions on neck (d) keratotic papules on elbows and extensor forearms

Figure 2.

(a) Nail dystrophy with yellowish to blackish pigmented and thickened finger nails (b) toenails (c) hoof-like great toe nail with keratotic plaque

PC is an autosomal dominant (AD) keratinization disorder chiefly affecting skin and nails and manifests as palmoplantar keratoderma (PPK) with underlying vesicles and bullae, plantar pain, and nail dystrophy with subungual hyperkeratosis. Other associations include leukokeratosis, cysts, and follicular hyperkeratosis. Mutations may involve keratin genes: KRT6A, KRT6B, KRT6C, KRT16, and KRT17. Up to 30% of cases may have sporadic mutations.[1] This is a relatively rare disease, with the International PC Registry having registered only 1240 proven cases.[1] The earlier classification of PC was based on clinical features and included three subtypes and a late-onset type IV disease was described by some authors [Table 1].[2]

Table 1.

Clinical findings in PC: Current triad and previous clinical classification

Hypertrophic nail dystrophy	First three clinical findings constitute the definitive triad
Palmoplantar keratoderma
Plantar pain
Cystic lesions
Milia
Follicular keratotic lesions
Oral leukokeratosis
Natal teeth
Palmoplantar hyperhidrosis	Botulinum toxin is effective
Cutaneous cysts	Epidermal inclusion cysts, sebaceous cysts, steatocystomas, vellus hair cysts
Alopecia	Very rare- but may be seen in severely affected individuals with homozygous dominant negative mutations in KRT17
EARLIER CLINICAL CLASSIFICATION OF PC
Type I disease (Jadassohn Lewandowsky syndrome)	Hoof-like nails, hyperkeratosis of palms and soles keratotic papules on knees and elbows oral leukokeratosis, helicotrichia
Type II disease (Murray Jackson Lawler syndrome)	Nail changes Palmopalntar keratoderma, neonatal teeth Sebaceous cysts Steatocystoma multiplex Bushy eyebrows
Type III diseaase (Schafer Brunaeur disease)	Clinical features of type I disease with corneal dyskeratosis
Type IV disease (PC tarda)	Late onset PC manifesting in the second or third decade of life

With advanced molecular genetics, PC is classified into 5 variants: PC-K6a, PC-K6b, PC-K6c, PC-K16, and PC-K17 based on mutations in corresponding keratin genes.[1] There are more than 100 genetic mutation variants, often specific to families with specific clinical associations. The unifying triad of PC is hypertrophic nail dystrophy, PPK with plantar pain.[3] Plantar keratoderma with fissures and blisters starts when the child begins to walk and can impact the quality of life. Palmar keratoderma is rare. There may be a neuropathic component.[1] Diagnosis is mainly clinical [Table 1]. Differentials include clinically similar genetic conditions [Table 2]. Histopathology is non-specific. Electron microscopy reveals bundles of densely aggregated keratin filaments in the upper spinous layers of the plantar epidermis. Genetic testing is available for free at International PC Foundation in cases with strong clinical suspicion.[4] Management is symptomatic, with genetic counselling of parents. Measures can be taken to reduce nail thickness, plantar hyperkeratosis, and pain. Plantar keratoderma: soaking and paring, trimming of calluses, use of soft footwear, care of feet, avoiding pressure, care of fissures, use of keratolytic agents like 3-6% salicylic acid, 10-20% urea, lactic acid, and regular use of emollients and moisturizers.

Table 2.

Possible clinical differential diagnoses for PC

Clouston’s syndrome:	Hidrotic ectodermal dysplasia with palmoplantar hyperkeratosis, nail dystrophy. Prominent alopecia. No plantar pain.
Olmsted syndrome:	Mutilating palmoplantar keratoderma with periorificial keratotic plaques. Here, digital contractures and ainhum leading to spontaneous amputation may occur. Alopecia is seen.
Striate and punctate PPK:	Features other than PPK are absent.
Epidermolysis bullosa simplex:	Though blisters occur on palms and soles with varying degrees of keratoderma, nail dystrophy and thickening is absent.
Dyskeratosis congenita:	Reticulate pigmentation, blood dyscrasias, and squamous cell carcinoma are predominant, though nail dystrophy, leukoplakia, and PPK may be present in some cases.
Keratosis Follicularis Spinulosa Decalvans (KFSD)	More in men, X-linked, starts in infancy or early childhood. It often starts in infancy or early childhood with spinous papules with alopecia
Keratosis Pilaris Atrophicans (KPA)	Consist of the triad of keratosis pilaris atrophicans faciei, atrophoderma vermiculata, and KFSD, all of which are scarring in nature. Keratotic follicular papules, nonpurulent inflammation, and irreversible hair loss or pitted scars are seen. PPK, long cuticles, ocular symptoms like photophobia, conjunctivitis, congenital glaucoma, and lenticular cataract may be seen
Differentials for cystic lesions: Steatocystoma multiplex: Vellus hair cysts:	Yellowish hue Characteristic biopsy findings

Nails: filing, grinding, use of pet nail trimmers, 40% urea for lysis, and topical antibiotics and antifungals for prevention of superadded infections. Cystic lesions: incision and drainage, topical antibiotics, systemic antibiotics, and systemic isotretinoin. Maintenance of oral hygiene is imperative. Regular follow-up and biopsy if required of oral leukokeratosis. Oral retinoids are useful for plantar keratoderma and cystic lesions, though nail thickening does not respond. Low-dose acitretin (25 mg per day) may be effective.[5] Botulinum toxin injections for hyperkeratosis and blistering, sirolimus for painful callosities, and rosuvastatin have also been tried. This case is being highlighted to showcase that though India is a treasure trove of rare diseases, a good reporting system is absent and often we have to resort to foreign aid for genetic testing and other sophisticated medical tests. A national registry and a sponsored genetic database for various diseases are the need of the day to reduce our dependence on international funding agencies.

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