Are You Confident of the Diagnosis?
What should be alert for in the history
A family history should be elicited, as well as any history of recurrent trauma or hobby-related chronic use of the hands and feet. Painful callusing on the feet is almost pathognomonic in a patient with keratoderma and thickened nails. Morning/starting pain is very typical. Natal teeth are often seen in patients with Keratin 17 mutations. Feeding as an infant may be problematic, presumably due to pain with suckling. Keratoderma may be absent until the patient begins to ambulate. Secondary infection, particularly paronychia, occurs secondary to bacterial, fungal, and occasionally polymicrobial infections.
Characteristic findings on physical examination
Characteristic findings in pachyonychia congenita (PC) include variable expression of the following clinical manifestations: painful plantar keratoderma with underlying blisters, variable palmar keratoderma (depending on trauma) (Figure 1, Figure 2) , oral leukokeratosi (Figure 3, Figure 4). steatocystoma multiplex (Figure 5, Figure 6), plantar bullae, subungual hyperkeratosis (Figure 7), fingernail and toenail dystrophy, hyperhidrosis (of hands and feet), follicular hyperkeratosis (Figure 8, Figure 9), laryngeal thickening, hoarseness, epidermal and sebaceous cysts, and natal teeth.
Expected results of diagnostic studies
The primary diagnostic study is keratin genetic testing of KRT6A, KRT6B, KRT16, and KRT17. Mild cases may be due to KRT6C. Hotspot regions may be tested first, followed by comprehensive analysis. Expected result: pathogenic mutation. If no mutation is found or if other clinical features such as alopecia are seen, consider testing for Clouston (CX30/JGB6).
Jadassohn-Lewandowsky, Jackson-Lawler, PC1, and PC2 nomenclature has been recently abandoned in favor of a nomenclature that includes reference to the underlying genetic mutation (ie., PC-6a represents a patient carrying a mutation in the K6a gene, PC-U reflects PC with an unknown mutation). PC-1 has been traditionally considered to be caused by mutations in KRT6A or KRT16 whereas PC-2 has been considered to be caused by KRT6B or KRT17. PC-1 and PC-2 were thought to be distingushed by the presence of cysts and natal teeth in PC-2. However, more recent analysis of clinical data from the International Pachyonychia Congenita Research Registry reveals that substantial overlap exists between PC-1 and PC-2 categories, although steatocystomas and natal teeth are more commonly seen in PC-17 than any other subtype.
Differential diagnoses include:
Clouston syndrome. (Usually has hair abnormalities/alopecia not present in PC and keratoderma is less painful)
Psoriasis. (Responsive to topical steroids, often has scalp and other cutaneous involvement not typically seen in PC and nail changes are not usually as severe or in all nails)
Onychomycosis. (Positive potassium hydroxide (KOH) and cultures without other features of PC)
Epidermolysis bullosa simplex (More blisters with less keratoderma, not as localized to plantar surfaces as PC)
Palmoplantar Keratoderma striata et areata of Siemens (Blistering and keratoderma possible on feet but no other features of PC)
Who is at Risk for Developing this Disease?
Inherited, Autosomal Dominant
What is the Cause of the Disease?
Genetic: Keratins 6a, 6b, 16, and 17. Keratin 6c may produce an attenuated phenotype known as hereditary painful callosities. Pathogenic mutation in one of the above keratins compromises appropriate filament formation.
Mutated keratin filaments aggregate, resulting in weakened filament structures and consequent cellular fragility. Cells under stress are less resilient. leading to greater trauma experienced, increased blister formation, and increased callusing. In addition, the PC keratins are “wound healing keratins” and transcription is activated by wounding, resulting in production of more mutant keratin during repetitive trauma and further aggravating the condition. Keratin 17 has been shown to take part in the regulation of cell growth and size through an effect on the mTOR complex. Mutations in K17 might therefore affect epidermal proliferation.
Systemic Implications and Complications
Systemic infection derived from the nails or skin is possible and is more common at sites of blister formation and barrier disruption.
Treatment options include nail paring with electric file, urea or salicylic acid in petrolatum under the nail plate, application of emollients to hyperkeratotic lesions (e.g., petrolatum, urea, alpha hydroxy acids, salicylic acid) , oral retinoids (individually titrated, consider selecting isotretinoin for women of childbearing age, beginning at 0.5-1.0 mg/kg for isotretinoin and 25-50 mg/day for acitretin, and adjusting down to minimal effective dose ), oral antibiotics (for secondary infection); additional therapeutics are being evaluated, including rapamycin and recently siRNA (Leachman et al 2008).
Optimal Therapeutic Approach for this Disease
No optimal approach currently exists and treatment is primarily routine maintenance with grooming and emollients and additional symptom-based therapy for exacerbations.
The painful plantar keratoderma is the most disabling feature for patients. Limiting friction to the soles of the feet will improve the pain and keratoderma. Some friction reduction can be achieved through individualized degrees of grooming, producing a thin residual callus that still provides some protection but does not result in increased friction during ambulation. In addition, ventilated footwear, wicking socks, limited walking, and maintaining a healthy body weight will minimize the trauma and subsequent damage experienced on the plantar surface. Daily application of emollients to the feet reduces painful cracking of the callosities.
Bleach soaks with 1 tablespoon of bleach per gallon of water will reduce polymicrobial flora (if secondary infection is suspected) or as prophylaxis if recurrent secondary infection occurs. Skin culture and antibiotics may be required for secondary infection and should be tailored to the organism(s) involved.
Treatment of cysts does not differ from standard therapy and includes incision and drainage, intralesional steroid injection of non-infected lesions, culturing and antibiotics in the case of potential infection, and excision when indicated due to recurrence or disabling/disfiguring manifestations.
Thickened nails are typically best reated with routine grooming on a regular basis and frequency should depend on the rate of growth experienced by the individual. In the case of severe nail hypertrophy or onychogryphosis, particularly if it is affecting ambulation, nail removal with ablation of the nail matrix can be considered. It is not uncommon for the nail bed to continue to have hyperkeratosis following nail removal.
Oral leukokeratosis responds favorably to aggressive oral hygiene, including brushing of the tongue, but recurrs. Follicular hyperkeratoses can be treated symptomatically with alpha-hydroxy acid-containing emollients or other mosturizures.
Treatment should be tailored to the patient’s individual symptoms. The treatments mentioned above have been listed as successful in certain cases. The patient should be seen in follow-up as needed to address the symptoms.
Genetic testing and counseling should be made available to PC patients and families because of its inherited nature. Enrollment in the International Pachyonychia Congenita Research Registry and involvement with the Pachyonychia Congenita Project should be offered for social support and patient advocacy purposes as well as possible financial help with genetic testing costs.
Unusual Clinical Scenarios to Consider in Patient Management
Transgrediens presentation (ie., extension of lesions onto the dorsal aspect of the foot) of blisters, erosions, and subsequent skin thickening is possible and may be secondary to trauma, edema, or secondary infection. A case of laryngeal obstruction has been reported secondary to laryngeal leukokeratosis in a 2 year old girl with pachyonychia congenita.
What is the Evidence?
Leachman, SA, Hickerson, RP, Hull, PR, Smith, FJ, Milstone, LM, Lane, EB. “Therapeutic siRNAs of dominant genetic skin disorders including pachyonychia congenita”. J Dermatol Sci.. vol. 51. 2008 Sep. pp. 151-7. (This paper reports the first use of a therapeutic siRNA in a skin disorder or in a genetic disorder. The siRNA was directed against the mutation site resulting in a keratin 6a N171K mutation and had been previously shown to selectively and potently knock down the mutant (and not wild-type) K6a. The study was a vehicle-controlled, double blinded, split-body study and siRNA was injected intralesionally into one plantar callus of a patient carrying a KRT6A N171K mutation. Injection of the siRNA, but not the vehicle, resulted in dramatic pain reduction and thinning of the callus at that site.)
(Leachman,, SA, Kaspar, RL, Fleckman, P, Florell, SR, Smith, FJD, McLean, WHI. “Clinical and pathological features of pachyonychia congenita”. J Invest Derm Symp Proc . vol. 10. 2005. pp. 3-17. (This paper reviews the worldwide literature on PC and presents a summary of clinical, pathological, and genetic data associated with the condition.)
Mclean, WHI, Hansen, CD, Eliason, MJ, Smith, FJD. “The phenotypic and molecular genetic features of Pachyonychia Congenita”. J Invest Dermatol. vol. 131. 2011 May. pp. 1015-17. (This paper summarizes clinical phenotypic and genetic data from a large cohort of PC Patients enrolled in the International Pachyonychia Congenita Research Registry. Due to much clinical overlap between the classic PC1 and PC2, a new genotypic nomenclature is proposed in which the condition (PC) is associated with the causative gene when known (KRT6A, KRT6B, KRT16, KRT17). FOr example, instead of PC1, resulting from K6a or K16 mutations, it will now be referred to as PC-6a or PC-16. WHen the mutation is not known, the nomencalture will be PC-U for unknown.)
McLean, WHI, Rugg, EL, Lunny, DP, Morley, SM, Lane, EB, Swensson, O. ” Keratin 16 and keratin 17 mutations cause pachyonychia congenita”. Nature Genet . vol. 9. 1995. pp. 273-8. (This paper reports the discovery of the first genes responsible for PC. A gene for Jackson-Lawler PC was mapped to the type I keratin cluster on 17q. A heterozygous missense mutation in the helix initiation motif of K17 (Asn92Asp) co-segregates with the disease in this kindred. Jadassohn-Lewandowsky PC is caused by a heterozygous missense mutation in the helix initiation peptide of K16 [Leu130Pro])
Milstone, LM, Fleckman, P, Leachman, SA, Leigh, IM, PAller, AS, van Steensel, MA. “Treatment of Pachyonychia Congenita”. J Invest Dermatol Symp Proc. vol. 1. 2005 Oct. pp. 18-20. An overview of current treatment and longitudinal follow-up for pachyonychia congenita as reported (and updated) through the PC project’s webpage (http://www.pachyonychia.org/Registry.html).
Spitz, JL, Krafchik, B, Scher, R, Pine,, J. “Pachyonychia congenita”. 1996. pp. 246-7. (A clinical guide to identifying, diagnosing, and treating pachyonychia congenita.)
Haber, RM. “Drummond D. Pachyonychia congenita with laryngeal obstruction”. Pediatr Dermatol. vol. 28. 2011. pp. 229-32. (Laryngeal leukokeratosis may be severe enough to cause obstruction, as was reported in this 2 year old girl with pachyonychia congenita. This may be life-theatening. Patients with laryngeal involvement usually present with hoarseness.)
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