|Ahead of print publication
Pachyonychia congenita: Always confirm, classify, and register
Anup Kumar Tiwary
Department of Dermatology, Subharti Medical College, Meerut, Uttar Pradesh, India
|Date of Submission||11-Feb-2020|
|Date of Decision||06-Apr-2020|
|Date of Acceptance||24-Jun-2020|
Anup Kumar Tiwary,
Department of Dermatology, Subharti Medical College, Meerut, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
Pachyonychia congenita (PC) is a rare genodermatosis caused by mutations in one of the five keratin genes: K6a, K6b, K6c, K16, and K17. The majority of these are missense mutations with a smaller number of deletions, insertions, and splice site mutations. The mode of inheritance is mostly autosomal dominant, however, autosomal recessive and sporadic cases have also been reported. It affects all ethnic backgrounds, and there is no gender predilection.
The classical clinical picture of PC consists of infantile onset of painful focal palmoplantar keratoderma with a history of blisters on the same sites, marked subungual hyperkeratosis, vertical or wedge-shaped nail hypertrophy, oral leukokeratosis, and follicular hyperkeratosis. Less common features include pilosebaceous cysts, and natal teeth. Eponymously, PC has two well-known types: Jadassohn–Lewandowsky syndrome/PC-1 [Figure 1], [Figure 2], [Figure 3], [Figure 4] and Murray–Jackson–Lawler syndrome/PC-2. Later, two more types were added, namely Schafer–Brunauer syndrome/PC-3 and PC tarda. PC-1 presents with the classical findings mentioned above, while the presence of cysts and natal teeth goes in favor of PC-2. There are some misinformation about PC-3 having corneal involvement, and PC-4 with mental retardation and hair changes which are falsely published and not confirmed by genetic testing. New classification of PC is based on underlying five causative keratin genes was proposed in 2011. These subtypes are PC-K6a, PC-K6b, PC-K6c, PC-K16, and PC-K17. There are compelling reasons to validate this new classification and increase its acceptance. First, patients with overlapping clinical presentations cannot be categorized in one specific type of older classification. Second, keratins are expressed in a tissue in a differentiation-specific manner and PC affects those sites where the mutant keratin protein is normally expressed. For example, K6a is normally expressed in palmoplantar epidermis, nail epithelia, and mucosal tissues. Since the severity of the manifestations and presence of minor features depend on the type of keratin gene mutation, subtyping of PC based on underlying five known causative keratin genes is justifiable. Third, strict acceptance of new classification will invoke the clinicians for mutation analysis to confirm the keratin gene mutation. Fourth, since there are many conditions such as psoriasis, pityriasis rubra pilaris, Clouston syndrome, Olmsted syndrome, and dermatophytosis which may present with palmoplantar hyperkeratosis and nail dystrophy, genetic testing of each clinically suspected case can refute the erroneous clinical diagnosis of PC.
|Figure 1: Bilateral plantar keratoderma with multiple calluses on pressure sites|
Click here to view
Each of the five genetic types of PC has distinct clinical characteristics. Of note, plantar keratoderma and toenail hypertrophy are seen in all the five types, but palmar keratoderma is a more common feature of PC-K16 mutation, followed by PC-K6a and PC-K17. Characteristically, fingernails are not involved in K6c type. Mutation in K17 gene leads to the development of natal teeth, sebaceous cyst, eruptive vellus hair cyst, and corneal dyskeratosis. Moreover, locus of missense mutation within a mutated keratin gene can also be different encoding different amino acids and ultimately leading to varied phenotypical expression.
Genetic confirmation of a clinically suspected case of PC becomes difficult due to higher cost, poor availability, and poor accessibility of centers which conduct mutation analysis. Of note, PC Project is the one such public charity project in the USA which enrolls patients in the International PC Research Registry (IPCRR) and offers free genetic testing, educational support, and counseling.
PC Project is the most efficient support group at international platform which regularly updates their all forms of genetic, clinical, and therapeutic data collected from patients of PC registered in IPCRR. There are no known prevalence studies conducted at any level till date. According to PC Project, a total number of genetically confirmed cases till January 2020 are 977, in 517 families, with 115 keratin mutations. The percentage of each keratin gene has been shown in [Figure 5]. Out of 977, 20 cases are from India. Clinical profile of 907 PC patients has also been summarized by IPCRR [Table 1].
|Figure 5: Percentage of all five keratin gene mutations among 977 patients of pachyonychia congenita reported by the International Pachyonychia Congenita Research Registry till January 2020|
Click here to view
|Table 1: Clinical profile of 907 genetically tested patients with all 5 genes included by the International Pachyonychia Congenita Research Registry as of June 2019|
Click here to view
As there is no specific treatment for PC, patients should be properly counseled about the disease and advised to pare/file/grind their calluses and clip their nails regularly. Topical keratolytics and oral acitretin have also been proved to be beneficial in many cases. To add, the knowledge of genetic mapping of genetically confirmed cases has been translated in its treatment. For example, mammalian target of rapamycin (mTOR) activity is partly regulated by keratin 6a, 6b, and 17. Based on this, rapamycin, an inhibitor of mTOR, has been tried in patients of PC and achieved good results. Another positive aspect of genetic testing is to advise the parent/s prenatal testing to detect any fetal affection.
| References|| |
Tiwary AK, Wilson NJ, Schwartz ME, Smith FJ. A novel KRT6A mutation in a case of pachyonychia congenita from India. Indian J Dermatol Venereol Leprol 2017;83:95-8.
] [Full text]
Eliason MJ, Leachman SA, Feng BJ, Schwartz ME, Hansen CD. A review of the clinical phenotype of 254 patients with genetically confirmed pachyonychia congenita. J Am Acad Dermatol 2012;67:680-6.
McLean WH, Hansen CD, Eliason MJ, Smith FJ. The phenotypic and molecular genetic features of pachyonychia congenita. J Invest Dermatol 2011;131:1015-7.
Goldberg I, Fruchter D, Meilick A, Schwartz ME, Sprecher E. Best treatment practices for pachyonychia congenita. J Eur Acad Dermatol Venereol 2014;28:279-85.
van Steensel MA, Coulombe PA, Kaspar RL, Milstone LM, McLean IW, Roop DR, et al
. Report of the 10th
Annual International Pachyonychia Congenita Consortium Meeting. J Invest Dermatol 2014;134:588-91.
Smith FJ, McKusick VA, Nielsen K, Pfendner E, Uitto J, McLean WH. Cloning of multiple keratin 16 genes facilitates prenatal diagnosis of pachyonychia congenita type 1. Prenat Diagn 1999;19:941-6.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]