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Last updated:
May 23, 2018
Years published: 2005, 2009, 2012, 2015, 2018
NORD gratefully acknowledges Frances Smith, PhD, Chief Geneticist, Pachyonychia Congentia Project, for assistance in the preparation of this report.
Summary
Pachyonychia congenita (PC) is a rare keratinizing skin disorder inherited in an autosomal dominant fashion. The predominant characteristics are severe plantar pain, palmoplantar keratoderma (PPK) including calluses with underlying blisters and variable hypertrophic nail dystrophy, often accompanied by oral leukokeratosis, cysts of various types, follicular hyperkeratosis, palmoplantar hyperhidrosis and sometimes natal teeth.
Introduction
Historically, PC was subdivided into PC-1 (caused by mutations in the KRT6A or KRT16 genes) and PC-2 (due to mutations in the KRT6B or KRT17 genes). However, based on clinical and molecular data collected by the International Pachyonychia Congenita Research Registry (IPCRR; www.pachyonychia.org) the nomenclature was revised in 2011. Those with mutations in KRT6A are named PC-K6a, those with mutations in KRT16 are PC-K16 etc.
The symptoms and severity of pachyonychia congenita can vary widely, even among individuals in the same family or among individuals with the same disease-causing gene mutation.
The most predominant feature, palmoplantar keratoderma usually begins when a child starts weight bearing and walking. Blisters develop beneath the calluses causing extreme pain. This can lead to the use of crutches, canes or wheelchairs. Nail dystrophy (fingernails and toenails) is typically noted within the first few months/year of life. Nails tend to either (a) grow to full length with an upward slant caused by prominent distal hyperkeratosis or (b) have a nail plate that terminates prematurely to leave a gently sloping distal region of hyperkeratosis and exposed distal fingertip. Infections can occur under the nails and be painful.
Cysts of various types including vellus hair cysts and steatocystomas usually develop at puberty and continue into adulthood. In some people with PC, particularly PC-K17, cysts can be the most painful and problematic characteristic. Multiple milia (particularly on the face) often occur in young children with PC-K17. Follicular keratoses occur in some patients on the trunk, elbows and knees, usually in early childhood. Oral leukokeratosis (white patches on the tongue and cheek) is more common in those with PC-K6a. It is often present at birth or within the first few months of life and can be misdiagnosed as a Candida albicans infection if no other symptoms of PC are apparent. Natal or prenatal teeth are more commonly seen in those with mutations in KRT17. Palmoplantar hyperhidrosis has been reported in about 50% of people with PC.
Other less common features include angular cheilitis, laryngeal involvement resulting in a hoarse cry or hoarse voice and ‘first bite syndrome’. First bite syndrome is more common in young children and is intense pain near the jaw or ears that lasts about 15-25 seconds when beginning to eat or swallow.
Variants of PC: Steatocystoma multiplex (SM) – widespread pilosebaceous cysts develop at puberty, but there is little or no nail involvement or palmoplantar keratoderma, can be due to mutations in KRT17.
Pachyonychia congenita is caused by a mutation in one of five keratin genes, KRT6A, KRT6B, KRT6C, KRT16 or KRT17. These mutations are inherited in an autosomal dominant manner, although approximately 30-40% of cases are the result of new spontaneous mutations with no previous family history. In an autosomal dominant disorder, only one copy of an abnormal gene is necessary to produce clinical symptoms. The risk of an affected individual passing the abnormal gene to offspring is 50 percent for each pregnancy. For unaffected parents of a child with PC there is a very low risk of having subsequent affected children; germline mosaicism is extremely rare, with as of Jan 2018, only one out of 792 cases reported in the IPCRR.
The majority of the mutations are heterozygous single base pair changes resulting in an amino acid change (missense mutations) with a small number of deletion/insertion mutations, splice site mutations and nonsense mutations. Some mutations are found in a number of families (recurrent mutations), while other rare mutations have only been observed in single families to date. All keratins share a similar protein structure consisting of an alpha helical central rod domain (subdivided into 4 domains connected by nonhelical linker regions). The majority of mutations causing PC are within the helix boundary domains at either end of the alpha helical rod domain. These regions are highly conserved in sequence between each type of keratin and are thought to play a vital role during end to end overlap interactions during keratin filament assembly.
PC affects both males and females. No ethnic differences have been reported. Prevalence is estimated at between 5,000 and 10,000 worldwide.
PC is normally diagnosed by clinical examination, which can now be confirmed at the molecular level. Molecular diagnosis (from a blood sample or saliva sample), of PC patients is available to identify the exact gene defect (mutation) in KRT6A, KRT6B, KRT6C, KRT16 or KRT17 and to confirm the clinical diagnosis. See the Pachyonychia Congenita Project website (www.pachyonychia.org) for details about genetic testing which is offered free of charge for patients that enroll in the IPCRR (https://www.pachyonychia.org/patient-registry/).
Treatment
At present, there is no cure or specific treatment for PC. Patients manage their symptoms in a variety of ways either at home or with professional care. The main issue of plantar hyperkeratosis is dealt with by paring/trimming/grinding/filing and, thickened nails by filing/grinding/clipping. Topical agents including keratolytics (eg. salicylic acid, urea) and moisturizers provide limited benefit in softening the skin. For some patients, retinoids can help in thinning the callus but may lead to increased pain. A small number of PC patients have been treated with plantar injections of botulinum toxin resulting in a reduction in plantar pain and blistering. A soft nipple with an enlarged opening on a feeding bottle can help young infants with oral leukokeratosis that are failing to thrive and may also have ‘first bite syndrome’. Cysts do not usually require treatment but if infected or painful can be incised and drained or surgically removed. Wicking socks and ventilated footwear can help with hyperhidrosis. For further information on patient care and tools see www.pachyonychia.org.
Several different therapeutic strategies to develop more specific and effective treatment for PC have recently been investigated. These include siRNAs, rapamycin, topical rapamycin and simvastatin. A number of studies are ongoing and a clinical trial is planned for 2018.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
JOURNAL ARTICLES
Brill S, Sprecher E, Smith FJD, et al. Chronic pain in pachyonychia congenita: evidence for neuropathic origin. Br J Dermatol 2017; Dec 6 [Epub ahead of print].
Pan, B, Byrnes K, Schwartz M, et al. Peripheral neuropathic changes in pachyonychia congenita. Pain 2016; 157:2843-53.
Wallis T, Poole CD, Hoggart B, Can skin disease cause neuropathic pain? A study in pachyonychia congenita. Clin Exp Dermatol. 2016; 41:26-33.
DeKlotz CMC, Schwartz ME, Milstone LM, Nail removal in pachyonychia congenita: Patient-reported survey outcomes. J Am Acad Dermatol 2017; 76:990-92.
Gonzalez-Ramos J, Sendagorta-Cudos E, Gonzalez-Lopez G, et al. Efficacy of botulinum toxin in pachyonychia congenita type 1: report of two new cases. Dermatol Ther. 2016; 29:32-36.
Hickerson RP, Speaker TJ, Lara MF, et al. Non-Invasive Intravital Imaging of siRNA-Mediated Mutant Keratin Gene Repression in Skin. Mol Imaging Biol. 2015; 18:34-42.
Wilson NJ, O’Toole EA, Milstone LM, et al. The molecular genetic analysis of the expanding pachyonychia congenita case collection. Br J of Dermatol. 2014; 171:343-55.
Shah S, Boen M, Kenner-Bell B, Schwartz M, et al. Pachyonychia congenita in pediatric patients: natural history, features, and impact. JAMA Dermatol. 2014; 150:146-53.
Goldberg I, Fruchter D, Meilick A, et al. Best treatment practices for pachyonychia congenita. JEADV. 2014; 28:279–85.
Eliason MJ, Leachman SA, Feng BJ, et al. A review of the clinical phenotype of 254 patients with genetically confirmed pachyonychia congenita. J Am Acad Dermatol. 2012; 67: 680–686.
Pho LN, Smith FJD, Konecki D, et al. Paternal germ cell mosaicism in autosomal dominant pachyonychia congenita. Arch Dermatol 2011; 147:1077-80.
McLean WH, Hansen CD, Eliason MJ, et al. The phenotypic and molecular genetic features of pachyonychia congenita. J Invest. Dermatol. 2011; 131:1015-7.
Zhao Y, Gartner U, Smith FJ, McLean WH. Statins downregulate K6a promoter activity: a possible therapeutic avenue for pachyonychia congenita. J Invest Dermatol. 2011; 131:1045–1052.
Wilson NJ, Leachman SA, Hansen CD, et al. A large mutational study in pachyonychia congenita. J Invest Dermatol. 2011; 131:1018-24.
Leachman SA, Hickerson RP, Schwartz ME, et al. First-in-human mutation-targeted siRNA phase Ib trial of an inherited skin disorder. Mol Ther. 2010; 18:442-6.
Wilson NJ, Messenger AG, Leachman SA, et al. Keratin K6c Mutations Cause Focal Palmoplantar Keratoderma. J Invest Dermatol. 2010; 130:425-429.
Hickerson RP, Leake D, Pho LN, et al. Rapamycin selectively inhibits expression of an inducible keratin (K6a) in human keratinocytes and improves symptoms in pachyonychia congenita patients. J Dermatol Sci. 2009:56:82-8.
Hickerson RP, Smith FJD, Reeves RE, et al. Single-nucleotide-specific siRNA targeting in a dominant negative skin model. J Invest Dermatol. 2008; 128:594–605.
Leachman SA, Kaspar RL, Fleckman P, et al. Clinical and pathological features of pachyonychia congenita. J Investig Dermatol Symp Proc. 2005; 10:3-17.
Smith FJD, Jonkman MF, van Goor H, et al. A mutation in human keratin K6b produces a phenocopy of the K17 disorder pachyonychia congenita type 2. Hum Mol Genet. 1998; 7:1143-1148.
Bowden PE, Haley JL, Kansky A, Rothnagel JA, Jones DO, Turner RJ. Mutation of a type II keratin gene (K6a) in pachyonychia congenita. Nat Genet. 1995; 10:363-365.
McLean WHI, Rugg EL, Lunny DP, et al. Keratin 16 and keratin 17 mutations cause pachyonychia congenita. Nat Genet. 1995; 9:273-278.
INTERNET
Smith FJD, Hansen CD, Hull PR, et al. Pachyonychia Congenita. 2006 Jan 27 [Updated 2017 Nov 30]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1280/ Accessed April 19, 2018.
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