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Pachyonychia Congenita

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Copyright 2005, 2009, 2012

NORD is very grateful to Mario Vaccaro, MD, PhD, Aggregate Professor of Dermatology and Venereology, University of Messina, Institute of Dermatology, Policlinico Universitario, Via Consolare Valeria, Messina, Italy, for assistance in the preparation of this report.

Synonyms of Pachyonychia Congenita

Disorder Subdivisions

General Discussion

Pachyonychia congenita is a rare disorder inherited in an autosomal dominant fashion. It can be divided into two main forms, PC type 1 and PC type 2. The predominant features common to both types are thick nails (hypertrophic nail dystrophy), thick skin on the palms and soles (focal palmoplantar keratoderma) and a white outer layer on the tongue and cheek (oral leukokeratosis). PC-2 is distinguished from PC-1 by the presence of widespread pilosebaceous (associated with hair and related glands) cysts, or cysts that normally develop during puberty; in PC-1 there may be a limited distribution of cysts. Teeth that are present at birth (natal teeth) are a specific feature of PC-2 but they are not always present (not fully penetrant). Pachyonychia congenita is caused by disruptions or changes (mutations) of one of several different genes.

Symptoms

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.

PC-1 (also known as Jadassohn-Lewandowsky syndrome)
One of the main clinical features of PC-1 is the presence of thick nails (hypertrophic nail dystrophy); onset can be from a few months old. The type of nail changes appear to fall into two types, those that grow to full length, have an upward slant due to the prominent distal hyperkeratosis, and often have accentuated curvature of the nail; and those that have a nail plate that ends prematurely leaving a gently sloping distal region of hyperkeratosis and exposed distal finger tip. Infections can occur under the nails and be particularly painful. Another major symptom of PC-1 is thick skin on the palms and soles (focal palmoplantar keratoderma). This usually presents during the first few years of life when an affected child starts walking. The thick skin on the soles of the feet (plantar hyperkeratosis) can cause severe pain and may result in an affected individual requiring crutches or a wheelchair later in life. Blisters often develop beneath the thickened skin (keratoderma). For many patients, blisters and the constant pain in their feet are more severe in warmer weather.

Thickened white patches on the tongue and cheek (oral leukokeratosis) are often present; in young babies this can result in difficulty in feeding and is often mistaken for thrush if no other symptoms of PC are apparent. Thrush is a yeast infection that causes white lesions to form on the tongue and inner cheeks

In some cases there are cysts (follicular keratosis) usually on the elbows and knees. Other clinical symptoms that may occur are excessive sweating (hyperhidrosis), excessive production of waxy material in the ear and hoarseness (laryngeal involvement). The severity of all symptoms can vary widely both within and between families.

PC-2 (also known as Jackson-Lawler syndrome)
In PC-2, thick nails (hypertrophic nail dystrophy) are also one of the main symptoms. Widespread pilosebaceous cysts are the major characteristic feature that clinically distinguishes PC-2 from PC-1. These cysts don't normally develop until puberty and therefore it can be difficult by clinical examination to determine the type of PC in young children. Thickened skin on the palms and soles (focal palmoplantar keratoderma) is another characteristic of PC-2 and may be less severe than in PC-1. Natal teeth are specific to PC-2 but neither this feature nor pilosebaceous cyst formation is always seen (not fully penetrant), making the distinction of PC-1 and PC-2 challenging on physical findings alone. Other features that may be present in PC-2 are white patches on the tongue and cheek (oral leukokeratosis), twisted hair (pili torti), sweating (hyperhidrosis), excessive production of waxy material in the ear and hoarseness (laryngeal involvement).

Variants of PC:
There are several autosomal dominant disorders that are classified as variants of pachyonychia congenita.

Focal non-epidermolytic palmoplantar keratoderma (FNEPPK): thick skin (keratoderma) of varying severity is present on the palms and soles similar to PC-1. In these individuals there are only very mild nail symptoms or no nail changes.

Steatocystoma multiplex (SM): widespread pilosebaceous cysts develop at puberty as in PC-2, but there is little or no nail involvement and little or no thickening of the skin on the palms or soles (palmoplantar keratoderma).

Late onset PC (PC tarda) resembles either PC-1 or PC-2, with onset usually within the first or second decades of life.

Causes

Pachyonychia congenita is caused by a mutation to one of several different genes. These mutations are inherited in an autosomal dominant manner, although there are many cases that 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.

PC is caused by a defect in a keratin gene. Keratin is a tough protein that is a major component of skin, hair, teeth and nails. Four keratin genes are involved with PC.

Mutations in KRT6A (which codes for keratin K6a) or KRT16 (encoding K16) cause PC-1 and mutations in KRT6B (encoding K6b) or KRT17 (coding for K17) result in PC-2. The majority of mutations are heterozygous single base pair changes resulting in an amino acid change (missense mutations) although some small in-frame deletion/insertion mutations (deletion/insertion of base pairs results in deletion/insertion of one or more amino acids) have been reported. Most mutations occur in regions of the keratin proteins known to be important for the structural function of keratins. There are some mutations that are found in several families (recurrent mutations). Other more rare mutations have only been observed in single families to date. One common site for mutation in K6a is amino acid N171which is either deleted (N171del) or a single base pair is changed (mutated) resulting in an amino acid change. In PC-2 there are several recurrent mutations in KRT17, particularly N92S.

The variants of PC are also caused by mutations in the same keratin genes associated with PC (see Diagnosis, below).

Affected Populations

PC affects both males and females. No ethnic differences have been reported. Approximately 400 cases (confirmed by mutation analysis) have been identified; another few hundred unconfirmed cases have also been identified. Some researchers believe that PC often goes misdiagnosed or undiagnosed making it difficult to determine the true frequency of PC in the general population.

Related Disorders

Another autosomal dominantly inherited disorder, Clouston syndrome, can mimic PC due to the similar clinical characteristics; occasionally this can lead to misdiagnosis of patients. The features of Clouston sydrome are thick nails (hypertrophic nail dystrophy), partial or total hair loss (alopecia) and thick skin on the palms and soles (palmoplantar keratoderma). This disorder is caused by mutations in the gap junction protein connexin 30 (GJB6 gene).

Epidermolysis bullosa simplex (EBS) is another inherited keratin disorder caused by mutations in keratins K5 or K14 (KRT5 or KRT14 genes). There are three main types of EBS; Dowling Meara (most severe form), Kobner and Weber-Cockayne (mildest form). The main clinical feature is blistering of the skin within the cells in the lower-most layer of the epidermis (basal keratinocytes). In Dowling-Meara blisters occur in clusters (herpetiform clusters) all over the body, in Koebner there is generalised blistering and in Weber-Cockayne form blistering is restricted to the palms and soles. Blistering in all forms can be induced by mild mechanical trauma. There is often thickened skin (hyperkeratosis) on the palms and soles. In very young children care is needed to distinguish between blistering seen in PC and that in EBS.

Standard Therapies

PC is normally diagnosed by clinical examination. Molecular diagnosis (from a blood sample or buccal scrape), of PC patients is now available to identify the exact gene defect (mutation) and to confirm the clinical diagnosis. See PC-Project website (www.PC-Project.org), for details about genetic testing. Mutations in KRT6A or KRT16 genes cause PC-1 and mutations in KRT6B or KRT17 cause PC-2.

The variant of PC, focal non-epidermolytic palmoplantar keratoderma (FNEPPK), is caused by mutations in KRT16. It is likely that mutations in the KRT6A gene can also cause FNEPPK, although none have been reported to date. Steatocystoma multiplex (SM), another variant of PC, is due to mutations in KRT17; mutations in KRT6B may also cause SM. The late onset forms of PC (PC tarda) can result from mutations in any of the four keratin genes associated with PC.

Treatment
At present there is no cure or effective treatment for PC. Patients manage their symptoms in a variety of ways either at home or with professional care. The main issue of thick skin on the soles (plantar keratosis) and thick nails (hypertrophic nail dystrophy) is dealt with by (1) soaking to soften, followed by (2) removal of thick skin and/or nails (debridement). Many patients have tried various drugs, shoes, socks, etc. to help alleviate the symptoms (see www.PC-Project.org). One example is wicking socks that are made from synthetic fibers that wick away any moisture from the feet and may be anti-blistering.

Investigational Therapies

Several research projects funded by the PC-Project are currently underway to develop therapeutic methods for treating PC (see PC-Project website for more details, www.PC-Project.org). TransDerm Inc. (www.transderm.org) is developing nucleic acid-based PC therapeutics in partnership with the PC-Project.

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

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

Organizations related to Pachyonychia Congenita

References

JOURNAL ARTICLES
Smith FJD, Cassidy AJ, Stewart A , et al.. The genetic basis of pachyonychia congenita. J Investig Dermatol Symp Proc. 2005;10(1):21-30.

Leachman SA, Kaspar RL, Fleckman P, et al.. Clinical and pathological features of pachyonychia congenita. J Investig Dermatol Symp Proc. 2005;10(1):3-17.

Smith F. The molecular genetics of keratin disorders. Am J Clin Dermatol. 2003;4:347-64.

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 Molec Genet. 1998;7:1143-1148.

Covello SP, Smith FJD, Sillevis Smitt JH, et al.. Keratin 17 mutations cause either steatocystoma multiplex or pachyonychia congenita type 2. Br J Dermatol. 1998;139:475-480.

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.

Shamsher MK, Navsaria HA, Stevens HP, et al.. Novel mutations in keratin 16 gene underly focal non-epidermolytic palmoplantar keratoderma (NEPPK) in 2 families. Hum Molec Genet. 1995;4:1875-1881.

INTERNET
Pachyonychia Congenita Project. http://www.pachyonychia.org/. Updated April 26, 2012. Accessed May 7, 2012.

Human Intermediate Filament Database. http://www.interfil.org/ .Updated May 23, 2011. Accessed May 7, 2012.

Caproni M, Fabbri P. Pachyonychia congenita. Orphanet encyclopedia. http://www.orpha.net/data/patho/GB/uk-PachyonychiaCongenita.pdf. November 2003. Accessed May 7, 2012.

Report last updated: 2012/05/08 00:00:00 GMT+0