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Pachyonychia Congenita

, PhD, , MD, , MD, PhD, FRCPC, , PhD, , LLD, , DSc, FRSE, , MD, , MD, PhD, , MD, PhD, FRCPI, FRCP, and , MD, PhD.

Author Information
, PhD
Centre for Dermatology and Genetic Medicine
Division of Molecular Medicine
Colleges of Life Sciences and Medicine, Dentistry & Nursing
Medical Sciences Institute
Dundee, United Kingdom
, MD
Department of Dermatology
University of Utah
Salt Lake City, Utah
, MD, PhD, FRCPC
Department of Medicine
University of Saskatchewan
Saskatoon, Saskatchewan, Canada
, PhD
Transderm, Inc
Santa Cruz, California
, LLD
PC Project
Salt Lake City, Utah
, DSc, FRSE
Centre for Dermatology and Genetic Medicine
Division of Molecular Medicine
Colleges of Life Sciences and Medicine, Dentistry & Nursing
Medical Sciences Institute
Dundee, United Kingdom
, MD
Department of Dermatology
Yale University
New Haven, Connecticut
, MD, PhD
Department of Dermatology
University Hospital Maastricht
Maastricht, The Netherlands
, MD, PhD, FRCPI, FRCP
Centre for Cutaneous Research
Barts & the London School of Medicine and Dentistry, Queen Mary
University of London
London, England, United Kingdom
, MD, PhD
Department of Dermatology
Tel Aviv Medical Center
Tel Aviv, Israel

Initial Posting: ; Last Update: July 24, 2014.

Summary

Disease characteristics. Pachyonychia congenita (PC) is characterized by hypertrophic nail dystrophy, painful palmoplantar keratoderma and blistering, oral leukokeratosis, pilosebaceous cysts (including steatocystoma and vellus hair cysts), palmoplantar hyperhydrosis, and follicular keratoses on the trunk and extremities.

Diagnosis/testing. PC is diagnosed by clinical findings and by molecular genetic testing to detect a heterozygous pathogenic variant in one of the five keratin genes known to cause PC: KRT6A, KRT6B, KRT6C, KRT16, and KRT17.

Management. Treatment of manifestations: Pain from the palmoplantar keratoderma may be reduced somewhat by limiting friction and trauma to the feet by minimizing walking or standing, reducing hydration of the stratum corneum by using wicking socks and ventilated footwear, selecting comfortable shoes, and maintaining ideal body weight. Foot care includes paring down hyperkeratotic areas and topical therapies for hyperkeratosis (emollients and lotions containing keratolyics). Care of thickened nails often requires the use of surgical or razor blades or sanders such as a Dremel® tool. Troublesome nails removed surgically frequently grow back in some form. Good oral hygiene and brushing gently with a soft toothbrush can improve thick, white patches on the tongue and oral mucosa. Secondary fungal and bacterial infections that require treatment are common; cysts usually do not require treatment but can be incised and drained if infected or painful. Bottle-fed infants with leukokeratosis may need a soft nipple with an enlarged opening. Rarely, young children with laryngeal thickening/growths need emergency surgery to re-establish the airway; however, surgery may exacerbate the condition.

Prevention of secondary complications: Attention to pre- and post-grooming hygiene to prevent infection.

Agents/circumstances to avoid: High temperatures and high humidity may worsen the condition.

Genetic counseling. Pachyonychia congenita is inherited in an autosomal dominant manner. Approximately 40% of cases appear to result from de novo mutation. A single case of germline mosaicism has been reported. The offspring of an affected individual have a 50% chance of inheriting the disorder. If the pathogenic variant has been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing for this disease/gene or custom prenatal testing.

Diagnosis

By age ten years a diagnostic triad of toenail thickening, plantar keratoderma, and plantar pain was reported by 97% of individuals with genetically confirmed pachyonychia congenita (PC) [International Pachyonychia Research Registry, Eliason et al 2012]. Other clinical features can include pilosebaceous cysts (including steatocystoma and vellus hair cysts), oral leukokeratosis, follicular keratosis, and palmar keratoderma.

Based on data from the International Pachyonychia Congenita Research Rregistry (IPCRR), a new classification for pachyonychia congenita based on the mutated gene was proposed at the 2010 IPC Symposium [McLean et al 2011, Wilson et al 2011]:

Note: For information on the old classification scheme see Nomenclature.

Suggestive Findings

The predominant and most common clinical feature of PC is plantar pain associated with plantar keratoderma including callus with underlying blisters. While various types of hypertrophic nail dystrophy are common, signs in some affected individuals are limited to toenails, or to a few toenails or fingernails (Table 2). See Figure 1.

Figure 1

Figure

Figure 1. Common findings of pachyonychia congenita include: thickened and dystrophic nails (both fingernails and toenails) (a-c); bullae (usually on the pressure points of the heels and soles); hyperkeratosis (d-e); cysts (f); and oral leukokeratosis (more...)

Other findings found in some types of PC:

  • Pilosebaceous cysts including widespread steatocystomas/steatocysts (benign lesions) and vellus hair cysts which usually develop at puberty and continue throughout adulthood
  • Oral leukokeratosis and thickened nails (present at birth or by age 1 month) more commonly seen in PC-K6a
  • Follicular keratoses on the trunk and extremities usually present by early childhood
  • Palmoplantar hyperhydrosis (<50%)
  • Natal or prenatal teeth (i.e., present at birth or by age 1 month) more commonly seen in PC-K17

    Of note, histologic, immunohistologic, or electron microscopic examination of the nails or skin from individuals with PC is not helpful in confirming the diagnosis of PC but can be performed to rule out other diagnoses.
  • Family history consistent with autosomal dominant inheritance

    Of note, 60% of individuals with PC have inherited it from an affected parent and 40% are simplex cases (i.e., a single occurrence in a family). If the family history suggests autosomal recessive inheritance, a condition other than PC should be considered (see Differential Diagnosis).

Establishing the Diagnosis

Identification of a heterozygous pathogenic variant in one of the five genes encoding keratin confirms the diagnosis of pachyonychia congenita (Table 1).

Sequence analysis of these five genes identifies pathogenic variants in approximately 90% of individuals with clinically diagnosed PC [Smith et al 2005, Liao et al 2007, Wilson et al 2011]. Note: In some laboratories, the highly conserved helix boundary domains, the site of the majority of pathogenic variants, are sequenced first; the remaining exons are sequenced as needed.

One approach to genetic testing is serial single gene molecular genetic testing (i.e., KRT6A, KRT6B, KRT6C, KRT16, and KRT17) based on specific clinical features that are associated with each gene (Table 2).

An alternative approach to genetic testing is use of a multi-gene panel that includes these five genes and other genes of interest (see Differential Diagnosis). Note: The genes included and the methods used in multi-gene panels vary by laboratory and over time.

Table 1. Summary of Molecular Genetic Testing Used in Pachyonychia Congenita (PC)

Gene 1, 2 ClassificationPhenotypeProportion of PC Attributed to Mutation of This GeneTest Method
KRT6APC-K6aPC222/535 (42%)Sequence analysis 3
KRT6BPC-K6bPC50/535 (9%)
KRT6CPC-K6cPC/FNEPPK 417/535 (3%)
KRT16PC-K16PC/FNEPPK 4155/535 (29%)
KRT17PC-K17PC/SM 591/535 (17%)

PC = pachyonychia congenita

FNEPPK = focal non-epidermolytic palmoplantar keratoderma

SM = steatocystoma multiplex

1. See Table A. Genes and Databases for chromosome locus and protein name. See Molecular Genetics for information on allelic variants detected in this gene.

2. Pathogenic variants in at least 535 individuals have been published to date [Human Intermediate Filament Database, Wilson et al 2011].

3. Sequence analysis detects variants that are benign, likely benign, of unknown significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4. To date all pathogenic variants causing FNEPPK are in KRT16 or KRT6C [Wilson et al 2010]. See Genetically Related Disorders and Differential Diagnosis.

5. To date all pathogenic variants causing SM (steatocystoma multiplex) are in KRT17. See Genetically Related Disorders.

Clinical Description

Natural History

Pachyonychia congenita (PC) is a combination of characteristics. The absence or presence of the condition as well as the age at onset varies according the gene that is mutated (see Table 2 for phenotypic features of PC). In all types of PC most characteristics are visible by age ten years [Shah et al 2014]. The severity of findings differs both within a family and among families with the same pathogenic variant.

Table 2. International Pachyonychia Congenita Research Registry (IPCRR) Data Summary as of 30 March 2014

Gene in which Mutation was ConfirmedKRT6AKRT6BKRT6CKRT16KRT17Total
Number Evaluated for Finding 1222501715591535
Toenails thickened
10 toenails 208 (94%)19 (38%)067 (43%)68 (75%)362 (68%)
7-9 toenails 6 (03%)11 (22%)018 (12%)6 (07%)41 (08%)
4-6 toenails 2 (01%)13 (26%)3 (18%)36 (23%)9 (10%)63 (12%)
1-3 toenails 4 (02%)6 (12%)7 (41%)27 (17%)7 (08%)51 (10%)
Total w/toenails thickened220 (99%)49 (98%)10 (59%)148 (95%)90 (99%)517 (97%)
Age at onsetBirth - <1 yr191 (87%)9 (18%)1 (10%)34 (23%)61 (68%)296 (57%)
1-4 yrs25 (11%)12 (24%)5 (50%)44 (30%)22 (24%)108 (21%)
5-14 yrs4 (02%)24 (49%)3 (30%)45 (30%)6 (07%)82 (16%)
≥15 yrs04 (08%)1 (10%)25 (17%)1 (01%)31 (06%)
Fingernails thickened
10 fingernails 194 (87%)4 (08%)054 (35%)40 (44%)292 (55%)
7-9 fingernails 6 (03%)3 (06%)06 (04%)11 (12%)26 (05%)
4-6 fingernails 14 (06%)12 (24%)019 (12%)21 (23%)66 (12%)
1-3 fingernails 6 (03%)6 (12%)015 (10%)7 (08%)34 (06%)
Total w/fingernails thickened220 (99%)25 (50%)0 (00%)94 (61%)79 (87%)418 (78%)
Age at onsetBirth - <1 yr194 (88%)4 (16%)026 (28%)56 (71%)280 (67%)
1-4 yrs23 (10%)6 (24%)030 (32%)18 (23%)77 (18%)
5-14 yrs3 (01%)11 (44%)018 (19%)4 (05%)36 (09%)
≥15 yrs1 (00.5%)4 (16%)020 (21%)1 (01%)26 (06%)
Plantar keratoderma 2
Always192 (86%)48 (96%)16 (94%)153 (99%)61 (67%)470 (88%)
Sometimes 3 (01%)0009 (10%)12 (02%)
Seldom3 (01%)0003 (03%)6 (01%)
Total w/plantar keratoderma198 (89%)48 (96%)16 (94%)153 (99%)73 (80%)488 (91%)
Age at onsetBirth - <1 yr26 (13%)1 (02%)1 (06%)12 (08%)11 (15%)51 (10%)
1-4 yrs119 (60%)17 (35%)7 (44%)85 (56%)26 (36%)254 (52%)
5-14 yrs51 (26%)29 (60%)8 (50%)49 (32%)29 (40%)166 (34%)
≥15 yrs2 (01%)1 (02%)07 (05%)7 (10%)17 (03%)
Plantar pain w/plantar keratoderma 3
Often require medication for pain49 (25%)8 (17%)3 (19%)48 (31%)14 (19%)122 (25%)
Very painful, but do not use medication83 (42%)24 (50%)10 (63%)74 (48%)23 (32%)214 (44%)
Somewhat painful59 (30%)16 (33%)3 (19%)27 (18%)28 (38%)133 (27%)
Total w/plantar keratoderma / pain191 (96%)48 (100%)16 (100%)149 (97%)65 (89%)469 (96%)
Gene in which Mutation was ConfirmedKRT6AKRT6BKRT6CKRT16KRT17Total
Number Evaluated for Finding222501715591535
Palmar keratoderma 2
Always62 (28%)8 (16%)1 (06%)99 (64%)15 (16%)185 (35%)
Sometimes 21 (09%)5 (10%)011 (07%)13 (14%)50 (09%)
Seldom38 (17%)7 (14%)2 (12%)13 (08%)19 (21%)79 (15%)
Total w/palmar keratoderma121 (55%)20 (40%)3 (18%)123 (79%)47 (52%)314 (59%)
Age at onsetSee footnote 412115211542295
Birth - <1 yr17 (14%)009 (08%)8 (19%)34 (12%)
1-4 yrs38 (31%)1 (07%)040 (35%)7 (17%)86 (29%)
5-14 yrs51 (42%)8 (53%)2 (100%)46 (40%)18 (43%)125 (42%)
≥15 yrs15 (12%)6 (40%)020 (17%)9 (21%)50 (17%)
Oral leukokeratosis
Total w/oral leukokeratosis195 (88%)15 (30%)3 (18%)64 (41%)25 (27%)302 (56%)
Age at onsetSee footnote 41551514718236
Birth - <1 yr120 (77%)3 (20%)1 (100%)17 (36%)6 (33%)147 (62%)
1-4 yrs17 (11%)1 (07%)05 (11%)4 (22%)27 (11%)
5-14 yrs13 (08%)6 (40%)09 (19%)4 (22%)32 (14%)
≥15 yrs5 (03%)5 (33%)016 (34%)4 (22%)30 (13%)
Additional findings
Cysts 151 (68%)36 (72%)4 (24%)40 (26%)84 (92%)315 (59%)
Follicular hyperkeratosis135 (61%)23 (46%)023 (15%)63 (69%)244 (46%)
Natal or prenatal teeth5 (02%)00069 (76%)74 (14%)

1. Data include 535 individuals with genetically confirmed pachyonychia congenita.

2. Always = symptoms never completely go away

Sometimes = feet/hands clear up completely at times

Seldom = feet/hands are usually clear/symptoms

3. By age ≤10 years

4. Total number of persons with indicated finding for whom age at onset was identified

Hypertrophic nail dystrophy, the predominant clinical feature of PC, is typically noted within the first few months of life, though in rare cases it presents later. The nail dystrophy appears to fall into two phenotypes:

  • Nails that grow to full length and have an upward slant caused by the prominent distal hyperkeratosis (often with an accentuated curvature of the nail)
  • Nails that have a nail plate that terminates prematurely leaving a gently sloping distal region of hyperkeratosis and exposed distal finger tip

Focal palmoplantar keratoderma usually presents during the first few years of life when a child starts bearing weight and walking. Blisters develop beneath the keratoderma resulting in intense pain. For many individuals, the blisters and constant foot pain are more severe in warmer weather than cooler weather. The pain associated with plantar focal blistering may require the use of crutches, canes, or wheelchairs. Rarely, keratosis palmoplantaris transgrediens (the contiguous extension of hyperkeratosis beyond the palmar and/or plantar skin) is present.

Oral leukokeratosis (thickened white patches on the tongue and cheek) is often present. In babies, oral leukokeratosis can be misdiagnosed as Candida albicans and may cause difficulty in sucking.

Follicular keratosis, usually on the elbows, knees or trunk, occurs in some persons. It is more prevalent in late childhood and teenage years and becomes less problematic in adults.

Pilosebaceous cysts including widespread steatocystomas/steatocysts (benign lesions) and vellus hair cysts. Cysts may increase in number at puberty. Early onset has been reported [Feng et al 2003] and is recorded in the International Pachyonychia Congenita Research Registry (IPCRR).

Natal teeth or prenatal teeth. Although some individuals have a few prenatal or natal teeth, this finding is not consistently present even within the same family [Leachman et al 2005]. Natal teeth are usually associated with pathogenic variants in KRT17.

Primary and secondary dentition is normal.

Other findings that may occur:

  • Excessive sweating of the palms and soles (palmoplantar hyperhydrosis) observed in approximately 50% of individuals
  • Axillary and inguinal cyst formation
  • Excessive production of waxy material in the ear
  • Severe and unexplained ear pain
  • Hoarseness (laryngeal involvement), reported primarily in young children. Although rare, laryngeal involvement may cause life-threatening respiratory distress.
  • Angular cheilitis (inflammation and fissuring at the angles of the mouth) which is sometimes secondarily infected
  • Paronychia with pronounced edema (and occasional blister formation) under the nails; can exhibit lymphatic extension and can sometimes be caused by infection

Primary and secondary dentition is normal.

Other findings that may occur:

  • Leukokeratosis with laryngeal involvement may; be present in infants and children with PC-K6a. It usually has no ill effect other than a hoarse voice. Although operative intervention is generally not indicated, rare cases of severe respiratory distress requiring intervention have been reported.
  • Angular cheilitis (inflammation and fissuring at the angles of the mouth), which is sometimes secondarily infected
  • Paronychia with pronounced edema (and occasional blister formation) under the nails; when associated with bacterial infection, lymphangitis may be present.

Genotype-Phenotype Correlations

Based on data on 535 individuals with PC in the IPCRR, clear genotype-phenotype correlations are evident [Spaunhurst et al 2012] (see Table 2).

Even within a family, the same pathogenic variant may result in variable severity (e.g., mild vs severe keratoderma).

In the following instances, the phenotype may vary in individuals with the same pathogenic variant:

  • The same KRT17 pathogenic variant in the highly conserved helix initiation motif has been observed in classic PC and in the milder variant SM with few or no nail changes. The modifying factors responsible for this variable expressivity are not known.
  • In a few reports of late-onset PC, pathogenic variants have been identified outside the helix boundary and some have questioned whether the location of the pathogenic variant affects the age at onset. However, the ages in these cases are the expected ages at onset for the particular type of PC and should likely not be referred to as ‘late-onset.’

Penetrance

Within families studied to date, inheritance of a pathogenic variant is uniformly associated with some manifestation of disease, suggesting that penetrance is 100%.

Nomenclature

The classification suggested for PC prior to the identification of the genetic basis of the disease was based solely on clinical findings. Historically, the two major subtypes of PC were based on subtle variable phenotypic features (primarily on the presence or absence of pilosebaceous cysts and natal or prenatal teeth) [Leachman et al 2005, Liao et al 2007]:

  • PC-1 (Jadassohn-Lewandowski syndrome)
  • PC-2 (Jackson-Lawler syndrome)

With detailed clinical histories and pathogenic variants identified in an increasing number of people with PC, it became clear that the older classification of PC-1 and PC-2 was not applicable to the broader population of individuals with PC. Subsequently, a more rational and useful classification, based on the mutated gene and International Pachyonychia Research Registry (IPCRR) data on nearly 400 persons, was proposed at the 2010 International Pachyonychia Congenita (IPCC) Symposium. See Diagnosis.

Prevalence

The rarity of PC makes it difficult to accurately assess its prevalence. Pathogenic variants in individuals from at least 325 families have been published to date [Human Intermediate Filament Database, Szeverenyi et al 2008, Wilson et al 2013, Wilson et al 2014].

The International PC Research Registry has identified 535 individuals with genetically confirmed PC and 128 with a clinical phenotype of PC who have other disorders. Approximately 600 individuals with some features of PC have not yet undergone genetic testing.

Differential Diagnosis

Onychomycosis. Although the hyperkeratotic nail thickening seen in pachyonychia congenita (PC) may be mistaken for onychomycosis, dermatophytic infections do not affect all finger and toenails particularly at an early age. In the rare conditions of autoimmune endocrinopathy-candidiasis-ectodermal dystrophy (APECED) and systemic mucocutaneous candidosis, all nails may be affected.

Oral leukokeratosis together with nail dystrophy is often an indication of pachyonychia congenita and may be mistaken for Candida albicans (thrush), white sponge nevus and/or leukoplakia.

Epidermolysis bullosa simplex (EBS) or other palmoplantar keratodermas can result in a similar pattern of plantar blister formation or hyperkeratosis, respectively; however, they do not share the characteristic nail changes of PC.

Note: EBS may be incorrectly diagnosed in young children with PC because they have a greater tendency toward blister formation and lesser tendency toward keratoderma.

Clouston syndrome, caused by mutation of GJB6, the gene encoding the gap junction protein connexin 30, can also mimic PC. Alopecia does not typically occur in PC but is a relatively common feature of Clouston syndrome.

Nonsyndromic congenital nail disorder 10 (OMIM 614157) without the associated palmoplantar keratoderma or other features of PC can be confused with PC. This is an autosomal recessive disorder caused by biallelic pathogenic variants in FZD6, encoding frizzled 6 [Wilson et al 2013].

Familial onychogryphosis without the associated palmoplantar keratoderma or other features of PC can be confused with PC. Individuals who have nail findings only are unlikely to demonstrate mutation in one of the PC keratins.

Twenty-nail dystrophy (OMIM 161050) may occur without keratoderma or other associated changes. Autosomal dominant inheritance has been described.

Dyskeratosis congenita manifests with features overlapping with PC including nail dystrophy, PPK, hyperhidrosis, and oral leukoplakia. Distinctive features include reticulate hyperpigmentation, skin tumors, and hematologic manifestation.

Palmoplantar keratoderma striata (PPKS1) (OMIM 148700), caused by pathogenic variants in DSG1, can be confused with focal non-epidermolytic palmoplantar keratoderma (FNEPPK). However, pain is typically either absent or less significant in PPKS1 than in FNEPPK or PC.

Punctate PPK type 1 (OMIM 148600), caused by pathogenic variants in AAGAB, can be painful and focal (due to coalescence of lesions) [Pohler et al 2012].

Olmsted syndrome (OMIM 614594) is charactereized by painful palmoplantar keratoderma that may occur with additional features including periorificial keratotic plaques and sometimes constricting digital bands on hands and feet that result in spontaneous amputation, mutilating PPK, alopecia, nail dystrophy and itching of lesions. It is caused by pathogenic variants in TRPV3 [Lin et al 2012].

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with pachyonychia congenita, the following evaluations are recommended:

  • Thorough clinical examination to assess each affected area. These will vary based on the specific gene involved (see Table 2) and may need to be repeated once genetic testing is completed in order to fully understand the phenotype of the affected individual.
  • Obtain medical history to determine what features actually are troubling the patient
  • Medical genetics consultation

Treatment of Manifestations

Preliminary treatment guidelines have been published [Goldberg et al 2014 (full text)] and continue to be refined.

The current treatment modalities primarily center on symptomatic relief of pain, hygienic grooming practices including paring of hyperkeratotic areas, treatment of secondary infection when indicated, and use of various walking aids, including wheelchairs, crutches and canes.

Palmoplantar keratoderma. Frequent grooming of the feet is essential and includes paring down the hyperkeratotic areas. However, trimming too aggressively can greatly increase pain. Some find it helpful to soak the feet prior to the paring. The surface of the skin and the instruments used should be clean to avoid infection. Blisters should be punctured with a sterile needle, the fluid drained, and the blister roof left in place until it dries and is shed away.

Special orthotics or insoles, wicking socks, ventilated footwear or cushioned footwear can help to lessen the pain although pain varies from day to day and at times can be intense even at rest.

Maintaining ideal body weight can be a factor in reducing the hyperkeratosis and pain. Limiting walking or standing can help to reduce trauma and slightly diminish the resulting blisters, callus, and pain.

Topical therapies to remove the hyperkeratosis:

  • Emollients such as Vaseline® or lanolin-containing products are frequently used. Note: Creams and lotions containing keratolyics such as urea, lactic acid, salicylic acid, or propylene glycol have little effect, with some reporting negative side effects. Occlusive ointments are often poorly tolerated.
  • Oral retinoids, while reducing the keratoderma, do not affect the underlying blistering and fragility of the skin and sometimes increase the pain. Careful regulation of the dosage is necessary [Gruber et al 2012].

Nail dystrophy. Thickened nails are not typically painful, but become so when infected or traumatized. An effective tool for very thick nails and for children is a guillotine-type pet nail clipper which places no pressure on the nails. Other tools frequently used are razor or surgical blades or sanders such as a Dremel® tool.

If bacterial or fungal infections occur, systemic antibiotics or antifungals are indicated.

Particularly troublesome nails can be successfully removed surgically; however, few patients have had this procedure and in most cases – regardless of the specific pathogenic variant – the nails have re-grown.

Oral leukokeratosis. Good oral hygiene and frequent gentle brushing with a toothbrush can significantly improve the appearance of the thick, white patches on the tongue and oral mucosa; however, if done too vigorously, brushing may also traumatize the mucosa resulting in reactive hyperkeratosis.

Some individuals have reported reduction of the leukokeratosis in response to oral antibiotics, suggesting a possible bacterial contribution; more likely, improvement may be a response to the anti-inflammatory properties of the antibiotics.

Follicular hyperkeratosis. Especially bothersome for children and teens, this finding can be treated with alpha-hydroxy acid creams or lotions or keratolytic emollients; however, these treatments may not be especially effective for PC. The use of emollients such as Vaseline® or lanolin-containing products is reported to be as effective.

Leukokeratosis with laryngeal involvement. Reported only in children with PC-K6a, respiratory insufficiency can on occasion become life-threatening, requiring emergent surgical intervention to re-establish the airway. The surgical procedures are repeated as necessary to maintain an open airway; however, surgical procedures to the larynx aimed at improving hoarseness should be avoided as they may tend to worsen the condition.

Cysts. Steatocystoma multiplex and other pilosebaceous cysts can be treated by incision with a number 11 blade and subsequent expression of the contents of the cyst (“incision and drainage”). Oral antibiotics may be indicated in the case of secondary infection. A culture should be obtained if infection is a consideration. Intralesional injection of steroid (e.g., triamcinolone) may reduce inflammation of the area if infection is not suspected. If necessary, cysts can be excised.

Failure to thrive. Poor feeding in infancy has been reported to be ameliorated by the use of a soft nipple with an enlarged opening to reduce the sucking required. All cases of ‘failure to thrive’ and poor feeding in infancy have been found to be type PC-K6a.

Prevention of Primary Manifestations

There are no known effective measures to prevent the primary manifestations of PC. Consistent, regular care of the conditions is necessary. Reduction of trauma, friction, and shear forces to the skin and nails does little to reduce symptoms.

Prevention of Secondary Complications

Infection of the skin and nails following grooming or trauma is the most common secondary complication seen in PC.

  • Pre- and post-grooming hygiene and use of clean instruments minimizes this complication.
  • Antibiotics may be indicated when infection occurs.
  • A simple ‘bleach bath’ regimen using a mild bleach solution can help prevent infections.

Surveillance

In general, individuals with PC have no known associated systemic diseases or predispositions that require routine surveillance.

Agents/Circumstances to Avoid

Some report that higher temperatures and higher humidity worsen the condition.

Evaluation of Relatives at Risk

Molecular genetic testing of at-risk relatives in a family with PC is not indicated because the phenotype is readily observed from a young age and no interventions can prevent the development of manifestations or reduce their severity.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Increased risk to the fetus during pregnancy has not been reported.

For a pregnant woman with PC, weight gain (increasing stress on the plantar surface) or altered hormonal environment during pregnancy may worsen the painful plantar keratoderma.

Therapies Under Investigation

A study is underway to determine whether any specific procedures make a difference in nail regrowth for PC

In 2014, a Phase 1b clinical trial sponsored by PC Project and TransDerm is underway using topical sirolimus. This 15-patient study is being conducted by Joyce Teng at Stanford University. Background research for this trial was previously published [Hickerson et al 2009].

A study is underway to determine whether any specific procedures make a difference in nail regrowth for PC (2014).

siRNA can selectively block expression of a specific K6a pathogenic variant [Hickerson et al 2008, Leachman et al 2008]. The siRNA trial included treatment of a single individual with a specific KRT6A pathogenic variant in a dose-escalation trial of an siRNA directed against the p.Asn171Lys mutant allele [Leachman et al 2010].

Botulinum toxin has been used in several patients [Swartling & Vahlquist 2006, Swartling et al 2010]. In addition to these published investigations, a number of individuals have been treated. A proposal is now being prepared for a unified study using botulinum toxin on persons with confirmed PC. No further information has been developed on topical botulinum toxin although this approach is of interest.

Several persons have been treated with statins. The results from studies are mixed. Further research is being conducted and additional animal testing is proposed [Zhao et al 2011].

Other therapies currently under investigation include anti-TNF biologics, duloxetine or duloxetine and a tricyclic combination, gabapentin, topical gabapentin, and capsaicin injections.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Pachyonychia congenita (PC) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Up to 60% of individuals diagnosed with pachyonychia congenita have an affected parent.
  • A proband with pachyonychia congenita may have the disorder as the result of de novo mutation. The proportion of cases caused by de novo mutation is approximately 40%. Of these, some may be novel pathogenic variants while others may be recurrent pathogenic variants identified in other families.
  • Recommendation for the evaluation of parents of a proband with an apparent de novo pathogenic variant is complete clinical examination by a dermatologist to confirm the lack of phenotype. If there are no phenotypic signs, no genetic testing is necessary.

Sibs of a proband

  • The risk of having other affected children depends on the genetic status of the proband's parents.
  • If a parent of the proband is affected, the risk to the sibs is 50%.
  • When the parents are clinically unaffected, the risk to the sibs of a proband is low, but greater than that of the general population because of the (theoretic, but unlikely) possibility of germline mosaicism.
  • The incidence of germline mosaicism is not known, but is extremely rare. Out of 535 cases, a single case of germline mosaicism (.001%) has been reported for PC [Pho et al 2011].

Offspring of a proband. Each child of an individual with pachyonychia congenita has a 50% chance of inheriting the pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents. If a parent is affected, his or her family members may be affected and at risk of having affected children.

Related Genetic Counseling Issues

Because PC is a very rare disorder, affected individuals and families often feel completely isolated. Connecting affected individuals and families to the PC patient advocacy group (see Resources), which offers many different support services, can often be extremely valuable [Schwartz et al 2013].

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant or clinical evidence of the disorder, the mutation is likely de novo. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the pathogenic variant has been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing of this gene or custom prenatal testing.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the pathogenic variant has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Pachyonychia Congenita Project and International Pachyonychia Congenita Research Registry (IPCRR)
    2386 East Heritage Way
    Suite B
    Salt Lake City UT 84109
    Phone: 877-628-7300 (toll-free)
    Fax: 877-628-7399 (toll-free)
    Email: info@pachyonychia.org
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
    1 AMS Circle
    Bethesda MD 20892-3675
    Phone: 877-226-4267 (toll-free); 301-565-2966 (TTY)
    Fax: 301-718-6366
    Email: niamsinfo@mail.nih.gov

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Pachyonychia Congenita: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Pachyonychia Congenita (View All in OMIM)

148041KERATIN 6A; KRT6A
148042KERATIN 6B; KRT6B
148067KERATIN 16; KRT16
148069KERATIN 17; KRT17
167200PACHYONYCHIA CONGENITA 1; PC1
167210PACHYONYCHIA CONGENITA 2; PC2

Molecular Genetic Pathogenesis

Keratins form a cytoskeletal intermediate filament network within all epithelial cells. Epithelia in different body regions utilize a range of different keratins. Keratins associated with PC are constitutively expressed in the nail, palmoplantar skin, oral mucosa, and hair. Thus, mutation of the genes encoding these keratins leads to pathology in these major body sites.

The majority of the pathogenic variants causing PC are in the highly conserved helix boundary domains at either end of the rod domain (see Figure 2), consistent with the location of pathogenic variants in most other keratin disorders [Wilson et al 2011]. A genotype/phenotype correlation is observed in the keratin disorder epidermolysis bullosa simplex (EBS), in which the more severe pathogenic variants occur in the helix boundary domains and those causing a milder phenotype occur within or outside these regions. So far, this has not been observed in PC. It could be that pathogenic variants in these less conserved regions in KRT6A, KRT6B, KRT6C, KRT16, or KRT17 are in general not severe enough to produce a clinical phenotype.

Figure 2

Figure

Figure 2. Schematic diagram showing the basic protein structure of a keratin filament. The α-helical rod domain is divided into four domains: 1A, 1B, 2A, and 2B, connected by non-helical linkers L1, L12, and L2. At the ends of the rod domain are (more...)

A schematic representation of the protein domain organization of each of the five keratins associated with PC is shown (K6a, K6b, K6c, K16, and K17) in Figure 2.

Pathogenic variants in at least 325 families have been published to date [Human Intermediate Filament Database, Wilson et al 2013, Wilson et al 2014] (see Table 3).

A number of the pathogenic variants are recurrent but others are family specific. More than 100 different pathogenic variants have been identified; the majority are found in or near the helix initiation motif (shaded red; see Figure 2) in the 1A domain or the helix termination motif (shaded red) at the end of the 2B domain. The domains shown include the variable domains V1 and V2, homology subdomains H1 and H2, and the coiled coil domains 1A, 1B, 2A, and 2B, separated by non-helical linkers L1, L12, and L2.

KRT6A

Gene structure. The cDNA comprises 2450 bp in nine exons. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. The majority of pathogenic variants are heterozygous missense variants; in some individuals, small in-frame deletions/insertions and splice site and nonsense variants have been reported. Most pathogenic variants occur in the highly conserved helix boundary motif domains located at either end of the alpha-helical keratin rod domain. There are a number of recurrent pathogenic variants; the major ones for PC-K6a, located at Asn171, are either a single amino-acid deletion c.516_518del or a missense variant affecting the neighboring amino acid residue Asn172 (Table 3).

Table 3. Selected KRT6A Pathogenic Variants

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid Change Reference Sequences
c.511A>Gp.Asn171AspNM_005554​.3
NP_005545​.1
c.511A>Tp.Asn171Tyr
c.512A>Gp.Asn171Ser
c.513C>Ap.Asn171Lys
c.516_518del
(514_516delAAC)
p.Asn172del

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants. Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

Normal gene product. The protein, keratin, type II cytoskeletal 6A (K6a keratin), consists of 564 amino acids. Keratins form a cytoskeletal intermediate filament network within all epithelial cells.

Abnormal gene product. Pathogenic variants cause disruption of the cytoskeleton resulting in keratin filament aggregation leading to collapse of the cytoskeleton and cell fragility. The highly conserved helix boundary domains where the majority of pathogenic variants occur are critical during normal keratin filament assembly.

KRT6B

Gene structure. The cDNA comprises 2331 bp in nine exons (reference sequence NM_005555.3). For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. The pathogenic variants reported to date are heterozygous missense variants or small in-frame deletion variants in either the highly conserved helix initiation or helix termination domains.

Normal gene product. The protein, keratin, type II cytoskeletal 6B (K6b keratin), consists of 564 amino acids. Keratins form a cytoskeletal network within all epithelial cells.

Abnormal gene product. Pathogenic variants cause disruption of the cytoskeleton resulting in keratin filament aggregation leading to collapse of the cytoskeleton and cell fragility. The highly conserved helix boundary domains where the majority of pathogenic variants occur are critical during normal keratin filament assembly.

KRT6C

Gene structure. The cDNA comprises 2345 bp in nine exons (reference sequence NM_173086.4). For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. The pathogenic variants reported to date are heterozygous missense variants or small in-frame deletion variants in regions encoding either the highly conserved helix initiation or helix termination domains.

Normal gene product. The protein, keratin, type II cytoskeletal 6C (K6c keratin), consists of 564 amino acids (NP_775109.2). Keratins form a cytoskeletal network within all epithelial cells.

Abnormal gene product. Pathogenic variants cause disruption of the cytoskeleton resulting in keratin filament aggregation leading to collapse of the cytoskeleton and cell fragility. The highly conserved helix boundary domains where the majority of pathogenic variants occur are critical during normal keratin filament assembly.

KRT16

Gene structure. The cDNA comprises 1720 bp in eight exons (reference sequence NM_005557.3). For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. The majority of pathogenic variants are heterozygous missense variants; in some individuals, small in-frame deletions and nonsense variants have been reported. Most pathogenic variants occur in the highly conserved helix boundary motif domains located at either end of the alpha-helical keratin rod domain.

Normal gene product. The protein, keratin, type I cytoskeletal 16 (K16), consists of 473 amino acids. Keratins form a cytoskeletal network within all epithelial cells.

Abnormal gene product. Pathogenic variants cause disruption of the cytoskeleton resulting in keratin filament aggregation leading to collapse of the cytoskeleton and cell fragility. The highly conserved helix boundary domains where the majority of pathogenic variants occur are critical during normal keratin filament assembly.

KRT17

Gene structure. The cDNA comprises 1574 bp in eight exons. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. The majority of pathogenic variants are heterozygous missense variants; in some individuals, small in-frame deletions have been reported. The majority of pathogenic variants in KRT17 occur in the helix initiation motif, in which several recurrent pathogenic variants have been observed, particularly c.275A>G (Table 4).

Table 4. Selected KRT17 Pathogenic Allelic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.275A>Gp.Asn92SerNM_000422​.2
NP_000413​.1

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants. Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. The protein, keratin, type I cytoskeletal 17 (K17), consists of 432 amino acids. Keratins form a cytoskeletal network within all epithelial cells.

Abnormal gene product. Pathogenic variants cause disruption of the cytoskeleton resulting in keratin filament aggregation leading to collapse of the cytoskeleton and cell fragility. The highly conserved helix boundary domains where the majority of pathogenic variants occur are critical during normal keratin filament assembly.

References

Literature Cited

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  2. Feng YG, Xiao SX, Ren XR, Wang WQ, Liu A, Pan M. Keratin 17 mutation in pachyonychia congenita type 2 with early onset sebaceous cysts. Br J Dermatol. 2003;148:452–5. [PubMed: 12653736]
  3. Fu T, Leachman SA, Wilson NJ, Smith FJD, Schwartz ME, Tang JY. Genotype-phenotype correlations among pachyonychia congenita patients with K16 mutations. J Invest Dermatol. 2011;131:1025–8. [PMC free article: PMC3775566] [PubMed: 21160496]
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  5. Gruber R, Edlinger M, Kaspar RL, Hansen CD, Leachman S, Milstone LM, Smith FJ, Sidoroff A, Fritsch PO, Schmuth M. An appraisal of oral retinoids in the treatment of pachyonychia congenita. J Am Acad Dermatol. 2012;66:e193–9. [PubMed: 21601946]
  6. Hickerson RP, Leake D, Pho LN, Leachman SA, Kaspar RL. 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. [PubMed: 19699613]
  7. Hickerson RP, Smith FJD, Reeves RE, Contag CH, Leake D, Leachman SA, Milstone LM, McLean WHI, Kaspar RL. Single-nucleotide-specific siRNA targeting in a dominant-negative skin model. J Invest Dermatol. 2008;128:594–605. [PubMed: 17914454]
  8. Leachman SA, Hickerson RP, Hull PR, Smith FJD, Milstone LM, Lane EB, Bale SJ, Roop DR, McLean WHI, Kaspar RL. Therapeutic siRNAs for dominant genetic skin disorders including pachyonychia congenita. J Dermatol Sci. 2008;51:151–7. [PMC free article: PMC2587483] [PubMed: 18495438]
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  10. Leachman SA, Kaspar RL, Fleckman P, Florell SR, Smith FJD, McLean WHI, Lunny DP, Milstone LM, van Steensel MA, Munro CS, O'Toole EA, Celebi JT, Kansky A, Lane EB. Clinical and pathological features of pachyonychia congenita. J Investig Dermatol Symp Proc. 2005;10:3–17. [PubMed: 16250204]
  11. Lin Z, Chen Q, Lee M, Cao X, Zhang J, Ma D, Chen L, Hu X, Wang H, Wang X, Zhang P, Liu X, Guan L, Tang Y, Yang H, Tu P, Bu D, Zhu X, Wang K, Li R, Yang Y. Exome sequencing reveals mutations in TRPV3 as a cause of Olmsted syndrome. Am J Hum Genet. 2012;90:558–64. [PMC free article: PMC3309189] [PubMed: 22405088]
  12. Liao H, Sayers JM, Wilson NJ, Irvine AD, Mellerio JE, Baselga E, Bayliss SJ, Uliana V, Fimiani M, Lane EB, McLean WHI, Leachman SA, Smith FJD. A spectrum of mutations in keratins K6a, K16 and K17 causing pachyonychia congenita. J Dermatol Sci. 2007;48:199–205. [PubMed: 17719747]
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  22. Swartling C, Vahlquist A. Treatment of pachyonychia congenita with plantar injections of botulinum toxin. Br J Dermatol. 2006;154:763–5. [PubMed: 16536826]
  23. Wilson NJ, Hansen CD, Azkur D, Kocabas CN, Metin A, Coskun Z, Schwartz ME, Hull PR, McLean WHI, Smith FJD. Recessive mutations in the gene encoding frizzled 6 cause twenty nail dystrophy--expanding the differential diagnosis for pachyonychia congenita. J Dermatol Sci. 2013;70:58–60. [PubMed: 23374899]
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  25. Wilson NJ, Messenger AG, Leachman SA, O'Toole EA, Lane EB, McLean WHI, Smith FJD. Keratin K6c mutations cause focal palmoplantar keratoderma. J Invest Dermatol. 2010;130:425–9. [PubMed: 19609311]
  26. Wilson NJ, O'Toole E, Milstone LM, Hansen CD, Shepherd AA, Al-Asadi E, Schwartz ME, McLean WHI, Sprecher E, Smith FJD. The molecular genetic analysis of the expanding pachyonychia congenita case collection. Br J Dermatol. 2014 [PubMed: 24611874]
  27. Zhao Y, Gartner U, Smith FJD, McLean WHI. Statins downregulate K6a promoter activity: a possible therapeutic avenue for pachyonychia congenita. J Invest Dermatol. 2011;131:1045–52. [PubMed: 21390048]

Suggested Reading

  1. Smith FJD, Hickerson RP, Sayers JM, Reeves RE, Contag CH, Leake D, Kaspar RL, McLean WHI. Development of therapeutic siRNAs for pachyonychia congenita. J Invest Dermatol. 2008;128:50–8. [PubMed: 17762855]

Chapter Notes

Author Notes

TransDerm, Inc is a therapeutic company dedicated to finding treatment for rare skin disorders.

Acknowledgments

We thank the many affected individuals and the clinicians without whose input our work into the genetic basis of PC would not have been possible. Thanks to Holly Evans of PC Project for helping with IPCRR data preparation. Research into the genetic basis and treatment of keratin disorders in the WHIM lab has been supported by The Wellcome Trust, DEBRA UK, and The PC Project.

Author History

C David Hansen, MD (2011-present)
Peter R Hull, MD, PhD, FRCPC (2011-present)
Roger L Kaspar, PhD (2006-present)
Sancy A Leachman, MD, PhD; University of Utah (2006-2014)
WH Irwin McLean, DSc, FRSE (2006-present)
Leonard M Milstone, MD (2011-present)
Edel O’Toole, MD, PhD, FRCPI, FRCP (2014-present)
Mary E Schwartz, LLD (2006-present)
Frances JD Smith, PhD (2006-present)
Eli Sprecher, MD, PhD (2011-present)
Maurice van Steensel, MD, PhD (2014-present)

Revision History

  • 24 July 2014 (me) Comprehensive updated posted live
  • 1 December 2011 (me) Comprehensive update posted live
  • 25 June 2009 (me) Comprehensive update posted live
  • 6 December 2007 (cd) Revision: clarification of PC phenotypes
  • 27 January 2006 (me) Review posted to live Web site
  • 14 July 2005 (rlk) Original submission
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