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Pachyonychia Congenita

Includes: KRT16-Related Pachyonychia Congenita, KRT17-Related Pachyonychia Congenita, KRT6A-Related Pachyonychia Congenita, KRT6B-Related Pachyonychia Congenita

, PhD, , MD, , MD, PhD, FRCPC, , MD, PhD, , PhD, , , DSc, FRSE, , MD, PhD, and , MD, PhD.

Author Information
, PhD
Epithelial Genetics Group
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
, MD, PhD
Department of Dermatology
University of Utah
Salt Lake City, Utah
, PhD
Transderm, Inc
Santa Cruz, California
PC Project
Salt Lake City, Utah
, DSc, FRSE
Epithelial Genetics Group
Division of Molecular Medicine
Colleges of Life Sciences and Medicine, Dentistry & Nursing
Medical Sciences Institute
Dundee, United Kingdom
, MD, PhD
Department of Dermatology
Yale University
New Haven, Connecticut
, MD, PhD
Department of Dermatology
Tel Aviv Medical Center
Tel Aviv, Israel

Initial Posting: ; Last Update: December 1, 2011.

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. Mutations in the keratin genes KRT6A, KRT6B, KRT16, and KRT17 are known to cause PC.

Management. Treatment of manifestations: Pain from the palmoplantar keratoderma can be reduced 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: Trauma, friction, and sheer forces to the skin and nails.

Genetic counseling. Pachyonychia congenita is inherited in an autosomal dominant manner. Approximately 50% of cases appear to result from a de novo mutation. A single case of germline mosaicism has been reported. Each offspring of an affected individual has a 50% chance of inheriting the disorder. Prenatal diagnosis is possible for pregnancies at increased risk if the disease-causing mutation in the family is known.

Diagnosis

Clinical Diagnosis

Pachyonychia congenita (PC) encompasses a phenotypic spectrum that includes nail dystrophy, painful palmoplantar keratoderma, oral leukokeratosis, follicular keratosis, and pilosebaceous cysts (including steatocystoma and vellus hair cysts).

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

  • PC-K6a (caused by mutation in KRT6A)
  • PC-K6b (KRT6B)
  • PC-K16 (KRT16)
  • PC-K17 (KRT17)

The term PC-U (for unknown) is used when PC is suspected but no molecular genetic testing has been performed or no mutation has been identified.

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

Clinical findings. The predominant and most common clinical feature in PC is hypertrophic nail dystrophy in association with painful palmoplantar keratoderma. 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 common to PC:

  • Palmoplantar blistering
  • Oral leukokeratosis
  • Follicular keratoses on the trunk and extremities
  • Pilosebaceous cysts including widespread steatocystomas/steatocysts (benign lesions) and vellus hair cysts which usually develop at puberty
  • Palmoplantar hyperhydrosis (<50%)
  • Palmoplantar keratoderma transgrediens (contiguous extension of hyperkeratosis beyond the palmar and/or plantar skin)
  • Natal or prenatal teeth (i.e., present at birth or by age 1 month) more commonly associated with mutations in KRT17 than mutations in the other four genes.

Testing

Biopsy examination. Histologic, immunohistologic, or electron microscopic examination of the nails or skin from individuals with PC is not helpful in confirming the diagnosis of PC.

Molecular Genetic Testing

Genes. Mutations in four keratin genes are known to cause pachyonychia congenita:

  • KRT6A (encoding keratin, type II cytoskeletal 6a)
  • KRT6B (encoding keratin, type II cytoskeletal 6b)
  • KRT16 (encoding keratin, type I cytoskeletal 16)
  • KRT17 (encoding keratin, type I cytoskeletal 17)

Clinical testing

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

Gene SymbolProportion of PC Attributed to Mutations in This Gene 1PhenotypeTest MethodMutations Detected
KRT6A109/224 (48.7%)PCSequence analysisSequence variants 2
KRT6B7/224 (3.1%)PC
KRT1655/224 (24.5%)PC/FNEPPK
KRT1753/224 (23.7%)PC/SM

FNEPPK = focal non-epidermolytic palmoplantar keratoderma (see Genetically Related Disorders)

SM = steatocystoma multiplex (see Genetically Related Disorders)

1. Mutations in at least 224 families have been published to date [www​.interfil.org, Wilson et al 2011].

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm/establish the diagnosis in a proband. Molecular genetic testing is guided by phenotype:

  • Pachyonychia congenita (PC) characterized by nail dystrophy, palmoplantar keratoderma, and plantar pain
    • Sequence analysis for mutations in KRT6A, KRT6B, KRT16, and KRT17 is performed.
    • In some laboratories, the highly conserved helix boundary domains, the site of the majority of mutations, are sequenced first; the remaining exons are sequenced as needed.
  • Focal non-epidermolytic palmoplantar keratoderma (FNEPPK). All mutations to date are in KRT16 or KRT6C [Wilson et al 2010]. See Genetically Related Disorders and Differential Diagnosis.
  • Steatocystoma multiplex (SM). All mutations to date are in KRT17. See Genetically Related Disorders.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Clinical Description

Natural History

The severity of all findings in pachyonychia congenita (PC) can vary widely, both within the same family and among families with the same disease-causing mutation (see Table 2 for phenotypic features of PC).

Table 2. International Pachyonychia Congenita Research Registry (IPCRR) Data Summary as of 30 March 2011

IPCRR Data 3/30/11
N=297 Genetically Confirmed
Pachyonychia CongenitaTotal
N=297
K6a
N=138
K16
N=83
K6b
N=24
K17
N=52
Toenails, thickened138/138 (100%)78/83 (94%)24/24 (100%)52/52 (100%)292/297 (98%)
All 10 thickened133/138 (96%)48/83 (58%)12/24 (50%)39/52 (75%)232/297 (78%)
7-9 thickened2/138 (01%)10/83 (12%)5/24 (21%)6/52 (12%)23/297 (08%)
4-6 thickened1/138 (01%)15/83 (18%)4/24 (17%)4/52 (08%)24/297 (08%)
1-3 thickened2/138 (01%)5/83 (06%)3/24 (13%)3/52 (06%)13/297 (04%)
Fingernails, thickened138/138 (100%)62/83 (75%)13/24 (54%)46/52 (88%)259/297 (87%)
All 10 thickened127/138 (92%)42/83 (51%)3/24 (13%)27/52 (52%)199/297 (67%)
7-9 thickened3/138 (02%)6/83 (07%)1/24 (04%)6/52 (12%)16/297 (05%)
4-6 thickened7/138 (05%)8/83 (10%)6/24 (25%)9/52 (17%)30/297 (10%)
1-3 thickened1/138 (01%)6/83 (07%)3/24 (13%)4/52 (08%)14/297 (05%)
Plantar keratoderma 1122/138 (88%)83/83 (100%)24/24 (100%)41/52 (79%)270/297 (91%)
Always118/138 (86%)83/83 (100%)24/24 (100%)37/52 (71%)262/297 (88%)
Sometimes2/138 (01%)0/83 (00%)0/24 (00%)3/52 (06%)5/297 (02%)
Seldom2/138 (01%)0/83 (00%)0/24 (00%)1/52 (02%)3/297 (01%)
Never16/138 (12%)0/83 (00%)0/24 (00%)11/52 (21%)27/297 (09%)
Plantar pain119/122 (98%)79/83 (95%)24/24 (100%)37/41 (90%)259/270 (96%)
Often require medication to handle pain30/122 (25%)29/83 (35%)2/24 (08%)6/41 (15%)67/270 (25%)
Very painful but do not use medication53/122 (43%)37/83 (45%)16/24 (67%)14/41 (34%)120/270 (44%)
Somewhat painful36/122 (30%)13/83 (16%)6/24 (25%)17/41 (41%)72/270 (27%)
Not painful3/122 (02%)4/83 (05%)0/24 (00%)4/41 (10%)11/270 (04%)
Palmar keratoderma 172/138 (52%)70/83 (84%)6/24 (25%)25/52 (48%)173/297 (58%)
Always38/138 (28%)62/83 (75%)3/24 (13%)8/52 (15%)111/297 (37%)
Sometimes15/138 (11%)5/83 (06%)1/24 (04%)6/52 (12%)27/297 (09%)
Seldom19/138 (14%)3/83 (04%)4/24 (17%)11/52 (21%)37/297 (12%)
Never66/138 (48%)13/83 (16%)16/24 (67%)27/52 (52%)122/297 (41%)
Cysts102/138 (74%)21/83 (25%)16/24 (67%)50/52 (96%)189/297 (64%)
Steatocystoma23/138 (17%)4/83 (05%)5/24 (21%)35/52 (67%)67/297 (23%)
Pilosebaceous47/138 (34%)5/83 (06%)12/24 (50%)36/52 (69%)100/297 (34%)
Follicular hyperkeratosis97/138 (70%)12/83 (14%)9/24 (38%)40/52 (77%)158/297 (53%)
Natal/prenatal teeth4/138 (03%)0/83 (00%)0/24 (00%)43/52 (83%)47/297 (16%)
Oral leukokeratosis127/138 (92%)47/83 (57%)10/24 (42%)15/52 (29%)199/297 (67%)
Ear: short/sharp pain28/138 (20%)6/83 (07%)3/24 (13%)1/52 (02%)38/297 (13%)
Ear: excessive wax53/138 (38%)16/83 (19%)8/24 (33%)14/52 (27%)91/297 (31%)
Larynx: hoarseness60/138 (43%)7/83 (08%)6/24 (25%)12/52 (23%)85/297 (29%)
Hyperhidrosis66/138 (48%)35/83 (42%)11/24 (46%)25/52 (48%)137/297 (46%)

1. Always = symptoms never completely go away

Sometimes = feet/hands clear up completely at times

Seldom = feet/hands are usually clear/symptoms

Hypertrophic nail dystrophy, the predominant clinical feature of PC, is typically noted within the first few months of life, though rarely 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 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 mutations 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

Genotype-Phenotype Correlations

Even within the same family, the same mutation can result in variable severity (e.g., mild vs severe keratoderma) or variable extent (e.g., oral findings vs no oral findings). For example, the same KRT17 mutation 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, mutations have been identified outside the helix boundary domains [Connors et al 2001, Xiao et al 2004]; however, the numbers are too small to determine if this finding is true for all persons with late-onset PC.

Penetrance

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

Nomenclature

The subclassification systems suggested for PC prior to the identification of the genetic basis of the disease were based solely on clinical findings [Irvine & McLean 1999]. 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 pre-natal teeth) [Terrinoni et al 2001, Leachman et al 2005, Liao et al 2007]:

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

With detailed clinical histories and mutations identified in a growing number of people with PC, it became clear 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 Clinical Diagnosis.

Prevalence

The rarity of PC makes it difficult to accurately assess its prevalence. Mutations in individuals from at least 227 families have been published to date [www.interfil.org, Szeverenyi et al 2008, Wilson et al 2011].

The IPCRR has identified a further 250 families with a clinical phenotype of PC who have not yet undergone genetic testing (see www.pachyonychia.org).

Differential Diagnosis

Onychomycosis. Although the hyperkeratotic nail thickening seen in pachyonychia congenita (PC) is similar to that of onychomycosis, fungal infections do not typically affect all nails from a few months of age or have a hereditary component (with the exception of rare disorders such as autoimmune endocrinopathy-candidiasis-ectodermal dystrophy (APECED) or systemic mucocutaneous candidosis, in which all nails can be affected).

Oral leukokeratosis is often mistaken for Candida albicans (thrush) and/or leukoplakia if no other findings of PC are apparent. A KOH preparation can be examined to determine if yeast is present. This should also be differentiated from white sponge nevus if other PC signs are mild.

Focal non-epidermolytic palmoplantar keratoderma (FNEPPK) defined as keratoderma of varying severity that may occur on the palms and soles with no (or very mild) nail dystrophy, occurs in association with mutations in KRT6C [Wilson et al 2010] and KRT16 (see Genetically Related Disorders).

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 mutations in GJB6, the gene encoding the gap junction protein connexin 30, can also mimic PC [van Steensel et al 2003]. Alopecia does not typically occur in PC, but is a relatively common feature of Clouston syndrome.

Familial onychogryphosis without the associated palmoplantar keratoderma or other features of PC can be confused with the syndrome. Individuals who have nail findings only are unlikely to demonstrate a 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 can be confused with focal non-epidermolytic palmoplantar keratoderma (FNEPPK). However, pain is typically either absent or less significant in PPKs than in FNEPPK.

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 in an individual diagnosed with pachyonychia congenita (PC), the following evaluations are recommended:

  • Thorough clinical examination to assess each affected area and the degree of involvement
  • Culture if infection is suspected
  • Genetic testing of one affected individual in the family

Treatment of Manifestations

Treatment guidelines have not yet been developed, but are in progress.

The current treatment modalities primarily center on symptomatic relief, hygienic grooming practices, and treatment of secondary infection when indicated.

Palmoplantar keratoderma. Painful plantar keratoderma is the most problematic finding among individuals with PC.

Pain can be reduced by limiting the 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 shoes that are comfortable (possibly with insoles), and maintaining an ideal body weight.

Blisters should be punched with a sterile needle, the fluid drained, and the blister roof left in place until it dries and is shed away.

Routine grooming of the feet is essential and includes paring down the hyperkeratotic areas to avoid painful buildup of the callosities that can add further friction and trauma to the foot. Soaking the feet prior to the paring is helpful when the callosities are hard. The surface of the skin and the instruments used should be clean to avoid infection.

Topical therapies to reduce the hyperkeratosis:

  • Emollients such as Vaseline®, lanolin-containing products, or creams and lotions containing keratolyics such as urea, lactic acid, salicylic acid, or propylene glycol. These are the most frequently used. Occlusive ointments are often poorly tolerated.
  • Oral retinoids, while reducing the keratoderma, do not affect the underlying blistering and fragility of the skin, sometimes increase the pain, and are associated with side effects that may be poorly tolerated. Thus, they are less commonly used.

Nail thickening. The hard, thickened nails are not typically painful as long as they are well groomed. Grooming often requires the use of surgical or razor blades or sanders such as a Dremel® tool. Failure to keep the nails trimmed or over-trimming of the nails can result in infection. If bacterial infection occurs, systemic antibiotics are indicated. Secondary fungal infections can also arise, which respond best to oral antifungals.

Particularly troublesome nails can be successfully removed surgically; however, the nails tend to re-grow if not completely ablated.

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 or inflammatory component.

Poor feeding in infancy may be ameliorated by the use of a bottle with a soft nipple with an enlarged opening.

Follicular hyperkeratosis. Especially bothersome for children and teens, this finding can be treated with alpha-hydroxy acid creams or lotions or keratolytic emollients or topical retinoids.

Laryngeal thickening/growths. The hoarseness associated with PC, especially following overuse, usually resolves spontaneously by resting the voice. However, the rare occurrence of respiratory insufficiency can be life-threatening, especially in young children, and requires 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 it 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., Kenalog®) may reduce inflammation of the area if infection is not suspected. If necessary, cysts can be excised.

Prevention of Primary Manifestations

Reduction of trauma, friction, and sheer forces to the skin and nails improves the condition.

Prevention of Secondary Complications

Infection of the skin and nails following grooming 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.

Surveillance

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

Agents/Circumstances to Avoid

Trauma, friction, or stress to the skin or nails should be avoided.

Heat and/or perspiration may 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; however, weight gain (increasing stress on the plantar surface) or altered hormonal environment during pregnancy may worsen the painful plantar keratoderma.

Therapies Under Investigation

Studies on the use of a K6a mutation-specific siRNA [Hickerson et al 2008, Leachman et al 2008], rapamycin [Hickerson et al 2009], simvastatin [Zhao et al 2011], anti-TNF biologics, and botulism toxin are underway, but have not yet reached the point of being applied generally to treatment of the disorder.

  • The siRNA trial included treatment of a single individual with a KRT6A mutation 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 persons with mutations in KRT6A and also in some individuals with clinical findings consistent with PC who have not undergone genetic testing [Swartling & Vahlquist 2006, Swartling et al 2010].
  • A study using topical botulinum toxin has been proposed.
  • Several persons are being treated with statins; results are not yet available.
  • A trial using topical rapamycin is also being conducted.

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 50% of individuals diagnosed with pachyonychia congenita have an affected parent.
  • A proband with pachyonychia congenita may have the disorder as the result of a de novo mutation. The proportion of cases caused by de novo mutations is approximately 50%.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include:
    • Complete clinical examination by a dermatologist to confirm the lack of phenotype; and
    • Molecular genetic testing if the mutation has been identified in the proband.

Sibs of a proband

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

Other family members of a proband. 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

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

Because inheritance of the mutation appears to always be associated with some manifestation of disease, relatives are usually aware of whether they are affected without the need for genetic testing. However, in the case of mild or subtle disease manifestations, some individuals may wish to have confirmatory testing performed.

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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing mutation has been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation) 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
    2386 East Heritage Way
    Suite B
    Salt Lake City UT 84109
    Phone: 877-628-7300 (toll-free)
    Fax: 877-628-7399 (toll-free)
    Email: pcproject@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
  • International Pachyonychia Congenita Research Registry (IPCRR)
    2386 East Heritage Way
    Suite B
    Salt Lake City UT 84109
    Phone: 877-628-7300 (toll-free); 801-401-6300
    Fax: 877-628-7399 (toll-free)
    Email: pcproject@pachyonychia.org; mary.schwartz@pachyonychia.org

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, mutations in these keratins lead to pathology in these major body sites.

The majority of the mutations 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 mutations in most other keratin disorders [Smith 2003, Smith et al 2005, Wilson et al 2011]. A genotype/phenotype correlation is observed in the keratin disorder epidermolysis bullosa simplex (EBS), in which the more severe mutations 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 mutations in these less conserved regions in KRT6A, KRT16, KRT6B, 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, K16, and K17) in Figure 2.

Mutations in at least 224 families have been published to date [www.interfil.org, Wilson et al 2011 (see table)].

A number of the mutations are recurrent but others are family specific. More than 80 different mutations 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

Normal allelic variants. The cDNA comprises 2450 bp in nine exons.

Pathologic allelic variants. The majority of mutations are heterozygous missense mutations; in some individuals, small in-frame deletions/insertions and splice site and nonsense mutations have been reported. Most mutations 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 mutations; the major ones for PC-K6a, located at Asn171, are either a single amino-acid deletion c.514_516delAAC (p.Asn172del) or a different missense mutation involving the same residue (Table 3).

Table 3. Selected KRT6A Pathologic Allelic Variants

DNA Nucleotide ChangeProtein 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.514_516delAACp.Asn172del

Note on variant classification: Variants listed in the table have been provided by the author(s). 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 II cytoskeletal 6A (K6a keratin), consists of 564 amino acids. Keratins form a cytoskeletal intermediate filament network within all epithelial cells.

Abnormal gene product. Mutations 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 mutations occur are critical during normal keratin filament assembly.

KRT6B

Normal allelic variants. The cDNA comprises 2331 bp in nine exons (reference sequence NM_005555.3).

Pathologic allelic variants. The mutations reported to date are heterozygous missense mutations or small in-frame deletion mutations 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. Mutations 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 mutations occur are critical during normal keratin filament assembly.

KRT16

Normal allelic variants. The cDNA comprises 1720 bp in eight exons (reference sequence NM_005557.3).

Pathologic allelic variants. The majority of mutations are heterozygous missense mutations; in some individuals, small in-frame deletions and nonsense mutations have been reported. Most mutations 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. Mutations 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 mutations occur are critical during normal keratin filament assembly.

KRT17

Normal allelic variants. The cDNA comprises 1574 bp in eight exons.

Pathologic allelic variants. The majority of mutations are heterozygous missense mutations; in some individuals, small in-frame deletions have been reported. The majority of mutations in KRT17 occur in the helix initiation motif, in which several recurrent mutations have been observed, particularly p.Asn92Ser (Table 4).

Table 4. Selected KRT17 Pathologic 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 author(s). 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. Mutations 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 mutations occur are critical during normal keratin filament assembly.

References

Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page Image PubMed.jpg

Literature Cited

  1. Connors JB, Rahil AK, Smith FJD, McLean WHI, Milstone LM. Delayed-onset pachyonychia congenita associated with a novel mutation in the central 2B domain of keratin 16. Br J Dermatol. 2001;144:1058–62. [PubMed: 11359398]
  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 FJ, 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]
  4. 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]
  5. 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]
  6. Irvine AD, McLean WHI. Human keratin diseases: the increasing spectrum of disease and subtlety of the phenotype-genotype correlation. Br J Dermatol. 1999;140:815–28. [PubMed: 10354017]
  7. 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]
  8. Leachman SA, Hickerson RP, Schwartz ME, Bullough EE, Hutcherson SL, Boucher KM, Hansen CD, Eliason MJ, Srivatsa GS, Kornbrust DJ, Smith FJD, McLean WHI, Milstone LM, Kaspar RL. First-in-human mutation-targeted siRNA Phase Ib trial of an inherited skin disorder. Mol Ther. 2010;18:442–6. [PMC free article: PMC2839285] [PubMed: 19935778]
  9. Leachman SA, Kaspar RL, Fleckman P, Florell SR, Smith FJD, McLean WH, 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]
  10. 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]
  11. McLean WHI, Hansen CD, Eliason M, Smith FJD. The phenotypic and molecular genetic features of pachyonychia congenita. J Invest Dermatol. 2011;131:1015–7. [PubMed: 21430705]
  12. Pho LN, Smith FJD, Konecki D, Bale S, McLean WHI, Cohen B, Eliaso M, Leachman SA. Paternal germ cell mosaicism in autosomal dominant pachyonychia congenita. Arch Dermatol. 2011;147:1077–80. [PubMed: 21576551]
  13. Smith F. The molecular genetics of keratin disorders. Am J Clin Dermatol. 2003;4:347–64. [PubMed: 12688839]
  14. Smith FJD, Liao H, Cassidy AJ, Stewart A, Hamill KJ, Wood P, Joval I, van Steensel MA, Bjorck E, Callif-Daley F, Pals G, Collins P, Leachman SA, Munro CS, McLean WHI. The genetic basis of pachyonychia congenita. J Investig Dermatol Symp Proc. 2005;10:21–30. [PubMed: 16250206]
  15. Szeverenyi I, Cassidy AJ, Chung CW, Lee BT, Common JE, Ogg SC, Chen H, Sim SY, Goh WL, Ng KW, Simpson JA, Chee LL, Eng GH, Li B, Lunny DP, Chuon D, Venkatesh A, Khoo KH, McLean WHI, Lim YP, Lane EB. The human intermediate filament database: comprehensive information on a gene family involved in many human diseases. Hum Mutat. 2008;29:351–60. [PubMed: 18033728]
  16. Swartling C, Vahlquist A. Treatment of pachyonychia congenita with plantar injections of botulinum toxin. Br J Dermatol. 2006;154:763–5. [PubMed: 16536826]
  17. Swartling C, Karlqvist M, Hymnelius K, Weis J, Vahlquist A. Botulinum toxin in the treatment of sweat-worsened foot problems in patients with epidermolysis bullosa simplex and pachyonychia congenita. Br J Dermatol. 2010;163:1072–6. [PubMed: 20618323]
  18. Terrinoni A, Puddu P, Didona B, De Laurenzi V, Candi E, Smith FJD, McLean WHI, Melino G. A mutation in the V1 domain of K16 is responsible for unilateral palmoplantar verrucous nevus. J Invest Dermatol. 2000;114:1136–40. [PubMed: 10844556]
  19. Terrinoni A, Smith FJ, Didona B, Canzona F, Paradisi M, Huber M, Hohl D, David A, Verloes A, Leigh IM, Munro CS, Melino G, McLean WHI. Novel and recurrent mutations in the genes encoding keratins K6a, K16 and K17 in 13 cases of pachyonychia congenita. J Invest Dermatol. 2001;117:1391–6. [PubMed: 11886499]
  20. van Steensel MA, Jonkman MF, van Geel M, Steijlen PM, McLean WH, Smith FJ. Clouston syndrome can mimic pachyonychia congenita. J Invest Dermatol. 2003;121:1035–8. [PubMed: 14708603]
  21. 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]
  22. Wilson NJ, Leachman SA, Hansen CD, McMullan AC, Milstone LM, Schwartz ME, McLean WH, Hull PR, Smith FJD. A large mutational study in pachyonychia congenita. J Invest Dermatol. 2011;131:1018–24. [PubMed: 21326300]
  23. Xiao SX, Feng YG, Ren XR, Tan SS, Li L, Wang JM, Shi YZ. A novel mutation in the second half of the keratin 17 1A domain in a large pedigree with delayed-onset pachyonychia congenita type 2. J Invest Dermatol. 2004;122:892–5. [PubMed: 15102078]
  24. 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 clinicians without whose input our work into the genetic basis of PC would not have been possible. 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. FJDS holds a Career Development Fellowship from The PC Project.

Revision History

  • 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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