DiagnosisClinical DiagnosisPachyonychia 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.FigureFigure 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 blisteringOral leukokeratosisFollicular keratoses on the trunk and extremitiesPilosebaceous cysts including widespread steatocystomas/steatocysts (benign lesions) and vellus hair cysts which usually develop at pubertyPalmoplantar 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 TestingGenes. 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 testingSequence analysis of KRT6A, KRT6B, KRT16, and KRT17 identifies mutations in approximately 90% of individuals with clinically diagnosed PC [Terrinoni et al 2001, Smith et al 2005, Liao et al 2007, Wilson et al 2011].Table 1. Summary of Molecular Genetic Testing Used in Pachyonychia Congenita (PC)View in own windowGene SymbolProportion of PC Attributed to Mutations in This Gene ^{1PhenotypeTest MethodMutations DetectedTest AvailabilityKRT6A109/224 (48.7%)PCSequence analysisSequence variants 2Clinical KRT6B7/224 (3.1%)PCClinical KRT1655/224 (24.5%)PC/FNEPPKClinical KRT1753/224 (23.7%)PC/SMClinical 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 StrategyTo 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 painSequence 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.Genetically Related (Allelic) DisordersKRT6A, KRT6B. No other phenotypes are associated with mutations in these genes.KRT17. Steatocystoma multiplex (SM), defined as widespread steatocystomas (benign lesions) that can develop at puberty with little or no nail involvement or palmoplantar keratoderma, occurs in association with mutations in KRT17.KRT16Focal non-epidermolytic palmoplantar keratoderma (FNEPPK), defined as keratoderma of varying severity that may occur on the palms and soles with no/very mild nail dystrophy, occurs in association with mutation of KRT16 [Fu et al 2011].In one person with unilateral palmoplantar verrucous nevus (UPVN), somatic mosaicism for a KRT16 mutation was present in the affected, but not unaffected, palm skin [Terrinoni et al 2000].}

Natural HistoryThe 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 2011View in own windowIPCRR Data 3/30/11
N=297 Genetically ConfirmedPachyonychia CongenitaTotal
N=297K6a
N=138K16
N=83K6b
N=24K17
N=52Toenails, 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/symptomsHypertrophic 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 tipFocal 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 individualsAxillary and inguinal cyst formationExcessive production of waxy material in the earSevere and unexplained ear painHoarseness (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 infectedParonychia with pronounced edema (and occasional blister formation) under the nails; can exhibit lymphatic extension and can sometimes be caused by infection

Genotype-Phenotype CorrelationsEven 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.

Differential DiagnosisOnychomycosis. 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 , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).KRT6A-related PCKRT6B-related PCKRT16-related PCKRT17-related PC

ManagementEvaluations Following Initial DiagnosisTo 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 involvementCulture if infection is suspectedGenetic testing of one affected individual in the familyTreatment of ManifestationsTreatment 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 ManifestationsReduction of trauma, friction, and sheer forces to the skin and nails improves the condition.Prevention of Secondary ComplicationsInfection 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.SurveillanceIn general, individuals with PC have no known associated systemic diseases or predispositions that require routine surveillance.Agents/Circumstances to AvoidTrauma, friction, or stress to the skin or nails should be avoided.Heat and/or perspiration may worsen the condition.Evaluation of Relatives at RiskMolecular 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 InvestigationStudies 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.

Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDKRT1617q21​.2Keratin, type I cytoskeletal 16Human Intermediate Filament Database KRT16
KRT16 homepage - Mendelian genesKRT16KRT6A12q13​.13Keratin, type II cytoskeletal 6AHuman Intermediate Filament Database KRT6A
KRT6A homepage - Mendelian genesKRT6AKRT1717q21​.2Keratin, type I cytoskeletal 17Human Intermediate Filament Database KRT17
KRT17 homepage - Mendelian genesKRT17KRT6B12q13​.13Keratin, type II cytoskeletal 6BHuman Intermediate Filament Database KRT6B
KRT6B homepage - Mendelian genesKRT6BData 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) View in own window 148041KERATIN 6A; KRT6A 148042KERATIN 6B; KRT6B 148067KERATIN 16; KRT16 148069KERATIN 17; KRT17 167200PACHYONYCHIA CONGENITA, TYPE 1; PC1 167210PACHYONYCHIA CONGENITA, TYPE 2; PC2Molecular 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.FigureFigure 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. KRT6ANormal 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 VariantsView in own windowDNA Nucleotide ChangeProtein Amino Acid Change Reference Sequencesc.511A>Gp.Asn171AspNM_005554​.3
NP_005545​.1c.511A>Tp.Asn171Tyrc.512A>Gp.Asn171Serc.513C>Ap.Asn171Lysc.514_516delAACp.Asn172delSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).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.KRT6BNormal 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.KRT16Normal 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.KRT17Normal 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 VariantsView in own windowDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequencesc.275A>Gp.Asn92SerNM_000422​.2
NP_000413​.1See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).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.