Pachyonychia congenita

INTRODUCTION — Pachyonychia congenita (PC) is a rare autosomal dominant disorder of keratinization affecting primarily the skin and nails. Typically, severe plantar pain, palmoplantar keratoderma with underlying blisters, and variable hypertrophic nail dystrophy are the predominant distinguishing features. Oral leukokeratosis, cutaneous cysts of various types, and follicular hyperkeratosis are often present. The underlying genetic cause is a mutation in one of five keratin genes: KRT6A, KRT6B, KRT6C, KRT16, or KRT17 [1,2].

The pathogenesis, clinical manifestations, diagnosis, and management of PC are reviewed in this topic. Other disorders of keratinization are discussed separately.

●(See "Keratinopathic ichthyoses" and "Ichthyosis vulgaris" and "Palmoplantar keratoderma" and "Overview and classification of the inherited ichthyoses" and "Peeling skin syndromes" and "Autosomal recessive congenital ichthyoses" and "X-linked ichthyosis".)

●(See "Keratinopathic ichthyoses" and "Ichthyosis vulgaris" and "Palmoplantar keratoderma" and "Overview and classification of the inherited ichthyoses" and "Peeling skin syndromes" and "Autosomal recessive congenital ichthyoses" and "X-linked ichthyosis".)

●(See "Keratinopathic ichthyoses" and "Ichthyosis vulgaris" and "Palmoplantar keratoderma" and "Overview and classification of the inherited ichthyoses" and "Peeling skin syndromes" and "Autosomal recessive congenital ichthyoses" and "X-linked ichthyosis".)

●(See "Keratinopathic ichthyoses" and "Ichthyosis vulgaris" and "Palmoplantar keratoderma" and "Overview and classification of the inherited ichthyoses" and "Peeling skin syndromes" and "Autosomal recessive congenital ichthyoses" and "X-linked ichthyosis".)

●(See "Keratinopathic ichthyoses" and "Ichthyosis vulgaris" and "Palmoplantar keratoderma" and "Overview and classification of the inherited ichthyoses" and "Peeling skin syndromes" and "Autosomal recessive congenital ichthyoses" and "X-linked ichthyosis".)

●(See "Keratinopathic ichthyoses" and "Ichthyosis vulgaris" and "Palmoplantar keratoderma" and "Overview and classification of the inherited ichthyoses" and "Peeling skin syndromes" and "Autosomal recessive congenital ichthyoses" and "X-linked ichthyosis".)

●(See "Keratinopathic ichthyoses" and "Ichthyosis vulgaris" and "Palmoplantar keratoderma" and "Overview and classification of the inherited ichthyoses" and "Peeling skin syndromes" and "Autosomal recessive congenital ichthyoses" and "X-linked ichthyosis".)

EPIDEMIOLOGY — PC is a rare disease. Its prevalence and incidence are unknown. There are between 1000 to 10,000 cases reported worldwide [3]. As of March 2021, the International Pachyonychia Congenita Research Registry includes 1240 individuals registered with genetically confirmed PC. This is a continually expanding registry of clinical and molecular data from PC patients worldwide.

CLASSIFICATION — Historically, PC was classified into two subtypes: PC-1 (due to variants in KRT6A and KRT16) and PC-2 (due to variants in KRT6B and KRT17). However, molecular and clinical data collected by the International Pachyonychia Congenita Research Registry showed overlap between these subtypes, leading to a new classification for PC based on molecular analysis [1,4]. Cases with variants in KRT6A are named PC-K6a (MIM #615726), those with variants in KRT6B as PC-K6b (MIM #615728), those with variants in KRT6C as PC-K6c (MIM #615735), those with variants in KRT16 as PC-K16 (MIM #167200), and those with KRT17 variants are PC-K17 (MIM #167210).

PATHOGENESIS

Molecular genetics — PC is caused by dominant negative variants in KRT6A, KRT6B, KRT6C, KRT16, or KRT17, which encode the keratins K6a, K6b, K6c, K16, and K17, respectively [2,5-7]. PC is inherited as an autosomal dominant trait. Approximately 30 percent of cases are caused by a de novo pathogenic variant. Germline mosaicism is thought to be extremely rare, with only 1 out of 814 cases reported in the International Pachyonychia Congenita Research Registry [8].

Most variants causing PC are found within the helix boundary domains of KRT6A, KRT6B, KRT6C, KRT16, or KRT17. Disruption to these conserved sequences results in a weakened keratin cytoskeleton and the formation of keratin aggregates. Variants underlying PC are predominantly missense variants, with a smaller number of in-frame insertion/deletion variants, splice-site variants, frameshift variants, and nonsense variants. More than 100 distinct variants have been identified for PC. Many are recurrent variants, and others are "family specific." The most commonly reported variants are K6a p.Asn172del, K16 p.Arg127Cys, K16 p.Asn125Ser, K17 p.Asn92Ser, and K6b p.Glu472Lys [2,9].

Data suggest that some genetic variants may be predictive of the clinical manifestations of the disease. For example, the KRT16 p.L132P variant is associated with younger age of onset, presence of palmar keratoderma, oral leukokeratosis, and a higher number of involved nails. By contrast, other KRT16 variants (ie, p.N125S and p.R127C) are associated with a milder phenotype [10]. A missense variant in KRT17 has been associated with a dual phenotype of PC and hidradenitis suppurativa in multiple members of a family [11].

In mice models, elevated oxidative stress due to hypoactive Keap1-Nrf2 signaling, a central regulator of the cellular antioxidant response, appears to have a role in the onset of palmoplantar keratoderma associated with PC [12,13].

Keratin expression and function — Keratins belong to the family of intermediate filament proteins and are divided into type I (acid) and type II (neutral to basic) keratins. There are 54 known functional keratin genes that are clustered in two chromosomal loci; 28 type I keratins K9 to K40 are located on chromosome 17q21.2, and 26 type II keratins K1 to K8 and K71 to K86 (plus type I keratin K18) are on chromosome 12q13.13 [14,15].

Keratins are expressed in a differentiation- and tissue-specific manner, and mutations in many keratins are associated with specific tissue fragility disorders [9,16,17]. The keratins K6a, K6b, K6c, K16, and K17 are normally expressed in the palmoplantar epidermis, nail bed, oral mucosa, hair shaft, and sebaceous glands (ie, the tissues affected in PC). Subtle, phenotypic differences among the subtypes of PC (eg, PC-K16 versus PC-K17) may be due to slightly different expression patterns within these tissues and also to the amount of each of these five genes expressed in these tissues.

All keratins share a similar protein structure consisting of an alpha helical central rod domain of 310 amino acids subdivided into four domains (1A, 1B, 2A, 2B), which are connected by three nonhelical linker regions (L1, L12, and L2). At either end of the rod domain are short regions that are highly conserved in sequence between each type of keratin; named helix boundary peptides (helix initiation and helix termination), these conserved regions are highly important in end-to-end overlap interactions during keratin filament assembly [18,19]. The rod domain is flanked by head (amino terminal) and tail (carboxy terminal) domains that vary both in size and sequence between keratins.

During keratin filament assembly, keratins form obligate heterodimers consisting of a type I and type II keratin. The 10 nm keratin filaments form cytoskeletal networks spanning from the nucleus to the plasma membrane, providing structural integrity and flexibility to epidermal cells.

CLINICAL MANIFESTATIONS

Major features — The predominant clinical manifestations of PC seen across all mutation subtypes are a triad of hypertrophic nail dystrophy, plantar keratoderma, and severe plantar pain [1,20-22]. The age of onset of PC is variable, but most cases are clinically apparent soon after birth or during the first few years of life. Adult-onset cases are extremely rare. Many patients have a positive family history for the same disorder.

Thickening of fingernails and toenails due to hyperkeratosis of the nail bed is usually the first manifestation of PC. It generally presents in the first few months to years of life and can be variable, with some or all nails affected (picture 1A-D). Affected nails either grow to full length, often with a distally upward slant due to distal hyperkeratosis (picture 2A-B), or the nail plate terminates prematurely, leaving an exposed distal finger (picture 3). In some patients, nail changes are mild to negligible.

Plantar keratoderma usually begins when a child starts weight bearing and walking, with diffuse or focal hyperkeratosis of the soles, calluses, and underlying frictional blisters that cause severe pain (picture 4A-C). Fissures and open wounds can also be seen. Many patients have also palmar keratoderma (picture 5).

Chronic plantar pain may be disabling and has a major impact on quality of life for patients with PC. It can be severe enough to limit mobility and ability to perform daily life activities. It has been hypothesized that plantar pain may have a neuropathic component in these patients [23-25].

Other findings — Additional clinical findings that are variably present in patients with PC include oral leukokeratosis, follicular hyperkeratosis on elbows and knees, palmoplantar hyperhidrosis, cutaneous cysts, and natal teeth [1].

Oral leukokeratosis presents with white-grayish patches on the tongue and on the cheek mucosa (picture 6A-C). In infants, it may cause feeding difficulties. Laryngeal involvement may cause hoarseness and even acute airway obstruction in young children [26,27].

Cutaneous cysts, including epidermal inclusion cysts and pilosebaceous cysts such as steatocystomas and vellus hair cysts, typically develop around or after puberty and continue into adulthood (picture 7A-B) [28,29]. They can occur in all subtypes of PC but are particularly common in PC-K17. Depending on their location on the body, cysts can cause pain and discomfort. Milia may occur, particularly on the face of newborns and young children.

Follicular keratosis may be present on the trunk, elbows, and knees (picture 8A-C), particularly at friction points. It usually occurs in childhood/teenage years and lessens during adulthood.

Excessive sweating of the palms and soles due to palmoplantar hyperhidrosis has been observed in some cases. Palmoplantar hyperhidrosis may underlie the formation of plantar, subepidermal blisters and explain the beneficial effect of botulinum toxin in PC [30]. (See 'Management' below.)

Natal or neonatal teeth (ie, erupted teeth present at birth or by age one month) are sometimes seen in neonates, in particular in those with mutations in KRT17 (PC-K17), but it is not a fully penetrant trait. Genetic variants in genes encoding PC-associated keratins may increase susceptibility to tooth decay [31]. (See "Developmental defects of the teeth", section on 'Natal and neonatal teeth'.)

Hair abnormalities are exceedingly rare in patients with PC. Generalized alopecia associated with severe manifestations of PC has been reported in a few individuals with homozygous dominant negative mutations in KRT17 [32].

Clinical features of hidradenitis suppurativa have been reported in patients with KRT17 variants and, less frequently, in patients with KRT6A and KRT6B variants [11].

PATHOLOGY — On histology, prominent ortho- and parakeratosis are seen in skin biopsies taken in areas of plantar hyperkeratosis from patients with PC [21,33,34]. By transmission electron microscopy, bundles of densely aggregated keratin filaments have been observed in the upper spinous layer of PC plantar epidermis [35].

DIAGNOSIS — The diagnosis of PC is usually clinical, based upon the presence of the classic triad of thickened nails, plantar keratoderma, and severe plantar pain and often a family history consistent with an autosomal dominant pattern of inheritance. Nail dystrophy and oral leukokeratosis, which are present at birth or become apparent in the first few months of life, may first suggest the diagnosis [20].

The clinical diagnosis can be confirmed by molecular genetic testing and identification of a heterozygous pathogenic variant in one of the five keratin genes (KRT6A, KRT6B, KRT6C, KRT16, or KRT17) associated with PC [2].

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of PC includes a number of genetic syndromes and acquired conditions that share similar clinical features.

Clouston syndrome — Clouston syndrome (hidrotic ectodermal dysplasia 2; MIM #129500) is an autosomal dominant disorder due to heterozygous mutations in the GJB6 (gap junction beta-6) gene that encodes connexin 30 [36-38]. It is characterized by palmoplantar hyperkeratosis (picture 9) and nail dystrophy that can mimic PC (picture 10A-B). The most useful feature distinguishing Clouston syndrome from PC is variable alopecia (mild to total alopecia), which is relatively common in Clouston syndrome. (See "Ectodermal dysplasias", section on 'Ectodermal dysplasia 2, Clouston type'.)

Olmsted syndrome — Olmsted syndrome (palmoplantar keratoderma [PPK], mutilating, with periorificial keratotic plaques; MIM #614594) is caused by gain of function mutations in the TRPV3 gene (transient receptor potential cation channel, subfamily V, member 3) [39] and is normally inherited in an autosomal dominant manner [40], although autosomal recessive inheritance can occur [41,42]. An X-linked form of Olmsted syndrome is caused by mutations in the zinc metalloprotease gene, MBTPS2 [43]. Individuals present with painful PPK (picture 11 and picture 12) with lesions that may itch. Sometimes constricting digital bands on hands and feet are present that may lead to spontaneous amputation. Periorificial keratoderma may occur. Abnormalities to the nails include thin nail plates and koilonychia. Hair may be thin, fine, sparse, and slow growing with varying degrees of alopecia, leading in some cases to total alopecia. Milder cases of Olmsted syndrome may be difficult to differentiate from PC [40].

Palmoplantar keratoderma striata — Palmoplantar keratoderma striata (PPKS1; MIM #148700) is an autosomal dominant disorder predominantly caused by heterozygous loss of function mutations (frameshift, splice-site, and nonsense mutations) leading to haploinsufficiency of the DSG1 gene [44,45]. A missense mutation in DSG1 has also been reported in a case of PPKS1 [46]. There is often marked phenotypic variation both within and among families. A striate pattern of keratoderma on the palms is a distinguishing feature but can be very subtle. There are varying degrees of focal and diffuse plantar keratoderma [47]. Nails are not normally affected, and no other features of PC are present.

Punctate palmoplantar keratoderma type 1 — Punctate palmoplantar keratoderma type 1 (MIM #148600) is an autosomal dominant disorder due to heterozygous loss of function mutations (frameshift, splice-site, and nonsense mutations) and haploinsufficiency of the alpha- and gamma-adaptin-binding protein gene AAGAB encoding protein p34. Multiple small, hard papules/hyperkeratotic lesions are present on the palms and soles. With age, these lesions increase in number and size and may join together to form larger areas of painful keratoderma with the appearance of focal PPK. The age of onset is generally later than for PC, usually in early adolescence or in adulthood [48,49].

Epidermolysis bullosa simplex — Epidermolysis bullosa simplex (EBS; MIM #131760, 131800, 131900) is characterized by blisters (within the basal layer of the epidermis) and hyperkeratosis of the palms and soles (picture 13), but the characteristic nail dystrophy of PC is not normally present. EBS is mostly due to dominant negative mutations in keratins, KRT5, or KRT14 [50]. Rare cases of autosomal recessive inheritance have been reported. PC can be mistaken for EBS, particularly in young children, as they are more likely to have blister formation at a young age rather than keratoderma. (See "Epidermolysis bullosa: Epidemiology, pathogenesis, classification, and clinical features", section on 'Epidermolysis bullosa simplex'.)

Tylosis with esophageal cancer — Tylosis with esophageal cancer (MIM #148500), inherited as an autosomal dominant trait, presents with oral leukoplakia, diffuse PPK, and esophageal cancer. Mutations have been identified in the rhomboid protein, iRhom2 (RHBDF2) [51].

Dyskeratosis congenita — Dyskeratosis congenita is a rare, genetically heterogeneous multisystem disorder that can be inherited as an autosomal dominant, recessive, or X-linked trait [52]. Mutations have been identified in ACD, DKC1, NOLA2 (NHP2), NOLA3 (NOP10), PARN, RTEL1, TERC, TERT, TINF2, and WRAP53. Reticulate hyperpigmentation, hematologic changes, and squamous cell carcinoma of the skin are common features, but nail dystrophy, oral leukoplakia, and PPK may also be present in some forms. (See "Dyskeratosis congenita and other telomere biology disorders".)

Nonsyndromic congenital nail disorder 10 — Nonsyndromic congenital nail disorder 10 (MIM #614157) is an autosomal recessive disorder only affecting the nails and caused by biallelic mutations in frizzled 6 (FZD6). Normally, all 20 nails are affected from birth or early childhood by onychauxis (thickening of the nails), onycholysis, and often claw-shaped nails [53-55]. It can be confused with PC, but there is no associated PPK or other features of PC.

Steatocystoma multiplex — Steatocystoma multiplex (MIM #184500) is inherited as an autosomal dominant disorder. Widespread multiple cysts occur during puberty and continue into adulthood. Very mild nail changes may be present. It can be associated with mutations in KRT17 [56,57]. (See "Overview of benign lesions of the skin", section on 'Steatocystoma multiplex'.)

Other — Other nail disorders that can be included in the differential diagnosis of PC are:

●Nail disorder, nonsyndromic congenital 1 (NDNC1) − NDNC1 (autosomal recessive nail dystrophy; MIM #161050) features early-onset and progressive nail dystrophy inherited in an autosomal recessive fashion and is caused by biallelic mutations in FDZ6, encoding frizzled class receptor 6 [53].

●PLACK syndrome – PLACK (peeling skin, leukonychia, acral punctate keratoses, cheilitis, and knuckle pads) syndrome (MIM #616295) is caused by recessive mutations in the CAST gene. PLACK syndrome may be misdiagnosed for PC [58].

●Twenty-nail dystrophy − Twenty-nail dystrophy (trachyonychia) is a congenital nail disorder that typically affects all 20 nails, with no other associated changes (picture 14 and picture 15). Autosomal dominance has been reported in some cases. (See "Overview of nail disorders", section on 'Trachyonychia'.)

●Nail psoriasis − Psoriasis may present with subungual hyperkeratosis involving all or some fingernails and/or toenails (picture 16). (See "Nail psoriasis".)

●Onychomycosis − Onychomycosis (tinea unguium) is a fungal infection of fingernails and toenails that may present with subungual hyperkeratosis and onycholysis (picture 17 and picture 18). Onychomycosis typically does not affect all nails and is uncommon in children. (See "Onychomycosis: Epidemiology, clinical features, and diagnosis".)

MANAGEMENT — There is currently no effective or specific therapy for PC. Treatment is mainly directed at reducing nail and palmoplantar hyperkeratosis and controlling pain and should be tailored to the patient's individual needs [59]. Given the rarity of PC, studies evaluating treatment strategies for PC are limited to a few case reports and case series.

Plantar keratoderma — Plantar keratoderma is managed by paring/trimming or filing the hyperkeratotic areas either by the patients themselves or a podiatrist [60]. How often this is done varies among patients from every few days to every few weeks. Similarly, the level to which calluses are trimmed is important and patient dependent; leaving a thin layer of callus as opposed to complete trimming appears to result in overall less pain. The skin can be softened by using topical agents, including keratolytics (eg, salicylic acid, urea), moisturizers, and emollients. Some patients find it beneficial to soak the feet prior to paring/trimming. (See "Palmoplantar keratoderma", section on 'Management'.)

Pharmacologic treatments for plantar keratoderma include:

●Oral retinoids – Oral retinoids (acitretin and isotretinoin) are used to treat several hyperkeratotic disorders and may be useful for PC patients to reduce palmoplantar keratoderma (PPK). Data from a retrospective study of 30 patients enrolled in the International Pachyonychia Congenita Research Registry and treated with systemic retinoids indicate that acitretin is more effective than isotretinoin and that low doses (≤25 mg per day) of systemic retinoids are as beneficial as higher doses in thinning plantar calluses and reducing pain [61]. Most patients reported no improvement in nails.

Oral retinoids are teratogenic. Extreme caution is recommended for use of acitretin in women of childbearing age and girls prior to childbearing age due to concern for teratogenicity and its longer half-life in comparison with isotretinoin. Pregnancy is contraindicated for three years after discontinuing acitretin. (See "Oral isotretinoin therapy for acne vulgaris", section on 'Teratogenicity'.)

●Botulinum toxin – In a small number of PC patients, plantar injections of botulinum toxin led to rapid improvement in pain, skin hyperkeratosis, and blistering lasting for several months [62-64]. A validated protocol for botulinum toxin-based treatment of PC-associated pain is now available [65].

●Rapamycin (sirolimus) – Oral and topical rapamycin has also shown a beneficial effect in small series of PC patients [66,67]. Definitive proof for a therapeutic effect awaits a formal, randomized, well-controlled trial.

●Statins – Statins have been reported to decrease the expression of KRT6a and, as such, may alleviate the consequences of dominant negative mutations in KRT6A. Accordingly, two case reports described the successful treatment of PC-associated PPK using rosuvastatin [68,69].

Hyperhidrosis — Wicking socks and ventilated footwear can help with increased hyperhidrosis. Plantar injections of botulinum toxin may improve hyperhidrosis as well as pain, hyperkeratosis, and blistering lasting for several months [62-64]. A validated protocol for botulinum toxin-based treatment of PC-associated pain is now available [65].

Nail thickening — Thickened nails are managed by filing/grinding or clipping using clippers (including pet clippers) and sanders, such as a Dremel tool. Nails can become painful if bacterial or fungal infections occur, and use of antibiotics or antifungals may be required. Surgical removal of nails has been beneficial for some patients, although in many instances the nails have regrown [70].

Pain control — Pain medication may be necessary for relief of painful plantar keratoderma. Special orthotics, insoles, or cushioned footwear can help reduce the pain. Patients with disabling plantar keratoderma may need to use crutches, canes, or wheelchairs.

Cutaneous cysts — Cutaneous cysts normally develop around puberty and during adulthood and can be very painful. Cysts may be incised and drained or surgically removed. Infected cysts may require a course of systemic antibiotics. (See "Skin abscesses in adults: Treatment", section on 'Indications for antimicrobial therapy'.)

Oral leukokeratosis — Good oral hygiene is recommended to improve the appearance of white patches on the tongue and oral mucosa. Young infants with oral leukokeratosis who are failing to thrive can be helped by using a feeding bottle with a soft nipple and an enlarged opening.

GENETIC COUNSELING — Approximately 30 percent of cases of PC are due to a de novo mutation. Unaffected parents of a child with PC can be reassured about the very low risk of having subsequent affected children, given the extreme rarity of germline mosaicism in unaffected parents [8,22]. There are no reported cases of PC with confirmed molecular testing inherited as an autosomal recessive trait, although semidominance has been reported [71].

If a parent of a child with PC is also affected, the risk for the siblings is 50 percent. Each child of an individual with PC has a 50 percent risk of inheriting the pathogenetic variant. An updated genetic consultation is recommended prior to childbearing years so that the affected individual can better understand their own reproductive risks and options. Early referral for genetics consultation prior to pregnancy and planning of pregnancies is recommended for couples interested in prenatal diagnosis.

ONLINE RESOURCES — Additional information on PC for patients and clinicians is available online at the Pachyonychia Congenita Project.

SUMMARY AND RECOMMENDATIONS

●Pachyonychia congenita (PC) is a rare autosomal dominant disorder characterized by the triad of hypertrophic nail dystrophy, plantar keratoderma with underlying blisters, and severe plantar pain. (See 'Introduction' above.)

●PC is caused by dominant negative mutations in one of five keratin genes (KRT6A, KRT6B, KRT6C, KRT16, or KRT17) that define five subtypes of the disease. (See 'Molecular genetics' above and 'Classification' above.)

●Thickening of fingernails and toenails is usually the first manifestation of PC and generally presents in the first few months to years of life (picture 2A-B). Plantar keratoderma usually begins when the child starts weight bearing and walking, with diffuse or focal hyperkeratosis of the soles and underlying frictional blisters that cause severe pain (picture 4B-C). Other clinical features include oral leukokeratosis, cutaneous cysts, and follicular hyperkeratosis. (See 'Clinical manifestations' above.)

●The diagnosis of PC is based upon the clinical findings and a family history consistent with autosomal dominant inheritance. The diagnosis can be confirmed by the presence of a pathogenic mutation by blood test. (See 'Diagnosis' above.)

●There is no effective or specific therapy for PC. Treatment is symptomatic and mainly directed at reducing nail and palmoplantar hyperkeratosis and controlling pain. Plantar keratoderma is managed by paring, trimming, or filing the hyperkeratotic plantar areas and thickened nails either by the patients themselves or a podiatrist. Some patients may benefit from treatment with systemic retinoids, although the appropriate dose and duration of treatment have not been determined. (See 'Management' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Eli Sprecher, MD, PhD, and Frances JD Smith, PhD, who contributed to earlier versions of this topic review.