Pachyonychia congenita

INTRODUCTION — 

Pachyonychia congenita (PC) is a group of rare autosomal dominant disorders of epidermal differentiation characterized by palmoplantar keratoderma (PPK) with plantar pain as a predominant feature, thickened nails, oral mucosal involvement, and cutaneous cysts [1]. PC is caused by pathogenic variants in several genes encoding keratins, structural proteins expressed in the skin, mucosa, nail bed, hair follicle, and teeth.

This topic will review the pathogenesis, diagnosis, and management of PC. Other disorders of keratinization are reviewed separately.

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

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

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

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

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

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

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

EPIDEMIOLOGY — 

PC is a very rare disorder, and its exact prevalence is unknown. Registry-based studies estimate a population prevalence of 0.9 to 2.1 per million individuals, with a study of the population in Denmark providing the higher bound [2,3].

GENETICS AND MOLECULAR PATHOGENESIS — 

PC is caused by autosomal dominant heterozygous missense variants in one of five genes (KRT6A, KRT6B, KRT6C, KRT16, and KRT17) that encode keratins K6a, K6b, K6c, K16, and K17, respectively [4-6]. Consistent with other dominant disorders, a significant proportion of disease-causing variants (up to 30 percent) occur spontaneously in kindreds without prior disease [7].

Keratins belong to the family of intermediate filament proteins that heterodimerize and have critical roles in cellular structural integrity, wound healing, and signaling [5]. Keratins have a tripartite structure consisting of nonhelical globular N- and C-terminal head and tails domains and a central helical road domain consisting of four subdomains. The rod domains are essential for the polymerization of intermediate filaments and harbor the majority of variants found in PC.

Keratins have site-restricted expression (eg, nail bed, hair follicle, mucosa, tooth, skin). Genotype-phenotype correlations observed in PC reflect the contributions of keratins to specific sites within the body [7]. However, the precise contribution of PC-associated variants to disease pathobiology remains unknown.

Studies in murine models (Krt16 knockout) that reproduced specific features of PC, including palmoplantar keratoderma (PPK) and oral lesions, revealed that cell oxidative stress, disruption of homeostatic keratin expression, defective keratinocyte differentiation, and barrier dysfunction all contribute to the pathogenesis of PC [8,9].

Gene expression studies have found alteration of transcripts relevant to cell proliferation and differentiation, immune responses, proteases, and cell structural elements [10]. In situ messenger ribonucleic acid (mRNA) hybridization studies using human tissue from plantar lesions of PC have also revealed overactive epidermal growth factor receptor (EGFR) signaling, suggesting EGFR inhibition as a potential therapy [11].

CLASSIFICATION — 

While initial efforts sought to group PC into clinical subtypes (PC1, PC2, PC3, and PC4), there has been a transition to classifying PC by genotype [2,7]. The accepted nomenclature for PC denotes genotype as follows (with "KRT" shortened to "K"):

●PC-K6a (MIM #615726)

●PC-K6b (MIM #615728)

●PC-K6c

●PC-K16 (MIM #167200)

●PC-K17 (MIM #167210)

Phenotypes are variable and range from mild, isolated nail dystrophy to disabling, painful palmoplantar keratoderma (PPK). Some phenotypic features are associated with variants in specific genes [7].

CLINICAL MANIFESTATIONS

Age of onset — Based on data on over 1000 patients enrolled in the International Pachyonychia Congenita Research Registry, the disease manifests within the first year of life in 20 percent of cases, after the first year but before age 20 in 77 percent, and after the age of 20 in 2 percent [12].

Major findings — PC primarily involves the nails, palms/soles, and mucosa. The most common clinical features are nail dystrophy, thickening of the palms and soles, plantar pain, oral leukokeratosis, and cutaneous cysts [7]. In contrast to other keratinopathies that feature significant skin fragility, visible blistering is not a prominent feature of PC, but there is evidence that blisters underly callouses [13].

The severity of the clinical manifestations is variable depending on the specific gene variant, ranging from mild, isolated nail dystrophy to disabling, painful palmoplantar keratoderma (PPK).

●Onychodystrophy – The term "pachyonychia" refers to thickening of the nails. All 20 nails are affected in most cases, though involvement can be limited to one or two nails.

Nail thickening, often prominent on the fingers (picture 1 and picture 2 and picture 3 and picture 4), is among the most common findings in PC. Nails can be significantly thickened and progressively elevated from the nail fold (picture 5), with debris under the nail (picture 6).

The nail surface can be smooth or rough, and nails can develop a pincer or omega appearance [14]. In some patients, the nail plate terminates prematurely, leaving an exposed distal finger (picture 7).

●Palm/sole calluses – Focal thickening of the palms (picture 8) and soles (picture 9 and picture 10) at sites of friction is common in PC. A feature that distinguishes PC from other forms of PPK is the severe associated pain, which can be worsened by underlying frictional blisters (picture 11).

●Oral leukokeratosis – White, adherent thickening can be present on the tongue and buccal mucosa, a finding that can be misdiagnosed as thrush (picture 12 and picture 13 and picture 14).

●Cutaneous cysts – Epidermal inclusion cysts, steatocystomas, pilosebaceous cysts, and vellus hair cysts are most common in PC due to KRT17 variants (picture 15 and picture 16). Cysts range in number from a few to hundreds; they can become large or painful.

●Coarse or twisted hair and alopecia – Affected individuals can have coarse/dry, brittle, excessively thick hair or coarse or twisted hair (pili torti).

●Natal teeth – Natal or neonatal teeth (ie, erupted teeth present at birth or by age one month) can be present, most commonly in individuals with KRT17 variants.

Other associated findings — Findings that are variably present in patients with PC include:

●Follicular keratoses can be present and are most prominent on the elbows, knees, and trunk (picture 17 and picture 18 and picture 19).

●Angular cheilitis can be present and persistent despite therapy. (See "Cheilitis", section on 'Angular cheilitis'.)

●Laryngeal involvement with hyperkeratosis of the larynx can cause a hoarse cry at birth and feeding difficulty [15,16]. Rarely, it can result in life-threatening laryngeal obstruction [17].

●Reduced or excessive sweating is reported in approximately 50 percent of patients [7].

●An increased incidence of hidradenitis suppurativa has also been reported in patients with PC [12].

DIAGNOSIS

Clinical — The diagnosis of PC is clinical in most cases, based on physical examination and the patient's personal and family medical history.

Clinical findings that support the diagnosis of PC include:

●Nail thickening

●Palmoplantar keratoderma (PPK) with severe plantar pain

●Oral leukokeratosis

●Abundant cutaneous cysts including vellus hair cysts, steatocystomas, and epidermal inclusion cysts

●Natal teeth

A family history consistent with an autosomal dominant pattern of inheritance can support the diagnosis.

Genetic testing — Genetic testing is the gold standard for confirming the diagnosis and PC subtype, thus providing useful information associated with prognosis and clinical features. A list of Clinical Laboratory Improvement Amendments (CLIA)-certified laboratories performing clinical genetic testing is available from the Genetic Testing Registry. (See "Genetic testing", section on 'Where to test/resources for testing'.)

Individuals with PC are also encouraged to enroll in research registries if they wish. An example is PC Project, a patient support organization that also offers free CLIA-certified genetic testing.

PATHOLOGY — 

A skin biopsy is of little utility for the diagnosis of PC. The histopathologic features of skin lesions associated with PC are not pathognomonic for PC [14].

●Palmoplantar hyperkeratosis – There is acanthosis of the epidermis with prominent orthokeratosis and areas of parakeratosis without cytologic atypia.

●Follicular keratoses – There is a focally acanthotic epidermis with a prominent granular layer and a region of orthohyperkeratosis with or without parakeratosis.

●Cysts – Epidermal inclusion cysts consist of dilated follicles with a central punctum and are lined with a keratinizing epithelium with an intact granular layer. The cyst wall typically lacks adnexal structures. The lumen is filled with laminated keratin. (See "Overview of benign lesions of the skin", section on 'Epidermoid cyst'.)

Steatocystoma lesions appear in the mid-dermis, have associated sebaceous glands, are lined with a stratified squamous epithelium, and have a hyaline cuticle with a sawtooth appearance. (See "Overview of benign lesions of the skin", section on 'Steatocystoma multiplex'.)

Vellus hair cysts are lined by a stratified squamous epithelium with a granular layer and a lumen filled with keratin and one or more hair shafts. (See "Overview of benign lesions of the skin", section on 'Vellus hair cyst'.)

DIFFERENTIAL DIAGNOSIS — 

The differential diagnosis of PC includes genetic syndromes and acquired conditions that share similar clinical features. These include:

●Hereditary palmoplantar keratoderma (PPK) – Focal, striate, or punctate PPK associated with variants in AAGAB, DSG1, DSP, KRT1, KANK2, and MVD. (See "Palmoplantar keratoderma (PPK)", section on 'Focal PPK' and "Palmoplantar keratoderma (PPK)", section on 'Striate PPK' and "Palmoplantar keratoderma (PPK)", section on 'Punctate PPK'.)

●Clouston syndrome – Clouston syndrome (hidrotic ectodermal dysplasia 2; MIM #129500) is an autosomal dominant disorder due to variants in GJB6 and is characterized by palmoplantar hyperkeratosis and onychodystrophy (picture 20A-B). (See "Ectodermal dysplasias", section on 'Ectodermal dysplasia 2, Clouston type'.)

●Olmsted syndrome – Olmsted syndrome is a rare keratinizing disorder caused in most cases by autosomal dominant variants in TRPV3 and is characterized by bilateral, diffuse, painful, mutilating PPK [18]. (See "Palmoplantar keratoderma (PPK)", section on 'Olmsted syndrome'.)

●Epidermolysis bullosa simplex – Localized epidermolysis bullosa simplex is the most common form of epidermolysis bullosa. It is caused by autosomal dominant variants in KRT5 or KRT14 and presents with blistering usually restricted to the hands and feet, PPK, and onychodystrophy (picture 21). (See "Epidermolysis bullosa: Epidemiology, pathogenesis, classification, and clinical features", section on 'Epidermolysis bullosa simplex'.)

●Nonsyndromic congenital nail disorder 10 – Nonsyndromic congenital nail disorder 10 (MIM #161050) is an autosomal recessive nail dystrophy disorder caused by biallelic variants in FZD6 [19]. It presents with thickened, hyperpigmented, and claw-shaped nails on the hands and feet. (See "Nail disorders in children: Congenital and hereditary nail diseases", section on 'Nonsyndromic congenital nail disorders'.)

●Steatocystoma multiplex – Steatocystoma multiplex is an uncommon disorder allelic with PC associated with KRT17 variants. It presents with multiple small dermal cysts predominantly located on the chest (picture 22) but lacks PPK. (See "Overview of benign lesions of the skin", section on 'Steatocystoma multiplex'.)

●Acquired nail disorders – Acquired nail disorders characterized by nail thickening that should be considered in the differential diagnosis of PC include onychomycosis (picture 23A-B), nail psoriasis (picture 24), and yellow nail syndrome (picture 25). (See "Overview of nail disorders".)

MANAGEMENT

Plantar keratoderma — Treatment of PC is directed toward reducing the thickness of plantar hyperkeratosis and the associated pain, which can be debilitating. Given the rarity of PC, studies evaluating treatment strategies for PC are limited to a few case reports and case series.

For most patients, management includes a combination of physical measures and topical and oral therapy [20].

●Foot care – Routine paring or trimming of callouses can reduce pain [21]. Custom orthotics can be used to offload pressure and reduce the tendency to develop thick callouses.

Keratolytics such as alpha- and beta-hydroxy acids can reduce the thickness of mild palmoplantar keratoderma (PPK) and reduce fissuring. (See "Inherited ichthyosis: Overview of management", section on 'Topical keratolytic agents'.)

Humectants (eg, urea) can make callouses softer, easier to trim, and less likely to fissure.

Plantar pain — The plantar pain of PC can be debilitating and may require pain medication, including analgesics, antiseizure medications, and opioids. (See "Overview of pharmacologic management of chronic pain in adults".)

●Pharmacologic therapies for hyperkeratosis

•Oral retinoids – Oral retinoids, including acitretin, isotretinoin, etretinate, and alitretinoin, can reduce the thickening of the palms and soles. However, treatment should aim to achieve a balance between reducing hyperkeratosis and increasing pain and skin fragility due to excessive desquamation.

If a decision is made to use retinoids, they should be initiated at a low dose, such as 0.25 mg/kg per day, and then slowly increased to 1 mg/kg per day with monthly increments of 0.1 to 0.2 mg/kg per day. (See "Inherited ichthyosis: Overview of management", section on 'Retinoids'.)

Their use is supported by limited evidence from small observational studies and expert consensus group recommendations [22]. In a retrospective study that included 30 patients enrolled in the International Pachyonychia Congenita Research Registry between 2004 and 2010 and previously treated with oral retinoids (eg, acitretin, etretinate, isotretinoin, vitamin A) at doses of 10 to 50 mg/kg per day for 1 to 240 months, 50 percent of patients self-reported reduced callus thickness with retinoid therapy [23]. However, 83 percent of patients reported spontaneous changes in plantar hyperkeratosis while not using any medication.

•Investigational therapies

-EGFR inhibitors – In a few case reports, the epidermal growth factor receptor (EGFR) inhibitor erlotinib induced significant improvement in plantar pain but minimal reduction of callous thickness [11,24].

-Statins – HMG-CoA reductase inhibitors reduce the expression of keratin K6a [25]. In a few patients carrying KRT6A variants, treatment with simvastatin or rosuvastatin improved pain and reduced callous thickness [26-29].

-mTOR inhibitors – Based on the observation that sirolimus selectively inhibits the expression of keratin K6a, sirolimus reduced callus and pain in a few patients with PC [30]. However, adverse effects associated with sirolimus led to early interruption of treatment. In two patients carrying a KRT6A variant, topical sirolimus applied for four months reduced painful plantar keratoderma without systemic toxicity [31]. However, relapse occurred after two weeks of discontinuing treatment.

Nail thickening — Thickened nails are managed by filing/grinding (eg, very gentle use of a small Dremel tool) or clipping with a double-action nail clipper. Nail avulsion may be beneficial for some patients, although serial avulsions are needed in many instances [32,33]. Systemic antibiotics or antifungals are required for bacterial or fungal infections.

Cutaneous cysts — Large or painful cysts may be incised and drained or surgically removed. Small cysts can be removed with cryotherapy or laser therapy.

PROGNOSIS AND FOLLOW-UP — 

Individuals with PC have normal lifespans, but skin disease can require daily, lifetime treatment to manage symptoms. PC is associated with poor quality of life and may have a profound impact on psychosocial functioning. Engagement of mental health professionals focused on living with chronic disease can be helpful.

SUPPORT GROUPS — 

The PC Project is an organization that supports individuals with PC and palmoplantar keratoderma (PPK) nationally, offers free Clinical Laboratory Improvement Amendments (CLIA)-certified genetic testing, maintains a large clinical registry, and offers a grant program to stimulate research. Information about PC and becoming involved with the International Pachyonychia Registry can be obtained at the PC Project's website.

SUMMARY AND RECOMMENDATIONS

●Definition and pathogenesis – Pachyonychia congenita (PC) is a group of rare autosomal dominant disorders of epidermal differentiation characterized by painful palmoplantar keratoderma (PPK), thickened nails, oral mucosal involvement, and cutaneous cysts. It is caused by pathogenic variants in genes encoding keratins (KRT6A, KRT6B, KRT6C, KRT16, or KRT17). (See 'Genetics and molecular pathogenesis' above.)

●Clinical presentation – PC may present in the first year of life, with most cases manifesting before the age of 20. Clinical manifestations include focal PPK (picture 9), plantar pain, nail dystrophy (picture 4), oral leukokeratosis (picture 12), and cutaneous cysts (picture 15). Associated findings include hyperkeratosis of the larynx and reduced or excessive sweating. (See 'Clinical manifestations' above.)

●Diagnosis – The diagnosis of PC is clinical in most cases, based on the following findings:

•Nail thickening

•PPK with severe plantar pain

•Oral leukokeratosis

•Numerous cutaneous cysts (eg, vellus hair cysts, steatocystomas, epidermal inclusion cysts)

Genetic testing is the gold standard for diagnosis and provides useful information on PC subtype, clinical features, and potential treatment. (See 'Diagnosis' above.)

●Management – Treatment of PC is primarily directed at thinning callouses and reducing pain and includes a combination of physical measures, topical keratolytics and humectants, and systemic retinoids. (See 'Management' above.)

•Foot care – Routine paring or trimming of callouses can reduce pain. Custom orthotics can be used to offload pressure and reduce the tendency to develop thick callouses. Thickened nails are managed by filing/grinding or clipping with a double-action nail clipper.

•Pain control – The plantar pain of PC can be debilitating and may require treatment with analgesics, antiseizure medications, and opioids. (See "Overview of pharmacologic management of chronic pain in adults".)

•Pharmacologic treatment of hyperkeratosis – Oral retinoids (acitretin, isotretinoin, etretinate, and alitretinoin) can reduce the thickening of the palms and soles and may be helpful in some patients. However, due to excessive desquamation, they can increase skin fragility and pain. Some experts initiate retinoids at a low dose (eg, 0.1 to 0.2 mg/kg per day) and then slowly increase it to 1 mg/kg per day with monthly increments of 0.1 to 0.2 mg/kg per day. (See 'Plantar keratoderma' above.)

●Support groups – Information about PC for patients and clinicians can be obtained from the PC Project, which also offers free Clinical Laboratory Improvement Amendments (CLIA)-certified genetic testing for individuals with PPK. (See 'Support groups' 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.