Pachyonychia congenita is a rare genodermatosis due to mutations in one of four keratin genes. It is characterized by dystrophic, thickened nails and painful palmoplantar keratoderma. Müller made one of the first documented observations of pachyonychia congenita in 1904.[1] The next reports were published in 1905 by Wilson[2] and in 1906 by Jadassohn and Lewandowsky.[3]
Based on available case reports and small series, the disorder has historically been divided into 2 main subtypes. Pachyonychia congenita type 1, or the Jadassohn-Lewandowsky type (Mendelian Inheritance in Man (MIM entry 167200), was attributed to mutations in genes encoding keratin 6A (KRT6A) or keratin 16 (KRT16) and constituted the most common form of the disorder.[4] Pachyonychia congenita type 2, or the Jackson-Lawler type (MIM entry 167210), was attributed to mutations in keratin 6B (KRT6B) or keratin 17 (KRT17) and could be distinguished from type 1 by the development of natal teeth, widespread steatocystomas, and occasionally pili torti.
Recent large phenotype-genotype studies of patients from the International Pachyonychia Congenita Research Registry (IPCRR)[5, 6] have provided a clearer picture of the disease and reveal a spectrum of overlapping clinical features that can be correlated genotypically to the specific mutations in patients with pachyonychia congenita.
Keratins are key structural proteins that form the cytoskeleton of epithelial cells. They are classified based on their biochemical properties into either type I (K9-K28, K31-K40) or type II keratins (K1-K8, K71-K86). Keratin intermediate filament assembly begins with the pairing of a type I keratin protein and type II keratin protein to form an alpha helical heterodimer. Two heterodimers then form a tetramer. The tetramers subsequently aggregate to form larger order polymers that give rise to a keratin intermediate filament.
Fifty four different keratin genes have been identified. Various epithelial cell types express a different range of keratins based on cell function. The mutations in pachyonychia congenita are found in the genes encoding keratin 6A (KRT6A), keratin 16 (KRT16), keratin 6B (KRT6B), and keratin 17 (KRT17).[7, 8, 9] Keratin 6A partners with keratin 16 whereas keratin 6B partners with keratin 17. These keratins are constitutively expressed in keratinocytes of the nail, palmoplantar skin, mucosa, and hair, leading to the manifestations of the disorder in these sites.
The basic protein structure of a keratin filament consists of an alpha-helical rod that is divided into 4 domains (1A, 1B, 2A, 2B) connected together by nonhelical linkers (L1, L12, L2). A helix initiation motif and a helix termination motif segment can be found at either end of the alpha-helical rod and are highly conserved in sequence between keratins. As with most other keratin disorders, most mutations in pachyonychia congenita occur in these highly conserved helix boundary domains at the end of the rod domain. Proper function of these highly conserved domains appears to be critical for normal keratin filament assembly and cytoskeletal integrity; mutations result in cell fragility.
Although the exact frequency of pachyonychia congenita is unknown, it appears to be rare. An estimated 5,000–10,000 cases have been reported worldwide.[10]
Sex
Pachyonychia congenita affects both sexes equally.[5, 11]
Age
Patients with pachyonychia congenita often present at birth or soon after with the characteristic hypertrophic toenail dystrophy.[5]
Patients and their relatives should be informed that pachyonychia congenita does not endanger an individual's life, but it may impair his or her quality of life. The patient may be informed that at present, no effective treatment is available; however, gene therapy treatment may become available in the future. A genetic counselor should inform the carrier that this gene has an autosomal dominant inheritance pattern and that pachyonychia congenita can affect half of his or her progeny.
Thickened toenails, plantar keratoderma, and plantar pain are the 3 cardinal findings of pachyonychia congenita (seen in >90% of patients) and are present in most patients before age 5 years.[5, 6] Clinical differences among pachyonychia congenita subtypes include earlier onset and more frequent occurrence of nail dystrophy and keratoderma in pachyonychia congenita type K6a, concurrent fingernail and toenail thickening in pachyonychia congenita types K6a and K17, more palmar keratoderma in pachyonychia congenita type K16, more frequent occurrence of cysts in pachyonychia congenita type K17, follicular hyperkeratoses primarily in pachyonychia congenita type K6a, oral leukokeratoses most often in pachyonychia congenita type K6a, and natal teeth almost exclusively in pachyonychia congenita K17.[5, 6]
Thickened toenails
The development of thickened toenails in childhood is seen in almost all patients with pachyonychia congenita.[12, 5] The thickened nails often require constant paring and grooming to prevent overgrowth and trauma, and they may be accompanied by painful paronychia (both pressure related and infectious). In a large study, 249 of 254 (98%) patients reported toenail changes, involving an average number of 8.8 toenails (range 0-10, mode = 10). Patients with KRT6A mutations were 11.1 times as likely to have all 10 toenails affected than those with the KRT6B, KRT16, or KRT17 mutations. The characteristic thickened toenails typically develop early in life. This appears to be especially true for patients with KRT6A mutations whose age of onset averaged 0.35 years (or 4 mo) compared with those with KRT6B, KRT16, or KRT17 mutations (9.5 y, 6.8 y, and 0.9 y, respectively).
Keratoderma
Plantar keratoderma is the next most common finding of the disorder and occurs in 91-96% of patients.[12, 5] It typically develops in early childhood with the start of prolonged walking and weight bearing. It most commonly manifests as persistent large callouses on weight-bearing surfaces and may be preceded or accompanied by blistering. Fissuring and secondary infection may also occur. Palmar keratoderma is also often present, especially among patients with KRT16 mutations.
Plantar pain
The third most commonly encountered finding among patients with pachyonychia congenita is pain, mostly involving weight-bearing areas such as the plantar surfaces. In a large study, 89% of patients (225 of 254) reported pain.[5] Of note, plantar pain appears to be the most important feature to negatively impact quality of life among people with pachyonychia congenita and may be severe enough to result in limitation of activities or require medications to manage it. Evidence supports the possibility of a neuropathic source of at least some of the chronic pain in pachyonychia congenita.[13, 14]
Fingernail dystrophy
Fingernail dystrophy is also a feature of pachyonychia congenita, although slightly less consistently than toenail dystrophy. Thickened fingernails were reported in 220 of 254 (87%) patients in a large study.[5] The prevalence of fingernail changes appears to be highest in patients with KRT6A mutation. All of the 115 patients with KRT6A mutations and 40 (93%) of 43 with KRT17 mutations reported fingernail changes, whereas 56 (74%) of 76 with KRT16 and only 9 (45%) of 20 with KRT6B mutation carriers reporting affected fingernails. KRT6B mutation carriers were also found to have far fewer fingernails affected than the other mutations carriers.
Mucosal findings
Oral leukokeratotic plaques (which are not felt to be premalignant) are estimated to occur in approximately 70% of patients with pachyonychia congenita.[5, 12] They may be seen at birth or develop within the first year. The plaques are most commonly seen on the tongue and buccal surfaces of the mouth. In newborns, the leukokeratoses may lead to difficulties in suckling and breastfeeding. In a large study, 97% (115/115) KRT6A and 59% (45/76) KRT16 mutation carriers reported the finding compared with 7/20 (35%) KRT6B and 14/43 (33%) KRT17 mutation carriers.
Cysts
Historically, the presence of various pilosebaceous cysts, such as steatocystomas or vellus hair cysts, were thought to be a reliable distinguishing feature of pachyonychia congenita type II.[12, 15, 16, 17] In a large study, cysts of any type were reported in 104 of 254 (41%) patients. Cysts were reported in 38 of 43 (88%) patients with KRT17 mutation, in 11 of 20 (55%) KRT6B mutation carriers, in 47 of 115 (41%) KRT6A mutation carriers, and 8 of 76 (11%) KRT16 mutation carriers.[5]
Natal teeth
Natal or prenatal teeth are associated with pachyonychia congenita and present at birth or within the first 30 days of life.[12, 15, 18] They are typically lost in infancy and replaced with normal permanent teeth during childhood. Natal teeth may lead to trauma or lacerations of the infant’s tongue or mother’s breast during breastfeeding and can pose an aspiration risk in infancy They were previously reported to be a feature of pachyonychia congenita type 2. In a large study, 39 of the 254 patients reported natal teeth. Thirty six were KRT17 mutation carriers. Only 3 of 115 (3%) KRT6A carriers reported natal teeth, and none of the 96 patients with KRT16 or KRT6B mutation carriers reported natal teeth.[5]
Nail involvement usually demonstrates significant subungual hyperkeratosis and sometimes presents with premature termination of nail. The nails may grow to full length and have an upward-slanted or heaped-up appearance due to a progressive distal thickening, or the plate may terminate prematurely with a gently sloped distal edge of hyperkeratosis and exposed distal finger tip. The surface of the plate can be smooth or rough and is often discolored. Note the image below.
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The most prominent feature is a substantially thickened, brownish gray nail plate with a rough surface.
Plantar keratoderma
The plantar keratoderma of pachyonychia congenita is typically symmetric and focal, developing in areas of friction, trauma, and weight bearing , although it may affect the entire plantar surface. Blisters, fissures, and open sores often develop within or adjacent to the calloused areas.
Follicular hyperkeratoses reminiscent of severe keratosis pilaris have been reported and are most frequently found on the elbows and knees and along the waistband area. Note the image below.
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Hyperkeratotic lesions of the skin may involve acanthosis, hyperkeratosis, and parakeratosis.
Oral leukokeratosis
Leukokeratosis of the oral mucosa, as shown below, is seen as patchy whitish areas most commonly seen on the tongue and buccal mucosa. The gingival mucosa is rarely involved. The clinical appearance of the lingual and buccal leukokeratosis can resemble candidiasis and premalignant leukoplakia, respectively. Buccal lesions are often accentuated at areas of trauma such as along the bite line.
View Image
Leukokeratosis of the oral mucosa is a prominent sign. Patchy whitish areas may be seen on the back of the tongue; the buccal mucosa; and sometimes, t....
Natal teeth
Natal or prenatal teeth can generally be seen in a frontal position and are often friable and prone to caries.
Pilosebaceous cysts
Although various pilosebaceous cysts have been reported in pachyonychia congenita, steatocystomas and vellus hair cysts have been historically most associated. Steatocystomas present as numerous small skin-colored to yellow-colored cysts that range from a few millimeters to a few centimeters and typically occur in sebaceous gland–dense areas such as the chest, arms, armpit, and neck.
Molecular DNA analysis in pachyonychia congenita reveals missense mutations, deletion mutations, substitution mutations, and other mutations of keratin genes K6a, K6b, K16, and K17.
Oral leukokeratosis is to be differentiated from leukoplakia or cancer either by performing an oral biopsy or by recognizing its presence in patients with other symptoms of pachyonychia congenita.
Microscopy or culture of nail clippings or scrapings can help differentiate candidal or fungal onychomycosis from pachyonychia.
Histologic examination of plantar hyperkeratotic plaques reveals an acanthotic epidermis with parakeratosis and orthokeratosis compatible with rapid keratinocyte proliferation and differentiation. Cytologic atypia is not seen. Immunostaining shows positive immunostaining of K14, as would be expected along with K6, K16, K17 in the basal cell layer. In the suprabasal layers, K6, K16, K17, and K14 staining persists and K10 staining appears.[12, 19, 20]
Electron microscopy on palmar or plantar plaques shows thickened and clumped intermediate filaments, as well as enlarged keratohyaline granules. In the broadened granular layer, thick masses of tonofilaments and large, irregular keratohyaline granules are present. In the spinous layer, thick masses of tonofilaments are found at the periphery of the cells.
Like most genodermatoses, no specific treatment or cure is known for pachyonychia congenita. Therapy is generally directed towards symptomatically improving the most bothersome manifestations of the disease and, because of the rarity of pachyonychia congenita, is based largely on anecdotal findings.
The palmoplantar keratoderma and its associated pain are thought to be one of the most debilitating aspects of the disease. Pressure, weight, and trauma are significant cofactors in the development of the keratoderma, and efforts to redistribute and minimize them are important. This can be achieved with specially constructed shoes, orthotic inserts, insoles, and protective socks and gloves. For patients with severe pain and fissuring, the use of an ambulatory aid such as crutches or a wheelchair may be helpful or even necessary for pain management and healing.[21]
Mechanical thinning of keratotic nails and calluses with a variety of tools such as pumice stones, emery boards, rasps, and files may be helpful. Some patients have reported the successful use of electrical tools, such as grinders, polishers, and sanders, to reduce thickened nails.[21]
Softening of the nails and calluses can also be achieved with water, humectants (eg, urea, propylene glycol), and weak organic acids (eg, salicylic acid, alpha-hydroxy acid).[21]
Treatment of hyperhidrosis, which is a bothersome and common feature of pachyonychia congenita, appears to be helpful in decreasing blistering and pain and has been achieved with agents such as aluminum chloride or plantar injections of botulinum toxin.[22, 23, 24]
Pharmaceutical treatment of pachyonychia congenita includes systemic retinoids, such as isotretinoin[25] and etretinate.[26] The retinoids may be successful in reducing the follicular keratoses and the palmoplantar keratoderma but often cause an increase in tenderness and blistering. Their use as long-term therapy is also limited by their adverse effects, such as teratogenicity, mucocutaneous adverse effects, liver toxicity, hyperlipidemia, and skeletal abnormalities.
Evidence suggests that treatment with rapamycin (or rapamycin analogues) may also be a promising option for treatment. The proposed mechanism of action is selective inhibition of expression of an inducible keratin (K6a) in human keratinocytes.[27] The US Food and Drug Administration (FDA) has designated sirolimus as an orphan drug for the treatment of pachyonychia congenita. The orphan sponsor is TransDerm, Inc (Santa Cruz, Calif).[28] A 2018 report of compounded topical 1% sirolimus ointment found it to be a safe and effective treatment for the plantar keratoderma in two patients.[29]
Based on in vitro evidence that simvastatin and a statin precursor, compactin, decrease KRT6A gene transcription,[30] statin therapy has been proposed as worthy of investigation; a 2018 case report of successful treatment with rosuvastatin in a pediatric patient with a KRT6A mutation suggests it may be a promising option.[31]
An innovative and new approach to treating pachyonychia congenita was investigated in a phase 1B trial involving a short-interfering RNA (siRNA) that specifically targets the N171k mutant keratin 6a (K6a) mRNA. The study was a single-patient prospective, vehicle-controlled trial in which the hyperkeratotic plantar plaques of a patient with the N171k mutation were injected with solution containing the siRNA and demonstrated callus regression in comparison to plaques injected with the vehicle control.[32, 33]
No effective methods are available for treatment of the oral leukokeratosis. Good dental hygiene is encouraged. Some patients report that brushing their tongue has beneficial effects on reducing the leukoplakia.[21]
Because of the discomfort associated with the keratoderma, pain management becomes an important intervention. In addition to measures such as reduction of weight bearing and treatment of hyperhidrosis, pain medications may be required. Nonnarcotic analgesics (especially nonsteroidal anti-inflammatory drugs) are often tried initially and may be sufficient, but occasionally narcotic analgesics are also required for pain control. Interestingly, evidence suggests that a significant portion of the pain experienced by patients with pachonychia congenita may be neuropathic in nature and thus warrants neuropathic pain medications, with which most pachyonychia congenita patients have traditionally been undertreated.[13, 14] Topical anesthetics for painful blisters and fissures have also been reported to be helpful for some patients.[12, 21]
Surgical treatment of pachyonychia congenita is usually most helpful for the treatment of cysts, which are treated no differently than cysts occurring outside of pachyonychia congenita, with standard measures such as incision and drainage or excision.
Treatment of the pachyonychia with avulsion of the affected nails has not been shown to be effective because regrowth of the nails occurs, sometimes with worse dystrophy and distortion. Ablation of the nail matrix has been inconsistently effective. Improved function and appearance of the nails following matrix ablation has been reported in some patients but not in others.[12, 21, 34]
Excision and grafting of plantar skin has not shown promise in pachyonychia congenita, owing to the reappearance of the hyperkeratosis.[21, 35]
Activities that require the use of fine movements with hands or fingers may be difficult for pachyonychia congenita patients. Activities that result in excessive friction, prolonged weight bearing, or repetitive trauma should be avoided or limited.
Clinical Context:
Retinoic acid analogues such as acitretin and isotretinoin are relatively widely used in dermatology. Etretinate is the main metabolite. The detailed mechanisms of action are still being studied.
Retinoids are a family of drugs related to vitamin A. They regulate the differentiation and proliferation of epithelial cells. Some also possess antitumoral activity.
Clinical Context:
By dissolving the intercellular cement substance, salicylic acid produces desquamation of the horny layer of skin, while not affecting structure of viable epidermis.
Hydrate skin and enhance the effects of the medication by soaking the affected area in warm water for 5 minutes prior to use. Remove any loose tissue with a brush, washcloth, or emery board and dry thoroughly. Improvement should generally occur in 1-2 weeks.
Saira J George, MD, Assistant Professor, Department of Dermatology, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center
Disclosure: Nothing to disclose.
Specialty Editors
David F Butler, MD, Former Section Chief of Dermatology, Central Texas Veterans Healthcare System; Professor of Dermatology, Texas A&M University College of Medicine; Founding Chair, Department of Dermatology, Scott and White Clinic
Disclosure: Nothing to disclose.
Lester F Libow, MD, Dermatopathologist, South Texas Dermatopathology Laboratory
Disclosure: Nothing to disclose.
Chief Editor
William D James, MD, Paul R Gross Professor of Dermatology, Vice-Chairman, Residency Program Director, Department of Dermatology, University of Pennsylvania School of Medicine
Disclosure: Received income in an amount equal to or greater than $250 from: Elsevier; WebMD.
Additional Contributors
Gregory J Raugi, MD, PhD, Professor, Department of Internal Medicine, Division of Dermatology, University of Washington at Seattle School of Medicine; Chief, Dermatology Section, Primary and Specialty Care Service, Veterans Administration Medical Center of Seattle
Disclosure: Nothing to disclose.
Acknowledgements
The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous author, Aleksej Kansky, MD, PhD, to the development and writing of this article.
References
Müller C. On the causes of congenital onychogryphosis. Mcn Med Wochenschr. 1904. 49:2180-2.
Wilson AG. Three cases of hereditary hyperkeratosis of the nail bed. Br J Dermatol. 1905. 17:13-14.
U.S. Food and Drug Administration (FDA). Orphan Drug Designations and Approvals. Sirolimus; treatment of pachyonychia congenita. Available at http://www.accessdata.fda.gov/scripts/opdlisting/oopd/OOPD_Results_2.cfm?Index_Number=391013. Accessed: January 24, 2014.
The most prominent feature is a substantially thickened, brownish gray nail plate with a rough surface.
Hyperkeratotic lesions of the skin may involve acanthosis, hyperkeratosis, and parakeratosis.
Leukokeratosis of the oral mucosa is a prominent sign. Patchy whitish areas may be seen on the back of the tongue; the buccal mucosa; and sometimes, the gingiva.
The most prominent feature is a substantially thickened, brownish gray nail plate with a rough surface.
Leukokeratosis of the oral mucosa is a prominent sign. Patchy whitish areas may be seen on the back of the tongue; the buccal mucosa; and sometimes, the gingiva.
Hyperkeratotic lesions of the skin may involve acanthosis, hyperkeratosis, and parakeratosis.
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