AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Pachyonychia congenita (PC) is a rare form of hereditary palmoplantar keratoderma (PPK). Müller made the first documented observation in 1904 (Müller, 1904). The next reports were published in 1905 by Wilson (Wilson, 1905) and in 1906 by Jadassohn and Lewandowsky (Jadassohn, 1906). In the dermatologic literature, PC is better known as Jadassohn-Lewandowsky syndrome.

The condition is rare. According to the Pachyonychia Congenita Project Mission Statement less than 300 were reported. Certain reports include larger series of cases: Moldenhauer and Ernst reviewed 93 cases and described 6 new cases (Moldenhauer, 1968). Puente reported 26 cases (Puente, 1955), Kumer and Loos reported 23 cases (Kumer, 1935), and Su reported 12 cases (Su, 1990). Fourteen cases from Slovenia (Franzot, 1981) and 25 cases from Croatia (Videnic, 1991) are reported. Additional reports on larger series of patients describe 19 patients from China (Xiao, 2004) and 13 patients of Italian descent (Terrinoni, 2001).

Various classifications for PC have been proposed. Currently 2 distinct syndromes of PC are recognized: (1) PC-1, or the Jadassohn-Lewandowsky type, which is designated as Mendelian Inheritance in Man (MIM) entry 167200 (McKusick, 1994), and (2) PC-2, or the Jackson-Lawler type, which is designated as MIM entry 167210.

For a definitive classification of PC, more data about genotypic-phenotypic correlation in the same patients is needed.

Pathophysiology

PC results from mutations in the genes encoding epidermal keratinocyte keratins. Specifically the 1A and 1B helical encasing regions of keratins K6a, K6b, K16, and K17 are the most frequent sites of mutations, for example, removal of 1 of 2 adjacent asparagus residues (N170/171) in the 1A encoding region of K6a. The mutation is likely to have a deleterious effect on protein structure as it interferes with the assembly of polypeptides forming the keratin skeleton of epidermal cells (Bowden, 1995). Further mutations are 325A to G in the 1A domain of K17 (Xiao, 2004) or 275A to G in the same domain (Feng, 2003).

Interestingly, a case was reported in which, in addition to the missense mutation 124L to R, a 23 bp deletion (1244-1266del) and a separate 1 bp deletion (1270delG) in exon 6 in the helix termination motif (HTM) in the K16 gene were described (Smith, 2000). The author believes that the loss of the HTM sequence may render the mutant less capable to influence the filament assembly and thus provoke a milder phenotype.

In most cases, an autosomal dominant mode of inheritance is described; however, autosomal recessive inheritance is also mentioned in the literature.

Sporadic PC cases in which no family linkage can be established may be the result of new mutations. However, an unknown affected father seems to be a further possibility.

The concept that in addition to the known mutation of the keratin gene, a second mechanism (probably an additional mutation) is needed for the expression of PC was first mentioned by Cockayne in 1933. He studied the then-available pedigrees of PC patients and noted that the pedigrees did not exactly match the principle of autosomal dominant inheritance (Cockayne, 1933). Lately, a similar view was expressed by MacLean, who introduced the term of a second modifying mutation within a keratin gene (Maclean, 2005). He also stated that approximately 10% of PC patients referred to his laboratory lacked detectable mutations in any of the 4 appropriate keratins

Findings from the present authors' clinical studies of a relatively large series of patients with PC support Cockayne's theory.

Frequency

United States

The disorder is rare. In the United States, only a few reports exist.

International

According to the Pachyonychia Congenita Project Mission Statement, less than 300 cases have been reported worldwide. No data are available about the incidence in various countries. However, in Slovenia, a rate 0.7 case per 100,000 inhabitants is reported. In Croatia, a comparable rate of 0.53 case per 100,000 persons is reported.

Mortality/Morbidity

The lesions in PC do not endanger the patient's life.

Race

Most likely, all races can be affected.

Sex

PC affects both sexes equally.

Age

• The affected nails are usually present at birth, but they may appear later, as they do in PC tarda.
• Paller et al described 5 patients in whom the disfigured nails appeared when they were aged 10-30 years. However, molecular biologic analysis was not available to verify the diagnosis. In PC tarda, thickened nails appear during adult life, which is probably not so rare. However, in the last 10 years, at least 2 cases of PC tarda were reported (Lucker, 1995; Hannaford, 2000). According to Connors, the PC tarda was, in one case, linked to the missense mutation K354N in the central 2B domain of K16. In the other case PC-2 2 was found to be caused by a missense mutation in the second half of the 1A domain of K17, N109D (Smith, 2004; Xiao, 2004).

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

• Parents notice the lesions soon after their child's birth.
• Paller et al described 5 patients in whom the disfigured nails appeared when they were aged 10-30 years, as they do in PC tarda.

Physical

• Jadassohn-Lewandowsky type, or PC-1, is the more common variant. Mutations of the genes encoding keratins K6a and K16, which disrupt the keratin filament assembly, characterize the disorder. In PC-2 mutations in the keratin genes K6b and K17 are found
• • The nail changes are the most prominent feature. The nail plate is substantially thickened and brownish-gray with a rough surface. Usually, all fingers are affected; the toenails may also be affected, but this finding is less characteristic. The thickened fingernails may expand into periungual tissue, causing a pressure-provoked paronychia.
  • Circumscribed or diffuse hyperkeratoses are expressed on the palms and soles. Periodically, blisters may appear in hyperkeratotic areas, especially in children. Hyperhidrosis often accompanies the hyperkeratoses.
  • Follicular hyperkeratosis is observed on the face (eg, temples, front, eyebrows) and on the extensor aspect of the proximal parts of the extremities.
  • Leukokeratosis of the oral mucosa is a prominent sign especially of PC-1. Patchy whitish areas may be seen on the back of the tongue, on the buccal mucosa, and, sometimes, on the gingiva. In some patients, early tooth decay is observed.
  • Oral leukokeratosis is not a precancerous lesion. It is differentiated from leukoplakia or cancer either by performing an oral biopsy or by recognizing its presence in patients with other symptoms of PC.
  • Steatocystoma multiplex is generally considered a hallmark for PC-2, but according to the author's observations and some data from the literature (Ward, 2003), it may also appear later in life in patients with PC-1.
• Jackson-Lawler type, or PC-2, is less frequent compared with PC-1.
• • Patients have a thickened nail plate, and, eventually, other symptoms appear. The symptoms are similar to those in PC-1; however, PC-2 is characterized by natal teeth and the consistent presence of steatocystoma multiplex. A subset of mutations in the keratin K17 gene cause steatocystoma multiplex (MacLean, 2005).
  • Hair anomalies (eg, unruly hair) are also described. A new PC subtype was described in 2 patients (van Steensel, 2001), which included severe and generalized hypotrichia with thickened nails, as in PC. No mutations in keratin genes encoding K6a, K6b, K16, or K17 were detected. The author has also observed a similar case.
  • PC-2 is linked to mutations in the genes for keratin 6b and K17.
  • Sebaceous cysts may appear later in life.
• Corneal opacities and cataracts are rare. Reports of such findings were made prior to the classification of PC into PC-1 and PC-2 types.
• Cicatricial alopecia is an uncommon symptom.
• A thickened nail plate may occasionally be observed in the dominant form of dystrophic epidermolysis bullosa. in Clouston syndrome, in fungal infections in immunologically suppressed patients

Causes

An autosomal dominant mode of inheritance is observed in most cases of PC, but sporadic cases do occur. An autosomal recessive mode of inheritance has also been mentioned.

• Cockayne was the first to express the opinion that the presence of an additional factor, probably a second genetic mutation, is necessary for the expression of the disease (Cockayne, 1933). A similar view was expressed by MacLean in 2005.
• Munro was the first to propose that the genetic defect in PC is linked to the keratin gene cluster on chromosome 17 (Munro, 1994).
• • In a detailed molecular biologic analysis, McLean et al found that PC is caused by mutations on chromosomes 16 and 17.
  • More detailed molecular analysis revealed that PC was caused by mutations in the genes encoding the epidermal keratinocyte keratins K6a, K6b, K16, or K17 (McLean, 1995); these mutations are responsible for the clinical manifestations.
  • Bowden reported in 1995 that one of the adjacent asparagus residues in the 1A helical encoding region of K6a (N170/N171) was deleted in 5 patients from Slovenia. The mutation is provoking a deleterious effect on assembly of peptides. A mutation of F174S phenylalanine to serine was found in 1 patient. Further described mutations are 325 A to G in the 1A domain of K17 (Xiao, 2004) and 275A to G in the same domain (Feng, 2003).
• Rare genetic variants are described in each syndrome. Some of these appear to be due to mutations that occur elsewhere in the keratin genes.
• • Most well-studied mutations occur at the ends of the helical-rod domains disrupting the keratin filament assembly.
  • More data on mutations and symptoms in a larger number of patients are needed, for an exact genotype/phenotype correlation.

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• Molecular DNA analysis 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 oral biopsy or by recognizing its presence in patients with other symptoms of PC.
• In babies, PC can be misdiagnosed as candidiasis; PC can be misdiagnosed as onychomycosis later in life.
• • The occasional detection of a few Candida spores but no hyphae excludes onychomycosis.
  • To confirm candidal infection, mycologic investigation should reveal multiple spores and hyphae.
  • A detailed investigation of the fingernails in 8 patients with PC-1 in whom the diagnosis was verified by molecular biologic analysis did not reveal a candidal infection. Only a few spores and no hyphae were seen in 4 patients, while in the other 4, neither spores nor hyphae were found (Kansky, 1998).

Histologic Findings

The hyperkeratotic lesions of the skin and oral mucosa show acanthosis, hyperkeratosis, and parakeratosis. Premalignant changes are not observed.

Electron microscopy can be performed by using plantar or palmar skin samples. Electron microscopy 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.

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical Care

Currently, no ideal treatment for the thickened nail plate is available, although a few therapeutic options have been suggested.

• The thickened nail plate can be softened by using 20% salicylic acid ointment or 20-40% urea and 10% salicylic acid in an emulsifying ointment with occlusive dressings.
• After the nail plate is softened, it can be mechanically abraded, which is sometimes performed by patients even without softening. This abrasion may be followed by additional softening of the nail plate.
• A 5% 5-fluorouracil cream can be applied twice daily. 5-Fluorouracil cream can be applied after thinning or abrasion of the nail plate to suppress the hyperproliferative activity of the nail matrix.
• Systemic treatment with retinoids (acitretin, retinoic acid) in a daily dose of 1 mg/kg is partially effective; the nail plate becomes thinner and its surface becomes smoother.
• • The adverse effects include potential liver damage, which can be demonstrated by increased liver enzyme levels; an increase in serum lipid levels; hyperostosis; and, the most dangerous, teratogenicity in pregnant women. The benefit-to-risk ratio must be carefully evaluated if treating females of childbearing age.
  • Minor adverse effects are dry and itchy skin, cracking of palmar and plantar skin, nose bleeding, dry mucosa, cheilitis, hair loss, and paronychia.Exostoses and calcination of ligaments and tendons are other minor adverse effect that particularly affect children.
  • Serious adverse effects are headache and brain edema.

Surgical Care

The affected nails can be removed under local or general anesthesia; however, unless the nail matrix is partially removed, nails regrow. After a complete removal of the nail matrix, a disfiguring anonychia may result.

In general, surgical ablation is not recommended, but it can be performed upon a patient's insistence.

Consultations

• A psychiatrist may be consulted if the patient has psychiatric problems related to the abnormal nails.
• A geneticist may be consulted for genetic counseling.

Diet

• Dietary changes seem to have no effect. During eventual systemic treatment with retinoids, the intake of saturated lipids must be limited.

Activity

Certain leisure activities (eg, bowling, soccer) or occupations that require the use of fine movements with hands or fingers should be discouraged.

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medications are used to reduce the symptoms associated with this syndrome. Cure is not yet possible.

Drug Category: Retinoids

Retinoids are a family of drugs related to vitamin A.They regulate the differentiation and proliferation of epithelial cells. Some also possess antitumoral activity.

Drug Category: Antineoplastics

These agents inhibit cell growth and proliferation.

Drug Category: Keratolytics

These agents cause cornified epithelium to swell, soften, macerate, and then desquamate.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Outpatient Care

• Patients receiving systemic retinoids require appropriate laboratory monitoring, including serum pregnancy testing.

Complications

• Paronychia may occur due to the ingrowing of the thickened nail plate.
• Adverse effects observed during treatment with retinoids include dryness of the skin and mucous membranes, nose bleeding, dry eyes, cheilitis, and transient hair loss.

Prognosis

• Nail findings persist, while other manifestations may become less severe later in life.

Patient Education

• Patients and their relatives should be informed that PC 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 PC can affect one half of his or her progeny.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Failure to correctly diagnose PC may result in the inability to provide genetic counseling, correct treatment, or adequate treatment.
• PC can be misdiagnosed as candidiasis or onychomycosis, and unnecessarily treated with antimycotics.

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  The most prominent feature is a substantially thickened, brownish gray nail plate with a rough surface.
	View Full Size Image
Media type:  Photo

Media file 2:  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.
	View Full Size Image
Media type:  Photo

Media file 3:  Hyperkeratotic lesions of the skin may involve acanthosis, hyperkeratosis, and parakeratosis.
	View Full Size Image
Media type:  Photo

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

• Bowden PE, Haley JL, Kansky A, et al. Mutation of a type II keratin gene (K6a) in pachyonychia congenita. Nat Genet. Jul 1995;10(3):363-5. [Medline].
• Cockayne EA. Inherited Abnormalities of the Skin and Appendages. London: Oxford University Press;1933.
• Dawber RPR, Baran R, de Berker D. Disorders of nails. In: Champion RH, et al, eds. Rook/Wilkinson/Ebling: Textbook of Dermatology. 6th ed. Oxford: Blackwell;1998:2834.
• Feinstein A, Friedman J, Schewach-Millet M. Pachyonychia congenita. J Am Acad Dermatol. Oct 1988;19(4):705-11. [Medline].
• Feng YG, Xiao SX, Li L, et al. [A novel keratin 17 gene mutation in a Chinese pedigree of delayed-onset pachyonychia congenita type II]. Zhonghua Yi Xue Za Zhi. Nov 10 2003;83(21):1860-2. [Medline].
• Feng YG, Xiao SX, Ren XR, et al. Keratin 17 mutation in pachyonychia congenita type 2 with early onset sebaceous cysts. Br J Dermatol. Mar 2003;148(3):452-5. [Medline].
• Franzot J, Kansky A, Kavcic S. Pachyonychia congenita (Jadassohn-Lewandowsky syndrome). A review of 14 cases in Slovenia. Dermatologica. 1981;162(6):462-72. [Medline].
• Griffiths WAD, Judge MR, Leigh IM. Disorders of Keratinization. Ibidem;1564-6.
• Hannaford RS, Stapleton K. Pachyonychia congenita tarda. Australas J Dermatol. Aug 2000;41(3):175-7. [Medline].
• Jadassohn J, Lewandowsky F. Pachyonychia congenita. Keratosis disseminata circumscripta (follicularis). Tylomata. Leukokeratosis linguae. In: Jacob's Ikonographia Dermatologica. Vol 1. Berlin: Urban und Schwarzenberg;1906:29-30.
• Kansky A, Dolenc-Voljic, Bowden PE, et al. Mycological examination in pachyonychia congenita. Acta Dermatoven APA. 1998;7:135-8.
• Kumer L, Loos HO. Congenital pachyonychia (Riehl type). Wien Klin Wochenschr. 1935;48:174-78.
• Lucker GP, Steijlen PM. Pachyonychia congenita tarda. Clin Exp Dermatol. May 1995;20(3):226-9. [Medline].
• McKusick V. Mendelian Inheritance in Man. 11th ed. Baltimore, Md: J Hopkins University Press;1994.
• McLean WH, Rugg EL, Lunny DP, et al. Keratin 16 and keratin 17 mutations cause pachyonychia congenita. Nat Genet. Mar 1995;9(3):273-8. [Medline].
• Moldenhauer E, Ernst K. [The Jadassohn-Lewandowsky syndrome]. Hautarzt. Oct 1968;19(10):441-7. [Medline].
• Muller C. On the causes of congenital onychogryphosis. Mcn Med Wochenschr. 1904;49:2180-2.
• Munro CS, Carter S, Bryce S, et al. A gene for pachyonychia congenita is closely linked to the keratin gene cluster on 17q12-q21. J Med Genet. Sep 1994;31(9):675-8. [Medline].
• Pachyonychia Congenita Project. Mission Statement: Find a cure for Pachyonychia Congenita. Accessed May 13, 2005. Available at: http://www.pachyonychia.org/. [Full Text].
• Paller AS, Moore JA, Scher R. Pachyonychia congenita tarda. A late-onset form of pachyonychia congenita. Arch Dermatol. May 1991;127(5):701-3. [Medline].
• Puente JJ. Heredit famili Pachyonychie. Zbl Haut Geschl Kr. 1955;50:309.
• Schnyder UW, Klunker W. Erbliche Verhornungsstörungen der Haut Jadassohn J. Handbuch der Haut und Geschlechtkrankheiten Ergänzungswerk VII. Berlin: Springer;1966:905-8.
• Smith FJ, Fisher MP, Healy E, et al. Novel keratin 16 mutations and protein expression studies in pachyonychia congenita type 1 and focal palmoplantar keratoderma. Exp Dermatol. Jun 2000;9(3):170-7. [Medline].
• Su WP, Chun SI, Hammond DE, Gordon H. Pachyonychia congenita: a clinical study of 12 cases and review of the literature. Pediatr Dermatol. Mar 1990;7(1):33-8. [Medline].
• Terrinoni A, Smith FJ, Didona B, et al. Novel and recurrent mutations in the genes encoding keratins K6a, K16 and K17 in 13 cases of pachyonychia congenita. J Invest Dermatol. Dec 2001;117(6):1391-6. [Medline].
• Touraine A. L'heretn medicine. Paris: Masson;1955:448-9.
• Videni N, Kansky A, Basta-Juzbai A. Pachyonychia congenita (Jadassohn-Lewandowsky syndrome). A review of 25 cases in Croatia. Acta Derm. 1991;18:173-80.
• Ward KM, Cook-Bolden FE, Christiano AM, Celebi JT. Identification of a recurrent mutation in keratin 6a in a patient with overlapping clinical features of pachyonychia congenita types 1 and 2. Clin Exp Dermatol. Jul 2003;28(4):434-6. [Medline].
• Wilson AG. Three cases of hereditary hyperkeratosis of the nail bed. Br J Dermatol. 1905;17:13-14.
• Xiao SX, Feng YG, Ren XR, et al. A novel mutation in the second half of the keratin 17 1A domain in a large pedigree with delayed-onset pachyonychia congenita type 2. J Invest Dermatol. Apr 2004;122(4):892-5. [Medline].
• van Steensel MA, Koedam MI, Swinkels OQ, et al. Woolly hair, premature loss of teeth, nail dystrophy, acral hyperkeratosis and facial abnormalities: possible new syndrome in a Dutch kindred. Br J Dermatol. Jul 2001;145(1):157-61. [Medline].

Article Last Updated: Mar 23, 2007