eMedicine Specialties > Dermatology > Nails

Pachyonychia Congenita

Author: Aleksej Kansky, MD, PhD, Professor, Department of Dermatology, Ljubljana University Faculty of Medicine, Slovenia
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Updated: Dec 3, 2009

Introduction

Background

Pachyonychia congenita (PC) is a rare form of hereditary palmoplantar keratoderma (PPK). Müller made the first documented observation in 1904.¹ The next reports were published in 1905 by Wilson² and in 1906 by Jadassohn and Lewandowsky.³ In the dermatologic literature, pachyonychia congenita is better known as Jadassohn-Lewandowsky syndrome.

Pachyonychia congenita is rare. According to the Pachyonychia Congenita Project Mission Statement, fewer than 300 cases have been reported. Certain reports include larger series of cases. Moldenhauer and Ernst reviewed 93 cases and described 6 new cases.⁴ Puente reported 26 cases. Kumer and Loos reported 23 cases.⁵ Su reported 12 cases.⁶ Fourteen cases from Slovenia⁷ and 25 cases from Croatia⁸ are reported. Additional reports on larger series of patients describe 19 patients from China⁹ and 13 patients of Italian descent.¹⁰

Various classifications for pachyonychia congenita have been proposed. Currently, 2 distinct syndromes of pachyonychia congenita are recognized: (1) pachyonychia congenita type 1, or the Jadassohn-Lewandowsky type, which is designated as Mendelian Inheritance in Man (MIM) entry 167200,¹¹ and (2) pachyonychia congenita type 2, or the Jackson-Lawler type, which is designated as MIM entry 167210.

For a definitive classification of pachyonychia congenita, more data about genotypic-phenotypic correlation in the same patients are needed.

Pathophysiology

Pachyonychia congenita 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 asparagine 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.¹² Further mutations are 325A to G in the 1A domain of K17⁹ or 275A to G in the same domain.¹³

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.¹⁴ 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 pachyonychia congenita 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 pachyonychia congenita was first mentioned by Cockayne in 1933. He studied the then-available pedigrees of pachyonychia congenita patients and noted that the pedigrees did not exactly match the principle of autosomal dominant inheritance.¹⁵ Lately, a similar view was expressed by MacLean, who introduced the term of a second modifying mutation within a keratin gene.¹⁶ He also stated that approximately 10% of pachyonychia congenita 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 pachyonychia congenita support Cockayne's theory.

Frequency

United States

Pachyonychia congenita is rare. In the United States, only a few reports exist.

International

According to the Pachyonychia Congenita Project Mission Statement, fewer 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 pachyonychia congenita do not endanger the patient's life.

Race

Most likely, all races can be affected by pachyonychia congenita.

Sex

Pachyonychia congenita affects both sexes equally.

Age

• The affected nails are usually present at birth, but they may appear later, as they do in pachyonychia congenita tarda.
• Paller et al described 5 patients in whom the disfigured nails appeared when they were aged 10-30 years.¹⁷ However, molecular biologic analysis was not available to verify the diagnosis. In pachyonychia congenita tarda, thickened nails appear during adult life, which is probably not so rare. However, in the last 10 years, at least 2 cases of pachyonychia congenita tarda were reported.^18,19 According to Connors, the pachyonychia congenita tarda was, in one case, linked to the missense mutation K354N in the central 2B domain of K16. In the other case pachyonychia congenita type 2 was found to be caused by a missense mutation in the second half of the 1A domain of K17, N109D.^9,14

Clinical

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 pachyonychia congenita tarda.

Physical

• Jadassohn-Lewandowsky type, or pachyonychia congenita type 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 pachyonychia congenita type 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, as shown in the image below. 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.
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    The most prominent feature is a substantially thickened, brownish gray nail plate with a rough surface.

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    The most prominent feature is a substantially thickened, brownish gray nail plate with a rough surface.

  • 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, as shown.
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    Hyperkeratotic lesions of the skin may involve acanthosis, hyperkeratosis, and parakeratosis.

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    Hyperkeratotic lesions of the skin may involve acanthosis, hyperkeratosis, and parakeratosis.

  • Leukokeratosis of the oral mucosa, as shown below, is a prominent sign especially of pachyonychia congenita type 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.
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    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.

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    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.

  • 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 pachyonychia congenita.
  • Steatocystoma multiplex is generally considered a hallmark for pachyonychia congenita type 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 pachyonychia congenita type 1.
  • One report describes skeletal abnormalities in a patient with pachyonychia congenita type 1.²⁰
• Jackson-Lawler type, or pachyonychia congenita type 2, is less frequent compared with pachyonychia congenita type 1.
  • Patients have a thickened nail plate, and, eventually, other symptoms appear. The symptoms are similar to those in pachyonychia congenita type 1; however, pachyonychia congenita type 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.¹⁶
  • Hair anomalies (eg, unruly hair) are also described. A new pachyonychia congenita subtype was described in 2 patients,²¹ which included severe and generalized hypotrichia with thickened nails, as in pachyonychia congenita. No mutations in keratin genes encoding K6a, K6b, K16, or K17 were detected. The author has also observed a similar case.
  • Pachyonychia congenita type 2 is linked to mutations in the genes for keratin 6b and K17.
  • Sebaceous cysts may appear later in life.
  • One case report describes an infant with pachyonychia congenita type 2 and the additional unusual findings of microcephaly, seizures, EEG abnormalities, failure to thrive, and heterochromia iridis.²²
• Corneal opacities and cataracts are rare. Reports of such findings were made prior to the classification of pachyonychia congenita into pachyonychia congenita type 1 and pachyonychia congenita type 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, and in fungal infections in immunologically suppressed patients

Causes

An autosomal dominant mode of inheritance is observed in most cases of pachyonychia congenita, 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.¹⁵ A similar view was expressed by MacLean in 2005.
• Munro was the first to propose that the genetic defect in pachyonychia congenita is linked to the keratin gene cluster on chromosome 17.²³
  • In a detailed molecular biologic analysis, McLean et al found that pachyonychia congenita is caused by mutations on chromosomes 16 and 17.
  • More detailed molecular analysis revealed that pachyonychia congenita was caused by mutations in the genes encoding the epidermal keratinocyte keratins K6a, K6b, K16, or K17¹⁶ ; these mutations are responsible for the clinical manifestations.
  • Bowden reported in 1995 that one of the adjacent asparagine residues in the 1A helical encoding region of K6a (N170/N171) was deleted in 5 patients from Slovenia.¹² 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 K17⁹ and 275A to G in the same domain.¹³
• 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.
  • Bai et al report 2 mutations (Y465H and N171D) in the KRT16A gene in 6 Chinese patients (5 from one pedigree, 1 sporadic) with type 1 pachyonychia congenita.²⁴

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