Pachyonychia Congenita

Updated: Mar 30, 2016
  • Author: Saira J George, MD; Chief Editor: William D James, MD  more...
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Overview

Background

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.

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Pathophysiology

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.

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Epidemiology

Frequency

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]

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Prognosis

Pachyonychia congenita is not associated with a reduced lifespan.

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Patient Education

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.

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