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Pachyonychia congenita

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Description

Pachyonychia congenita is a condition that primarily affects the skin and nails. The signs and symptoms of this condition usually become apparent within the first few years of life.

Almost everyone with pachyonychia congenita shows some signs of hypertrophic nail dystrophy, which causes the fingernails and toenails to become thick and abnormally shaped. Most affected children also develop very painful blisters and calluses on the soles of the feet and, less commonly, on the palms of the hands. This condition is known as palmoplantar keratoderma. Severe blisters and calluses on the feet usually first begin to form in childhood when they first start to walk, and can make walking painful or impossible.

Pachyonychia congenita can have several additional features, which vary among affected individuals. These features include thick, white patches on the tongue and inside of the cheeks (oral leukokeratosis); bumps called follicular keratoses that develop around hair follicles on the elbows, knees, and waistline; cysts in the armpits, groin, back, or scalp; and excessive sweating on the palms and soles (palmoplantar hyperhidrosis). Some affected individuals also develop widespread cysts called steatocystomas, which are filled with an oily substance called sebum that normally lubricates the skin and hair. Some babies with pachyonychia congenita have prenatal or natal teeth, which are teeth that are present at birth or in early infancy. In some cases, pachyonychia congenita can affect the voice box (larynx), causing hoarseness or breathing problems.

Researchers used to distinguish pachyonychia congenita as one of two types, PC-1 or PC-2, based on the genetic cause and pattern of signs and symptoms. However, as more affected individuals were identified, it became clear that the features of the two types overlapped considerably. Now researchers prefer a description of pachyonychia congenita based on the gene that is altered.

Frequency

Although the prevalence of pachyonychia congenita is unknown, it is a rare disorder with several thousand people likely affected worldwide.

Causes

Mutations in several genes, including KRT6A, KRT6B, KRT6C, KRT16, and KRT17, can cause pachyonychia congenita. All of these genes provide instructions for making tough, fibrous proteins called keratins. These proteins form networks that provide strength and resilience to the tissues that make up the skin, hair, and nails.

When pachyonychia congenita is caused by mutations in the KRT6A gene, it is classified as PC-K6a. Similarly, KRT6B gene mutations cause PC-K6b, KRT6C gene mutations cause PC-K6c, KRT16 gene mutations cause PC-K16, and KRT17 gene mutations cause PC-K17.

Mutations in keratin genes alter the structure of keratin proteins, which prevents these proteins from forming strong, stable networks within cells. Without this network, skin cells become fragile and are easily damaged, making the skin less resistant to friction and minor trauma. Even normal activities such as walking can cause skin cells to break down, resulting in the formation of severe, painful blisters and calluses. Defective keratins also disrupt the growth and function of cells in the hair follicles and nails, resulting in the other features of pachyonychia congenita.

Inheritance

Pachyonychia congenita is considered an autosomal dominant condition, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In about 60 to 70 percent of all cases, an affected person inherits the mutation from one affected parent. Thirty to 40 percent of cases result from a new (de novo) mutation in the gene that occurs during the formation of reproductive cells (eggs or sperm) or in early embryonic development. These cases occur in people with no history of the disorder in their family.

Other Names for This Condition

  • congenital pachyonychia
  • Jackson-Lawler syndrome (PC-2)
  • Jadassohn-Lewandowski syndrome (PC-1)
  • pachyonychia congenita syndrome

References

  • Eliason MJ, Leachman SA, Feng BJ, Schwartz ME, Hansen CD. A review of the clinical phenotype of 254 patients with genetically confirmed pachyonychia congenita. J Am Acad Dermatol. 2012 Oct;67(4):680-6. doi: 10.1016/j.jaad.2011.12.009. Epub 2012 Jan 20. Citation on PubMed
  • McLean WH, Hansen CD, Eliason MJ, Smith FJ. The phenotypic and molecular genetic features of pachyonychia congenita. J Invest Dermatol. 2011 May;131(5):1015-7. doi: 10.1038/jid.2011.59. Epub 2011 Mar 24. Review. Citation on PubMed
  • O'Toole EA, Kaspar RL, Sprecher E, Schwartz ME, Rittié L. Pachyonychia congenita cornered: report on the 11th Annual International Pachyonychia Congenita Consortium Meeting. Br J Dermatol. 2014 Nov;171(5):974-7. doi: 10.1111/bjd.13341. Epub 2014 Oct 15. Citation on PubMed
  • Shah S, Boen M, Kenner-Bell B, Schwartz M, Rademaker A, Paller AS. Pachyonychia congenita in pediatric patients: natural history, features, and impact. JAMA Dermatol. 2014 Feb;150(2):146-53. doi: 10.1001/jamadermatol.2013.6448. Citation on PubMed
  • Smith FJ, Liao H, Cassidy AJ, Stewart A, Hamill KJ, Wood P, Joval I, van Steensel MA, Björck E, Callif-Daley F, Pals G, Collins P, Leachman SA, Munro CS, McLean WH. The genetic basis of pachyonychia congenita. J Investig Dermatol Symp Proc. 2005 Oct;10(1):21-30. Review. Citation on PubMed
  • Smith FJD, Hansen CD, Hull PR, Kaspar RL, McLean WHI, O’Toole E, Sprecher E. Pachyonychia Congenita. 2006 Jan 27 [updated 2017 Nov 30]. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from http://www.ncbi.nlm.nih.gov/books/NBK1280/ Citation on PubMed
  • Wilson NJ, O'Toole EA, Milstone LM, Hansen CD, Shepherd AA, Al-Asadi E, Schwartz ME, McLean WH, Sprecher E, Smith FJ. The molecular genetic analysis of the expanding pachyonychia congenita case collection. Br J Dermatol. 2014 Aug;171(2):343-55. doi: 10.1111/bjd.12958. Epub 2014 Aug 6. Citation on PubMed or Free article on PubMed Central
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