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Palmoplantar keratoderma with deafness

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Description

Palmoplantar keratoderma with deafness is a disorder characterized by skin abnormalities and hearing loss. Affected individuals develop unusually thick skin on the palms of the hands and soles of the feet (palmoplantar keratoderma) beginning in childhood. Hearing loss ranges from mild to profound. It begins in early childhood and gets worse over time. Affected individuals have particular trouble hearing high-pitched sounds.

The signs and symptoms of this disorder may vary even within the same family, with some individuals developing only skin abnormalities and others developing only hearing loss.

Frequency

Palmoplantar keratoderma with deafness is a rare disorder; its prevalence is unknown. At least 10 affected families have been identified.

Causes

Palmoplantar keratoderma with deafness can be caused by mutations in the GJB2 or MT-TS1 genes.

The GJB2 gene provides instructions for making a protein called gap junction beta 2, more commonly known as connexin 26. Connexin 26 is a member of the connexin protein family. Connexin proteins form channels called gap junctions that permit the transport of nutrients, charged atoms (ions), and signaling molecules between neighboring cells that are in contact with each other. Gap junctions made with connexin 26 transport potassium ions and certain small molecules.

Connexin 26 is found in cells throughout the body, including the inner ear and the skin. In the inner ear, channels made from connexin 26 are found in a snail-shaped structure called the cochlea. These channels may help to maintain the proper level of potassium ions required for the conversion of sound waves to electrical nerve impulses. This conversion is essential for normal hearing. In addition, connexin 26 may be involved in the maturation of certain cells in the cochlea. Connexin 26 also plays a role in the growth, maturation, and stability of the outermost layer of skin (the epidermis).

The GJB2 gene mutations that cause palmoplantar keratoderma with deafness change single protein building blocks (amino acids) in connexin 26. The altered protein probably disrupts the function of normal connexin 26 in cells, and may interfere with the function of other connexin proteins. This disruption could affect skin growth and also impair hearing by disturbing the conversion of sound waves to nerve impulses.

Palmoplantar keratoderma with deafness can also be caused by a mutation in the MT-TS1 gene. This gene provides instructions for making a particular type of RNA, a molecule that is a chemical cousin of DNA. This type of RNA, called transfer RNA (tRNA), helps assemble amino acids into full-length, functioning proteins. The MT-TS1 gene provides instructions for a specific form of tRNA that is designated as tRNASer(UCN). This molecule attaches to a particular amino acid, serine (Ser), and inserts it into the appropriate locations in many different proteins.

The tRNASer(UCN) molecule is present only in cellular structures called mitochondria. These structures convert energy from food into a form that cells can use. Through a process called oxidative phosphorylation, mitochondria use oxygen, simple sugars, and fatty acids to create adenosine triphosphate (ATP), the cell's main energy source. The tRNASer(UCN) molecule is involved in the assembly of proteins that carry out oxidative phosphorylation.

The MT-TS1 gene mutation that causes palmoplantar keratoderma with deafness leads to reduced levels of tRNASer(UCN) to assemble proteins within mitochondria. Reduced production of proteins needed for oxidative phosphorylation may impair the ability of mitochondria to make ATP. Researchers have not determined why the effects of the mutation are limited to cells in the inner ear and the skin in this condition.

Inheritance

Palmoplantar keratoderma with deafness can have different inheritance patterns.

When this disorder is caused by GJB2 gene mutations, it is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In most cases, an affected person inherits the mutation from one affected parent. Other cases result from new mutations in the gene and occur in people with no history of the disorder in their family.

When palmoplantar keratoderma with deafness is caused by mutations in the MT-TS1 gene, it is inherited in a mitochondrial pattern, which is also known as maternal inheritance. This pattern of inheritance applies to genes contained in mitochondrial DNA (mtDNA). Because egg cells, but not sperm cells, contribute mitochondria to the developing embryo, children can only inherit disorders resulting from mtDNA mutations from their mother. These disorders can appear in every generation of a family and can affect both males and females, but fathers do not pass traits associated with changes in mtDNA to their children.

Other Names for This Condition

  • palmoplantar hyperkeratosis-deafness syndrome
  • palmoplantar hyperkeratosis-hearing loss syndrome
  • palmoplantar keratoderma-deafness syndrome
  • palmoplantar keratoderma-hearing loss syndrome
  • PPK with deafness
  • PPK-deafness syndrome

Additional Information & Resources

Genetic and Rare Diseases Information Center

Patient Support and Advocacy Resources

Research Studies from ClinicalTrials.gov

Catalog of Genes and Diseases from OMIM

Scientific Articles on PubMed

References

  • Birkenhäger R, Lüblinghoff N, Prera E, Schild C, Aschendorff A, Arndt S. Autosomal dominant prelingual hearing loss with palmoplantar keratoderma syndrome: Variability in clinical expression from mutations of R75W and R75Q in the GJB2 gene. Am J Med Genet A. 2010 Jul;152A(7):1798-802. doi: 10.1002/ajmg.a.33464. Citation on PubMed
  • Caria H, Matos T, Oliveira-Soares R, Santos AR, Galhardo I, Soares-Almeida L, Dias O, Andrea M, Correia C, Fialho G. A7445G mtDNA mutation present in a Portuguese family exhibiting hereditary deafness and palmoplantar keratoderma. J Eur Acad Dermatol Venereol. 2005 Jul;19(4):455-8. Citation on PubMed
  • de Zwart-Storm EA, Hamm H, Stoevesandt J, Steijlen PM, Martin PE, van Geel M, van Steensel MA. A novel missense mutation in GJB2 disturbs gap junction protein transport and causes focal palmoplantar keratoderma with deafness. J Med Genet. 2008 Mar;45(3):161-6. Epub 2007 Nov 9. Citation on PubMed
  • de Zwart-Storm EA, van Geel M, van Neer PA, Steijlen PM, Martin PE, van Steensel MA. A novel missense mutation in the second extracellular domain of GJB2, p.Ser183Phe, causes a syndrome of focal palmoplantar keratoderma with deafness. Am J Pathol. 2008 Oct;173(4):1113-9. doi: 10.2353/ajpath.2008.080049. Epub 2008 Sep 11. Citation on PubMed or Free article on PubMed Central
  • Feldmann D, Denoyelle F, Blons H, Lyonnet S, Loundon N, Rouillon I, Hadj-Rabia S, Petit C, Couderc R, Garabédian EN, Marlin S. The GJB2 mutation R75Q can cause nonsyndromic hearing loss DFNA3 or hereditary palmoplantar keratoderma with deafness. Am J Med Genet A. 2005 Aug 30;137(2):225-7. Citation on PubMed
  • Iossa S, Chinetti V, Auletta G, Laria C, De Luca M, Rienzo M, Giannini P, Delfino M, Ciccodicola A, Marciano E, Franzé A. New evidence for the correlation of the p.G130V mutation in the GJB2 gene and syndromic hearing loss with palmoplantar keratoderma. Am J Med Genet A. 2009 Feb 15;149A(4):685-8. doi: 10.1002/ajmg.a.32462. Citation on PubMed
  • Lee JR, White TW. Connexin-26 mutations in deafness and skin disease. Expert Rev Mol Med. 2009 Nov 19;11:e35. doi: 10.1017/S1462399409001276. Review. Citation on PubMed
  • Lee JY, In SI, Kim HJ, Jeong SY, Choung YH, Kim YC. Hereditary palmoplantar keratoderma and deafness resulting from genetic mutation of Connexin 26. J Korean Med Sci. 2010 Oct;25(10):1539-42. doi: 10.3346/jkms.2010.25.10.1539. Epub 2010 Sep 17. Citation on PubMed or Free article on PubMed Central
  • Maász A, Komlósi K, Hadzsiev K, Szabó Z, Willems PJ, Gerlinger I, Kosztolányi G, Méhes K, Melegh B. Phenotypic variants of the deafness-associated mitochondrial DNA A7445G mutation. Curr Med Chem. 2008;15(13):1257-62. Review. Citation on PubMed
  • Xu J, Nicholson BJ. The role of connexins in ear and skin physiology - functional insights from disease-associated mutations. Biochim Biophys Acta. 2013 Jan;1828(1):167-78. doi: 10.1016/j.bbamem.2012.06.024. Epub 2012 Jul 13. Review. Citation on PubMed or Free article on PubMed Central
  • Yuan Y, Huang D, Yu F, Zhu X, Kang D, Yuan H, Han D, Dai P. A de novo GJB2 (connexin 26) mutation, R75W, in a Chinese pedigree with hearing loss and palmoplantar keratoderma. Am J Med Genet A. 2009 Feb 15;149A(4):689-92. doi: 10.1002/ajmg.a.32461. Citation on PubMed
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