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Genetics Home Reference: your guide to understanding genetic conditions
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Kuskokwim syndrome

Reviewed November 2013

What is Kuskokwim syndrome?

Kuskokwim syndrome is characterized by joint deformities called contractures that restrict the movement of affected joints. This condition has been found only in a population of native Alaskans known as Yup'ik Eskimos, who live in and around a region of southwest Alaska known as the Kuskokwim River Delta.

In Kuskokwim syndrome, contractures most commonly affect the knees, ankles, and elbows, although other joints, particularly of the lower body, can be affected. The contractures are usually present at birth and worsen during childhood. They tend to stabilize after childhood, and they remain throughout life.

Some individuals with this condition have other bone abnormalities, most commonly affecting the spine, pelvis, and feet. Affected individuals can develop an inward curve of the lower back (lordosis), a spine that curves to the side (scoliosis), wedge-shaped spinal bones, or an abnormality of the collarbones (clavicles) described as clubbing. Affected individuals are typically shorter than their peers and they may have an abnormally large head (macrocephaly).

How common is Kuskokwim syndrome?

Kuskokwim syndrome is extremely rare. It affects a small number of people from the Yup'ik Eskimo population in southwest Alaska.

What genes are related to Kuskokwim syndrome?

Kuskokwim syndrome is caused by mutations in the FKBP10 gene, which provides instructions for making the FKBP65 protein. This protein is important for the correct processing of complex molecules called collagens, which provide structure and strength to connective tissues that support the body's bones, joints, and organs. Collagen molecules are cross-linked to one another to form long, thin fibrils, which are found in the spaces around cells (the extracellular matrix). The formation of cross-links results in very strong collagen fibrils. The FKBP65 protein attaches to collagens and plays a role in their cross-linking.

A mutation in the FKBP10 gene alters the FKBP65 protein, making it unstable and easily broken down. As a result, people with Kuskokwim syndrome have only about 5 percent of the normal amount of FKBP65 protein. This reduction in protein levels impairs collagen cross-linking and leads to a disorganized network of collagen molecules. It is unclear how these changes in the collagen matrix are involved in the development of joint contractures and other abnormalities in people with Kuskokwim syndrome.

Related Gene(s)

Changes in this gene are associated with Kuskokwim syndrome.

  • FKBP10

How do people inherit Kuskokwim syndrome?

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Where can I find information about diagnosis or management of Kuskokwim syndrome?

These resources address the diagnosis or management of Kuskokwim syndrome and may include treatment providers.

  • Genetic Testing Registry: Kuskokwim disease (http://www.ncbi.nlm.nih.gov/gtr/conditions/C1859709)
  • New York University Langone Medical Center: Contractures (http://www.med.nyu.edu/content?ChunkIID=11932)

You might also find information on the diagnosis or management of Kuskokwim syndrome in Educational resources (http://www.ghr.nlm.nih.gov/condition/kuskokwim-syndrome/show/Educational+resources) and Patient support (http://www.ghr.nlm.nih.gov/condition/kuskokwim-syndrome/show/Patient+support).

General information about the diagnosis (http://ghr.nlm.nih.gov/handbook/consult/diagnosis) and management (http://ghr.nlm.nih.gov/handbook/consult/treatment) of genetic conditions is available in the Handbook. Read more about genetic testing (http://ghr.nlm.nih.gov/handbook/testing), particularly the difference between clinical tests and research tests (http://ghr.nlm.nih.gov/handbook/testing/researchtesting).

To locate a healthcare provider, see How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

Where can I find additional information about Kuskokwim syndrome?

You may find the following resources about Kuskokwim syndrome helpful. These materials are written for the general public.

You may also be interested in these resources, which are designed for healthcare professionals and researchers.

What other names do people use for Kuskokwim syndrome?

  • arthrogryposis-like syndrome
  • Kuskokwim disease

For more information about naming genetic conditions, see the Genetics Home Reference Condition Naming Guidelines (http://ghr.nlm.nih.gov/ConditionNameGuide) and How are genetic conditions and genes named? (http://ghr.nlm.nih.gov/handbook/mutationsanddisorders/naming) in the Handbook.

What if I still have specific questions about Kuskokwim syndrome?

Ask the Genetic and Rare Diseases Information Center (http://rarediseases.info.nih.gov/GARD/).

What glossary definitions help with understanding Kuskokwim syndrome?

arthrogryposis ; autosomal ; autosomal recessive ; cell ; collagen ; extracellular ; extracellular matrix ; gene ; inherited ; joint ; lordosis ; macrocephaly ; mutation ; pelvis ; population ; protein ; recessive ; scoliosis ; syndrome

You may find definitions for these and many other terms in the Genetics Home Reference Glossary (http://www.ghr.nlm.nih.gov/glossary).

References

  • Barnes AM, Duncan G, Weis M, Paton W, Cabral WA, Mertz EL, Makareeva E, Gambello MJ, Lacbawan FL, Leikin S, Fertala A, Eyre DR, Bale SJ, Marini JC. Kuskokwim syndrome, a recessive congenital contracture disorder, extends the phenotype of FKBP10 mutations. Hum Mutat. 2013 Sep;34(9):1279-88. doi: 10.1002/humu.22362. Epub 2013 Jul 8. (http://www.ncbi.nlm.nih.gov/pubmed/23712425?dopt=Abstract)
  • Petajan JH, Momberger GL, Aase J, Wright DG. Arthrogryposis syndrome (Kuskokwim disease) in the Eskimo. JAMA. 1969 Sep 8;209(10):1481-6. (http://www.ncbi.nlm.nih.gov/pubmed/4241085?dopt=Abstract)
  • Schwarze U, Cundy T, Pyott SM, Christiansen HE, Hegde MR, Bank RA, Pals G, Ankala A, Conneely K, Seaver L, Yandow SM, Raney E, Babovic-Vuksanovic D, Stoler J, Ben-Neriah Z, Segel R, Lieberman S, Siderius L, Al-Aqeel A, Hannibal M, Hudgins L, McPherson E, Clemens M, Sussman MD, Steiner RD, Mahan J, Smith R, Anyane-Yeboa K, Wynn J, Chong K, Uster T, Aftimos S, Sutton VR, Davis EC, Kim LS, Weis MA, Eyre D, Byers PH. Mutations in FKBP10, which result in Bruck syndrome and recessive forms of osteogenesis imperfecta, inhibit the hydroxylation of telopeptide lysines in bone collagen. Hum Mol Genet. 2013 Jan 1;22(1):1-17. doi: 10.1093/hmg/dds371. Epub 2012 Sep 4. (http://www.ncbi.nlm.nih.gov/pubmed/22949511?dopt=Abstract)

 

The resources on this site should not be used as a substitute for professional medical care or advice. Users seeking information about a personal genetic disease, syndrome, or condition should consult with a qualified healthcare professional. See How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

 
Reviewed: November 2013
Published: November 24, 2014