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Nakajo-Nishimura syndrome

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Description

Nakajo-Nishimura syndrome is an inherited condition that affects many parts of the body and has been described only in the Japanese population. Beginning in infancy or early childhood, affected individuals develop red, swollen lumps (nodular erythema) on the skin that occur most often in cold weather; recurrent fevers; and elongated fingers and toes with widened and rounded tips (clubbing).

Later in childhood, affected individuals develop joint pain and joint deformities called contractures that limit movement, particularly in the hands, wrists, and elbows. They also experience weakness and wasting of muscles, along with a loss of fatty tissue (lipodystrophy), mainly in the upper body. The combination of muscle and fat loss worsens over time, leading to an extremely thin (emaciated) appearance in the face, chest, and arms.

Other signs and symptoms of Nakajo-Nishimura syndrome can include an enlarged liver and spleen (hepatosplenomegaly), a shortage of red blood cells (anemia), a reduced amount of blood cells called platelets (thrombocytopenia), and abnormal deposits of calcium (calcification) in an area of the brain called the basal ganglia. Intellectual disability has been reported in some affected individuals.

The signs and symptoms of Nakajo-Nishimura syndrome overlap with those of two other conditions: one called joint contractures, muscular atrophy, microcytic anemia, and panniculitis-induced lipodystrophy (JMP) syndrome; and the other called chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome. All three conditions are characterized by skin abnormalities and lipodystrophy. Although they are often considered separate disorders, they are caused by mutations in the same gene, and some researchers believe they may represent different forms of a single condition.

Frequency

Nakajo-Nishimura syndrome appears to be rare and has been described only in the Japanese population. About 30 cases have been reported in the medical literature.

Causes

Nakajo-Nishimura syndrome is caused by mutations in the PSMB8 gene. This gene provides instructions for making one part (subunit) of specialized cell structures called immunoproteasomes, which are found primarily in immune system cells. Immunoproteasomes play an important role in regulating the immune system's response to foreign invaders, such as viruses and bacteria. One of the primary functions of immunoproteasomes is to help the immune system distinguish the body's own proteins from proteins made by foreign invaders, so the immune system can respond appropriately to infection.

Mutations in the PSMB8 gene greatly reduce the amount of protein produced from the PSMB8 gene, which impairs the normal assembly of immunoproteasomes and causes the immune system to malfunction. For unknown reasons, the malfunctioning immune system triggers abnormal inflammation that can damage the body's own tissues and organs; as a result, Nakajo-Nishimura syndrome is classified as an autoinflammatory disorder.

Abnormal inflammation likely underlies many of the signs and symptoms of Nakajo-Nishimura syndrome, including the nodular erythema, recurrent fevers, joint problems, and hepatosplenomegaly. It is less clear how mutations in the PSMB8 gene lead to muscle wasting and lipodystrophy. Studies suggest that the protein produced from the PSMB8 gene may play a separate role in the maturation of fat cells (adipocytes), and a shortage of this protein may interfere with the normal development and function of these cells.

Inheritance

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.

Other Names for This Condition

  • ALDD
  • autoinflammation, lipodystrophy, and dermatosis syndrome
  • Japanese autoinflammatory syndrome with lipodystrophy
  • JASL
  • Nakajo syndrome
  • NKJO

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

  • Arima K, Kinoshita A, Mishima H, Kanazawa N, Kaneko T, Mizushima T, Ichinose K, Nakamura H, Tsujino A, Kawakami A, Matsunaka M, Kasagi S, Kawano S, Kumagai S, Ohmura K, Mimori T, Hirano M, Ueno S, Tanaka K, Tanaka M, Toyoshima I, Sugino H, Yamakawa A, Tanaka K, Niikawa N, Furukawa F, Murata S, Eguchi K, Ida H, Yoshiura K. Proteasome assembly defect due to a proteasome subunit beta type 8 (PSMB8) mutation causes the autoinflammatory disorder, Nakajo-Nishimura syndrome. Proc Natl Acad Sci U S A. 2011 Sep 6;108(36):14914-9. doi: 10.1073/pnas.1106015108. Epub 2011 Aug 18. Citation on PubMed or Free article on PubMed Central
  • Kanazawa N. Nakajo-Nishimura syndrome: an autoinflammatory disorder showing pernio-like rashes and progressive partial lipodystrophy. Allergol Int. 2012 Jun;61(2):197-206. doi: 10.2332/allergolint.11-RAI-0416. Epub 2012 Mar 25. Review. Citation on PubMed
  • Kitamura A, Maekawa Y, Uehara H, Izumi K, Kawachi I, Nishizawa M, Toyoshima Y, Takahashi H, Standley DM, Tanaka K, Hamazaki J, Murata S, Obara K, Toyoshima I, Yasutomo K. A mutation in the immunoproteasome subunit PSMB8 causes autoinflammation and lipodystrophy in humans. J Clin Invest. 2011 Oct;121(10):4150-60. doi: 10.1172/JCI58414. Epub 2011 Sep 1. Citation on PubMed or Free article on PubMed Central
  • Kitano Y, Matsunaga E, Morimoto T, Okada N, Sano S. A syndrome with nodular erythema, elongated and thickened fingers, and emaciation. Arch Dermatol. 1985 Aug;121(8):1053-6. Citation on PubMed
  • Kunimoto K, Kimura A, Uede K, Okuda M, Aoyagi N, Furukawa F, Kanazawa N. A new infant case of Nakajo-Nishimura syndrome with a genetic mutation in the immunoproteasome subunit: an overlapping entity with JMP and CANDLE syndrome related to PSMB8 mutations. Dermatology. 2013;227(1):26-30. doi: 10.1159/000351323. Epub 2013 Aug 8. Citation on PubMed
  • Tanaka M, Miyatani N, Yamada S, Miyashita K, Toyoshima I, Sakuma K, Tanaka K, Yuasa T, Miyatake T, Tsubaki T. Hereditary lipo-muscular atrophy with joint contracture, skin eruptions and hyper-gamma-globulinemia: a new syndrome. Intern Med. 1993 Jan;32(1):42-5. Review. Citation on PubMed
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