Nakajo-Nishimura Syndrome - Clinical Features, Cause, Diagnosis, and Treatment

Introduction:

Nakajo-Nishimura syndrome was first identified by Dr. Nakajo in 1939 and by Dr. Nishimura in 1950. It is a type of inherited disorder that affects multiple parts of the body and this disorder is seen only in the Japanese population. This syndrome is also referred to as an autoinflammatory disorder because of a mutation in a gene that results in an inflammatory process that destroys the body’s own organs. Nakajo-Nishimura syndrome occurs due to a mutation in PSMB8 (proteasome 20S subunit beta 8) gene. Nakajo-Nishimura syndrome is primarily associated with recurrent fever, nodular erythema (a skin disorder), loss of fat tissue from the upper body, pernio-like rashes (painful rashes on feet), and clubbed fingers. Management includes the use of corticosteroids for rashes, Baricitinib for lipodystrophy, analgesics to reduce the pain, and antibiotics to treat the infections.

What Is Nakajo-Nishimura Syndrome?

Nakajo-Nishimura syndrome is a condition that is inherited in an autosomal recessive pattern in which two copies of the mutated gene from each parent are required to cause the disease and the parents who carry this mutated gene are not affected by this disorder. It is characterized by an inflammatory condition of the skin called nodular erythema and later in childhood contractures (joints that become stiff and short due to tightening of the nearby muscles, tendons, and skin) can develop which can limit movements of elbows, hands, and wrists. Loss of fat tissues and muscle wasting can also occur, which altogether can give a thin appearance to the chest, face, and arms.

What Are the Other Names for Nakajo-Nishimura Syndrome?

Nakajo-Nishimura syndrome is also called:

• Autoinflammation, lipodystrophy, and dermatosis syndrome (ALDD).

• Japanese autoinflammatory syndrome with lipodystrophy (JASL).

• Nakajo syndrome.

What Are the Clinical Features of Nakajo-Nishimura Syndrome?

The onset of this disease occurs at two years of age but in some, the features start to appear at the age of 6 to 12. The clinical features of Nakajo-Nishimura syndrome are

• Nodular erythema (an inflammatory condition of the skin which is characterized by fat lumps under the skin which are painful, and reddish).

• Pernio-like rash (purplish rashes on the feet which are associated with burning sensation, pain, and itching).

• Recurrent fever.

• Hepatosplenomegaly (enlarged spleen and liver).

• Joint problems like contractures (stiffening of joints due to tightening of skin, muscles, and tissues.).

• Lipodystrophy (absence of fat tissue) mainly occurs in the upper body.

• Wasting of muscles.

• Weak muscles.

• Thin body.

• Clubbing (rounded enlargement at the end of the toes and fingers).

• Elongated toes and fingers.

• Anemia (a blood condition in which there is a reduced number of red blood cells).

• Thrombocytopenia (a condition in which there is a reduced number of platelet counts).

• Basal ganglia calcification (a neurodegenerative condition in which there is an abnormal deposition of calcium in the parts of the brain).

• Intellectual disability.

• Osteoperiostosis (inflammatory condition of the bone and outer covering of the bone known as periosteum) occurs rarely.

• Dermatomyositis (muscle inflammation).

What Is the Cause of Nakajo-Nishimura Syndrome?

Nakajo-Nishimura syndrome occurs due to a mutation in the PSMB8 (proteasome 20S subunit beta 8) gene, other syndromes that are caused due to this mutation include joint contractures, muscular atrophy, microcytic anemia, and panniculitis-induced lipodystrophy (JMP) syndrome and chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome. These three conditions are referred to as proteasome-associated autoinflammatory syndromes (PRAASs). The features of this gene are:

• The PSMB8 gene is located on chromosome 6.

• This gene provides information for the production of a part of a cell structure called immunoproteasomes subunit β5i which are a specialized form of proteasomes (a complex that degrades damaged or unwanted proteins) and are found in immune system cells.

• Immunoproteasomes play a role in distinguishing the proteins that are formed by the body from the proteins that are formed by foreign invaders.

• Immunoproteasomes also help in regulating protein homeostasis (balancing proteins intracellularly).

• Immunoproteasomes are also involved in cell growth, cell differentiation, division, chemical signaling within the cells, and maturation of adipocytes (fat cells).

Mutation in the PSMB8 gene can result in the reduction of immunoproteasomes which causes malfunctioning of the immune system. Therefore triggering abnormal inflammation that results in damaging own organs and tissues.

What Is the Diagnosis of Nakajo-Nishimura Syndrome?

The diagnosis of Nakajo-Nishimura syndrome includes:

• Blood test reveals elevated levels of erythrocyte sedimentation rate (the rate at which the red blood cells gets separated from the blood sample and settles down at the bottom of the test tube), C-reactive protein (CRP, a protein that is formed by the liver and increased levels indicated inflammation of the body), and creatine kinase (CK, an enzyme that is found in the heart muscle, skeletal muscle and brain)

• The blood test also shows hypergammaglobulinemia (increased antibodies in the body) and anti-nuclear antibodies (antibodies that occur due to autoimmune disorder).

• The genetic test shows a mutation in the PSMB8 gene.

• The diagnostic criteria for Nakajo-Nishimura syndrome include eight features and even if individuals have four to five features and no mutations, it is considered as Nakajo-Nishimura syndrome. The eight features are:

  • Autosomal Recessive heritability.

  • Calcified basal ganglia.

  • Nodular erythema.

  • Pernio-like rash.

  • Recurrent fever.

  • Lipomuscular dystrophy.

  • Clubbing or joint contractures.

  • hepatosplenomegaly.

What Is the Treatment for Nakajo-Nishimura Syndrome?

Nakajo-Nishimura syndrome does not have any gold standard treatment protocols. But management includes treatment of the discomfort, pain and preventing complications which includes:

• Use of corticosteroids such as Prednisolone 1 to 2 milligrams per kilogram in the case of children and 5 to 10 milligrams per kilogram in adults for skin rashes and fever.

• The use of Baricitinib, a Janus kinase (JAK) inhibitor is effective in the treatment of lipodystrophy.

• Analgesics are given to reduce the pain related to nodular erythema and in case of infections, antibiotics are given.

Conclusion:

Nakajo-Nishimura syndrome is a rare inherited disorder that occurs due to a mutation in the PSMB8 gene. Individuals without the mutation but showing clinical features of these conditions are also categorized in Nakajo-Nishimura syndrome. The prognosis varies among individuals. Some may die in infancy and some in their 30s. Individuals who have severe lipodystrophy, joint contractures, and muscular atrophy have been reported to live till their 60s.