Nakajo Nishimura syndrome

Alternate names

Amyotrophy fat tissue anomaly

Definition

Nakajo-Nishimura syndrome (NNS) is a rare autoinflammatory disorder belonging to the proteasome disability syndrome group, and characterized by pernio-like lesions appearing in infancy followed by recurrent fever, nodular skin eruption, partial lipodystrophy (mainly in upper extremities and face) and joint contractures.

Epidemiology

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.

Cause

• 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.

Gene mutations

• 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

Autosomal recessive inheritance, a 25% chance

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.

Signs and symptoms

• 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.

Diagnosis

• Diagnosis is based on the presence of at least 5 out of 8 proposed criteria for NNS: an autosomal recessive inheritance pattern, pernio-like purplish lesions (on hands and feet), haunting nodular erythema, repetitive spiking fever, long clubbed fingers and toes with joint contractures, progressive upper body lipomuscular atrophy/emaciation, hepatosplenomegaly and basal ganglion calcification on computed tomography (CT) scans.
• Not all of these features are apparent until childhood.
• Histopathologic examination reveals focal mononuclear cell infiltration with vasculopathy.
• Laboratory findings include constantly elevated C-reactive protein (CRP) levels and hyper-gamma-globulinemia.
• Autoantibody titers increase as the disease progresses in some but remain negative in others.
• Molecular genetic testing can identify a disease causing mutation, confirming diagnosis.

Treatment

• There is no effective therapeutic regimen for NNS.
• Fever and skin lesions respond well to systemic steroid administration but usually reoccur after tapering.
• Also, there are many side effects (growth retardation, glaucoma and central obesity) associated with long-term systemic steroid use.
• Tocilizumab has shown efficacy in some patients.
• Although kallidinogenase and dapsone have been reported to be effective in some, the effect is temporary.
• These treatments are all ineffective in halting lipodystrophy progression.

Prognosis

• Although some of the symptoms of NNS can be lessened with treatment, the prognosis remains relatively poor.
• Some may die from sudden cardiac failure, probably due to lung insufficiency.

NIH genetic and rare disease info

• NIH info on Nakajo Nishimura syndrome

Nakajo Nishimura syndrome is a rare disease.

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