Nakajo syndrome

Overview

Nakajo syndrome, also known as Nakajo-Nishimura syndrome (NNS), is a very rare inherited autoinflammatory disorder first described in Japan in 1939. The condition is characterized by chronic inflammation, skin rashes, progressive muscle and fat wasting (especially in the upper body and limbs), joint contractures, and periodic fevers. Over time, affected individuals develop elongated fingers and toes with clubbed tips, making the syndrome distinctive in appearance. It is classified as a proteasome-associated autoinflammatory syndrome (PRAAS), sharing features with related disorders like CANDLE syndrome and JMP syndrome.

Nakajo syndrome is most commonly observed in individuals of Japanese descent, but cases have also been reported in other populations. Onset typically occurs in infancy or early childhood, and the disease gradually worsens over time. While it is a lifelong condition, early diagnosis and management can help alleviate symptoms and improve the patient’s quality of life.

Causes

Nakajo syndrome is caused by mutations in the PSMB8 gene, which provides instructions for making a subunit of the immunoproteasome, a protein complex essential for degrading and recycling damaged or misfolded proteins inside cells. The immunoproteasome also plays a vital role in regulating inflammation and immune responses.

When the PSMB8 gene is mutated, the resulting protein dysfunction leads to an accumulation of cellular waste products and dysregulation of inflammatory pathways. This causes persistent activation of the immune system, resulting in chronic inflammation and the clinical features associated with Nakajo syndrome.

The disorder follows an autosomal recessive inheritance pattern, meaning both copies of the gene (one from each parent) must be mutated for the disease to manifest. Parents who carry one copy of the mutated gene typically do not show symptoms.

Symptoms

The symptoms of Nakajo syndrome typically begin in infancy or early childhood and progressively worsen over time. The clinical presentation includes a wide range of inflammatory, dermatologic, and musculoskeletal features:

Early Symptoms

• Recurrent fevers, often unexplained

• Skin rash, particularly a red or purplish rash on the face and extremities

• Swelling in the fingers and toes (dactylitis)

Progressive Features

• Partial lipodystrophy: Progressive loss of subcutaneous fat, especially in the face, upper limbs, and trunk

• Muscle wasting: Reduction in muscle mass over time

• Joint contractures: Limited range of motion in joints, especially elbows and fingers

• Elongated and clubbed fingers/toes: Characteristic deformity developing over time

• Skin lesions: Recurrent nodular erythema and pernio-like lesions (resembling chilblains)

Systemic Features

• Chronic inflammation and elevated inflammatory markers (e.g., CRP, ESR)

• Hepatosplenomegaly (enlargement of the liver and spleen)

• Growth delay or short stature

• Mild cognitive impairment in some cases

Diagnosis

Diagnosis of Nakajo syndrome is based on clinical evaluation, laboratory testing, imaging, and confirmatory genetic analysis. Due to the rarity of the condition and the overlap of symptoms with other autoinflammatory syndromes, diagnosis may be delayed or initially misattributed.

• Clinical evaluation: Detailed assessment of symptoms including fever patterns, skin findings, and skeletal abnormalities

• Laboratory tests: Elevated markers of inflammation (CRP, ESR), anemia, elevated liver enzymes, and low levels of immunoglobulin

• Muscle and fat imaging: MRI or CT to assess lipodystrophy and muscle atrophy

• Skin biopsy: May show perivascular inflammatory infiltrates and panniculitis

• Genetic testing: Identification of biallelic mutations in the PSMB8 gene confirms the diagnosis

Treatment

There is currently no cure for Nakajo syndrome, and treatment focuses on reducing inflammation, managing symptoms, and improving quality of life. A combination of medications and supportive therapies is typically used:

Medical Treatment

• Corticosteroids: Often prescribed to control inflammation, although long-term use has side effects

• Immunosuppressive agents: Such as methotrexate, cyclosporine, or azathioprine for steroid-sparing effect

• Biologics: TNF inhibitors or IL-1/IL-6 blockers may be used with varying success in reducing inflammatory symptoms

• JAK inhibitors: Emerging therapy that may help manage interferon-driven inflammation in some patients

Supportive Therapy

• Physical and occupational therapy to maintain joint function and mobility

• Dietary support for managing fat loss and nutritional deficiencies

• Pain management strategies

Management requires a multidisciplinary approach involving rheumatologists, dermatologists, endocrinologists, and physical therapists. Regular monitoring of organ function and inflammatory markers is important for ongoing care.

Prognosis

The prognosis for Nakajo syndrome varies based on the severity of symptoms and the individual’s response to treatment. The disease is progressive and chronic, with periods of exacerbation and relative remission. While life-threatening complications are rare, the quality of life can be significantly affected by pain, fatigue, physical deformities, and growth failure.

With careful medical management and supportive therapies, many individuals can experience symptom relief and maintain some degree of independence. However, due to the lack of curative treatment and limited global data, long-term outcomes remain uncertain. Ongoing research and genetic studies may help identify more effective targeted therapies in the future.