NNS usually begins to manifest around age 2 years, but onset may be as early as age 2 months or later, around age 6-12 years. The typical features include a pernio-like eruption that occurs in winter, erythematous nodules, elongated clubbed fingers, and lipodystrophy that predominantly affects the face and upper extremities. Periodic fever is also frequent, and joint contractures may develop as the disease progresses. Hepatosplenomegaly, basal ganglia calcifications, and anemia are prevalent phenomena, and developmental disabilities can occur in some cases.
D89.89 – Other specified disorders involving the immune mechanism, not elsewhere classified
E88.1 – Lipodystrophy, not elsewhere classified
L98.9 – Disorder of the skin and subcutaneous tissue, unspecified
702449004 – Autoinflammation, lipodystrophy and dermatosis syndrome
Differential Diagnosis & Pitfalls
- JMP syndrome – PSMB8-related disease, but the syndrome presents with seizure, microcytic anemia, strong joint contracture, no fever, and no developmental disability, unlike NNS.
- CANDLE syndrome – PSMB8-related disease, but affected patients don't present with joint contracture, unlike NNS.
- Aicardi-Goutières syndrome (AGS) – Patients present with basal ganglia calcification and pernio-like rash but do not show lipodystrophy.
- Werner syndrome – Early-onset cataracts and gray hair are not observed in NNS.
- Polymyositis / dermatomyositis
- Inclusion body myositis
- Systemic lupus erythematosus
- Cryopyrin-associated periodic syndrome (CAPS) – Arthritis and IL-1β overproduction are not revealed in NNS.
- Tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS)