Nakajo-Nishimura syndrome (NNS) is a rare autoinflammatory disorder belonging to the proteasome disability syndrome (see this term) 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.
The prevalence is unknown. In Japan, 30 cases have been identified to date.
Onset appears in early infancy with pernio-like lesions (mainly on fingertips and earlobes) that usually appear during the first winter after birth. This is followed by periodic fever and nodular erythema with infiltration and induration. Progressive lipomuscular atrophy (mainly in the upper body) and interphalangeal joint contractures lead to the characteristic thin and angular facial appearance and to the long clubbed fingers seen eventually in all patients. Central obesity and myositis, leading to muscle weakness, is also noted in some. Other less common manifestations include short stature, heliotrope-like rash on eyelids, severe tylosis on feet and hyperhidrosis of hands and feet. Hepatosplenomegaly is also reported. Lipodystrophy is progressive and irreversible.
NNS is due to a mutation in the PSMB8 gene (6p21.3) encoding the beta5i subunit of immunoproteasome. To date, all examined Japanese patients show the same homozygous c.602G>T (Gly201Val) mutation with a founder effect. Immunoproteasome is involved in proteolysis and maintenance of cell homeostasis. If proteolysis is disrupted this can lead to the accumulation of ubiquitinated and oxidized proteins and the hyperactivation of p38 MAPK signaling with cell stress. The p38 MAPK-induced IL-6 overproduction is thought to be responsible, at least in part, for the manifestations seen in this disease.
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.
Differential diagnoses include other forms of proteasome disability syndrome, mucopolysaccharidosis, familial partial lipodystrophy, systemic lupus erythematosus, lupus erythematosus panniculitis, dermatomyositis, Sjögren syndrome, inclusion body myositis, Aicardi-Goutières syndrome, Weber-Christian disease and cryopyrin-associated periodic syndrome (see these terms).
Prenatal diagnosis is possible but has never been performed.
NNS is inherited in an autosomal recessive manner and genetic counseling is possible.
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.
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.
Last update: March 2014
- Dr Abhimanyu GARG
- Dr Nobuo KANAZAWA