Nakajo-Nishimura syndrome (NNS) is a rare autoinflammatory disorder belonging to the group of proteasome disability syndromes. It is characterized by lesions similar to those of perniosis that appear in childhood followed by recurrent fever , nodular skin eruptions, partial lipodystrophy (mainly in the upper extremities and face) and joint contractures.
Summary
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- 1 Synonyms
- 2 Epidemiology
- 3 Clinical description
- 4 Etiology
- 5 Diagnostic methods
- 1 Differential diagnosis
- 2 Prenatal diagnosis
- 6 Genetic advice
- 7 Management and treatment
- 8 Forecast
- 9 Sources
Synonyms
- NNS
- Hypertrophic secondary osteoperiostitis with hinge.
- Fat tissue amyotrophy-abnormality syndrome
epidemiology
Its prevalence is unknown. In Japan , 30 cases have been identified to date.
Clinical description
It is a disorder that begins in early childhood with lesions similar to those of perniosis (mainly on the tips of the fingers and on the ear lobes ) 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 (primarily in the upper body) and interphalangeal joint contractures lead to a characteristic slim, angular facial appearance and long hypocratic fingers finally seen in all patients. Obesity is also seen in somecentral and myositis, which leads to muscle weakness. Other less common manifestations include short stature, a heliotrope rash on the eyelids, severe tylosis on the feet, and hyperhidrosis on the hands and feet. Hepatosplenomegaly has also been described. Lipodystrophy is progressive and irreversible.
Etiology
The NNS is due to a mutation in the PSMB8 gene (6p21.3) that codes for the beta5i subunit of the immunoproteosome. To date, all Japanese patients examined show the same homozygous c.602G> T (Gly201Val) mutation with founder effect. The immunoproteosome is involved in proteolysis and the maintenance of cellular homeostasis . If proteolysis is disrupted, this can lead to accumulation of ubiquitinated and oxidized proteins and hyperactivation of the MAPK p38 signaling pathway with cellular stress. The overproduction of IL-6 induced by MAPK p38 is believed to be responsible, at least in part, for the manifestations seen in this disease .
Diagnostic methods
The diagnosis is based on the presence of at least 5 of the 8 criteria proposed for the NSS: an autosomal recessive pattern of inheritance, violaceous lesions similar to perniosis (in hands and feet), erythemaPersistent nodular syndrome, repetitive fever spikes, long hypocratic fingers and feet with joint contractures, progressive upper-body lipomuscular atrophy / thinning, hepatosplenomegaly, and basal ganglia calcification on computed tomography (CT) scans. Not all of these characteristics are evident until childhood. Histopathological examination reveals focal mononuclear cell infiltration with vascular disease. Laboratory findings include elevated C-reactive protein (CRP) levels and hyper-gamma-globulinemia. Autoantibody titers increase as the disease progresses in some cases, but remains negative in others. Molecular genetics tests identify the disease-causing mutation, confirming the diagnosis.
Differential diagnosis
Differential diagnosis includes other forms of proteasome disability syndrome , mucopolysaccharidosis, familial partial lipodystrophy, systemic lupus erythematosus, lupus erythematosus panniculitis, dermatomyositis, Sjögren’s syndrome, inclusion body myositis, Aicardi-Goutières syndrome, Weber-Christian disease and periodic syndrome associated with cryopyrin.
Prenatal diagnosis
Prenatal diagnosis is possible but has not been carried out to date.
Genetic advice
NNS is inherited autosomal recessively and genetic counseling is possible.
Management and treatment
There is no effective therapeutic treatment for NNS. The fever and skin lesions respond well to the administration of systemic steroids but often recurs after reduction. Additionally, it has many side effects (stunting, glaucoma, and central obesity) associated with long-term use of systemic steroids. Tocilizumab has been shown to be effective in some patients. Although kalidinogenase and dapsone have been reported to be effective in some cases, the effect is temporary. These treatments are all ineffective in stopping the progression of lipodystrophy.
Forecast
Although some of the symptoms of the NNS may be alleviated with treatment, the prognosis remains relatively poor. Some patients may die of heart failure , probably due to lung failure.
