A number sign (#) is used with this entry because of evidence that proteasome-associated autoinflammatory syndrome-1 (PRAAS1) is caused by homozygous mutation in the PSMB8 gene (177046) on chromosome 6p21.

Digenic forms of PRAAS1 can be caused by heterozygous mutation in the PSMB8 gene and heterozygous mutation in either the PSMA3 (176843) gene on chromosome 14q23 or in the PSMB4 (602177) on chromosome 1q21.

Proteasome-associated autoinflammatory syndrome-1 (PRAAS1) is an autosomal recessive disorder characterized by early childhood onset of annular erythematous plaques on the face and extremities with subsequent development of partial lipodystrophy and laboratory evidence of immune dysregulation. More variable features include recurrent fever, severe joint contractures, muscle weakness and atrophy, hepatosplenomegaly, basal ganglia calcifications, and microcytic anemia (summary by Agarwal et al., 2010; Kitamura et al., 2011; Arima et al., 2011).

This disorder encompasses Nakajo-Nishimura syndrome (NKJO); joint contractures, muscular atrophy, microcytic anemia, and panniculitis-induced lipodystrophy (JMP syndrome); and chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome (CANDLE). Among Japanese patients, this disorder is best described as Nakajo-Nishimura syndrome, since both Nakajo (1939) and Nishimura et al. (1950) contributed to the original phenotypic descriptions.

Genetic Heterogeneity of Proteasome-Associated Autoinflammatory Syndrome

See also PRAAS2 (618048), caused by mutation in the POMP gene (613386) on chromosome 13q12; PRAAS3 (617591), caused by mutation in the PSMB4 gene (602177) on chromosome 1q21; PRAAS4 (619183), caused by mutation in the PSMG2 gene (609702) on chromosome 18p11; PRAAS5 (619175), caused by mutation in the PSMB10 gene (176847) on chromosome 16q22; and PRAAS6 (620796), caused by mutation in the PSMB9 gene (177045) on chromosome 6p21.

Nakajo (1939) described 2 sibs, born of consanguineous parents, with nodular erythema, elongated and thickened fingers, and emaciation. He called the disorder 'secondary hypertrophic osteoperiostosis with pernio.' Both sibs had cardiomegaly and cardiac insufficiency. Nakajo (1939) thought the changes in the fingers were due to cardiac disease. Nishimura et al. (1950) reported 3 Japanese patients from 2 families with hypertrophic pulmonary osteoarthropathy with pernio-like skin eruptions.

Kitano et al. (1985) found a total of 12 cases including 4 of their own in the Japanese literature. No cases had been reported in Caucasians at that time. The 12 cases were distributed in 8 kindreds, most of which were consanguineous. Other features included large eyes, nose, lips and ears, disproportionately long and thick fingers, and loss of adipose tissue in the upper part of the body.

Yamada et al. (1984) and Tanaka et al. (1993) reported a Japanese brother and sister, born of consanguineous parents, with childhood onset of systemic joint pain and severe deformities of the fingers as well as recurrent skin eruptions followed by progressive loss of fat in the upper and then the lower extremities. The skin eruptions were similar to erythema nodosum, were associated with fever, and were steroid-responsive. The patients also had muscle atrophy and weakness in the areas of lipodystrophy, which resulted in the inability to walk in 1 patient by age 44 years and in the other at age 35 years. Other features included mild mental retardation, hepatomegaly, macroglossia, and extensor plantar responses. Laboratory study of the sister at age 44 years showed increased erythrocyte sedimentation rate (ESR), hypergammaglobulinemia, and impaired glucose tolerance. Brain CT scan showed calcification of the basal ganglia.

Oyanagi et al. (1987) provided follow-up of the brother reported by Yamada et al. (1984) who had died of heart failure at age 47 years after developing cardiac arrhythmias at age 39. Postmortem examination showed severely atrophic skeletal muscles with fibrosis apparent on microscopic examination. There were rimmed vacuoles and lobulated fibers. Electron microscopy showed myofibrillary necrosis, Z-disc streaming, and intramitochondrial paracrystalline inclusions. These changes were considered to be indicative of ischemia. Similar, but less severe, findings were observed in the tongue, extraocular muscles, and heart. Blood vessels in skeletal muscle showed hyperplasia of the media with and narrowing and obstruction of the lumen. Small vessels showed hypertrophy of endothelial cells, whereas arterioles showed hyperplasia of smooth muscle cells with hypertrophy of endothelial cells and some degeneration of endothelial cells. The heart was hypertrophic, with patchy calcification of some vessels. There were also some calcium deposits in vessels of the basal ganglia. Tanaka et al. (1993) noted that 13 other Japanese patients with similar clinical manifestations had been reported, suggesting a distinct clinical entity.

Kitamura et al. (2011) provided clinical details of 3 Japanese patients with Nakajo syndrome, including the patients reported by Tanaka et al. (1993). Patients presented with recurrent high fever with nodular erythema between 1 month and 3 years of age, and began to develop partial lipodystrophy between 6 and 12 years of age. Lipodystrophy was particularly prominent in the face, fingers, and upper limbs. Other features included muscle weakness, deformities of the hands, and frostbitten hands. Laboratory studies showed increased serum C-reactive protein, IgG, and IgA, but autoantibodies were not detected.

Arima et al. (2011) reported 7 patients with the disorder, including the patient reported by Oyanagi et al. (1987). Clinical features included thin facial appearance, partial lipomuscular atrophy, and long clubbed fingers. All had a pernio-like, heliotrope-like, or nodular erythema-like skin rash, and most had periodic fever and joint contractures. All had evidence of chronic inflammation, as indicated by elevated ESR and hypergammaglobulinemia. Most had microcytic anemia, hepatosplenomegaly, and basal ganglia calcification. More variable features included hyperhidrosis and short stature; only 1 had low IQ. About half of patients had various autoantibodies.

Garg et al. (2010) reported a Portuguese man and 2 Mexican sibs with what they termed JMP syndrome, for joint contractures, muscular atrophy, microcytic anemia, and panniculitis-induced lipodystrophy. All had marked generalized lipodystrophy with a progeroid appearance and severe joint contractures of the elbows, hands, fingers, feet, and toes. Onset of lipodystrophy appeared in childhood, after appearance of erythematous nodular skin lesions. Skin biopsy of the skin lesions from 1 patient showed panniculitis. All patients had short stature and muscle atrophy and weakness. Other features included dry, stiff skin, hepatosplenomegaly, microcytic anemia, and hypergammaglobulinemia. Two had mild hypertriglyceridemia, and all 3 had low HDL cholesterol. The Mexican sibs both had seizures, but none of the patients had mental retardation. Garg et al. (2010) noted the phenotypic similarities to the Japanese patients reported by Tanaka et al. (1993), and postulated an autoinflammatory disorder. Laboratory studies of the 2 Mexican sibs performed by Agarwal et al. (2010) showed that both had significantly increased levels of serum IL6 (147620) and gamma-interferon (IFNG; 147570), and 1 had increased IL8 (146930). Other cytokines were not elevated, suggesting a particular biomarker signature. Arima et al. (2011) asserted that the most striking differences between NJKO and JMP (Garg et al., 2010) were the absence of fever in JMP syndrome and the absence of seizures in NJKO.

Torrelo et al. (2010) reported 4 patients, including 2 sibs, with an autoinflammatory disorder characterized by onset in infancy of recurrent fever, annular erythematous skin lesions, persistent violaceous eyelid swelling, poor overall growth, partial lipodystrophy, hepatomegaly, and arthralgias. Laboratory studies showed increased erythrocyte sedimentation rate, C-reactive protein, and hypochromic anemia. All also had intermittent elevated liver enzymes. Two patients had hypertriglyceridemia, 2 had increased platelet counts, and 2 had basal ganglia calcifications. Histologic analysis of skin lesions showed atypical mononuclear infiltrates and mature neutrophils. Torrelo et al. (2010) proposed the acronym chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome (CANDLE) to refer to this presumably autosomal recessive disorder. In 3 of the patients reported by Torrelo et al. (2010), Liu et al. (2012) identified the same homozygous mutation in the PSMB8 gene (T75M; 177046.0001); the fourth patient, who had died at age 14 years, was presumed to carry the same mutation as her sister.

Papendorf et al. (2023) reported a patient (patient 5) who presented at 3 weeks of age with swollen fingertips, fevers, and erythematous maculopapular and nodular episodic rashes. At 4 years of age, she was treated with hydroxychloroquine, but the flares of the rashes continued and she developed arthralgia, headache, and abdominal pain. At 12 years of age, she developed myositis/fasciitis and bilateral basal ganglia calcifications. She was dependent on high-dose steroids, but eventually treatment with tofacitinib resulted in disease remission.

Digenic Inheritance

Brehm et al. (2015) reported 2 brothers (patients 6 and 7) of Irish descent (family 5) with digenic inheritance of PRAAS. The patients carried a heterozygous nonsense mutation in the PSMB4 gene (Y222X; 602177.0001) on 1 allele and a missense mutation in the PSMB8 gene (K105Q; 177046.0005) on the other allele. The patients presented in the first 3 to 4 weeks of life with skin lesions, fever, and anemia. They had annular plaques, violaceous eyelids, hyperpigmented macules, and scarring. Additional features included poor overall growth, lymphadenopathy, hepatosplenomegaly, myositis, arthritis/arthralgias, recurrent infections, joint contractures, and lipodystrophy. Laboratory studies showed elevated acute phase reactants, microcytic anemia, and lymphopenia. Both patients also had intracranial basal ganglia calcifications. One patient had autoantibodies.

Brehm et al. (2015) also reported 2 additional unrelated patients (patients 2 and 3) with digenic PRAAS1. The patients had previously been reported as patients 7 and 9 by Liu et al. (2012), who identified a heterozygous missense mutation in the PRMB8 gene (T75M; 177046.0001) in both patients, but a second mutation could not be found. Using a combination of whole-exome sequencing and screening of proteasomal candidate genes in these patients, Brehm et al. (2015) found that these patients carried a heterozygous mutation in the PSMA3 gene (176843.0001 and 176843.0002, respectively) on 1 allele and the common heterozygous heterozygous T75M missense mutation in the PSMB8 gene on the other allele. The mutations segregated with the disorder in the families, although 1 of the patients had a de novo mutation in the PSMA3 gene. The patients had onset of symptoms in the first months of life. Features were somewhat variable, but included periorbital erythema and edema, violaceous eyelids, fever, skin lesions, myositis, arthralgia, joint contracture, increased acute phase reactants, lymphadenopathy, lipodystrophy, and poor overall growth. Laboratory studies showed thrombocytopenia, hypochromic anemia, lymphopenia, autoantibodies, lipid abnormalities, abnormal liver enzymes, increased acute phase reactants, and hypergammaglobulinemia.

Papendorf et al. (2023) reported a patient (patient 1) with di- or trigenic inheritance of PRAAS1 (see MOLECULAR GENETICS) who presented at 2 weeks of life with redness and swelling of her foot. At 2 months of age, she developed fevers and skin eruptions, and at 7 months of age she developed hepatosplenonmegaly. She continued to have recurrent panniculitis, and laboratory testing showed elevated C-reactive protein. She eventually achieved remission with a combination of tofacitinib and tocilizumab.

The affected sibs reported by Tanaka et al. (1993) were born of consanguineous parents, indicating an autosomal recessive pattern of inheritance. Agarwal et al. (2010) confirmed consanguinity of the parents of the Portuguese patient reported by Garg et al. (2010).

In a detailed review of PRAAS/CANDLE syndrome, Ebstein et al. (2019) discussed the common pathogenetic disease mechanism, which begins with impaired proteasome function and abnormal accumulation of ubiquitinated proteins. This disruption of intracellular homeostasis triggers the unfolded protein response (UPR) in the endoplasmic reticulum (ER), which causes ER stress and activates signaling pathways that lead to induction of the type I interferon inflammatory response by promoting nuclear translocation of inflammatory signaling molecules, such as NFKB (see 164011) and IRF3 (603734). There is also evidence of activation of the integrated stress response (ISR) and inhibition of the mTORC1 (see 601231) signaling pathway.

By genomewide homozygosity mapping followed by candidate gene sequencing of the 3 patients reported by Garg et al. (2010), Agarwal et al. (2010) identified the same homozygous mutation in the PSMB8 gene (T75M; 177046.0001). Studies of patient lymphocytes showed that the mutant protein had markedly decreased chymotrypsin-like activity compared to wildtype, consistent with a decrease in proteasomal activity and loss of function. The findings indicated that dysfunction of the immunoproteasome can result in an autoinflammatory disease.

Kitamura et al. (2011) identified a homozygous PSMB8 mutation (G197V; 177046.0002) in 3 Japanese patients from 2 consanguineous families with Nakajo syndrome. One of the families had previously been reported by Tanaka et al. (1993). The mutation increased assembly intermediates of immunoproteasomes, resulting in decreased proteasome function and ubiquitin-coupled protein accumulation in patient tissues. In vitro studies showed that downregulation of PSMB8 inhibited the differentiation of murine and human adipocytes in vitro, and injection of siRNA against Psmb8 in mouse skin reduced adipocyte tissue volume. The findings indicated that PSMB8 has a role in both inflammation and adipocyte differentiation, explaining the pleiotropic feature of this disorder.

In 5 unrelated Japanese patients with Nakajo-Nishimura syndrome, including 1 of the patients originally reported by Yamada et al. (1984), Arima et al. (2011) identified a homozygous mutation in the PSMB8 gene (G201V; 177046.0003). Haplotype analysis indicated a founder effect. Patient-derived lymphoblastoid cell lines showed markedly decreased chymotrypsin-like, trypsin-like, and caspase-like activity. Arima et al. (2011) noted that the T75M mutant protein reported by Garg et al. (2010) caused only diminished chymotrypsin-like activity, whereas other pepsidase activities remained normal, suggesting a possible biochemical basis for the slightly different phenotype reported by them (JMP syndrome).

In 5 patients with CANDLE syndrome, Liu et al. (2012) identified homozygous mutations in the PSMB8 gene (177046.0001 and 177046.0004). Three of the patients (patients 1, 2, and 4) had previously been reported by Torrelo et al. (2010). The patients had high levels of gamma-interferon-induced protein-10 (CXCL10; 147310), as well as other inflammatory markers. Microarray profiling suggested dysregulation of the interferon signaling pathway, particularly gamma-interferon. Two additional patients (patients 7 and 9) were heterozygous for a PSMB8 T75M mutation, but a second pathogenic mutation could not be found.

In a patient (patient 5) with PRAAS1, Papendorf et al. (2023) identified compound heterozygous mutations in the PSMB8 gene, Q55X (177046.0006) and S118P (177046.0007). The parents were shown to be mutation carriers. Expression of PSMB8 with the Q55X mutation in HeLa cells resulted in no protein expression. Expression of PSMB8 with the S118P mutation in HeLa cells resulted in a protein that was inefficiently incorporated into mature proteasomes.

In 2 unrelated patients reported by Liu et al. (2012) (patients 7 and 9) with a heterozygous T75M PSMB8 mutation, Brehm et al. (2015) identified heterozygous mutations in the PSMA3 gene (176843.0001 and 176843.0002) on the other allele, consistent with digenic inheritance. Brehm et al. (2015) referred to the patients as patient 2 (American/Caucasian origin) and patient 3 (of Spanish origin). Two sibs from another family (family 5) carried a missense mutation in the PSMB8 gene (K105Q; 176843.0005) on 1 allele and a nonsense mutation in the PSMB4 gene (Y222X; 602177.0004) on the other allele, also consistent with digenic inheritance. Detailed functional studies, including in vitro studies of patient cells, expression of the mutations into HeLa cells, and siRNA-mediated knockdown of the PSMB4, PSMB3, and PSMB9 genes, demonstrated that the mutations resulted in variable defects in proteasome 20S and 26S assembly and maturation, with accumulation of proteasome precursor complexes, as well as impaired proteolytic activity. The defects were associated with induction of a type I interferon response with strong expression of IFN-inducible genes and an increase in chemokines and cytokines. Brehm et al. (2015) concluded that mutations in proteasomal subunit genes adversely affect proteasomal function, leading to cell stress and the triggering of a type I IFN gene response, causing a vicious cycle of uncontrolled inflammation in both hematopoietic and nonhematopoietic cells.

In a patient (patient 1) with PRAAS, Papendorf et al. (2023) identified heterozygosity for a T75M mutation in the PSMB8 gene (177046.0001) inherited from her mother, a de novo heterozygous R168X mutation in the PSMA5 gene (176844), and a heterozygous c.1080_1080+10del mutation in the PSMC5 gene (601681), resulting in skipping of exon 10, inherited from her father, consistent with trigenic inheritance. Expression of PSMB8 with the T75M mutation in HeLa cells resulted in a protein that had less efficient maturity compared to wildtype as well as decreased incorporation into 20S/26S complexes. Expression of PSMA5 with the R168X mutation in HeLa cells resulted in no protein expression. Expression of PSMC5 with the c.1080_1080+10del mutation in HeLa cells resulted in protein levels similar to wildtype PSMC5, but the mutant protein was not efficiently incorporated into mature 26S proteasome complexes.