The proteasome associated autoinflammatory syndromes (PRAAS) are characterized by autosomal recessive mutations in the PSMB8 gene. These mutations result in an early childhood overproduction of inflammatory cytokines due to dysregulation of the interferon gamma pathway with manifestations of recurring fever, nodular erythema, acute phase response and anemia. PRAAS entities include the chronic atypical dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome, Nakajo-Nishimura syndrome (NNS), and joint contractures, muscle atrophy, microcytic anemia and panniculitis-induced lipodystrophy (JMP). Various mutations of the PSMB8 gene result in the overlapping clinical phenotypes seen in these syndromes. Common features of all PRAAS are skin eruptions, progressive lipodystrophy and muscular atrophy/myositis. We describe the clinical features and therapeutic response of a patient at our institution with novel compound heterozygous mutations in the PSMB8 gene.

Methods:

We retrospectively reviewed the medical records of a 14 year old Caucasian female who developed recurring cutaneous eruptions of the face, neck and extremities starting at 3 weeks of age, initially thought to be Sweet’s syndrome. She has maintained continuity of care by a single pediatric rheumatologist at our institution (MD) who has kept a journal of photographs and clinical data.

Results:

The patient was noted to have microcytic anemia from birth. Her rash was resistant to topical agents but responsive to oral corticosteroids. A skin biopsy was suggestive of interstitial granulomatous dermatitis. She had episodic fever and abdominal pain that led to multiple EGDs with only evidence of mild non-specific inflammation. Initial rheumatology evaluation at age 6 revealed an elevated acute phase response and pro-inflammatory analysis demonstrated elevated TNF and IL-8. She developed arthropathy at age 10 and a body MRI obtained due to bone pain demonstrated myositis and panniculitis in the extremities and body wall. She had calcifications in bilateral globus pallidi on MRI. She has been refractory to multiple immunomodulating agents and disease control has been exquisitely sensitive to oral prednisone. Whole exome sequencing revealed compound heterozygous variants in the PSMB8 gene: c.163C>T (p.Q55X) inherited from the mother and c.352T>C (p.S118P) inherited from the father, mutations not previously desribed. Studies elucidating the mechanisms underlying PRAAS have identified the type I interferon pathway as a potential target for therapy. Therefore, we prescribed the Janus kinase (JAK) inhibitor tofacitinib. Subsequently, the patient demonstrated clinical improvement and has successfully decreased oral prednisone to her lowest dose of 1mg daily with only intermittent mild disease flares, triggered by physical and psychoemotional stressors.

Conclusion:

We describe a patient with novel mutations in the PSMB8 gene leading to a PRAAS phenotype, who has demonstrated excellent response to JAK inhibition. Insurance barriers have precluded increasing the dose, however we remain optimistic that titration of therapy will allow successful discontinuation of prednisone and maintain full clinical remission.