SDHA gain-of-function engages inflammatory mitochondrial retrograde signaling via KEAP1-Nrf2.

Whether screening the metabolic activity of immune cells facilitates discovery of molecular pathology remains unknown. Here we prospectively screened the extracellular acidification rate as a measure of glycolysis and the oxygen consumption rate as a measure of mitochondrial respiration in B cells from patients with primary antibody deficiency. The highest oxygen consumption rate values were detected in three study participants with persistent polyclonal B cell lymphocytosis (PPBL). Exome sequencing identified germline mutations in SDHA, which encodes succinate dehydrogenase subunit A, in all three patients with PPBL. SDHA gain-of-function led to an accumulation of fumarate in PPBL B cells, which engaged the KEAP1-Nrf2 system to drive the transcription of genes encoding inflammatory cytokines. In a single patient trial, blocking the activity of the cytokine interleukin-6 in vivo prevented systemic inflammation and ameliorated clinical disease. Overall, our study has identified pathological mitochondrial retrograde signaling as a disease modifier in primary antibody deficiency.

The VEXAS Syndrome: Uncontrolled Inflammation and Macrocytic Anaemia in a 77-Year-Old Male Patient.

The VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a recently described X-linked autoinflammatory condition caused by a somatic mutation of the UBA1 gene and characterized by an evolving phenotype. This includes inflammatory processes such as recurrent fever, Sweet's syndrome of the skin, pulmonary fibrosis, relapsing polychondritis and venous thromboembolism. An important feature, present in almost all cases, is the development of a macrocytic anaemia with vacuolization of myeloid and erythroid precursors. Usually, these patients require high doses of steroids to control symptoms and respond poorly to disease-modifying drugs. We describe a new case of the VEXAS syndrome presenting with Sweet's syndrome which has now been followed for 6 years. LEARNING POINTS: An inflammatory syndrome with skin and pulmonary involvement in an elderly male patient with haematological abnormalities such as a macrocytic anaemia, myelodysplastic syndrome or venous thrombotic events should raise suspicion of the VEXAS syndrome.Close collaboration between rheumatologists and haematologists is important in diagnosing and managing this complex disorder.

Hypophosphataemia-inducing mesenchymal tumour in the foot.

Tumour-induced (or oncogenic) osteomalacia is a paraneoplastic syndrome characterised by progressive fatigue, muscle weakness, bone pain, non-healing and recurrent fractures caused by mesenchymal tumours that secrete proteins that inhibit renal phosphate transport and 1α-hydroxylation of 25-OH-vitamin D. The potentially curative treatment of choice is complete surgical excision of the tumour.