Extended clinical phenotypes and treatment modalities in 32 JAGN1-deficient patients: a multicenter study by ESID and EBMT IEWP.

Jagunal-homolog1 (JAGN1) is an endoplasmic reticulum-resident protein, which is part of the early secretory pathway and granulocyte colony-stimulating factor (CSF; G-CSF) receptor-mediated signaling. Autosomal recessively inherited variants in JAGN1 lead to congenital neutropenia, early-onset bacterial infections, aphthosis, and skin abscesses due to aberrant differentiation and maturation of neutrophils. Bone metabolism disorders and syndromic phenotype, including facial features, short stature, and neurodevelopmental delay, have been reported. Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a treatment option for patients who respond poorly to therapy with G-CSF and those who suffer from complicated infections. In a retrospective multicenter study, data from 32 patients with JAGN1 deficiency were collected to describe the disease, perform phenotype-genotype analysis, and evaluate treatment modalities. Patients presented with 9 homozygous mutations in JAGN1. All patients experienced infectious complications. Twelve patients presented with short stature and facial features. Neurodevelopmental delay was observed in 4 patients from 3 families. Variant c.3G>A p.Met1, found in 9 patients, was never connected to extramedullary symptoms, except for short stature in 1 patient. Patients with the variants c.63G>T, p.Glu21Asp and c130c>T p.His44 Tyr presented more often with syndromic facial features and bone metabolism disorders. Six patients underwent allogeneic stem cell transplantation due to therapy-refractory neutropenia and severe infections, 1 received the graft because of myelodysplastic syndrome and secondary acute myeloid leukemia. Two patients had to undergo a second transplantation because of autologous reconstitution. One patient who did not undergo transplantation died at age 5 years due to pancolitis and septicemia. All 31 other patients were alive and healthy at the last follow-up.