Hypomorphic biallelic LIFR variants define a multisystem disorder with survival beyond infancy and hyperinflammatory vulnerability

LIFR

Biallelic hypomorphic LIFR variants reducing cell-surface receptor abundance and STAT/ERK signaling, with defective endolysosomal recycling

Recessive, predominantly truncating LIFR variants cause Stüve-Wiedemann syndrome, historically a neonatal-lethal skeletal dysplasia. An international cohort of 22 previously unreported individuals with biallelic LIFR variants describes an expanded phenotype among survivors: neurodevelopmental disorders, allergy and hyperinflammatory courses, including COVID-19-associated multisystem inflammatory syndrome in children (MIS-C). The hypomorphic missense variant p.Cys270Gly reduces cell-surface receptor abundance, STAT/ERK phosphorylation and proliferation upon LIF stimulation. N-terminal extracellular missense variants retain partial activity whereas C-terminal cytoplasmic ones are near-complete loss of function, and bronchoalveolar lavage cell proteomics shows defective endolysosomal recycling of the receptor.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

This work moves LIFR deficiency from a lethal neonatal dysplasia to a multisystem disorder of surviving children, with immuno-inflammatory vigilance to be built into follow-up. Domain-based stratification helps interpret an LIFR missense variant found on the exome, but rests on a limited number of tested alleles. The authors themselves frame this repositioning as tentative ("may position").

Analysis by Dr Thibaut Benquey