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

The leukemia inhibitory factor receptor (LIFR) is a key signaling receptor within the IL-6 cytokine-family, and its integrity is essential for STAT3 and ERK activation in developmental and immune pathways. Recessive, predominantly truncating variants in LIFR cause Stüve-Wiedemann syndrome (SWS), historically a neonatal-lethal skeletal dysplasia. As more individuals survive beyond infancy, the clinical spectrum and its biological basis remain incompletely defined.

We describe the clinical heterogeneity with considerable survival beyond infancy and phenotypic expansions in neurodevelopment and immune dysregulation and determine how missense variants alter cytokine and receptor trafficking. To define the expanded disease spectrum and underlying mechanisms, we assembled an international cohort of 22 previously unreported individuals with biallelic LIFR variants, combined with functional characterization of missense alleles using cellular receptor abundance and STAT/ERK signaling assays, and proteomic profiling of patient-derived bronchoalveolar lavage (BAL) cells.

We identified a markedly expanded phenotype among survivors beyond infancy, including neurodevelopmental disorders, allergy, and hyperinflammatory courses, including COVID-19-associated multisystem inflammatory syndrome in children (MIS-C). In cellular assays, the hypomorphic missense variant p.Cys270Gly showed reduced cell-surface LIF-receptor abundance, STAT/ERK phosphorylation and cellular proliferation upon LIF stimulation. Analysis of additional missense variants revealed functional domain-specific effects: N-terminal extracellular variants retained partial activity, whereas C-terminal cytoplasmic variants showed near-complete loss-of-function. Patient bronchoalveolar-cell proteomics identified dysregulations in endolysosomal recycling of defective LIF-receptor.

Our cohort's findings may position LIFR deficiency as a survivable multisystem disorder with relevant neurological and autoimmune-inflammatory vulnerability. Variant-level functional stratification and proteomic signatures provide a coherent biological framework to support risk assessment and long-term clinical management in affected individuals.