IL11RA‐related Crouzon‐like autosomal recessive craniosynostosis in 10 new patients: Resemblances and differences

Abstract

By describing 10 new patients recruited in centres for Human Genetics, we further delineate the clinical spectrum of a Crouzon-like craniosynostosis disorder, officially termed craniosynostosis and dental anomalies (MIM614188). Singularly, it is inherited according to an autosomal recessive mode of inheritance. We identified six missense mutations in IL11RA, a gene encoding the alpha subunit of interleukin 11 receptor, 4 of them being novel, including 2 in the Ig-like C2-type domain. A subset of patients had an associated connective tissue disorder with joint hypermobility and intervertebral discs fragility. A smaller number of teeth anomalies than that previously reported in the two large series of patients evaluated in dental institutes points toward an ascertainment bias.

Evolution of the phenotype of craniosynostosis with dental anomalies syndrome and report of IL11RA variant population frequencies in a Crouzon‐like autosomal recessive syndrome

“…Autosomal recessive CRSDA does share many clinical features of FGFR2 ‐related Crouzon syndrome and many patients have been suggested to have a Crouzon‐like phenotype (Brischoux‐Boucher et al, ; Keupp et al, ; Miller et al, ; Nieminen et al, ). Multisuture craniosynostosis is most common, but single suture involvement of the sagittal or coronal suture is also reported.…”

“…Hearing impairment has not been comprehensively evaluated in the previous reports of CRSDA, although Brischoux‐Boucher et al () specifically noted that it was not present in their 10 patients. Our Patient 1 had documented normal hearing as a teenager, but Patient 2 is the first to have documented ossicular malformation leading to conductive hearing loss.…”

“…Since then, 12 additional families have been reported as Crouzon‐like or as an unknown craniosynostosis syndrome. These consanguineous and non‐consanguineous families from Europe, Algeria, Morocco, and Turkey are reported with biallelic mutations in IL11RA supporting autosomal recessive inheritance (Brischoux‐Boucher et al, ; Keupp et al, ; Miller et al, ). We report detailed clinical information on two adult brothers with IL11RA ‐related craniosynostosis syndrome including serial photographs of the evolving phenotype.…”

IL-11 neutralising therapies target hepatic stellate cell-induced liver inflammation and fibrosis in NASH

“…Here we show that key NASH 32 factors induce IL-11, which drives an autocrine and ERK-dependent activation loop 33 to initiate and maintain HSC-to-myofibroblast transformation, causing liver fibrosis. 34 IL-11 is upregulated in NASH and Il11ra1-deleted mice are strongly protected from 35 liver fibrosis, inflammation and steatosis in murine NASH. Therapeutic inhibition of 36 IL11RA or IL-11 with novel neutralizing antibodies robustly inhibits NASH pathology 37 in preclinical models and reverses established liver fibrosis by promoting HSC 38 senescence and favourable matrix remodelling.…”

“…Human34 and mouse 17 knockouts of IL11RA have mild developmental abnormalities 371 of the skull but are otherwise healthy and IL-11 appears largely redundant in adult…”