Non-truncating LIFR mutation: causal for prominent congenital pain insensitivity phenotype with progressive vertebral destruction?
We present a Qatari family with two children who displayed a characteristic phenotype of congenital marked pain insensitivity with hypohidrosis and progressive aseptic destruction of joints and vertebrae resembling that of hereditary sensory and autonomic neuropathies (HSANs). The patients, aged 10 and 14, remained of uncertain genetic diagnosis until whole genome sequencing was pursued. Genome sequencing identified a novel homozygous C65S mutation in the LIFR gene that is predicted to markedly destabilize and alter the structure of a particular domain and consequently to affect the functionality of the whole multi-domain LIFR protein. The C65S mutant LIFR showed altered glycosylation and an elevated expression level that might be attributed to a slow turnover of the mutant form. LIFR mutations have been reported in Stüve-Wiedemann syndrome (SWS), a severe autosomal recessive skeletal dysplasia often resulting in early death. Our patients share some clinical features of rare cases of SWS long-term survivors; however, they also phenocopy HSAN due to the marked pain insensitivity phenotype and progressive bone destruction. Screening for LIFR mutations might be warranted in genetically unresolved HSAN phenotypes.
Section of Neurology, Pediatrics Department, Hamad Medical Corporation, Doha, Qatar.
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Elsaid
Neurogenetics Program, Weill Cornell Medical College, Doha, Qatar.|Neurology and Neuroscience Department, Weill Cornell Medical College, New York, NY, USA.
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Chalhoub
Section of Radiology, Pediatrics Department, Hamad Medical Corporation, Doha, Qatar.
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Kamel
Section of Allergy and Immunology, Pediatrics Department, Hamad Medical Corporation, Doha, Qatar.
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Ehlayel
Medical Molecular Genetics, Department, National Research Centre, Cairo, Egypt.
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Ibrahim
Faculty of Medicine, Suez Canal University, Cairo, Egypt.
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Elsaid
Bioinformatics Core, Weill Cornell Medical College, Doha, Qatar.
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Kumar
Advanced Computing, Weill Cornell Medical College, Doha, Qatar.
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Khalak
Lane Center for Computational Biology, Carnegie Mellon University, Pittsburgh, PA, USA.|Lane Center for Computational Biology, Carnegie Mellon University, Doha, Qatar.
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Ilyin
Bioinformatics Core, Weill Cornell Medical College, Doha, Qatar.|Physiology and Biophysics Department, Weill Cornell Medical College, New York, NY, USA.|Physiology and Biophysics Department, Weill Cornell Medical College, Doha, Qatar.
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Suhre
Neurogenetics Program, Weill Cornell Medical College, Doha, Qatar.|Neurology and Neuroscience Department, Weill Cornell Medical College, New York, NY, USA.
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Abdel Aleem
D000293:Adolescent; D000595:Amino Acid Sequence; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit / Q000737:chemistry / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D000699:Pain Insensitivity, Congenital / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology*; D010641:Phenotype; D011859:Radiography; D013131:Spine / Q000000981:diagnostic imaging / Q000473:pathology*
C507840:LIFR protein, human; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit
AR-HSANs; IL-6; LIFR-altered glycosylation; SWS; congenital pain insensitivity