title: Effects of leukemia inhibitory receptor gene mutations on human hypothalamo-pituitary-adrenal function.
abstract: BACKGROUND
  Stuve-Wiedemann syndrome (STWS) (MIM #601559) is a rare autosomal recessive disorder caused by mutations in the leukemia inhibitory factor receptor (LIFR) gene. STWS has a diverse range of clinical features involving hematopoietic, skeletal, neuronal and immune systems. STWS manifests a high mortality due to increased risk of sudden death. Heterodimerization of the LIFR mediates leukemia inhibitory factor (LIF) signalling through the intracellular Janus kinase (JAK)/STAT3 signalling cascade. The LIF/LIFR system is highly expressed in and regulates the hypothalamo-pituitary-adrenal (HPA) axis.
  
  
  OBJECTIVE
  HPA function was investigated in three STWS patients to characterise consequences of impaired LIF/LIFR signalling on adrenal function.
  
  
  METHODS
  Six genetically proven STWS patients from four unrelated Turkish families were included in the study. Sudden death occurred in three before 2 years of age. Basal adrenal function tests were performed by measurement of early morning serum cortisol and plasma ACTH concentrations on at least two different occasions. Low dose synacthen stimulation test and glucagon stimulation tests were performed to explore adrenal function in three patients who survived.
  
  
  RESULTS
  All patients carried the same LIFR (p.Arg692X) mutation. Our oldest patient had attenuated morning serum cortisol and plasma ACTH levels at repeated measurements. Two of three patients had attenuated cortisol response (<18 μg/dl) to glucagon, one of whom also had borderline cortisol response to low dose (1 μg) ACTH stimulation consistent with central adrenal insufficiency.
  
  
  CONCLUSIONS
  STWS patients may develop central adrenal insufficiency due to impaired LIF/LIFR signalling. LIF/LIFR system plays a role in human HPA axis regulation.
authors.affiliation: Department of Pediatric Endocrinology, Faculty of Medicine, Marmara University Hospital, Fevzi Cakmak Mh.Mimar Sinan Cd.No 41., Ustkaynarca/Pendik, 34899, Istanbul, Turkey, t.guran@bham.ac.uk.
authors.forename: Tulay
authors.initials: T
authors.lastname: Guran
authors.forename: Omer
authors.initials: O
authors.lastname: Guran
authors.forename: Cem
authors.initials: C
authors.lastname: Paketci
authors.forename: Osman
authors.initials: O
authors.lastname: Kipoglu
authors.forename: Irfan
authors.initials: I
authors.lastname: Firat
authors.forename: Serap
authors.initials: S
authors.lastname: Turan
authors.forename: Zeynep
authors.initials: Z
authors.lastname: Atay
authors.forename: Belma
authors.initials: B
authors.lastname: Haliloglu
authors.forename: Abdullah
authors.initials: A
authors.lastname: Bereket
mesh_terms: D000309:Adrenal Insufficiency / Q000235:genetics* / Q000378:metabolism; D000324:Adrenocorticotropic Hormone / Q000097:blood*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005097:Exostoses, Multiple Hereditary / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000097:blood*; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism*; D007223:Infant; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit / Q000235:genetics*; D008297:Male; D009154:Mutation; D010009:Osteochondrodysplasias / Q000235:genetics* / Q000378:metabolism; D010913:Pituitary-Adrenal System / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C507840:LIFR protein, human; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; D000324:Adrenocorticotropic Hormone; D006854:Hydrocortisone