Pituitary

, Volume 18, Issue 4, pp 456–460 | Cite as

Effects of leukemia inhibitory receptor gene mutations on human hypothalamo–pituitary–adrenal function

  • Tulay Guran
  • Omer Guran
  • Cem Paketci
  • Osman Kipoglu
  • Irfan Firat
  • Serap Turan
  • Zeynep Atay
  • Belma Haliloglu
  • Abdullah Bereket
Article
First Online:

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.

Objectives

HPA function was investigated in three STWS patients to characterise consequences of impaired LIF/LIFR signalling on adrenal function.

Design

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.

Keywords

LIFR Stuve–Wiedemann Hypothalamo–pituitary–adrenal JAK-STAT 
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Notes

Acknowledgments

The authors are indebted to Dr Valerie Cormier-Daire and her group who performed mutation screening and haplotype analysis of the patients, to Dr Shlomo Melmed for reading the manuscript and for invaluable suggestions. We are also grateful to the patients and families for their participation in our study over the course of laboratory studies.

Conflict of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the study.

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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Tulay Guran
    • 1
    • 2
  • Omer Guran
    • 3
  • Cem Paketci
    • 2
  • Osman Kipoglu
    • 2
  • Irfan Firat
    • 2
  • Serap Turan
    • 1
  • Zeynep Atay
    • 1
  • Belma Haliloglu
    • 1
  • Abdullah Bereket
    • 1
  1. 1.Department of Pediatric Endocrinology, Faculty of MedicineMarmara University HospitalIstanbulTurkey
  2. 2.Department of PediatricsZeynep Kamil Maternity and Children’s Diseases Research and Training State HospitalIstanbulTurkey
  3. 3.Department of NeonatologySisli Etfal Research and Training State HospitalIstanbulTurkey

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