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Genetic analysis of adult Slovenian patients with combined pituitary hormone deficiency

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Abstract

Purpose

Among genetic causes of combined pituitary hormone deficiency (CPHD), mutations of genes coding for transcription factors involved in pituitary development have been implicated. Congenital CPHD is a rare disease; therefore, it is important to expand the knowledge about incidence and regional distribution of specific mutations. The aim of this paper is to report results of genetic analyses of adult Slovenian patients with CPHD.

Methods

Twenty-three adult Slovenian patients with early childhood onset CPHD were included in the study. Blood samples were collected through the GENHYPOPIT network to assess possible mutations of six genes (PROP1/HESX1/LHX4/LHX3/POU1F1) involved in the pituitary development following an established algorithm.

Results

In seven out of 23 patients (30%) a specific mutation in genes encoding pituitary transcription factors was discovered. In five patients, two different mutations of the PROP1 gene (c.150delA and c.301-302delAG) were identified. One patient was heterozygous for a missense variant in the LHX4 gene. Additionally, one patient was positive for a mutation in the gene coding for prokineticin receptor-2.

Conclusions

Our study confirms that the two most common mutations of the PROP1 gene globally are also the most frequent mutations in the cohort of adult Slovenian patients with CHPD. Other mutations of pituitary transcription factor genes are extremely rare.

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References

  1. K.S. Alatzoglou, M.T. Dattani, Genetic forms of hypopituitarism and their manifestation in the neonatal period. Early Hum. Dev. 85, 705 (2009)

    Article  PubMed  CAS  Google Scholar 

  2. F. Castinetti, R. Reynaud, M.-H. Quentien, N. Jullien, E. Marquant, C. Rochette, J.-P. Herman, A. Saveanu, A. Barlier, A. Enjalbert, T. Brue, Combined pituitary hormone deficiency: current and future status. J. Endocrinol. Invest. 38, 1 (2015)

    Article  PubMed  CAS  Google Scholar 

  3. F. Castinetti, R. Reynaud, A. Saveanu, N. Jullien, M.H. Quentien, C. Rochette, A. Barlier, A. Enjalbert, T. Brue, Mechanisms in endocrinology: an update in the genetic aetiologies of combined pituitary hormone deficiency. Eur. J. Endocrinol. 174, R239 (2016)

    Article  PubMed  CAS  Google Scholar 

  4. K.S. Alatzoglou, M.T. Dattani. Development of the pituitary and genetic forms of hypopituitarism. in Oxford Textbook Endocrinology Diabetes, eds J. Wass, P. Stewart (Oxford University Press, New York, 2011) 99–112.

  5. M.T. Dattani, I.C. Robinson, The molecular basis for developmental disorders of the pituitary gland in man. Clin. Genet. 57, 337 (2000)

    Article  PubMed  CAS  Google Scholar 

  6. E.A. Webb, M.T. Dattani, Septo-optic dysplasia. Eur. J. Hum. Genet. 18, 393 (2010)

    Article  PubMed  Google Scholar 

  7. M.J. McCabe, C. Gaston-Massuet, L.C. Gregory, K.S. Alatzoglou, V. Tziaferi, O. Sbai, P. Rondard, K. Masumoto, M. Nagano, Y. Shigeyoshi, M. Pfeifer, T. Hulse, C.R. Buchanan, N. Pitteloud, J.-P. Martinez-Barbera, M.T. Dattani, Variations in PROKR2, But Not PROK2, Are Associated With Hypopituitarism and Septo-optic Dysplasia. J. Clin. Endocrinol. Metab. 98, E547 (2013)

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  8. C. Rochette, N. Jullien, A. Saveanu, E. Caldagues, I. Bergada, D. Braslavsky, M. Pfeifer, R. Reynaud, J.-P. Herman, A. Barlier, T. Brue, A. Enjalbert, F. Castinetti, Identifying the deleterious effect of rare LHX4 allelic variants, a challenging issue. PLoS One 10, e0126648 (2015)

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  9. L.A. Rainbow, S.A. Rees, M.G. Shaikh, N.J. Shaw, T. Cole, T.G. Barrett, J.M.W. Kirk, Mutation analysis of POUF-1, PROP-1 and HESX-1 show low frequency of mutations in children with sporadic forms of combined pituitary hormone deficiency and septo-optic dysplasia. Clin. Endocrinol. 62, 163 (2005)

    Article  CAS  Google Scholar 

  10. O.V. Fofanova, N. Takamura, E. Kinoshita, J.S. Parks, M.R. Brown, V.A. Peterkova, O.V. Evgrafov, N.P. Goncharov, A.A. Bulatov, I.I. Dedov, S. Yamashita, A mutational hot spot in the Prop-1 gene in Russian children with combined pituitary hormone deficiency. Pituitary 1, 45 (1998)

    Article  PubMed  CAS  Google Scholar 

  11. R. Navardauskaite, P. Dusatkova, B. Obermannova, R.W. Pfaeffle, W.F. Blum, D. Adukauskiene, N. Smetanina, O. Cinek, R. Verkauskiene, J. Lebl, High prevalence of PROP1 defects in Lithuania: phenotypic findings in an ethnically homogenous cohort of patients with multiple pituitary hormone deficiency. J. Clin. Endocrinol. Metab. 99, 299 (2014)

    Article  PubMed  CAS  Google Scholar 

  12. R. Reynaud, M. Gueydan, A. Saveanu, S. Vallette-Kasic, A. Enjalbert, T. Brue, A. Barlier, Genetic Screening of Combined Pituitary Hormone Deficiency: Experience in 195 Patients. J. Clin. Endocrinol. Metab. 91, 3329 (2006)

    Article  PubMed  CAS  Google Scholar 

  13. J. Lebl, J. Vosáhlo, R.W. Pfaeffle, H. Stobbe, J. Cerná, D. Novotná, J. Zapletalová, B. Kalvachová, V. Hána, V. Weiss, W.F. Blum, Auxological and endocrine phenotype in a population-based cohort of patients with PROP1 gene defects. Eur. J. Endocrinol. 153, 389 (2005)

    Article  PubMed  CAS  Google Scholar 

  14. M. Elizabeth, A.C.S. Hokken-Koelega, J. Schuilwerve, R.P. Peeters, T.J. Visser, L.C.G. de Graaff, Genetic screening of regulatory regions of pituitary transcription factors in patients with idiopathic pituitary hormone deficiencies. Pituitary 21, 76 (2018)

    Article  PubMed  CAS  Google Scholar 

  15. F. De Rienzo, S. Mellone, S. Bellone, D. Babu, I. Fusco, F. Prodam, A. Petri, R. Muniswamy, F. De Luca, M. Salerno, P. Momigliano-Richardi, G. Bona, M. Giordano, Frequency of genetic defects in combined pituitary hormone deficiency: a systematic review and analysis of a multicentre Italian cohort. Clin. Endocrinol. 83, 849 (2015)

    Article  CAS  Google Scholar 

  16. M. Giordano, Genetic causes of isolated and combined pituitary hormone deficiency. Best. Pract. Res. Clin. Endocrinol. Metab. 30, 679 (2016)

    Article  PubMed  CAS  Google Scholar 

  17. K.T. Podkrajsek, N. Bratanic, C. Krzisnik, T. Battelino, Autoimmune regulator-1 messenger ribonucleic acid analysis in a novel intronic mutation and two additional novel AIRE gene mutations in a cohort of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy patients. J. Clin. Endocrinol. Metab. 90, 4930 (2005)

    Article  PubMed  CAS  Google Scholar 

  18. M. Avbelj, H. Tahirovic, M. Debeljak, M. Kusekova, A. Toromanovic, C. Krzisnik, T. Battelino, High prevalence of thyroid peroxidase gene mutations in patients with thyroid dyshormonogenesis. Eur. J. Endocrinol. 156, 511 (2007)

    Article  PubMed  CAS  Google Scholar 

  19. C. Krzisnik, S. Grguric, K. Cvijovic, Z. Laron, Longevity of the Hypopituitary Patients from the Island Krk: a Follow-Up Study. Pediatr. Endocrinol. Rev. 7, 357 (2010)

    PubMed  Google Scholar 

  20. S. Pekic, M. Doknic, D. Miljic, A. Saveanu, R. Reynaud, A. Barlier, T. Brue, V. Popovic, Case seminar: a young female with acute hyponatremia and a sellar mass. Endocrine 40, 325 (2011)

    Article  PubMed  CAS  Google Scholar 

  21. P. Dusatkova, R. Pfäffle, M.R. Brown, N. Akulevich, I.J. Arnhold, M.A. Kalina, K. Kot, C. Krzisnik, M.C. Lemos, J. Malikova, R. Navardauskaite, B. Obermannova, Z. Pribilincova, A. Sallai, G. Stipancic, R. Verkauskiene, O. Cinek, W.F. Blum, J.S. Parks, F. Austerlitz, J. Lebl, Genesis of two most prevalent PROP1 gene variants causing combined pituitary hormone deficiency in 21 populations. Eur. J. Hum. Genet. 24, 415 (2016)

    Article  PubMed  CAS  Google Scholar 

  22. M. Avbelj Stefanija, P. Kotnik, N. Bratanič, M. Žerjav Tanšek, S. Bertok, N. Bratina, T. Battelino, K. Trebušak Podkrajšek, Novel mutations in HESX1 and PROP1 genes in combined pituitary hormone deficiency. Horm. Res. Paediatr. 84, 153 (2015)

    Article  PubMed  CAS  Google Scholar 

  23. S. Richards, N. Aziz, S. Bale, D. Bick, S. Das, J. Gastier-Foster, W.W. Grody, M. Hegde, E. Lyon, E. Spector, K. Voelkerding, H.L. Rehm; ACMG Laboratory Quality Assurance Committee, Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet. Med. 17, 405 (2015)

    Article  PubMed  PubMed Central  Google Scholar 

  24. L.C. Gregory, K.N. Humayun, J.P.G. Turton, M.J. McCabe, S.J. Rhodes, M.T. Dattani, Novel lethal form of congenital hypopituitarism associated with the first recessive LHX4 mutation. J. Clin. Endocrinol. Metab. 100, 2158 (2015)

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  25. H.F. Nyström, A. Saveanu, E.J.L. Barbosa, A. Barlier, A. Enjalbert, C. Glad, J. Palming, G. Johannsson, T. Brue, Detection of genetic hypopituitarism in an adult population of idiopathic pituitary insufficiency patients with growth hormone deficiency. Pituitary 14, 208 (2011)

    Article  PubMed  CAS  Google Scholar 

  26. M.T. Dattani, J.P. Martinez-Barbera, P.Q. Thomas, J.M. Brickman, R. Gupta, I.L. Mårtensson, H. Toresson, M. Fox, J.K. Wales, P.C. Hindmarsh, S. Krauss, R.S. Beddington, I.C. Robinson, Mutations in the homeobox gene HESX1/Hesx1 associated with septo-optic dysplasia in human and mouse. Nat. Genet. 19, 125 (1998)

    Article  PubMed  CAS  Google Scholar 

  27. D.E.G. McNay, J.P. Turton, D. Kelberman, K.S. Woods, R. Brauner, A. Papadimitriou, E. Keller, A. Keller, N. Haufs, H. Krude, S.M. Shalet, M.T. Dattani, HESX1 mutations are an uncommon cause of septooptic dysplasia and hypopituitarism. J. Clin. Endocrinol. Metab. 92, 691 (2007)

    Article  PubMed  CAS  Google Scholar 

  28. C.L. Coulter, R.W. Leech, G.B. Schaefer, B.W. Scheithauer, R.A. Brumback, Midline cerebral dysgenesis, dysfunction of the hypothalamic-pituitary axis, and fetal alcohol effects. Arch. Neurol. 50, 771 (1993)

    Article  PubMed  CAS  Google Scholar 

  29. J. Sarfati, A. Guiochon-Mantel, P. Rondard, I. Arnulf, A. Garcia-Piñero, S. Wolczynski, S. Brailly-Tabard, M. Bidet, M. Ramos-Arroyo, M. Mathieu, A. Lienhardt-Roussie, G. Morgan, Z. Turki, C. Bremont, J. Lespinasse, H. Du Boullay, N. Chabbert-Buffet, S. Jacquemont, G. Reach, N. De Talence, P. Tonella, B. Conrad, F. Despert, B. Delobel, T. Brue, C. Bouvattier, S. Cabrol, M. Pugeat, A. Murat, P. Bouchard, J.-P. Hardelin, C. Dodé, J. Young, A comparative phenotypic study of Kallmann Syndrome patients carrying monoallelic and biallelic mutations in the prokineticin 2 or prokineticin receptor 2 genes. J. Clin. Endocrinol. Metab. 95, 659 (2010)

    Article  PubMed  CAS  Google Scholar 

  30. C. Monnier, C. Dodé, L. Fabre, L. Teixeira, G. Labesse, J.-P. Pin, J.-P. Hardelin, P. Rondard, PROKR2 missense mutations associated with Kallmann syndrome impair receptor signalling activity. Hum. Mol. Genet. 18, 75 (2009)

    Article  PubMed  CAS  Google Scholar 

  31. K.H. Cox, L.M.B. Oliveira, L. Plummer, B. Corbin, T. Gardella, R. Balasubramanian, W.F. Crowley, Modeling mutant/wild-type interactions to ascertain pathogenicity of PROKR2 missense variants in patients with isolated GnRH deficiency. Hum. Mol. Genet. 27, 338 (2018)

    Article  PubMed  CAS  Google Scholar 

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Author information

Authors and Affiliations

  1. Department of Nuclear Medicine, University Medical Centre Ljubljana, Zaloška 7, 1000, Ljubljana, Slovenia

    Katica Bajuk Studen

  2. Department of Pediatric Endocrinology, Diabetes and Metabolism, University Children’s Hospital, University Medical Centre Ljubljana, Bohoriceva 20, 1000, Ljubljana, Slovenia

    Magdalena Avbelj Stefanija

  3. Assistance Publique-Hôpitaux de Marseille (AP-HM), Laboratory of Molecular Biology, Hôpital de la Conception, 13005, Marseille, France

    Alexandru Saveanu & Anne Barlier

  4. Aix-Marseille Université, Institut National de la Santé et de la Recherche Médicale (INSERM), U1251, Marseille Medical Genetics (MMG), Marseille, France

    Alexandru Saveanu, Anne Barlier & Thierry Brue

  5. Assistance Publique-Hôpitaux de Marseille (AP-HM), Centre de Référence des Maladies Rares de l’hypophyse HYPO, Department of Endocrinology, Hôpital de la Conception, 13005, Marseille, France

    Anne Barlier & Thierry Brue

  6. Faculty of Medicine, University of Ljubljana, Vrazov trg 2, 1000, Ljubljana, Slovenia

    Marija Pfeifer

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  1. Katica Bajuk Studen
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Correspondence to Katica Bajuk Studen.

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Bajuk Studen, K., Stefanija, M.A., Saveanu, A. et al. Genetic analysis of adult Slovenian patients with combined pituitary hormone deficiency. Endocrine 65, 379–385 (2019). https://doi.org/10.1007/s12020-019-01949-2

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  • DOI: https://doi.org/10.1007/s12020-019-01949-2

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