Skip to main content

Advertisement

SpringerLink
Log in

Detection of genetic hypopituitarism in an adult population of idiopathic pituitary insufficiency patients with growth hormone deficiency

  • Published:
Pituitary Aims and scope Submit manuscript

Abstract

Idiopathic pituitary insufficiency (IPI) is diagnosed in 10% of all hypopituitary patients. There are several known and unknown aetiologies within the IPI group. The aim of this study was to investigate an adult IPI population for genetic cause according a screening schedule. From files of 373 GH deficient (GHD) patients on GH replacement 50 cases with IPI were identified. Of the 39 patients that approved to the study, 25 patients were selected for genetic investigation according to phenotype and 14 patients were not further tested, as sporadic isolated GHD (n = 9) and GHD with diabetes insipidus (n = 5) have low probability for a known genetic cause. Genotyping of all coding exons of HESX1, LHX4, PROP1, POU1F1 and GH1 genes were performed according to a diagnostic algorithm based on clinical, hormonal and neuroradiological phenotype. Among the 25 patients, an overall rate of 8% of mutations was found, and a 50% rate in familial cases. Among two sibling pairs, one pair that presented with complete anterior pituitary insufficiency, had a compound heterozygous PROP1 gene mutation (codons 117 and 120: exon 3 p Phe 117 Ile (c349 T>A) and p Arg 120 Cys (c358 C>T)) with a phenotype of very late onset ACTH-insufficiency. In the other sibling pair and in the sporadic cases no mutation was identified. This study suggests that currently known genetic causes are rare in sporadic adult IPI patients, and that systematic genetic screening is not needed in adult-onset sporadic cases of IPI. Conversely, familial cases are highly suspect for genetic causes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Regal M, Paramo C, Sierra SM, Garcia-Mayor RV (2001) Prevalence and incidence of hypopituitarism in an adult caucasian population in Northwestern Spain. Clin Endocrinol (Oxf) 55:735–740

    Article  CAS  Google Scholar 

  2. Filipsson H, Monson JP, Koltowska-Haggstrom M, Mattsson A, Johannsson G (2006) The impact of glucocorticoid replacement regimens on metabolic outcome and comorbidity in hypopituitary patients. J Clin Endocrinol Metab 91:3954–3961

    Article  PubMed  CAS  Google Scholar 

  3. Dattani MT (2005) Growth hormone deficiency and combined pituitary hormone deficiency: does the genotype matter? Clin Endocrinol (Oxf) 63:121–130

    Article  CAS  Google Scholar 

  4. Dattani MT, Robinson IC (2000) The molecular basis for developmental disorders of the pituitary gland in man. Clin Genet 57:337–346

    Article  PubMed  CAS  Google Scholar 

  5. Kelberman D, Dattani MT (2007) Hypothalamic and pituitary development: novel insights into the aetiology. Eur J Endocrinol 157(Suppl 1):S3-14

    PubMed  Google Scholar 

  6. Hernandez LM, Lee PD, Camacho-Hubner C (2007) Isolated growth hormone deficiency. Pituitary 10:351–357

    Article  PubMed  CAS  Google Scholar 

  7. Deladoey J, Fluck C, Buyukgebiz A, Kuhlmann BV, Eble A et al (1999) “Hot spot” in the PROP1 gene responsible for combined pituitary hormone deficiency. J Clin Endocrinol Metab 84:1645–1650

    Article  PubMed  CAS  Google Scholar 

  8. Bottner A, Keller E, Kratzsch J, Stobbe H, Weigel JF et al (2004) PROP1 mutations cause progressive deterioration of anterior pituitary function including adrenal insufficiency: a longitudinal analysis. J Clin Endocrinol Metab 89:5256–5265

    Article  PubMed  Google Scholar 

  9. Vallette-Kasic S, Barlier A, Teinturier C, Diaz A, Manavela M et al (2001) PROP1 gene screening in patients with multiple pituitary hormone deficiency reveals two sites of hypermutability and a high incidence of corticotroph deficiency. J Clin Endocrinol Metab 86:4529–4535

    Article  PubMed  CAS  Google Scholar 

  10. Vieira TC, da Silva MR, Abucham J (2006) The natural history of the R120C PROP1 mutation reveals a wide phenotypic variability in two untreated adult brothers with combined pituitary hormone deficiency. Endocrine 30:365–369

    Article  PubMed  CAS  Google Scholar 

  11. Turton JP, Mehta A, Raza J, Woods KS, Tiulpakov A et al (2005) Mutations within the transcription factor PROP1 are rare in a cohort of patients with sporadic combined pituitary hormone deficiency (CPHD). Clin Endocrinol (Oxf) 63:10–18

    Article  CAS  Google Scholar 

  12. Osorio MG, Marui S, Jorge AA, Latronico AC, Lo LS et al (2002) Pituitary magnetic resonance imaging and function in patients with growth hormone deficiency with and without mutations in GHRH-R, GH-1, or PROP-1 genes. J Clin Endocrinol Metab 87:5076–5084

    Article  PubMed  CAS  Google Scholar 

  13. Reynaud R, Gueydan M, Saveanu A, Vallette-Kasic S, Enjalbert A et al (2006) Genetic screening of combined pituitary hormone deficiency: experience in 195 patients. J Clin Endocrinol Metab 91:3329–3336

    Article  PubMed  CAS  Google Scholar 

  14. Vieira TC, Boldarine VT, Abucham J (2007) Molecular analysis of PROP1, PIT1, HESX1, LHX3, and LHX4 shows high frequency of PROP1 mutations in patients with familial forms of combined pituitary hormone deficiency. Arq Bras Endocrinol Metabol 51:1097–1103

    Article  PubMed  Google Scholar 

  15. Sloop KW, Walvoord EC, Showalter AD, Pescovitz OH, Rhodes SJ (2000) Molecular analysis of LHX3 and PROP-1 in pituitary hormone deficiency patients with posterior pituitary ectopia. J Clin Endocrinol Metab 85:2701–2708

    Article  PubMed  CAS  Google Scholar 

  16. Kim SS, Kim Y, Shin YL, Kim GH, Kim TU et al (2003) Clinical characteristics and molecular analysis of PIT1, PROP1, LHX3, and HESX1 in combined pituitary hormone deficiency patients with abnormal pituitary MR imaging. Horm Res 60:277–283

    Article  PubMed  CAS  Google Scholar 

  17. Rainbow LA, Rees SA, Shaikh MG, Shaw NJ, Cole T et al (2005) 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 (Oxf) 62:163–168

    Article  CAS  Google Scholar 

  18. Melo ME, Marui S, Carvalho LR, Arnhold IJ, Leite CC et al (2007) Hormonal, pituitary magnetic resonance, LHX4 and HESX1 evaluation in patients with hypopituitarism and ectopic posterior pituitary lobe. Clin Endocrinol (Oxf) 66:95–102

    CAS  Google Scholar 

  19. McNay DE, Turton JP, Kelberman D, Woods KS, Brauner R et al (2007) HESX1 mutations are an uncommon cause of septooptic dysplasia and hypopituitarism. J Clin Endocrinol Metab 92:691–697

    Article  PubMed  CAS  Google Scholar 

  20. Lemos MC, Gomes L, Bastos M, Leite V, Limbert E et al (2006) PROP1 gene analysis in Portuguese patients with combined pituitary hormone deficiency. Clin Endocrinol (Oxf) 65:479–485

    Article  CAS  Google Scholar 

  21. Coya R, Vela A, Perez de Nanclares G, Rica I, Castano L et al (2007) Panhypopituitarism: genetic versus acquired etiological factors. J Pediatr Endocrinol Metab 20:27–36

    Article  PubMed  CAS  Google Scholar 

  22. Arroyo A, Pernasetti F, Vasilyev VV, Amato P, Yen SS et al (2002) A unique case of combined pituitary hormone deficiency caused by a PROP1 gene mutation (R120C) associated with normal height and absent puberty. Clin Endocrinol (Oxf) 57:283–291

    Article  Google Scholar 

  23. Reynaud R, Barlier A, Vallette-Kasic S, Saveanu A, Guillet MP et al (2005) An uncommon phenotype with familial central hypogonadism caused by a novel PROP1 gene mutant truncated in the transactivation domain. J Clin Endocrinol Metab 90:4880–4887

    Article  PubMed  CAS  Google Scholar 

  24. Castinetti F, Saveanu A, Reynaud R, Quentien MH, Buffin A et al (2008) A novel dysfunctional LHX4 mutation with high phenotypical variability in patients with hypopituitarism. J Clin Endocrinol Metab 93:2790–2799

    Article  PubMed  CAS  Google Scholar 

  25. Rajab A, Kelberman D, de Castro SC, Biebermann H, Shaikh H et al (2008) Novel mutations in LHX3 are associated with hypopituitarism and sensorineural hearing loss. Hum Mol Genet 17:2150–2159

    Article  PubMed  CAS  Google Scholar 

  26. Besson A, Salemi S, Gallati S, Jenal A, Horn R et al (2003) Reduced longevity in untreated patients with isolated growth hormone deficiency. J Clin Endocrinol Metab 88:3664–3667

    Article  PubMed  CAS  Google Scholar 

  27. Laron Z (2005) Do deficiencies in growth hormone and insulin-like growth factor-1 (IGF-1) shorten or prolong longevity? Mech Ageing Dev 126:305–307

    Article  PubMed  CAS  Google Scholar 

  28. Bergthorsdottir R, Leonsson-Zachrisson M, Oden A, Johannsson G (2006) Premature mortality in patients with Addison’s disease: a population-based study. J Clin Endocrinol Metab 91:4849–4853

    Article  PubMed  CAS  Google Scholar 

  29. Rosen T, Bengtsson BA (1990) Premature mortality due to cardiovascular disease in hypopituitarism. Lancet 336:285–288

    Article  PubMed  CAS  Google Scholar 

  30. McLennan K, Jeske Y, Cotterill A, Cowley D, Penfold J et al (2003) Combined pituitary hormone deficiency in Australian children: clinical and genetic correlates. Clin Endocrinol (Oxf) 58:785–794

    Article  CAS  Google Scholar 

  31. Halasz Z, Toke J, Patocs A, Bertalan R, Tombol Z et al (2006) High prevalence of PROP1 gene mutations in Hungarian patients with childhood-onset combined anterior pituitary hormone deficiency. Endocrine 30:255–260

    Article  PubMed  CAS  Google Scholar 

  32. Arlt W, Krone N (2007) Adult consequences of congenital adrenal hyperplasia. Horm Res 68(Suppl 5):158–164

    Article  PubMed  Google Scholar 

  33. Wu W, Cogan JD, Pfaffle RW, Dasen JS, Frisch H et al (1998) Mutations in PROP1 cause familial combined pituitary hormone deficiency. Nat Genet 18:147–149

    Article  PubMed  CAS  Google Scholar 

  34. Lazar L, Gat-Yablonski G, Kornreich L, Pertzelan A, Phillip M (2003) PROP-1 gene mutation (R120C) causing combined pituitary hormone deficiencies with variable clinical course in eight siblings of one Jewish Moroccan family. Horm Res 60:227–231

    Article  PubMed  CAS  Google Scholar 

  35. Fluck C, Deladoey J, Rutishauser K, Eble A, Marti U et al (1998) Phenotypic variability in familial combined pituitary hormone deficiency caused by a PROP1 gene mutation resulting in the substitution of Arg → Cys at codon 120 (R120C). J Clin Endocrinol Metab 83:3727–3734

    Article  PubMed  CAS  Google Scholar 

  36. Duquesnoy P, Roy A, Dastot F, Ghali I, Teinturier C et al (1998) Human Prop-1: cloning, mapping, genomic structure. Mutations in familial combined pituitary hormone deficiency. FEBS Lett 437:216–220

    Article  PubMed  CAS  Google Scholar 

  37. de Graaff LC, Argente J, Veenma DC, Herrebout MA, Friesema EC et al (2009) Genetic screening of a Dutch population with isolated GH deficiency (IGHD). Clin Endocrinol (Oxf) 70:742–750

    Article  Google Scholar 

Download references

Acknowledgments

The GENHYPOPIT network for the study of genetic determinants of hypopituitarism, coordinated by TB (thierry.brue@mail.ap-hm.fr), was funded by the Groupement d’Intérêt Scientifique (GIS) Institut des Maladies Rares (GISMR0201) and the Programme Hospitalier de Recherche Clinique (PHRC 25/2003, French Ministry of Health). The present study was supported by the Association pour le Développement des Recherches Biologiques et Médicales au Centre Hospitalier Régional de Marseille (ADEREM). Acknowledgement to the personnel at CEM and to Carina Karlsson and Fredrik Enlund at the Department of Clinical Molecular Pathology at Sahlgrenska University Hospital for the help with preparation of DNA. We also thank Nicole Peyrol and Nadine Pluchino of the Molecular Biology Laboratory for the genetic analysis of transcription factors, Marie Legendre and Serge Amselem from the Department of Clinical and Molecular Genetics, Hôpital Armand Trousseau, Paris for the GH1 gene analysis. Thanks to all participating patients.

Conflict of interest

There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Author information

Authors and Affiliations

  1. Department of Endocrinology, Sahlgrenska Academy, University of Gothenburg, Gröna Stråket 8, 41345, Gothenburg, Sweden

    Helena Filipsson Nyström, Edna J. L. Barbosa, Camilla Glad, Jenny Palming & Gudmundur Johannsson

  2. Department of Endocrinology, Centre Hospitalo-Universitaire Timone, Marseille, France

    Alexandru Saveanu, Anne Barlier & Thierry Brue

  3. Laboratory of Biochemistry and Molecular Biology, Centre Hospitalo-Universitaire Conception, Marseille, France

    Alexandru Saveanu, Anne Barlier & Alain Enjalbert

  4. Laboratory CNRS—UMR 6231, Centre de Recherche en Neurobiologie—Neurophysiologie de Marseille—CRN2M, Université de la Méditerranée—Université Paul Cézanne-CNRS, Marseille, France

    Alexandru Saveanu, Anne Barlier, Alain Enjalbert & Thierry Brue

Authors
  1. Helena Filipsson Nyström
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alexandru Saveanu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Edna J. L. Barbosa
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anne Barlier
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Alain Enjalbert
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Camilla Glad
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jenny Palming
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Gudmundur Johannsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Thierry Brue
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Helena Filipsson Nyström.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nyström, H.F., Saveanu, A., Barbosa, E.J.L. et al. Detection of genetic hypopituitarism in an adult population of idiopathic pituitary insufficiency patients with growth hormone deficiency. Pituitary 14, 208–216 (2011). https://doi.org/10.1007/s11102-010-0278-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11102-010-0278-8

Keywords

Search

Navigation