Download PDF
Semin Reprod Med 2000; 18(1): 021-030
DOI: 10.1055/s-2000-13473
Copyright © 2000 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Pituitary Gene Mutations and the Growth Hormone Pathway

Chanda T. Moseley, John A. Phillips III
  • Division of Medical Genetics, Vanderbilt University School of Medicine, Nashville, Tennessee
Further Information

Publication History

Publication Date:
31 December 2000 (online)

    Permissions and Reprints

ABSTRACT

Hereditary forms of pituitary insufficiency not associated with anatomic defects of the central nervous system, hypothalamus, or pituitary are a heterogeneous group of disorders that result from interruptions at different points in the hypothalamic-pituitary-somatomedin-peripheral tissue axis. These different types of pituitary dwarfism can be classified on the level of the defect; mode of inheritance; whether the phenotype is isolated growth hormone deficiency (IGHD) or combined pituitary hormone deficiency (CPHD); whether the hormone is absent, deficient, or abnormal; and, in patients with GH resistance, whether insulin-like growth factor 1 (IGF1) is deficient due to GH receptor or IGF1 defects. Information on each disorder is summarized. More detailed information can be obtained through the electronic database Online Mendelian Inheritance in Man which is available at http://www3.ncbi.nlm.nih.gov/Omim/.

KEYWORD

hormone (GH) - isolated GH deficiency (IGHD) - combined pituitary hormone deficiency (CPHD)

REFERENCES

  • 1 Rimoin D L, Phillips III A J. Genetic disorders of the pituitary gland. In: Rimoin DL, Connor JM, Pyeritz RE, eds. Principles and Practice of Medical Genetics. 3rd ed. New York: Churchill Livingstone 1997: 1331-1364
    Google Scholar
  • 2 Phillips III J A. Inherited defects in growth hormone synthesis and action. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic Basis of Inherited Disease. 6th ed. New York: McGraw-Hill 1995: 3023-3044
    Google Scholar
  • 3 Carel J-C, Tresca J-P, Letrait M. Growth hormone testing for the diagnosis of growth hormone deficiency in childhood: a population register-based study.  J Clin Metab . 1997;  82 2117-2121
    PubMedGoogle Scholar
  • 4 Cacciari E, Zucchini S, Carla G. Endocrine function and morphological findings in patients with disorders of the hypothalamo-pituitary area: a study with magnetic resonance.  Arch Dis Child . 1990;  65 1199-1202
    PubMedGoogle Scholar
  • 5 Laron Z, Kelijman M, Pertzelan A, Keret R, Shoffner J M, Parks J S. Human growth hormone gene deletion without antibody formation or arrest during treatment: a new disease entity?.  Isr J Med Sci . 1985;  21 999-1006
    PubMedGoogle Scholar
  • 6 Matsuda I, Hata A, Jinno Y. Heterogeneous phenotypes of Japanese cases with a growth hormone gene deletion.  Jpn J Hum Genet . 1987;  32 227-235
    PubMedGoogle Scholar
  • 7 Vnencak-Jones C L, Phillips III A J, Chen E Y, Seeburg P H. Molecular basis of human growth hormone gene deletions.  Proc Natl Acad Sci U S A . 1988;  85 5615-5619
    PubMedGoogle Scholar
  • 8 Vnencak-Jones C L, Phillips III A J, De-fen W. Use of polymerase chain reaction in detection of growth hormone gene deletions.  J Clin Endocrinol Metab . 1990;  70 1550-1553
    PubMedGoogle Scholar
  • 9 Mullis P E, Akinci A, Kanaka C, Eble A, Brook C GD. Prevalence of human growth hormone-1 gene deletions among patients with isolated growth hormone deficiency from different populations.  Pediatr Res . 1992;  31 532-534
    PubMedGoogle Scholar
  • 10 Duquesnoy P, Amselem S, Gourmelen M, LeBouc Y, Goossens M. A frameshift mutation causing isolated growth hormone deficiency type 1A.  Am J Hum Genet . 1990;  47 A110
    PubMedGoogle Scholar
  • 11 Cogan J D, Phillips III A J, Sakati N, Frisch H, Schober E, Milner R DG. Heterogeneous growth hormone (GH) gene mutations in familial GH deficiency.  J Clin Endocrinol Metab . 1993;  76 1224-1228
    CrossrefPubMedGoogle Scholar
  • 12 Cogan J D, Phillips III A J, Schenkman S S, Milner R DG, Sakati N. Familial growth hormone deficiency: a model of dominant and recessive mutations affecting a monomeric protein.  J Clin Endocrinol Metab . 1994;  79 1261-1265
    CrossrefPubMedGoogle Scholar
  • 13 Miller-Davis S, Phillips III A J, Milner R DG, Al-Ashwal A, Sakati N A, Summar M L. Detection of mutations in GH genes and transcripts by analysis of DNA from dried blood spots and mRNA from lymphoblastoid cells. Endocrine Society Program and Abstracts 333, 1993
    Google Scholar
  • 14 Abdul-Latif H D, Brown M R, Parks J S. Mutation of intron 4 of the GH-1 gene causes GH deficiency. Endocrine Society Programs and Abstracts 470, 1995
    Google Scholar
  • 15 Igarashi Y, Ogawa M, Kamijo T. A new mutation causing inherited growth hormone deficiency: a compound heterozygote of a 6.7 kb deletion and two base deletion in the third exon of the GH-1 gene.  Hum Mol Genet . 1993;  2 1073-1074
    PubMedGoogle Scholar
  • 16 Cogan J D, Ramel B, Lehto M. A recurring dominant-negative mutation causes autosomal dominant growth hormone deficiency.  J Clin Endocrinol Metab . 1995;  80 3591-3595
    CrossrefPubMedGoogle Scholar
  • 17 Phillips III A J, Cogan J D. Genetic basis of endocrine disease 6: molecular basis of familial human growth hormone deficiency.  J Clin Endocrinol . 1994;  78 11-16
    PubMedGoogle Scholar
  • 18 Binder G, Ranke M B. Screening for growth hormone (GH) gene splice-site mutations in sporadic cases with severe isolated GH deficiency using ectopic transcript analysis.  J Clin Endocrinol Metab . 1995;  80 1247-1252
    CrossrefPubMedGoogle Scholar
  • 19 Cogan J D, Prince M A, Lekhakula S. A novel mechanism of aberrant pre-mRNA splicing in humans.  Hum Mol Genet . 1997;  6 909-912
    CrossrefPubMedGoogle Scholar
  • 20 Wajnrajch M P, Gertner J M, Moshang T, Saenger P, Leibel R L. Isolated growth hormone (GH) deficiency, type II (IGHD II) caused by substitution of arginine by histidine in C-terminal portion of the GH molecule. Endocrine Society Program Abstracts P2-313, 1996
    Google Scholar
  • 21 Duriez B, Duquesnoy P, Dastot F, Bougneres P, Amselem S, Goossens M. An exon-skipping mutation in the btk gene of a patient with X-linked agammaglobulinemia and isolated growth hormone deficiency.  FEBS Lett . 1994;  346 165-170
    CrossrefPubMedGoogle Scholar
  • 22 Kowarski A A, Schneider J J, Ben-Galim E, Weldon W, Daughaday W H. Growth failure with normal serum RIA-GH and low somatomedin activity: somatomedin restoration and growth acceleration after exogenous GH.  J Clin Endocrinol . 1978;  47 461-464
    PubMedGoogle Scholar
  • 23 Valenta L J, Sigel M B, Lesniak M A. Pituitary dwarfism in a patient with circulating abnormal growth hormone polymers.  N Engl J Med . 1985;  312 214-217
    PubMedGoogle Scholar
  • 24 Takahashi Y, Kaji H, Okimura Y, Goji K, Abe H, Chihara K. Brief report: short stature caused by a mutant growth hormone.  N Engl J Med . 1996;  334 432-436
    CrossrefPubMedGoogle Scholar
  • 25 Wajnrajch M P, Gertner J M, Harbison M D, Chua Jr C S, Leibel R L. Nonsense mutation in the human growth hormone-releasing hormone receptor causes growth failure analogous to the little (lit) mouse.  Nat Genet . 1996;  12 88-90
    PubMedGoogle Scholar
  • 26 Maheshwari H, Silverman B L, Dupuis J, Baumann G. Dwarfism of Sindh: a novel form of familial isolated GH deficiency linked to the locus for the GH releasing hormone receptor. Endocrine Society Program Abstracts OR46-2, 1996
    Google Scholar
  • 27 Salvatori R, Gondo R G, de Aguirar Oliveira H M. Familial isolated growth hormone deficiency due to a novel mutation in the growth hormone-releasing hormone receptor.  J Clin Endocrinol Metab . 1999;  84 917-923
    CrossrefPubMedGoogle Scholar
  • 28 Woods K A, Fraser N C, Postel-Vinay M C, Savage M O, Clar A JL. A homozygous splice site mutation affecting the intracellular domain of the growth hormone (GH) receptor resulting in Laron syndrome with elevated GH-binding protein.  J Clin Endocrinol Metab . 1996;  81 1686-1690
    CrossrefPubMedGoogle Scholar
  • 29 Berg M A, Argente J, Chernausek S. Diverse growth hormone receptor gene mutations in Laron syndrome.  Am J Hum Genet . 1993;  52 998-1005
    PubMedGoogle Scholar
  • 30 Lanes R, Plotnick L P, Spencer E M. Dwarfism associated with normal serum growth hormone and increased bioassayable, receptorassayable, and immunoassayable somatomedin.  J Clin Endocinol . 1980;  50 485
    PubMedGoogle Scholar
  • 31 Woods K A, Camacho-Hubner C, Savage M O, Clark A JL. Intrauterine growth retardation and postnatal growth failure associated with deletion of the insulin-like growth factor 1 gene.  N Engl J Med . 1996;  335 1363-1367
    CrossrefPubMedGoogle Scholar
  • 32 Hermesz E, Mackem S, Mahon K A. Rpx: a novel anterior-restricted homeobox gene progressively activated in the prechordal plate, anterior neural plate and Rathke's pouch of the mouse embryo.  Development . 1996;  122 41-52
    PubMedGoogle Scholar
  • 33 Dattani M T, Martinez-Barbera J-P, Thomas P Q. Mutations in the homeobox gene HESX1/Hesx1 associated with septo-optic dysplasia in human and mouse.  Nat Genet . 1998;  19 125-133
    CrossrefPubMedGoogle Scholar
  • 34 Zhadanov A B, Bertuzzi S, Taira M, Dawid I B, Westphal H. Expression pattern of the murine LIM class homeobox gene Lhx3 in subsets of neural and neuroendocrine tissues.  Dev Dyn . 1995;  202 354-364
    PubMedGoogle Scholar
  • 35 Netchine I, Sobrier M-L, Krude H. Mutations in LHX3 result in a new syndrome revealed by combined pituitary hormone deficiency.  Nat Genet . 2000;  25 182-186
    PubMedGoogle Scholar
  • 36 Tatsumi K, Miyai K, Notomi T. Cretinism with combined pituitary hormone deficiency caused by a mutation in the PIT1 gene.  Nat Genet . 1992;  1 56-58
    PubMedGoogle Scholar
  • 37 Ohta K, Nobukuni Y, Mitsubuchi H. Mutations in the Pit-1 gene in children with combined pituitary hormone deficiency.  Biochem Biophys Res Commun . 1992;  189 851-855
    CrossrefPubMedGoogle Scholar
  • 38 Wit J M, Drayer N M, Jansen M. Total deficiency of growth hormone and prolactin, and partial deficiency of thyroid stimulating hormone in two Dutch families: a new variant of hereditary pituitary deficiency.  Horm Res . 1989;  32 170-177
    PubMedGoogle Scholar
  • 39 Pfaffle R W, DiMattia G E, Parks J S. Mutation of the POU-specific domain of Pit-1 and hypopituitarism without pituitary hypoplasia.  Science . 1992;  257 1118-1121
    PubMedGoogle Scholar
  • 40 Irie Y, Tatsumi K, Ogawa M. A novel E250X mutation of the Pit-1 gene in a patient with combined pituitary hormone deficiency.  Endocr J . 1995;  42 351-354
    PubMedGoogle Scholar
  • 41 Pelligrini-Bouiller I, Belicar P, Barlier A. A new mutation of the gene encoding the transcription factor Pit-1 is responsible for combined pituitary hormone deficiency.  J Clin Endocrinol Metab . 1996;  81 2790-2796
    CrossrefPubMedGoogle Scholar
  • 42 Radovick S, Nation M, Du Y, Bergh L A, Weintraub B D, Wondisford F E. A mutation in the POU-homeodomain of Pit-1 responsible for combined pituitary hormone deficiency.  Science . 1992;  257 1115-1118
    CrossrefPubMedGoogle Scholar
  • 43 Cohen L E, Wondisford F E, Salvantoni A. A hot spot in the Pit-1 gene responsible for combined pituitary hormone deficiency: clinical and molecular correlates.  J Clin Endocrinol Metab . 1995;  80 679-684
    CrossrefPubMedGoogle Scholar
  • 44 Sornson M W, Wu W, Dasen J S. Pituitary lineage determination by the Prophet of Pit-1 homeodomain factor defective in Ames dwarfism.  Nature . 1996;  384 327-333
    CrossrefPubMedGoogle Scholar
  • 45 Wu W, Cogan J D, Pfaffle R W. Mutations in PROP1 cause familial combined pituitary hormone deficiency.  Nat Genet . 1998;  18 147-149
    CrossrefPubMedGoogle Scholar
  • 46 Cogan J D, Wu W, Phillips III A J. The PROP1 2-bp deletion is a common cause of CPHD.  J Clin Endocrinol Metab . 1998;  83 3346-3349
    CrossrefPubMedGoogle Scholar
  • 47 Fofanova O, Takamura N, Kinoshita E. Compound heterozygous deletion of the PROP-1 gene in children with combined pituitary hormone deficiency.  J Clin Endocrinol Metab . 1998;  83 2601-2604
    CrossrefPubMedGoogle Scholar
  • 48 Lagerstrom-Fermer M, Sundvall M, Johnsen E. X-linked recessive panhypopituitarism associated with a regional duplication in Xq25-q26.  Am J Hum Genet . 1997;  60 910-916
    PubMedGoogle Scholar
  • 49 Landis C A, Masters S B, Spada A, Pace A M, Bourne H R, Vallar L. GTPase inhibiting mutations activate the alpha chain of Gs and stimulate adenylyl cyclase in human pituitary tumors.  Nature . 1989;  340 692-696
    Google Scholar
  • 50 Shenker A. Activating mutations in G protein-coupled signaling pathways as a cause of endocrine disease.  Growth Genet Horm . 1996;  12 33-38
    PubMedGoogle Scholar
  • 51 Weinstein L S, Shenker A, Gejman P V, Merino M J, Friedman E, Spiegel A M. Activating mutations of the stimulatory G protein in the McCune-Albright syndrome.  N Engl J Med . 1991;  12 325:1738-1740
    PubMedGoogle Scholar
  • 52 Ranke M B. Growth hormone therapy in children: when to stop?.  Horm Res . 1995;  43 122-125
    PubMedGoogle Scholar
  • 53 Rosen T, Johannsson G, Johansson J O, Bengtsson B A. Consequences of growth hormone deficiency in adults and the benefits and risks of recombinant human growth hormone treatment.  Horm Res . 1995;  43 93-99
    PubMedGoogle Scholar
  • 54 Strasburger C J. Implications of investigating the structure-function relationship of human growth hormone in clinical diagnosis and therapy.  Horm Res . 1994;  41 113-120
    PubMedGoogle Scholar
  • 55 Neely E K, Rosenfeld R G. Use and abuse of human growth hormone.  Annu Rev Med . 1994;  45 407-420
    CrossrefPubMedGoogle Scholar
  • 56 Wyatt D T, Mark D, Slyper A. Survey of growth hormone treatment practices by 251 pediatric endocrinologists.  J Clin Endocrinol Metab . 1995;  80 3292-3297
    CrossrefPubMedGoogle Scholar
      >