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Gene Review

IGHD  -  immunoglobulin heavy constant delta

Homo sapiens

Synonyms: FLJ00382, FLJ46727, Ig delta chain C region, MGC29633
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Disease relevance of IGHD

  • This second GHRH-LI peak and the rise of plasma GH after hypoglycemia were absent in patients with IGHD, whereas the first peak of plasma GHRH-LI appeared shortly after glucose ingestion in these patients as well as in normal subjects [1].
  • We describe a novel mutation in the GHRHR gene as cause of dwarfism in the largest kindred with familial IGHD described to date [2].
  • Finally, it was found that children who later develop IGHD (n = 220) had a median birth length of 0.87 SDS below the mean and a median birth weight of 0.60 SDS below the mean of the standard [3].
  • In patients previously exposed to prepubertal or adult levels of endogenous GnRH secretion (IGHD, IGD, AN at low body weight), a rapid initial FSH response occurred that subsequently declined when plasma estradiol rose to concentrations greater than 40-50 pg/ml [4].
  • In all normal children and 6/7 patients with IGHD, hpGRF 1-40 at all doses used induced a clear and sustained lowering of plasma prolactin levels; this effect was lacking in the patient with craniopharyngioma. hpGRF 1-40 had no effect on plasma FSH, LH, TSH or glucose levels nor did it influence pulse rate, blood pressure, or body temperature [5].

High impact information on IGHD


Chemical compound and disease context of IGHD

  • Eleven patients with GH deficiency (GHD) underwent i.v. GH-RH tests (1 mu/kg); 7 had idiopathic GH deficiency (IGHD) and 4 had multiple pituitary hormone deficiencies (MPHD)--diagnosed on the basis of the insulin hypoglycemia, clonidine and sleep tests [11].
  • As pubertal growth accounts for 15% of total growth and gonadotropin-releasing hormone agonist (GnRH-Ag) therapy has successfully prolonged the "prepubertal" growth phase in central precocious puberty, the addition of GnRH-Ag to GH in IGHD has been widely utilized to try to enhance linear growth [12].

Biological context of IGHD

  • All 3 mutations segregated with the IGHD phenotype [13].
  • More recently, kindreds in which IGHD subjects are compound heterozygotes for two distinct mutations indicate that faulty GHRHR alleles may be prevalent and that these mutations may need to be suspected even in sporadic IGHD cases [14].
  • Point mutations of the donor splice site of intron 3 of the human GH-1 gene cause autosomal dominant inherited isolated growth hormone deficiency (IGHD II) [15].
  • We conclude that mutations responsible for IGHD are not within or near the structural gene for GHRH on chromosome 20 in the 23 families studied [16].
  • This large volume of data gathered from a caucasian population indicates that the great majority of patients with IGHD has no structural abnormalities of the hGH gene cluster, particularly no hGH-1 gene deletion [17].

Anatomical context of IGHD

  • A variety of IGHJ and IGHD genes were used in hybridomas, and somatic mutations were also seen in some hybrids [18].
  • We suggest that patients with GHD and congenital hypothalamic-pituitary abnormalities do not require further investigation of GH secretion, whereas patients with IGHD and normal or small pituitary gland should be retested well before the attainment of adult height [19].
  • Genomic DNA was extracted and studied by restriction endonuclease analysis after extraction from the circulating lymphocytes of 53 children with IGHD [17].
  • In contrast the T-->C IGHD II mutant allele product retains these sequences and is transported to secretory granules where it can interact with the normal allele product producing a dominant-negative effect at the protein level [20].
  • These findings indicate that the IVS3 + 6T --> G mutation arose in a germ cell of the father and caused IGHD in the patient [21].

Associations of IGHD with chemical compounds

  • Using a specific and sensitive RIA for GH-releasing hormone (GHRH), we examined the effect of oral administration of 75 g glucose on peripheral plasma GHRH-like immunoreactivity (GHRH-LI) in normal subjects (n = 12) and patients with idiopathic GH deficiency (IGHD) (n = 6) [1].
  • METHODS: The National Cooperative Growth Study database was used to identify patients between 3 and 20 years of age with IGHD or ISS and those within these groups who were treated with methylphenidate or pemoline for ADHD [22].
  • In CGD or IGHD children mean plasma GH peak after acute clonidine (14.8 +/- 2.6 and 4.1 +/- 1.2 ng/mL, respectively) was not significantly different from that observed after either dose of Gal.(ABSTRACT TRUNCATED AT 250 WORDS)[23]
  • Amino acid sequence composition is highly conserved between Rhesus and human, with IGHD insertions and deletions limited to three-nucleotide multiples, which serve to preserve enrichment for tyrosine, glycine, and serine residues in IGHD reading frame 1 [24].
  • In our previous studies we had demonstrated that, in children affected with isolated GH deficiency (IGHD), a short-term recombinant growth hormone (rGH) therapy increases the 11-deoxycortisol (S) secretion and induces an IGF-I responsiveness to the ACTH challenge [25].

Regulatory relationships of IGHD

  • In contrast, the IGHD I mutation activates a cryptic donor splice site 73 bases upstream of the normal exon IV donor splice site causing loss of amino acids 103-126 of exon IV followed by a reading frameshift and synthesis of 94 novel amino acids before chain termination 88 nucleotides downstream of the normal GH stop codon [20].
  • The increased level of IGF-I binding due to increased IGF-I receptor gene expression may represent a compensatory up-regulation process activated in response to the low levels of IGF-I in the circulation of patients with LTD or IGHD [26].

Other interactions of IGHD

  • However, the prevalence of GHRHR mutations in patients with IGHD IB is unknown [13].
  • Bolus doses of GH-releasing hormone (GHRH), 1 microgram/kg i.v., were given to two groups of adult patients with growth hormone deficiency (GHD): 9 with Hand-Schüller-Christian disease (HSCD, presumed hypothalamic GHD) and 9 with idiopathic GHD (IGHD, etiology unknown) [27].
  • Only 5 of 9 patients with IGHD had GH responses above the detection limits of the assay; their mean peak response, 1.3 +/- 0.2 ng/ml, was significantly lower than the GH responses of the HSCD patients (p less than 0.05) [27].
  • RESULTS: In the IGHD cohort, there were 184 patients who were being treated for ADHD and 2313 who were not [22].
  • RESULTS: Basal insulin and SHBG levels were within normal range in the LS, IGHD and CSS patients [28].

Analytical, diagnostic and therapeutic context of IGHD

  • Digestion patterns of the PCR amplification products of these sequences from DNA of IGHD type IA patients with the restriction endonucleases BglI, HaeII, or SmaI showed characteristic differences for each of the three deletion sizes studied [29].
  • We have analysed the expression of the IGF-I receptor gene in lymphocytes of patients with low levels of circulating IGF-I (four patients with isolated GH deficiency (IGHD) and one Laron-type dwarf (LTD)) in comparison with a control group exhibiting normal serum IGF-I levels and endocrine profiles [26].
  • Patients with multiple pituitary hormone deficiencies (MPHD, n = 30), who were all receiving conventional hormone replacement therapy, were more obese than patients with isolated GHD (IGHD, n = 16) [30].
  • Although genetic analysis (Southern blotting method) could not detect any mutations in their GH genomes, the IGHD lesion of them seemed to be pituitary in origin [31].
  • Immunofluorescence microscopy of the neoplastic plasma cells demonstrated diffuse cytoplasmic staining with accentuated Golgi region staining specific for immunoglobulin delta heavy and lambda light chains [32].


  1. Effect of oral glucose administration on plasma growth hormone-releasing hormone (GHRH)-like immunoreactivity levels in normal subjects and patients with idiopathic GH deficiency: evidence that GHRH is released not only from the hypothalamus but also from extrahypothalamic tissue. Kashio, Y., Chihara, K., Kita, T., Okimura, Y., Sato, M., Kadowaki, S., Fujita, T. J. Clin. Endocrinol. Metab. (1987) [Pubmed]
  2. Familial dwarfism due to a novel mutation of the growth hormone-releasing hormone receptor gene. Salvatori, R., Hayashida, C.Y., Aguiar-Oliveira, M.H., Phillips, J.A., Souza, A.H., Gondo, R.G., Toledo, S.P., Conceicão, M.M., Prince, M., Maheshwari, H.G., Baumann, G., Levine, M.A. J. Clin. Endocrinol. Metab. (1999) [Pubmed]
  3. Birth data for patients who later develop growth hormone deficiency: preliminary analysis of a national register. The Executive Scientific Committee of the Kabi International Growth Study and the Swedish Paediatric Study Group for Growth Hormone Treatment. Albertsson-Wikland, K., Niklasson, A., Karlberg, P. Acta paediatrica Scandinavica. Supplement. (1990) [Pubmed]
  4. Selective inhibition of follicle-stimulating hormone secretion by estradiol. Mechanism for modulation of gonadotropin responses to low dose pulses of gonadotropin-releasing hormone. Marshall, J.C., Case, G.D., Valk, T.W., Corley, K.P., Sauder, S.E., Kelch, R.P. J. Clin. Invest. (1983) [Pubmed]
  5. Synthetic hpGRF 1-40 stimulates growth hormone and inhibits prolactin secretion in normal children and children with isolated growth hormone deficiency. Pintor, C., Fanni, V., Loche, S., Locatelli, V., Cella, S.G., Villa, F., Minuto, F., Corda, R., Müller, E.E. Peptides (1983) [Pubmed]
  6. Immunoglobulin delta expression in Burkitt's lymphoma cell lines. Kiwanuka, J., Marti, G., Moore, J., Cheah, M., Magrath, I. J. Natl. Cancer Inst. (1989) [Pubmed]
  7. Parameters that govern the regulation of immunoglobulin delta heavy-chain gene expression. Tisch, R., Kondo, N., Hozumi, N. Mol. Cell. Biol. (1990) [Pubmed]
  8. The Growth Response to Growth Hormone (GH) Treatment in Children with Isolated GH Deficiency Is Independent of the Presence of the Exon 3-Minus Isoform of the GH Receptor. Blum, W.F., Machinis, K., Shavrikova, E.P., Keller, A., Stobbe, H., Pfaeffle, R.W., Amselem, S. J. Clin. Endocrinol. Metab. (2006) [Pubmed]
  9. Lack of evidence of premature atherosclerosis in untreated severe isolated growth hormone (GH) deficiency due to a GH-releasing hormone receptor mutation. Menezes Oliveira, J.L., Marques-Santos, C., Barreto-Filho, J.A., Ximenes Filho, R., de Oliveira Britto, A.V., Oliveira Souza, A.H., Prado, C.M., Pereira Oliveira, C.R., Pereira, R.M., Ribeiro Vicente, T.d.e. .A., Farias, C.T., Aguiar-Oliveira, M.H., Salvatori, R. J. Clin. Endocrinol. Metab. (2006) [Pubmed]
  10. Adult height in patients with permanent growth hormone deficiency with and without multiple pituitary hormone deficiencies. Maghnie, M., Ambrosini, L., Cappa, M., Pozzobon, G., Ghizzoni, L., Ubertini, M.G., di Iorgi, N., Tinelli, C., Pilia, S., Chiumello, G., Lorini, R., Loche, S. J. Clin. Endocrinol. Metab. (2006) [Pubmed]
  11. Discrimination between growth hormone (GH) deficiency of hypothalamic or pituitary origin: an aid in selecting patients for GH-releasing hormone (RH) prolonged therapy. Keret, R., Josefsberg, Z., Kinarti, H., Silbergeld, A., Szoke, B., Schally, A.V., Laron, Z. Isr. J. Med. Sci. (1988) [Pubmed]
  12. A brief review of the addition of gonadotropin-releasing hormone agonists (GnRH-Ag) to growth hormone (GH) treatment of children with idiopathic growth hormone deficiency: Previously published studies from America. Reiter, E.O. Mol. Cell. Endocrinol. (2006) [Pubmed]
  13. Three new mutations in the gene for the growth hormone (gh)-releasing hormone receptor in familial isolated gh deficiency type ib. Salvatori, R., Fan, X., Phillips, J.A., Espigares-Martin, R., Martin De Lara, I., Freeman, K.L., Plotnick, L., Al-Ashwal, A., Levine, M.A. J. Clin. Endocrinol. Metab. (2001) [Pubmed]
  14. Familial Growth Hormone Deficiency and Mutations in the GHRH Receptor Gene. Alba, M., Salvatori, R. Vitam. Horm. (2004) [Pubmed]
  15. Mechanisms responsible for dominant expression of human growth hormone gene mutations. Binder, G., Brown, M., Parks, J.S. J. Clin. Endocrinol. Metab. (1996) [Pubmed]
  16. Exclusion of growth hormone (GH)-releasing hormone gene mutations in familial isolated GH deficiency by linkage and single strand conformation analysis. Pérez Jurado, L.A., Phillips, J.A., Francke, U. J. Clin. Endocrinol. Metab. (1994) [Pubmed]
  17. Isolated growth hormone deficiency: analysis of the growth hormone (GH)-releasing hormone gene and the GH gene cluster. Mullis, P., Patel, M., Brickell, P.M., Brook, C.G. J. Clin. Endocrinol. Metab. (1990) [Pubmed]
  18. Rearrangement of only one human IGHV gene is sufficient to generate a wide repertoire of antigen specific antibody responses in transgenic mice. Suárez, E., Magadán, S., Sanjuán, I., Valladares, M., Molina, A., Gambón, F., Díaz-Espada, F., González-Fernández, A. Mol. Immunol. (2006) [Pubmed]
  19. Growth hormone (GH) deficiency (GHD) of childhood onset: reassessment of GH status and evaluation of the predictive criteria for permanent GHD in young adults. Maghnie, M., Strigazzi, C., Tinelli, C., Autelli, M., Cisternino, M., Loche, S., Severi, F. J. Clin. Endocrinol. Metab. (1999) [Pubmed]
  20. Familial growth hormone deficiency: a model of dominant and recessive mutations affecting a monomeric protein. Cogan, J.D., Phillips, J.A., Schenkman, S.S., Milner, R.D., Sakati, N. J. Clin. Endocrinol. Metab. (1994) [Pubmed]
  21. A novel and de novo splice-donor site mutation in intron 3 of the GH-1 gene in a patient with isolated growth hormone deficiency. Katsumata, N., Matsuo, S., Sato, N., Tanaka, T. Growth Horm. IGF Res. (2001) [Pubmed]
  22. Response to growth hormone in attention deficit hyperactivity disorder: effects of methylphenidate and pemoline therapy. Rao, J.K., Julius, J.R., Breen, T.J., Blethen, S.L. Pediatrics (1998) [Pubmed]
  23. The effects of galanin on growth hormone secretion in children of normal and short stature. Loche, S., Cella, S.G., Puggioni, R., Stabilini, L., Pintor, C., Müller, E.E. Pediatr. Res. (1989) [Pubmed]
  24. The Rhesus monkey immunoglobulin IGHD and IGHJ germline repertoire. Link, J.M., Hellinger, M.A., Schroeder, H.W. Immunogenetics (2002) [Pubmed]
  25. Further evaluation of IGF-I responsiveness to ACTH in children affected with IGHD. Merola, B., Rossi, E., Longobardi, S., Selleri, A., Esposito, V., Colao, A., Cataldi, M., Ferone, D., Lombardi, G. Horm. Res. (1992) [Pubmed]
  26. Up-regulation of insulin-like growth factor-I (IGF-I) receptor gene expression in patients with reduced serum IGF-I levels. Eshet, R., Werner, H., Klinger, B., Silbergeld, A., Laron, Z., LeRoith, D., Roberts, C.T. J. Mol. Endocrinol. (1993) [Pubmed]
  27. Growth hormone responses to growth hormone-releasing hormone in Hand-Schüller-Christian Disease. Gelato, M.C., Loriaux, D.L., Merriam, G.R. Neuroendocrinology (1989) [Pubmed]
  28. Comparative effects of GH, IGF-I and insulin on serum sex hormone binding globulin. Gafny, M., Silbergeld, A., Klinger, B., Wasserman, M., Laron, Z. Clin. Endocrinol. (Oxf) (1994) [Pubmed]
  29. Detection of molecular heterogeneity in GH-1 gene deletions by analysis of polymerase chain reaction amplification products. Kamijo, T., Phillips, J.A. J. Clin. Endocrinol. Metab. (1992) [Pubmed]
  30. Changes in subcutaneous and visceral fat mass during growth hormone replacement therapy in adult men. de Boer, H., Blok, G.J., Voerman, B., Derriks, P., van der Veen, E. Int. J. Obes. Relat. Metab. Disord. (1996) [Pubmed]
  31. A family case with autosomal-dominantly inherited pituitary dwarfism. Tani, N., Kaneko, K., Momotsu, T., Takasawa, T., Ito, S., Shibata, A., Miki, T., Tateishi, H., Kumahara, Y. Tohoku J. Exp. Med. (1987) [Pubmed]
  32. IgD myeloma with intracytoplasmic crystalline inclusions. Jennette, J.C., Wilkman, A.S., Benson, J.D. Am. J. Clin. Pathol. (1981) [Pubmed]
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