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

• Immunoglobulin delta expression in Burkitt's lymphoma cell lines [6].
• Parameters that govern the regulation of immunoglobulin delta heavy-chain gene expression [7].
• Objective: The objective was to study the impact of the GHR genotype on the phenotype and growth response in patients with isolated GH deficiency (IGHD) treated with GH [8].
• OBJECTIVE: The aim of this study was to determine the consequences of lifetime isolated GHD (IGHD) on the metabolic and cardiovascular status of adult members of a large Brazilian cohort with severe IGHD due to a homozygous mutation in the GHRH receptor gene [9].
• Median height SDS at the beginning of puberty was similar in the IGHD and MPHD subjects [10].

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].

References