GHRHR, IVS1, G-A, +1 AND Isolated growth hormone deficiency type 1B

Clinical significance:Pathogenic (Last evaluated: Dec 1, 2007)

Review status:(0/4) 0 stars out of maximum of 4 stars

no assertion criteria provided

Based on:
1 submission [Details]
Record status:

Allele description [Variation Report for GHRHR, IVS1, G-A, +1]

GHRHR, IVS1, G-A, +1

GHRHR:growth hormone releasing hormone receptor [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Preferred name:
GHRHR, IVS1, G-A, +1
    Nucleotide change:
    IVS1, G-A, +1
    OMIM: 139191.0002


    Isolated growth hormone deficiency type 1B (IGHD1B)
    IGHD IB; Isolated Growth Hormone Deficiency, Type IB
    MedGen: C2748571; Orphanet: 631; OMIM: 612781

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    Assertion and evidence details

    Submission AccessionSubmitterReview Status
    (Assertion method)
    Clinical Significance
    (Last evaluated)
    SCV000037633OMIMno assertion criteria providedPathogenic
    (Dec 1, 2007)
    germlineliterature only

    PubMed (5)
    [See all records that cite these PMIDs]

    Summary from all submissions

    EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
    not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only



    Familial dwarfism due to a novel mutation of the growth hormone-releasing hormone receptor gene.

    Salvatori R, Hayashida CY, Aguiar-Oliveira MH, Phillips JA 3rd, Souza AH, Gondo RG, Toledo SP, Conceicão MM, Prince M, Maheshwari HG, Baumann G, Levine MA.

    J Clin Endocrinol Metab. 1999 Mar;84(3):917-23.

    PubMed [citation]

    Effect of severe growth hormone (GH) deficiency due to a mutation in the GH-releasing hormone receptor on insulin-like growth factors (IGFs), IGF-binding proteins, and ternary complex formation throughout life.

    Aguiar-Oliveira MH, Gill MS, de A Barretto ES, Alcântara MR, Miraki-Moud F, Menezes CA, Souza AH, Martinelli CE, Pereira FA, Salvatori R, Levine MA, Shalet SM, Camacho-Hubner C, Clayton PE.

    J Clin Endocrinol Metab. 1999 Nov;84(11):4118-26.

    PubMed [citation]
    See all PubMed Citations (5)

    Details of each submission

    From OMIM, SCV000037633.1

    #EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
    1not providednot providednot providednot providedliterature only PubMed (5)


    Salvatori et al. (1999) examined 22 affected members of a large, extended Brazilian kindred (Itabaianinha cohort) containing at least 105 members with autosomal recessive short stature (isolated growth hormone deficiency IB; 612781). Extensive endocrine evaluation confirmed markedly reduced or undetectable serum concentrations of GH that did not increase in response to different stimuli. Analysis of the GHRHR gene detected a novel homozygous 5-prime splice site mutation, a G-to-A transition at position +1 of intron 1. Thirty of the affected subjects tested were homozygous for this mutation, and of 64 clinically unaffected patients, 41, including 9 obligate carriers, were heterozygous for the mutation and 23 were homozygous for the wildtype sequence.

    Aguiar-Oliveira et al. (1999) measured insulin-like growth factor I (IGF1; 147440), IGF2 (147470), IGF-binding protein-1 (IGFBP1; 146730), IGFBP2 (146731), IGFBP3 (146732), and acid labile subunit (ALS; 601489) in 27 subjects with GHD (aged 5 to 82 years) from the Itabaianinha cohort with the intron 1 splice site GHRHR mutation and in 55 indigenous controls (aged 5 to 80 years). All components of the IGF axis, measured and theoretical, showed complete separation between GHD and control subjects, except IGFBP1 and IGFBP2 concentrations, which did not differ. The most profound effects of GHD were on total IGF1, IGF1 in the ternary complex, and ALS. The proportion of IGF1 associated with IGFBP3 remained constant throughout life, but was significantly lower in GHD due to an increase in IGF1/IGFBP2 complexes. As diagnostic tests, IGF1 in the ternary complex and total IGF1 provided the greatest separation between GHD and controls in childhood. The authors concluded that severe GHD not only reduces the amounts of IGFs, IGFBP3, and ALS, but also modifies the distribution of the IGFs bound to each IGFBP. Diagnostic tests used in the investigation of GHD should be tailored to the age of the individual. In particular, measurement of IGF1 in the ternary complex may prove useful in the diagnosis of GHD in children and older adults, whereas free ALS may be more relevant to younger adults.

    Gondo et al. (2001) compared the pituitary hormone response to GHRP-2, a potent growth hormone secretagogue, in 11 affected individuals from the Itabaianinha cohort with this mutation and in 8 normal unrelated controls. Basal serum GH levels were lower in the GHD group compared with controls. After GHRP-2 administration, there was a 4.5-fold increase in serum GH relative to baseline values in the GHD group, which was significantly less than the 79-fold increase in the control group. The authors concluded that an intact GHRH signaling system is not an absolute requirement for GHRP-2 action on GH secretion and that GHRP-2 has a GHRH-independent effect on pituitary somatotroph cells.

    Pereira et al. (2007) compared 76 adult subjects (age, 25-75 years) from the Itabaianinha cohort who were heterozygous for the IVS1+1G-A mutation with 77 sex-matched controls from the same population who were homozygous for the wildtype GHRHR allele. They found no difference in adult height or SD score for serum IGF-I between the 2 groups. However, body weight, body mass index, skin folds, waist and hip circumferences, and lean mass were all reduced in heterozygous subjects. The authors concluded that heterozygosity for a null GHRHR mutation is associated with changes in body composition and possibly an increase in insulin sensitivity.

    Oliveira et al. (2007) reported that in patients with lifetime isolated GHD due to IVS1G-A+1 homozygosity, 6-month treatment with GH had reversible beneficial effects on body composition and metabolic profile, but caused a progressive increase in intima-media thickness and in the number of atherosclerotic carotid plaques.

    OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
    1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

    Last Updated: Dec 15, 2017