Isolated Growth Hormone Deficiency, Type Iv

A number sign (#) is used with this entry because isolated growth hormone deficiency type IV (IGHD4) is caused by homozygous or compound heterozygous mutation in the GHRHR (139191) gene on chromosome 7p14.

Description

IGHD type IV is an autosomal recessive disorder characterized by early and severe growth failure (height SDS up to -7.4), a blunted growth hormone (GH) response to different provocation tests and low insulin-like growth factor-I (IGF1; 147440) and IGF-binding protein-3 (IGFBP3; 146732) concentrations, and a good response to growth hormone treatment (summary by Alatzoglou et al., 2014).

For general phenotypic information and a discussion of genetic heterogeneity of IGHD, see 262400.

Nomenclature

In an early classification of IGHD (Phillips and Cogan, 1994), IGHD IB was caused by mutation in either the GHRHR gene or the GH1 gene (139250). In a new classification, IGHD IB (612781) is caused by mutation in the GH1 gene, and IGHD IV is caused by mutation in the GHRHR gene.

Clinical Features

Wajnrajch et al. (1996) described 2 first cousins, a boy and a girl, from a consanguineous Indian Moslem kindred with the typical phenotype of severe growth hormone deficiency. The 3.5-year-old girl and her 16-year-old cousin had shown poor growth since infancy and both were extremely short. They were prepubertal with frontal bossing and predominantly truncal obesity. Both failed to produce growth hormone in response to standard provocative tests and to repetitive stimulation with growth hormone-releasing hormone (GHRH; 139190). They responded to administration of growth hormone.

Salvatori et al. (1999) reported members of a large extended pedigree with familial dwarfism from Itabaianinha, a rural county in the state of Sergipe, located in northeastern Brazil. Inhabitants of this region are thought to be of Portuguese descent. They have a high frequency of consanguineous marriages. The diagnosis of dwarfism was based on early growth failure, proportionate short stature, and radiologic evidence of delayed bone age. Affected subjects were very short and attained an adult stature that ranged between 105 and 135 cm. In addition, patients had high-pitched voices and increased abdominal fat accumulation. Except for a somewhat delayed onset of puberty, which did not affect their fertility, they did not manifest any signs or symptoms that suggest deficiency of other pituitary hormones. Ten patients were treated with recombinant human growth hormone for 1 year, and each showed a brisk increase in growth velocity without reduced responsiveness over time.

Diagnosis

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 (139191.0002) 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.

Clinical Management

Gondo et al. (2001) compared the pituitary hormone response to GHRP2, a potent growth hormone secretagogue, in 11 individuals with isolated GH deficiency due to a homozygous mutation of the GHRHR gene (139191.0002) and in 8 normal unrelated controls. Basal serum GH levels were lower in the IGHD group compared with controls. After GHRP2 administration, there was a 4.5-fold increase in serum GH relative to baseline values in the IGHD 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 GHRP2 action on GH secretion and that GHRP2 has a GHRH-independent effect on pituitary somatotroph cells.

Walenkamp et al. (2008) described the evolution of growth and skeletal age of a brother and sister of Moroccan descent with a homozygous GHRHR mutation who presented at the ages of 16 and 14.9 years, respectively. Heights were -5.1 and -7.3 SD, and pubertal stages were advanced. Combined GH and GNRH analog (GNRHa) treatment resulted in a height gain of 24 and 28.2 cm, respectively, compared with the initial predicted adult height by the method of Bayley and Pinneau. Adult height was within the population range and well within the target range.

Menezes Oliveira et al. (2006) studied the consequences of lifetime IGHD on the metabolic and cardiovascular status of adult members of the large Brazilian kindred (Itabaianinha cohort) with severe IGHD reported by Salvatori et al. (1999), who were found to have a homozygous IVS1+1G-A mutation in the GHRHR gene (139191.0002). GHD subjects had increased abdominal obesity, higher total and low density lipoprotein cholesterol, and higher C-reactive protein (123260) than controls. They did not have an increase in carotid wall thickness, and there was no evidence of premature atherosclerosis as evaluated by exercise echocardiography. The authors concluded that in this homogeneous cohort, untreated severe IGHD is not associated with evidence of premature atherosclerosis despite unfavorable cardiovascular risk profile.

Oliveira et al. (2007) reported that in patients with lifetime isolated GHD due to IVS1+1G-A 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.

Mapping

Salvatori et al. (2001) analyzed 30 families with isolated growth hormone deficiency in which more than 1 member was affected. Linkage analysis was performed in 28 of the families, and in 3 families sib-pair analysis indicated linkage to the GHRHR gene locus on chromosome 7p14.

Molecular Genetics

In at least 2 members of a consanguineous Indian Moslem family with profound growth hormone deficiency, Wajnrajch et al. (1996) demonstrated a nonsense mutation in the GHRHR gene (E72X; 139191.0001). The phenotype in this kindred was comparable to that in the 'little' mouse (see ANIMAL MODEL), which carries a mutation in the growth hormone-releasing factor receptor (Ghrfr). The authors pointed out that other members of the G protein-coupled receptor superfamily are subject to mutations that can cause an increase in ligand-mediated signaling or constitutive receptor activation and resulted in hyperfunction of target cells. Endocrine disorders resulting from such activating mutations include familial male precocious puberty (176410) caused by mutation in the LH receptor (152790), Jansen metaphyseal dysplasia with hypercalcemia (156400) caused by mutation in the PTH receptor (168468), and hyperparathyroidism caused by mutation in the calcium-sensing receptor (145980.0004). Wajnrajch et al. (1996) suggested that analogous mutations in the GHRHR gene should be sought in patients with excessive production of growth hormone causing gigantism or acromegaly.

Salvatori et al. (1999) examined 22 affected members of the large, extended Brazilian kindred (Itabaianinha cohort) containing at least 105 members with autosomal recessive short stature. Analysis of the GHRHR gene detected a novel homozygous splice site mutation (139191.0002).

In 3 kindreds segregating autosomal recessive IGHD, Salvatori et al. (2001) identified homozygous or compound heterozygous mutations in the GHRHR gene (139191.0003-139191.0005). All 3 mutations segregated with the phenotype in the families. Salvatori et al. (2001) expressed all 3 mutant receptors in CHO cells, and each failed to show a cAMP response after treatment of the cells with GHRH. The authors concluded that missense mutations in the GHRHR gene are a cause of autosomal recessive isolated growth hormone deficiency, and that defects in the GHRHR gene may be a more common cause of GH deficiency than previously suspected.

Animal Model

Lin et al. (1993) demonstrated that the molecular basis for the 'little' (lit) mouse phenotype, characterized by a hypoplastic anterior pituitary gland, is a point mutation in the growth hormone releasing factor receptor that alters asp60 to gly. Detailed analysis of the anterior pituitary in the mutant mouse revealed spatially distinct proliferative zones of growth hormone-producing stem cells and mature somatotrophs, each regulated by a different trophic factor. This sequential growth factor requirement for a specific cell type may exemplify a common strategy for regulating cellular proliferation in other mammalian organs. Pit1 is another factor critical for the activation of prolactin and growth hormone genes and is the site of the mutation underlying the male dwarf mouse (dw). Lin et al. (1993) were prompted to search for a mutation in the Ghrhr gene when the cloned gene was shown, by studies of a restriction fragment length variant (RFLV) in interspecific crosses, to map to chromosome 6 in the same region as the lit mutation. No obvious rearrangements or deletions in the Ghrhr gene could be detected by Southern blot analysis. Lin et al. (1993) presented evidence from expression studies that the Ghrhr gene is a direct target of the Pit1 gene. The defective dw Pit1 protein was unable to transactivate the Ghrhr gene. Godfrey et al. (1993) identified a missense mutation in the extracellular domain of the Ghrhr gene that disrupted receptor function and was responsible for the 'little' phenotype.