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Extensive Phenotypic Analysis of a Family with Growth Hormone (GH) Deficiency Caused by a Mutation in the GH-Releasing Hormone Receptor Gene¹

Institut National de la Santé et de la Recherche Médicale (INSERM), Unité 468 (I.N., F.D., M.G., S.A.), Centre Hospitalier Universitaire Henri Mondor, 94010 Créteil, France; Service de Pédiatrie (P.T.) and Laboratoire de Radio-Immunologie (F.V.), Hôpital de Montfermeil, 93370, Montfermeil, France; and Service d’Endocrinologie Pédiatrique (I.N.), Hôpital Necker-Enfants Malades, 75743 Paris, France

Address all correspondence and requests for reprints to: Serge Amselem, INSERM U. 468, C.H.U. Henri Mondor, 94010 Créteil, France. E-mail: amselem{at}im3.inserm.fr

	Abstract

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GH secretion and release are complex phenomena depending on activation of several genes, including those encoding GH, GHRH, and its receptor (GHRH-R). The GH gene, which is the most extensively analyzed sequence in patients with familial GH deficiency (GHD), represents the main known target of mutations. To test the involvement of the GHRH-R gene in this disease phenotype, we investigated one candidate Tamoulean family originating from Sri Lanka. Two brothers, with extremely short stature (<-4 SD) and no dysmorphy, were diagnosed as having complete GHD, unresponsive to exogenous GHRH and associated with PRL levels within the lower normal range. Magnetic resonance imaging examination showed anterior pituitary hypoplasia with a normal pituitary stalk. Both patients increased their growth rate while under GH therapy. Molecular investigations revealed a homozygous GHRH-R gene mutation that introduces a stop codon at residue 72. This mutation, which predicts a severely truncated receptor lacking the seven membrane-spanning domains, is identical to that recently reported in one Indian Moslem family, raising the possibility of a founder effect. There was no clear evidence for height reduction in the three heterozygous individuals studied. This observation, which underlines the phenotypic criteria associated with a loss of GHRH-R function, raises the question of the frequency of GHRH-R abnormalities among GHD patients.

	Introduction

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GH DEFICIENCY (GHD) may be responsible for severe growth failure if not treated. It may have various causes: brain tumor, traumatism, cranial irradiation, or rare genetic abnormalities (1). Among patients with isolated familial GHD, deletions and mutations of the GH gene have been reported, but exclusion of linkage between the GH gene and GHD phenotype has also been demonstrated (2). Because GH release is under hypothalamic control, i.e. stimulated by GHRH and inhibited by SRIH, in theory, a defect of these hypothalamic factors or their receptors could also account for the GHD phenotype. The GHRH gene has been excluded in the numerous familial cases of GHD studied so far (3). In contrast, the gene encoding the GHRH receptor (GHRH-R), which is expressed by pituitary somatotroph cells and which belongs to the family of G protein-coupled receptors containing seven transmembrane domains, was first involved in a recessively inherited GHD phenotype in mice (4). In the dwarf little mouse, a homozygous missense GHRH-R mutation was indeed identified in the extracellular domain of the receptor (5, 6). Very recently, in humans, the first molecular GHRH-R defect has been reported in one consanguineous family (7).

To further test the involvement of the GHRH-R gene in familial GHD, we investigated one candidate family in which the phenotype was extensively analyzed.

	Materials and Methods

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Subjects

Two brothers of five siblings (II₄ and II₅) (Fig. 1) were referred to the Montfermeil Hospital pediatric department for evaluation of extremely short stature, after their arrival from Delf, an Indian Ocean island. There was no known consanguinity.

View larger version (13K): [in this window] [in a new window]   Figure 1. Genealogical tree of the studied family. Patients are indicated by filled symbols. Heights are final heights, except for the patients (heights on first examination). SD is evaluated according to the French standards of Children’s International Center and Sempé (27).

GH and insulin-like growth factor 1 concentrations were evaluated by RIA. Spontaneous nighttime GH secretion was studied by blood sampling every 20 min over a period of 8 h. In addition, GH plasma values were measured after three provocative tests; an ornithine test (20 g/m², iv), a glucagon test (0.1 mg/kg, im), and a GHRH test (2 µg/kg GHRH44, iv). Investigation of the lactotroph and thyrotroph axes was performed by a TRH challenge, with measurements of PRL and TSH levels at 0, 15, 30, 60, and 120 mn after an iv bolus (7 µg/kg). Plasma-free T4 was evaluated by RIA. Cortisol was evaluated under baseline conditions. Vasopressin function was evaluated indirectly by plasma and urine osmolalities after water deprivation test.

Magnetic resonance imaging (MRI) study

Pituitary MRI was performed for both patients on a 1.5-T magnet with spin echo T1-weighted images (repetition time = 300 msec; echo time = 20 msec; slice thickness = 4 mm). Pre- and postgadolinium examinations were performed in the coronal and sagittal planes.

PCR-based linkage and mutational analysis

Genomic DNA was isolated from peripheral-blood samples obtained from the seven members of the family, according to standard techniques. Linkage analysis between the GHD phenotype and the GH locus was performed using the dinucleotide repeat polymorphism located in the GH cluster (8).

PCR amplification of genomic DNA was performed with primers designed to amplify a 290-bp portion of the region coding for the extracellular domain of GHRH-R as described (7). Rapid diagnostic identification of the previously described single-point mutation of the GHRH-R gene was accomplished by Bfa1 digestion of the PCR-amplified products. Digestion products were analyzed on a 3% Nusieve (FMC Bioproducts, Rockland, ME) gel stained with ethidium bromide. A 100-bp ladder (Gibco BRL, Life Technologies, Cergy Pontoise, France) was used as a molecular size marker. The PCR products were also subjected to direct sequencing using an ABI373A automated DNA sequencer.

	Results

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Clinical presentation

On first examination, II₅ (Fig. 1) was 6.9 yr old (bone age of 3 yr old, Fig. 2) and was below -5 SD in height and -4 SD in weight (Fig. 2, Table 1), and II₄ (Fig. 1) was 7.7 yr old (bone age of 4 yr old, Fig. 2), with a height of -4 SD and a weight of -3.5 SD (Fig. 2, Table 1). They both presented a harmonious phenotype and did not have the frontal bossing, faciotruncal obesity (Fig. 3), or micropenis usually seen in patients with complete GHD. They had a normal psychomotor development. Neither of them had a history of hypoglycemic seizure. After confirmation of GHD, GH therapy was started at 8.4 yr for II₅ and 9.1 yr for II₄. Both children have increased their growth rate under GH therapy: II₅ gained 9 cm of height the first year of treatment, and II₄ gained 11cm. After 4 yr of treatment, the height of II₅ and II₄ was approximately -1.8 SD and -1 SD, respectively, with a bone age corresponding to the chronological age (Fig. 2). They both began puberty at 13 yr of age.

View larger version (22K): [in this window] [in a new window]   Figure 2. Heights of II4 (A) and II5 (B) reported on Sempé curves (27), before and after the beginning (arrow) of GH therapy. +, Bone ages.

View larger version (84K): [in this window] [in a new window]   Figure 3. II5, at time of diagnosis. Note the absence of frontal bossing and faciotroncular obesity.

For the two probands, plasma GH was very low during sleep or after three stimulation tests (i.e. GH peak below 1.5 µg/L), including GHRH test. Nighttime GH sampling showed absence of spontaneous GH secretion. Insulin-like growth factor 1 plasma values were low. PRL levels were within the normal lower limit at baseline (9) and after TRH stimulation (10), whereas TSH increased normally under exogenous TRH. Detailed hormonal data are shown in Table 1. All other pituitary hormone values were normal (data not shown).

MRI study

For both children, MRI was performed after 1 yr of GH therapy. It showed a pituitary gland with a significantly small anterior pituitary but a normal pituitary stalk and posterior pituitary (Fig. 4). The pituitary height is 3 mm for both II₄ and II₅ (at 10.1 yr old and 9.3 yr old, respectively), which is below -2 SD for their age (11).

View larger version (90K): [in this window] [in a new window]   Figure 4. Pituitary gadolinium-enhanced MRI of II5. Sagittal plane (left), coronal plane (right). Note the existence of a normal pituitary stalk (arrow head) and an hypoplastic anterior pituitary (arrow).

Segregation analysis of a highly polymorphic marker at the GH locus excluded a linkage between this locus and the GHD phenotype (data not shown).

To investigate whether the disease phenotype could be caused by a GHRH-R defect, a GHRH-R gene fragment that was shown to contain a mutation in one family with isolated GHD (7) was amplified by PCR. The PCR products generated from all family members had the expected size (290 bp) (Fig. 5, A and B). To screen for the presence of the previously described mutation, the PCR products were subjected to analysis using restriction enzyme Bfa1. The two parents (I₁ and I₂) and one healthy brother (II₁) were found to be heterozygous for this mutation, whereas the two affected children (II₄ and II₅) were found to be homozygous. The two other healthy brothers (II₂ and II₃) did not carry the mutation (Fig. 5B). Sequence analysis of the GHRH-R gene PCR products confirmed the existence, in the two affected children (II₄ and II₅), of a homozygous G-to-T transversion at position 265, which introduces a premature stop codon at residue 72 (E72X) (data not shown).

View larger version (43K): [in this window] [in a new window]   Figure 5. Restriction enzyme mapping of PCR-amplified DNA from the GHD family members. A, A 290-bp GHRH-R genomic DNA fragment, bracketing an intronic sequence (thick line), was amplified in each family member, using two primers (arrows) complementary to exonic sequences (open boxes), and digested by Bfa1 that recognizes one site on both the wild-type and mutant alleles (•||) and an additional site on the mutant allele only (||); B, gel electrophoresis (3% nusieve) of PCR-generated DNA, before (ND) and after Bfa1 digestion, stained with ethidium bromide. Individuals I1, I2, and II1 yield a banding pattern consistent with the presence of both wild-type and mutant alleles, whereas both patients (II4 and II5) bear only the mutant allele, and the siblings II2 and II3 display both the wild-type alleles only. The size marker (M) is a 100-bp ladder from Gibco/BRL.

	Discussion

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Interestingly, in most families studied, the involvement of the GH locus in the disease phenotype could be excluded by linkage analysis (2), raising the hypothesis of abnormalities in other genes, such as those encoding GHRH or GHRH-R. Here, we report a GHD family in which the phenotype of the two probands was consistent with a GHRH-R dysfunction, because injection of exogenous GHRH did not result in GH secretion, and a GH gene abnormality was excluded by linkage analysis. We therefore analyzed the GHRH-R gene and indeed identified a mutation that introduces a premature stop codon at position 72 (E72X) identical to that recently reported in one family with isolated GHD (7). This mutation predicts a severely truncated protein lacking all of the seven membrane-spanning domains of the receptor, therefore leading to a total disruption of the hormonal signal. This defect is different from the molecular abnormality underlying a dwarf phenotype in the little mouse with a recessively inherited GHD caused by a missense mutation at codon 60 that results in a loss of function (5, 6).

What are the phenotypic features that are associated with the human mutation? First, the two probands have a harmonious phenotype. This is in contrast with the observation by Wajnrajch et al. (7), who reported a frontal bossing and a faciotruncal obesity. Second, GH levels were extremely low in the two probands’ plasma after stimulation tests (including exogenous GHRH) or during sleep. Third, a small anterior pituitary gland and a normal pituitary stalk were documented in both patients by means of MRI. Although MRI was performed after 1 yr of therapy, it is important to note that pituitary size is not influenced by hormonal therapy (18). In addition, the MRI phenotype is consistent with the anterior pituitary hypoplasia documented in the little mouse (6). The size of the developing anterior pituitary is similar in the wild-type and little mice during embryologic development (on e16, e17, and e18), whereas 60-day-old little mice display a clear pituitary hypoplasia (6). Such a pituitary hypoplasia is likely to be the result of a depletion of somatotroph cells, as shown in the adult little mouse (6). In our observation, the abnormal MRI phenotype documented in the two affected children demonstrates that pituitary hypoplasia is already present during childhood. Furthermore, unlike the observation by Wajnrajch et al. (7), the two patients displayed a possible partial PRL deficiency, because both the basal PRL levels and the PRL levels under TRH are at the normal lower limit, in keeping with the results of several in vitro and in vivo studies suggesting that GHRH interferes with PRL secretion (19): several reports showed that GHRH stimulates lactotrophs (20, 21), whereas others (22, 23) did not reveal any influence of GHRH on PRL production. However, the study of homogenates of whole pituitary glands from little mice showed a very low PRL concentration (4). In addition, in vitro studies (24, 25) have clearly demonstrated that the PRL gene transcription is positively regulated by cAMP, the production of which being increased by GHRH-R activation. Finally, both patients started puberty at a normal age, an observation which is in contrast with the murine phenotype, in which both males and females exhibit delayed sexual maturation (5). This observation, however, should take into account the fact that the patients started puberty while under GH therapy.

Three individuals (I₁, I₂, and II₁) are heterozygous carriers for the E72X mutation and have a slight height reduction (-1 SD, -2 SD, and -1 SD, respectively). However II₂ and II₃, who have a height of -1 SD and -1.8 SD, respectively, do not carry this mutation. Although these data are not in favor of height reduction in heterozygous carriers, this must be further evaluated on a large sample of carriers.

So far, despite extensive sequencing of the entire extracellular encoding domain of the GHRH-R gene in a large cohort of patients (26), no molecular abnormality has been identified. A GHRH-R mutation, therefore, seems to be unlikely in the majority of children with GHD. Because the mutation identified in the present study is identical to that very recently reported (7), a common origin (i.e. a founder effect) for this mutation cannot be ruled out. Indeed, both families originate from the same geographic area: the recently reported family is an Indian Moslem family, whereas the family presented here is of Tamoulean extraction, originating from a small island between Sri Lanka and India. To address this question, GHRH-R polymorphic markers of the two kindred may be analyzed and compared to determine whether the mutation has the same origin or is recurrent.

	Footnotes

 
¹ This work was supported by the Institut National de la Santé et de la Recherche Médicale and by grants from the Assistance Publique/Hôpitaux de Paris (Contrat de Recherche Clinique) and the Association Française contre les Myopathies.

Received June 9, 1997.

Revised October 17, 1997.

Accepted October 27, 1997.

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