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Paediatric Endocrinology (P.E.M., S.S., A.E., A.B., J.-M.V., J.D.), University Children’s Hospital, Inselspital, CH-3010 Bern, Switzerland; National Institute for Medical Research (I.C.A.F.R.), London NW7 1AA, United Kingdom; Department of Paediatric Endocrinology and Diabetology (D.S., P.C.), Hôpital Robert Debré, F-75019 Paris, France; and University-Children’s Hospital and Growth Research Center (G.B.), D-72076 Tübingen, Germany
Address all correspondence and requests for reprints to: Professor Primus E. Mullis, M.D., Pediatric Endocrinology, Diabetology, and Metabolism, University Children’s Hospital, Inselspital, CH-3010 Bern, Switzerland. E-mail: primus.mullis{at}insel.ch.
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Abstract |
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 Top Abstract IntroductionPatients and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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In the present study, we focus on the autosomal dominant form of IGHD, type II (IGHD II). This is most commonly caused by mutations within the first 6 bp of intervening sequences 3 (5'IVS-3) (12), which result in a missplicing at the mRNA level and the subsequent loss of exon 3 (E3), producing a 17.5-kDa human GH (hGH) variant (13). This GH product lacks aa 32–71, which is the entire loop that connects helix 1 and helix 2 in the tertiary structure of hGH (14, 15). Skipping of exon 3 caused by GH-1 gene alterations other than those at the donor splice site in 5'IVS-3 has also been reported in other patients with IGHD II. These include mutations in exon splice enhancer (ESE) [ESE1 in E3] (E3 + 1G->T: ESE1m1; E3 + 5A->G: ESE1m2) and within suggested intron splice enhancer (ISE) (IVS-3 + 28 G->A: ISEm1; IVS-3del+28–45: ISEm2) sequences (12, 16, 17, 18, 19, 20, 21). Such mutations lie within purine-rich sequences and cause increased levels of E3-skipped transcripts (12, 17, 18, 19, 20, 21), suggesting that the usage of the normal splicing elements (ESE1 at the 5' end of exon 3 as well as ISE in intron 3) may be disrupted (19, 20, 21). The first seven nucleotides in E3 (ESE1) are crucial for the splicing of GH mRNA (22) such that some nonsense mutations might cause skipping of one or even more exons during mRNA splicing in the nucleus. This phenomenon is called nonsense-mediated altered splicing; its underlying mechanisms are still unknown (23). In addition to the above-described splice site mutations that result in the production of GH product lacking aa 32–71, three other mutations within the GH-1 gene (missense mutations) are reported to be responsible for IGHD II, namely the substitution of leucine for proline, histidine for arginine, and phenylalanine for valine at aa positions 89 (P89L), 183 (R183H), and 110 (V110F), respectively (24, 25, 26).
At the functional level, the 17.5-kDa variant exhibits a dominant-negative effect on the secretion of the 22-kDa isoforms in both tissue cultures and transgenic animals (27, 28, 29). The 17.5-kDa variant is initially retained in the endoplasmic reticulum, disrupts the Golgi apparatus, impairs both GH and other hormonal trafficking (30), and partially reduces the stability of the 22-kDa isoform (27). Furthermore, transgenic mice overexpressing the 17.5-kDa variant exhibit a defect in the maturation of GH secretory vesicles and anterior pituitary gland hypoplasia due to a loss of the majority of somatotropes (20, 27, 28). Trace amounts of the 17.5-kDa variant, however, are found present at the mRNA in normal pituitaries (31, 32). Furthermore, although preliminary data from our laboratory also support its existence in small amounts in the serum of children and adults of normal growth and stature, the presence in serum cannot be considered as fully established yet, and heterozygosity for A731G mutation (K41R) within the newly defined ESE2 (which is important for E3 inclusion) led to approximately 20% E3 skipping resulting in both normal and short stature (20, 22).
From a clinical point of view, severe short stature [< –4.5 SD score (SDS)] is not present in all affected individuals, indicating that in some forms growth failure in IGHD II is less severe than one might expect (26). It has been hypothesized that children with splice site mutations may be younger and shorter at diagnosis than their counterparts with missense mutations (26). Furthermore, more recent in vitro and animal data suggest that both a quantitative and qualitative difference in phenotype may result from variable splice site mutations, causing differing degrees of E3 skipping (12, 18, 25, 26, 28, 33, 34, 35, 36, 37, 38). To summarize, these data suggest that the variable phenotype of autosomal dominant GH deficiency (GHD) may reflect a threshold and a dose-dependent effect of the amount of 17.5-kDa relative to 22-kDa hGH (28, 29, 34). Specifically, this has a variable impact on pituitary size and onset and severity of GHD, and, unexpectedly, the most severe, rapid onset forms of GHD might be subsequently associated with the evolution of other pituitary hormone deficiencies.
The aim of the present studies was to test the relevance of these notions for clinical IGHD II. We therefore assembled data from a group of these rare subjects, in which we could analyze the impact of different GH-1 gene alterations in terms of progression and severity of primary GHD as well as follow-up of other pituitary-derived hormonal axes. We set out to compare splice site mutations affecting the inclusion of E3, and missense mutations within GH-1 gene such as R183H GH (arginine to histidine; G6664A); V110F GH (valine to phenylalanine; G6191T), P89L GH (proline to leucine; C6129T). In addition to the endocrine evaluation, we sought to evaluate the extent of pituitary gland hypoplasia by measuring the changes in size of the pituitary gland between diagnosis and final height, in relation to IGHD II genotype. Finally, in addition to the children and adolescents treated with GH throughout childhood, we included affected but GH-untreated adult subjects in our analysis to obtain long-term data on the effect of the disorder.
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Patients and Methods |
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This study included affected members of families, children, and adults who had previously been diagnosed and analyzed at the molecular level for IGHD II. Summarized in Tables 1
and 2, the pedigrees of 19 families were studied. Thirty-three subjects (23 males; 10 females) belonged to the GH-treated group (Table 1), and 24 subjects (10 males; 14 females) comprised the GH-untreated group (Table 2). Eleven families were of Caucasian origin (northern, western, and eastern Europe: Germany, Netherlands, France, Switzerland, Kosovo, Serbia); five of Mediterranean origin (Italy, France, Spain, Greece); and three of Turkish origin (Kurds).
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GH-untreated group: adult subjects (Table 2
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At the time of diagnosis, two independent GH stimulation tests were performed. The tests included insulin tolerance test, arginine stimulation, combined arginine and insulin tolerance test, clonidine, and GHRH-stimulation tests according to the guidelines as described by Ranke (39). In addition, all the other pituitary-derived hormonal axes were assessed following identical protocols (39). Furthermore, magnetic resonance imaging (MRI) with narrow scanning of the pituitary region and gadolinium injection was performed.
GH-treated group: children and adolescents (Table 1)
Children who had been diagnosed as type II GH deficient with an identified mutation in the GH-1 gene and who had been treated for several years (mean 13 yr; range 6–18 yr) with recombinant human GH (rhGH) were included in this study. When near adult height (AH) was reached, GH treatment was stopped for 2 months and the patients’ pituitary hormonal axes were retested (see above). Near AH was defined on the basis of a height velocity of 1 cm/yr or less over an interval of at least 6 months and age. Both chronological age and bone age had to be at least 14 yr (females) and 16 yr (males). The bone age was estimated according to the method of Greulich and Pyle (40). One boy was retested at 12 yr of age for suspect compliance, and at that time a follow-up MRI was performed. Because all the subjects went through puberty normally, no sexual abnormalities were reported, and basal levels of gonadotropins and sex steroids were normal, this axis was not examined further.
Hormone measurements
Serum GH levels were measured in different clinical centers by several assays (RIA, ELISA, and enzyme immunoassay), and according to the Eilat consensus paper (Growth Research Society), a provocation peak GH concentration less than 10 µg/liter was in support of the diagnosis of GHD (41). IGF-I concentrations were determined by either IGF-I kit (Nichols Institute Diagnostics, Bad Vilbel, Germany) or using the assays described by Blum (42). TSH and free T4 were assessed using an ultrasensitive human TSH II (microparticle enzyme immunoassay) on the AxSYM system (Abbott Laboratories, Abbott Park, IL). ACTH was assessed applying a sequential immunometric assay (Immulite, Diagnostic Products Corp., Los Angeles, CA), and cortisol was measured using a chemiluminescence immunoassay (ADVIA Centauer, Bayer Corp., Tarrytown, PA).
MRI
MRI examinations were carried out in different radiology centers. Sagittal and coronal T1 images were taken using various repetition times from 320 to 472 msec and an echo time of 20 to 25 msec through the sella region with contiguous slices between 2.5- and 3-mm thickness. In addition, axial T1 and T2 images of the whole brain were obtained. Images were acquired on a 256 x 256 or 512 x 512 matrix. Gadolinium injection for contrast was performed in all patients. All images were analyzed according the same protocol by one experienced neuroradiologist. Adenophypophyseal height was determined in a strict midline-positioned sagittal scan, which displayed the anterior lobe, posterior lobe, stalk of the pituitary gland, and Sylvius aqueduct simultaneously. Maximal height of the pituitary gland was measured perpendicular to the sella turcica floor after magnification with an overhead projector using the scaling provided on the films (accuracy of measurements 0.1 mm). Because the height of the pituitary gland increases with age, the data were compared with the normative data reported by Argyropoulou et al. (43, 44) and Tsunoda et al. (45).
Statistical analysis
A two-sample t test was performed to calculate the P values. Sagittal hypophyseal height, a continuous variable, was analyzed after correction for age to SDS by a 95% confidence interval for the difference of means between the study groups (43, 44, 45).
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Results |
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GH-treated subjects (Table 1)
Hormonal data. Children previously diagnosed as type II GH deficient were retested at final height (AH) after 6–18 yr of rhGH treatment. As previously observed, the children with splice site mutations were younger at diagnosis than their counterparts with missense mutations, mean age 3 vs. 9.3 yr (P < 0.001). Comparing all patients with splice site mutations with those with missense mutations, there was no difference concerning pituitary gland-derived hormones and their serum levels when the pituitary hormone axes were retested. However, comparing the subjects with a 5'IVS-3 splice site mutations within the first 2 bp (5'IVS-3 + 1; 5'IVS-3 + 2) with those at positions +5 and +6 bp (5'IVS-3 + 5; 5'IVS-3 + 6), the mean serum ACTH concentration was 15.7 and 28.4 ng/liter, with a mean cortisol level of 201 and 278 nmol/liter, respectively. Although within the normal range, these values differed from each other, suggesting a potential impact of IGHD II on ACTH secretion. Note also the subjects of family 8 presenting with rather low TSH (0.4 and 1.9 mU/liter) and ACTH (12 and 15 ng/liter) when analyzed in relation to free T4 (9.4 and 13.1 pmol/liter; normal 10–20 pmol/liter) and cortisol (132 and 128 nmol/liter; normal 137–600 nmol/liter) as well as the two patients of family 19 with a missense mutation (P89L), who were partially ACTH deficient at the time when AH was achieved.
Size of the pituitary gland (Fig. 1)
At diagnosis, there was overall no statistical difference between the pituitary height among the patients of the different groups of the 5'IVS-3 splice site mutations [mean values: –1.5 SDS (5'IVS-3 + 5 and +6 bp), –1.1 SDS (5'IVS-3 + 1 and +2 bp), –0.6 SDS (missense mutations)], whereas the pituitary height was significantly bigger in the missense-mutated group (P < 0.01). Because it was not possible to perform a control MRI scan of the pituitary gland at the end of GH replacement therapy in all the patients, pituitary gland size was reevaluated in randomly selected patients at final height, and data were compared with the size of the pituitary gland measured at diagnosis and corrected for age-related increase in pituitary height, using the normative data reported by Argyropoulou (43, 44). By the time final height was achieved, differences in pituitary size with respect to genotype among the splice site mutations clearly emerged. Figure 1 compares data from 10 patients with either the splice site mutation at position +5 /+6 or +1/+2 bp within the 5'IVS-3. Although at the outset no statistical difference was present (–1.4 SDS vs. –0.8 SDS) by final height, the pituitary size in the patients suffering from a 5'IVS-3 splice site mutation with either +1 or +2 bp was significantly smaller than in the +5 and +6 bp splice site group (–1.56 SDS vs. –2.59 SDS) (P < 0.01), suggesting that +1 and +2 bp splice site mutations within the 5'IVS-3 have more profound impact on pituitary gland growth.
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)Hormonal data. Although the number studied is small, similar findings were made in the untreated adult IGHD II subjects. None of the patients suffering from either 5'IVS-3 +5 and +6 bp splice site mutations presented with any other abnormalities of the hormonal axes tested. However, two subjects with 5'IVS +1 bp splice site mutation (+1GT–> TT; +1GT–> AT) and one subject with a missense mutation (P89L GH) presented with other pituitary derived hormonal deficiencies (TSH as well as ACTH deficiency).
Size of the pituitary gland (Fig. 2)
Analysis of pituitary heights in the adult GH-untreated group showed that 5'IVS-3 + 1 /+2bp subjects presented with smaller pituitary glands than the 5'IVS-3 + 5 /+6bp subjects, in line with their corresponding hormonal data. In three subjects with an R183H GH missense mutation, two males aged 55 and 57 yr were in the normal range, according the normative data reported by Tsunoda et al. (45), whereas the woman aged 73 yr presented with a pituitary gland reduced in size. Unfortunately the 51-yr-old man presenting with the P89L GH (family 19) and a partial ACTH deficiency is not available for pituitary imaging.
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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IGHD II is a rare autosomal dominant form of GHD, usually caused by hGH splicing mutations that generate internally truncated GH forms that block the secretion of wild-type GH produced from the normal allele (2, 3, 12, 13, 18, 46).
From the clinical point of view, there is some evidence that there is great variability of the IGHD II phenotype in terms of onset, severity, and rate of progression, according to the mutation (splice site vs. missense) within the GH-1 gene (24, 25, 26, 33, 34). Severe short stature was present in only one third of the affected individuals at diagnosis in the study by Binder et al. (26); furthermore, children with splice site mutations were younger and shorter at diagnosis than those with missense mutations. To model this condition in transgenic mice, McGuinness et al. (28) drove E3-skipped hGH expression specifically in somatotrophs of transgenic mice, using a 5'IVS-3 + 1G–>A mutant construct that could generate only an hGH product lacking E3 in a normal mouse background (i.e. with two copies of the mouse GH gene). The results showed that the most severely affected lines rapidly developed severe GHD and dwarfism, with profound pituitary hypoplasia and almost total loss of somatotrophs (28). Importantly, however, the onset and severity of IGHD II was transgene copy number dependent; high-copy lines rapidly developed profound GHD by weaning, whereas low-copy mice showed milder adult-onset GHD (28). These data were supported by an in vitro splicing study showing that other human IGHD II mutations within splice-enhancer or repressor sequences generated a variable ratio of mutant to wild-type-hGH transcripts, which might help to explain some variability seen in IGHD II patients with a similar range of mutations (20, 28). An unexpected observation was that in the most severely affected high-copy number IGHD II transgenic mice, the marked anterior pituitary gland hypoplasia was associated with deficits in other pituitary-derived hormones (20, 28). Prolactin, TSH, and LH (in males only) were all significantly reduced in adult high-copy transgenic mice, whereas these deficits were absent or mild, with a much later onset in low-copy lines. This could simply reflect an artificially high ratio of E3-skipped hGH to mouse GH but raised the question of whether other hormone deficits might evolve spontaneously in the more severe forms of human IGHD II.
Variable clinical course depending on the GH-1 gene alteration
Nineteen families with the autosomal dominant form of IGHD caused by variable GH-1 gene defects (Tables 1 and 2) were selected and studied on the basis of our previous clinical data. These included previously diagnosed IGHD II-deficient children who were GH treated and had reached AH as well as a group of affected but GH-untreated adults.
Diagnosis
Focusing on the time of diagnosis during infancy and childhood, there is clearly a tendency to diagnose the children with IGHD II presenting a 5'IVS-3 +1/+2 bp mutations earlier than those with a splice site mutation within 5'IVS-3 +5/+6 bp and a missense mutation. However, one should interpret this with caution because awareness of a familial GHD will likely increase awareness to diagnose a second affected child earlier, and it is interesting that on GH stimulation testing, peak GH values did not vary among the different groups.
Follow-up of endocrine parameters
At the time that final height was achieved, GH treatment was stopped for 2 months and then the pituitary-derived hormonal axes were retested. In the 5'IVS-3 +5/+6 bp group, no hormonal deficiencies were apparent. In contrast, in families 7 and 8 (5'IVS-3 +1; GT–>CT), either ACTH (family 7) or ACTH and TSH deficiency (family 8), which needed replacement therapy, was found. Interestingly, two patients with the P89L GH missense mutation (family 19) became partially ACTH deficient at the ages of 16.2 and 15.5 yr after 7 and 6 yr on rhGH therapy, respectively (Table 1). In this study we also took the opportunity to analyze the impact of age and/or GH treatment on the disorder by studying the affected family members who did not receive rhGH treatment (Table 2). Of these 24 older subjects (mean age 44 yr, range 21–73 yr), four (two males, two females) with 5'IVS-3 +5/+6 bp splice site mutations could be retested, and other than GHD, no further pituitary hormonal deficiencies were present. In contrast, the 5'IVS-3 +1/+2 bp subgroup (n = 7) contained two women (family 6: 5'IVS-3 + 1G–>A; family 10: 5'IVS-3 + 1G–>T) who exhibited partial TSH and ACTH deficiency, which needed replacement therapy. As stated above, the GH-treated adolescents of families 7 and 8 presented with pituitary gland-derived hormonal deficiencies. Data, however, from the affected adult of family 7 (female, 31 yr of age) and the adult member of family 8 (male, 41 yr of age) showed no additional hormonal deficiency. This emphasizes the notion that there is also variability in phenotype within family members bearing the same mutation.
In addition, although the patients with missense mutations have previously been reported to be less affected, a number of patients presenting with the P89L missense GH form showed some pituitary hormone impairment (Tables 1 and 2).
Size of pituitary gland
Analyzing the size of the pituitary gland of the GH-treated group supported the endocrine observations, in the sense that patients developing any additional pituitary hormone deficiency showed a more hypoplastic pituitary gland with time (Table 1 and Fig. 1). We believe it noteworthy that, whereas no difference in pituitary size was evident at diagnosis in the two groups of 5'IVS-3 splice site-mutated subjects, a significant difference clearly emerged at final height, with the pituitaries significantly smaller in the 5'IVS-3 +1/+2 bp than in the 5'IVS-3 +5/+6 bp patients. Furthermore, in the affected family members who did not receive rhGH treatment, the size of the pituitary gland is in line with the hormonal deficiencies, with the 5'IVS-3 +1/+2 bp group having smaller pituitary size than the 5'IVS-3 +5/+6 bp group, although the numbers are small (Fig. 2). The mechanism affecting other endocrine axes is not obvious, but it might reflect bystander damage from activated macrophages clearing dying somatotroph debris, as observed in the transgene mouse study (28).
Possible mechanism causing variable phenotypes, depending on the splice site mutation
It is of high interest why different splice site mutations generating the same E3-deleted product may end up with a variable phenotype. Our clinic-derived data, however, are broadly in line with the results reported in the transgenic mice by McGuinness et al. (28). The high-copy lines showed compromised numbers of corticotrophs, gonadotrophs, and lactotrophs by electron microscopy; thyrotroph deficits were not evaluated directly but were probably reduced because the TSH contents were markedly lower (28). In the most severely affected mouse lines, LH was reduced but not in the milder lines with later-onset GHD, which were fully fertile. In our subjects, clinically the gonadotroph axis seems to be normal, whereas the corticotroph and thyrotroph axes are compromised in some patients mainly suffering from the 5'IVS-3 +1 bp caused E3-skipped IGHD II variant.
Based on the fact that the splice sites in GH-1, particularly those flanking E3, are supposed to be rather weak, Ryther et al. (20, 22) developed a model of IGHD II pathogenesis in which mutations that weaken E3 definition, either at the splice sites or within defined splice enhancers (ESE, ISE) lead to an enhanced E3 skipping. In that sense, it seems that a splice site mutation at position 5'IVS-3 +1/+2 bp has a greater impact on spliceosome assembly and splicing efficiency than a splice site mutation at position 5'IVS-3 +5/+6 bp. This may possibly increase the E3 skipping and, consequently, may be responsible for the higher quantity of 17.5-kDa GH variant, which apparently exerts a dominant-negative effect on the packaging and secretion of 22-kDa GH, and leads, therefore, eventually to a more severe phenotype.
In addition, McGuinness et al. (28) raised the concern that untreated GHD could exacerbate the pituitary damage because the lack of GH feedback clearly increased GHRH expression in the mice, which might drive the exhaustion of pituitary somatotrophs, directly or indirectly damaging other pituitary axes. Our data comparing treated vs. untreated groups suggest this is not a clinical concern.
In conclusion, these findings clearly support the notion that, depending on the GH-1 gene alteration, there is a clinical variability in the severity of the IGHD II phenotype. Furthermore, subjects suffering from IGHD II caused by a 5'IVS-3 +1/+2 bp splice site mutations leading to a skipping of E3 may also present with other pituitary hormone deficiencies, mainly in the ACTH and TSH, but not in the gonadotroph axis. Although missense mutations were reported to generate a less severe phenotype, this generalization may not hold true for patients presenting the P89L GH form. Because the occurrence of multiple hormonal deficiencies does not obviously increase with age or prior GH treatment, the concern that enhanced GHRH drive in the absence of GH would aggravate and support the development of other hormonal abnormalities at the pituitary level does not seem warranted in human IGHD II. However, the imaging data strongly suggest that pituitary growth deficits continue to develop with time on GH treatment, so this should be born in mind when considering such patients for GH replacement in adulthood (28). Our analysis also suggests that variability in onset, severity, and progression, evident between mutation genotypes, may also occur within families with the same mutation. Perhaps the most important message is that other hormone deficits can develop in IGHD II patients, underscoring the clinical importance of maintaining vigilance for the development of other hormonal deficiencies over the years.
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Acknowledgments |
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Footnotes |
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First Published Online January 25, 2005
Abbreviations: aa, Amino acid; AH, adult height; E3, exon 3; ESE, exon splice enhancer; GHD, GH deficiency; hGH, human GH; IGHD, isolated GH deficiency; IGHD II, IGHD, type II; ISE, intron splice enhancer; 5'IVS-3, intervening sequences 3; MRI, magnetic resonance imaging; P89L, substitution of leucine for proline at aa position 89; R183H, substitution of histidine for arginine at aa position 183; rhGH, recombinant human GH; SDS, SD score; V110F, substitution of phenylalanine for valine at aa position 110.
Received July 2, 2004.
Accepted January 19, 2005.
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