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Original Article |
Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research (S.O.A., N.C., P.G.R., M.T.C.), National Institutes of Health (NIH), Bethesda, Maryland 20892-4320; Department of Nursing (S.B.), Developmental Endocrinology Branch (P.F.), National Institute of Child Health and Human Development, NIH, Bethesda, Maryland 20892-4320; Molecular Endocrinology Branch (D.L.), National Institute of Diabetes, Digestive and Kidney Diseases, NIH, Bethesda, Maryland 20892-4320; Department of Orthopedic Surgery, University of Maryland (C.C.), Baltimore, Maryland 21201; Biomedical Computer Research Institute (H.K.), Philadelphia, Pennsylvania 19115; Department of Experimental Medicine (P.B.), University of Rome "La Sapienza," I-100161 Rome, Italy; and Department of Pediatric Orthopedic Surgery (S.W.), Dana Children’s Hospital, Tel Aviv Medical Center, 64139 Tel Aviv, Israel
Address all correspondence and requests for reprints to: Michael T. Collins, M.D., Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Building 30, Room 228, MSC 4320, Bethesda, Maryland 20892-4320. E-mail: mcollins{at}dir.nidcr.nih.gov.
Abstract
McCune-Albright syndrome (MAS) is a disorder characterized by the triad of café-au-lait skin pigmentation, polyostotic fibrous dysplasia of bone, and hyperfunctioning endocrinopathies, including GH excess. The molecular etiology of the disease is postzygotic activating mutations of the GNAS1 gene product, Gs
. The term gsp oncogene has been assigned to these mutations due to their association with certain neoplasms. The aim of this study was to estimate the prevalence of GH excess in MAS, characterize the clinical and endocrine manifestations, and describe the response to treatment.
Fifty-eight patients with MAS were screened, and 22 with stigmata of acromegaly and/or elevated GH or IGF-I underwent oral glucose tolerance testing. Twelve patients (21%) had GH excess, based on failure to suppress serum GH on oral glucose tolerance test, and underwent a TRH test, serial GH sampling from 2000–0800 h, and magnetic resonance imaging of the sella.
We found that vision and hearing deficits were more common in patients with GH excess (4 of 12, 33%) than those without (2 of 56, 4%). Of interest, patients with a history of precocious puberty and GH excess who had reached skeletal maturity achieved normal adult height despite a history of early epiphyseal fusion. All 9 patients tested had an increase in serum GH after TRH, 11 of 12 (92%) had hyperprolactinemia, and all 8 tested had detectable or elevated nighttime GH levels. Pituitary adenoma was detected in 4 of 12 (33%) patients. All patients with elevated IGF-I levels were treated with cabergoline (7 patients), long-acting octreotide (LAO; 8 patients), or a combination of cabergoline and LAO (4 patients). In six of the seven patients (86%) treated with cabergoline, serum IGF-I decreased, but not to the normal range. In the eight patients treated with LAO alone, IGF-I decreased, and, in four, returned to the normal range. The remaining 4 patients were treated with a combination of cabergoline and LAO. For them, symptoms of GH excess diminished, and IGF-I decreased further, but did not enter the normal range.
GH excess is common in MAS and results in a distinct clinical phenotype characterized by inappropriately normal stature, TRH responsiveness, prolactin cosecretion, small or absent pituitary tumors, a consistent but inadequate response to treatment with cabergoline, and an intermediate response to LAO.
MCCUNE-ALBRIGHT SYNDROME (MAS) is a rare and sporadic condition that was first defined by the triad of polyostotic fibrous dysplasia of bone (FD), café-au-lait skin hyperpigmentation, and precocious puberty (PP; Refs. 1 and 2). A number of endocrine disorders, including GH excess (for review, see Ref. 3), may accompany the disease. Other endocrinopathies that may be present in addition to GH excess include hyperthyroidism (for review, see Ref. 4) and Cushing syndrome (5). Also, frequently associated with polyostotic FD is a proximal renal tubulopathy characterized by phosphaturia, aminoaciduria, low molecular weight proteinuria, and renal 1--hydroxylase inhibition (6). Rarer associations also exist, including involvement of hepatic, cardiac, muscular, and other tissues (Ref. 7 ; for review, see Ref. 8).
The disease is the result of postzygotic activating mutations of the cAMP-regulating protein, GNAS1 gene product, Gs (9, 10). The vast majority of the Gs mutations are point mutations at the Arg201 position (11), with most being Arg201 His or Cys (11). The somatic mosaicism is reflected by the identification of normal and mutated cells throughout the body (9). The term gsp oncogene has been assigned to these activating Gs mutations due to their association with certain neoplasms (12, 13, 14). The phenotypic presentation of tissues involved in MAS, including the somatotrophs of the pituitary, is the result of the cellular response to activation of hormone-sensitive adenylyl cyclase signal transduction pathways (15, 16).
Our understanding of GH excess in MAS has been derived primarily from case reports and a small series of patients (for review, see Refs. 3 and 17, 18, 19, 20, 21, 22, 23, 24, 25, 26). This, coupled with the overall rarity of the disease, results in a limited understanding of the prevalence, clinical spectrum, comorbidities, and effective treatment. Involvement of the craniofacial (CF) bones with FD often results in overgrowth of bone, and recognition of GH excess in these patients may be missed if one relies on the characteristic stigmata of acromegaly (i.e. frontal bossing and prognathism) to trigger a specific diagnostic evaluation. There have been no previous studies of the GH dynamics in a large population of MAS patients. We describe here the presentation, prevalence, biochemical characterization, complications, and response to treatment of a large group of patients with MAS and GH excess. We also discuss the implications for understanding the molecular pathophysiology of acromegaly caused by the gsp oncogene.
Patients and Methods
Diagnosis of MAS and GH excess
Fifty-eight patients with MAS or MAS variant (MASV; MASV is FD plus café-au-lait and/or a hyperfunctioning endocrinopathy other than PP) were evaluated as part of an ongoing institutional review board-approved study of FD/MAS at the National Institutes of Health. All patients or their representatives gave written informed consent to participate. The diagnosis of MAS or MASV was based on a combination of clinical history and physical examination, typical radiographic findings, bone histology, and, when necessary, analysis of appropriate sequences of the GNAS1 gene. Patient 3 was being treated with tamoxifen for PP, and patient 8 was on a very low-dose oral contraceptive preparation.
Special attention was given to the signs, symptoms, and biochemical features of GH excess listed in Table 1
. In addition, initial testing included duplicate measures on hospital d 1 and 2, after an overnight fast, of serum GH and IGF-I at 0800 h. If there was any suggestion of GH excess on history and physical examination or if the serum GH or serum IGF-I was elevated, an oral glucose tolerance test (OGTT) was performed. The diagnosis of GH excess was established by a serum GH concentration greater than 2.0 ng/ml at 60 and 120 min after 75 g (1.75 g/kg in children) of oral glucose (OGTT). In patients that failed to suppress GH to less than 2 ng/ml on OGTT, additional testing of GH excess was performed (see below).
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Patient heights were the mean of three 0800 h stadiometric measurements. Because many patients with severe FD lose significant height due to fractures and shepherd’s crooking of the proximal femur, arm span was also measured, and if arm span was more than 2.0 cm greater than the height, it was used as a surrogate for height. The predicted height was based on the parental target height: mean parental height plus 6.5 cm for males and minus 6.5 cm for females. The height control patients (nine females and one male) were adult MAS patients with PP, but without GH excess.
GH excess-specific testing
GH excess patients underwent additional testing, including additional measurement of serum IGF-I, TRH test, overnight serum GH sampling (every 20 min from 2000 h to 0800 h), and a magnetic resonance image (MRI) of the sella. Patients previously diagnosed and treated for GH excess were off treatment for at least 3 months before GH excess-specific testing was performed, a generally accepted washout period for long-acting octreotide (LAO; Ref. 27). The TRH test consisted of the iv administration of 7 µg/kg (up to a maximum dose of 500 µg) of TRH (Thyrel TRH, Ferring Pharmaceuticals Ltd., Tarrytown, NY), followed by serum GH measurement at 0, 15, 30, 60, and 90 min. A TRH test was considered positive when the serum GH rose by more than 50% above the baseline value (28). Prolactin (PRL) specimens were drawn at 0800 h from an indwelling iv catheter after an overnight fast while the patients were at rest. All reported serum IGF-I, PRL, and GH levels (other than serial testing values) were the average of at least two values. Four patients (no. 4, 7, 10, and 11) were unable or unwilling to undergo overnight GH sampling. MRI of the pituitary entailed coronal and sagittal T1-weighted spin echo images obtained at 3-mm intervals before and after the iv administration of gadolinium on a 1.5 Tesla MRI system.
Assays
Serum GH was measured using a commercially available immunochemiluminometric assay with a lower limit of detection of 0.1 ng/ml and inter- and intra-assay coefficient of variance of 11% and 10%, respectively (Mayo Medical Laboratories, Rochester, MN). Serum IGF-I was measured by one of two standard commercial assays, an extracted RIA assay (Mayo Medical Laboratories; assay 1) or a two-site chemiluminescence immunoassay (Nichols Advantage IGF-I Assay, Nichols Institute Diagnostics, San Juan Capistrano, CA; assay 2). The correlation between the 2 assays was determined by measuring serum IGF-I levels in 39 normal and acromegalic subjects. Using a paired t test, the comparison of the IGF-I values from the same specimens generated a highly significant correlation (R = 0.9696; P < 0.001; y = 1.368x + 46.849, where y is the assay 2 value and x is the assay 1 value; data not shown). All serum IGF-I values and Z-scores are reported as assay 1 values. PRL was assessed using a standard commercially available assay (Abbott Laboratories, Chicago, IL).
GNAS1 mutation analysis
Mutation detection was performed as previously described (29). Briefly, standard PCR-based amplification, followed by sequencing of the appropriate region of the GNAS1 gene, was performed. Alternatively, in tissues with a low percentage of mutated cells, a novel, highly sensitive, protein nucleic acid primer was used to block amplification of the normal allele, allowing for the detection of mutated allele (29).
Statistics analysis
Fisher’s exact test and Pearson linear regression correlations and degree of significance were calculated using SAS version 6.12 (SAS Institute, Inc., Cary, NC). Z-scores were calculated using the following equation with the 95th and 5th centile values from assay 1: Z = X - 
/SD, where SD = (95th centile - 5th centile)/3.29.
Results
Clinical signs, symptoms, and complications
Twenty-two of the 58 patients with MAS/MASV had signs, symptoms, or hormonal features suggestive of GH excess (Table 1
). GH excess was confirmed in 12 of 58 (21%) by failure to suppress GH on an OGTT (Table 2). Serum GH decreased to less than 1.0 ng/ml in the remaining 10 patients. Of interest, eight patients with a history of PP and GH excess achieved normal height (Fig. 1). Because PP causes early growth plate maturation and closure with resultant short stature, the height of the patients with PP would have been predicted to be well below their predicted midparental height. In addition, there was a significant increase in the prevalence of hearing and vision deficits in patients with GH excess. Only 2 of 56 patients without GH excess (4%) had hearing and/or vision deficits, whereas the deficits were present in 4 of 12 with GH excess (33%; P < 0.05; Fisher’s exact test).
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The IGF-I Z-scores exhibited a broad range (-2.5 to >5; Table 2). All patients who were tested responded to TRH administration with an increase in serum GH, and 11 (92%) had elevated serum PRL levels (Table 2). The degree of PRL elevation correlated with the serum IGF-I concentration (R = 0.91; P < 0.001; Fig. 2A).
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), and there was a significant correlation between the mean overnight serum GH concentration and the serum IGF-I concentration (R = 0.86; P < 0.01; Fig. 2B).
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. The most striking feature on the MRIs is the massive expansion of the CF bones with FD (Fig. 4, A and C).
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The 10 patients with a serum IGF-I Z-score greater than 2.0 were treated. Initial therapy was cabergoline (Dostinex, Pharmacia and Upjohn, Kalamazoo, MI) 0.5 mg po twice a week, and it was increased over 8 wk to 4 mg po twice a week. The maximum dose for a 4-yr-old patient (patient 3) was 3.0 mg twice a week. In patients who failed to respond (i.e. serum IGF-I remained above the normal range), cabergoline was discontinued for 4 wk, and treatment with LAO (Sandostatin LAR Depot, Novartis, East Hanover, NJ) was started. The initial dose was 20 mg im once a month; it was increased to 30 mg im once a month (7 patients) and 40 mg im once a month (patient 12) as indicated by the failure of the serum IGF-I to return to normal. The 4 yr old received 0.15 mg/kg im once a month. The four patients who did not respond to LAO alone were given the combination of cabergoline (8 mg po twice a week) plus LAO (30 mg im once a month).
Six of the seven patients (86%) treated had a partial response to cabergoline (Table 3). The one nonresponder (patient 3) was a prepubertal girl who was also receiving tamoxifen treatment for PP. In none of the patients did cabergoline alone normalize IGF-I. Only one of the eight patients treated with cabergoline had an adverse symptom (nausea), and this was not severe enough to cause discontinuation. LAO treatment normalized IGF-I in four of eight patients (50%). In none of the three patients who failed treatment with LAO and who went on to be treated with the combination of cabergoline and LAO was the combination of drugs effective, although all three exhibited an additive partial response to the combination of drugs with respect to serum IGF-I and clinical symptoms.
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The group of 58 patients with MAS or MASV from which the subgroup of 12 patients with GH excess was derived represents the largest group of patients with this condition studied to date and affords the opportunity to examine a population of patients in whom the molecular etiology of the disease is gsp oncogene. This allows us to make what is likely to be an accurate estimate of the prevalence of GH excess in patients with MAS (21%).
What emerged as an important sign of GH excess was the finding of normal height in patients who had had PP. This useful clinical finding represents the cumulative (and presumably antagonistic) effects of early sex steroid and excess GH/IGF-I exposure on the growth plate. This experiment in nature suggests that the tonically elevated GH/IGF-I effect predominates over that of early sex steroid exposure.
The importance of early detection and treatment is highlighted by the fact that morbidity related to FD in the CF bones is more common in patients with GH excess. Although only 2 of 56 (4%) patients with CF FD without GH excess had hearing loss or blindness, 4 of 12 (33%) of the patients with GH excess did. Exposure to excess GH most likely worsens CF FD (30), as demonstrated here by the fact that the patients with the highest GH and IGF-I levels (patients 11 and 12) had the worst CF FD (Fig. 4). These same patients are also the only ones in our series who had the associated morbidity of combined vision and hearing loss. The hope is that early detection and treatment at the subclinical stage will prevent disease progression-associated morbidity.
A number of findings and patterns emerged that are likely to be characteristic of gsp-mediated GH excess. The percentage of these patients with a positive TRH test (100%) is greater than would be expected in a population of patients with sporadic acromegaly in which 50–60% of the patients have a positive TRH test (31, 32). This is consistent with the findings of Yang et al. (32) in which 78% of the patients with gsp-mediated acromegaly had a positive response to TRH, compared to 50% without. This may be the result of the presence of ectopic TRH receptors, which have been noted to be induced by cAMP signaling in certain cell lines (33). TRH receptors normally act through the inositol 1,4,5-trispohspohate pathway, but when ectopically expressed and activated they have been shown to cross-couple with cAMP and regulate GH secretion by somatotrophs (34).
A second feature of gsp-mediated GH excess is PRL cosecretion. Eleven of the 12 patients (92%) had an elevation in serum PRL (Table 2), and the degree of elevation correlated with the degree of elevation in serum IGF-I (Fig. 2A). Consistent with previous reports of gsp-mediated acromegaly (32, 35, 36), the proportion of cosecretors of GH and PRL in our group (92%) is higher than in sporadic acromegaly (
33%; Ref. 37). It is possible that constitutive activation of the cAMP pathway leads to a derangement in somatotroph differentiation and results in cells with bihormonal activity. This would be consistent with the established role of the cAMP/protein kinase A/cAMP-responsive element binding protein pathway activation in regulating normal somatotroph differentiation (38, 39).
Another feature of our population that may be of significance is that tumors were either absent (by MRI scanning) or relatively small. This is consistent with the studies of others (32, 35, 36, 40, 41) in which they note that the gsp positive tumors were smaller than the gsp negative tumors. In our series, absent (and/or smaller) tumors may represent lead-time bias, due to increased suspicion and early detection. But, given the consistency with previous studies in which there was no lead-time bias, this may represent a feature of gsp-mediated disease.
Medical treatment is often the only option in these patients because transsphenoidal surgery is not possible due to massive thickening of the skull base with FD (Fig. 4). And radiation therapy was not considered as an option, because it is believed to predispose FD to sarcomatous transformation (42). The results of treatment with cabergoline and LAO are informative. All patients had some response to cabergoline and/or octreotide. The only patient who did not respond to cabergoline monotherapy was patient 3, the patient being treated with tamoxifen for PP. Because the effect of tamoxifen appears to be one of decreasing GH secretion (43, 44), it is not clear why she would be unresponsive to cabergoline. Even in those patients with higher basal serum basal GH values, cabergoline had a significant effect on lowering serum IGF-I and GH. For example, in patient 11, the basal serum IGF-I went from 512 to 315 ng/ml on cabergoline alone. In all patients treated, LAO significantly lowered both serum GH and IGF-I values. In 4 of the 8 patients (patients 3, 5, 6, and 7) with serum IGF-I values of 127, 288, 299, and 130 ng/ml, and serum IGF-I Z-scores of 2.5, 3.2, 3.2, and 3.3, respectively, LAO was effective in normalizing serum IGF-I. The group in whom LAO produced a partial response had serum IGF-I levels of 142, 441, 658, and 758 ng/ml and serum IGF-I Zscores of 3.2, more than 5.0, more than 5.0, and more than 5.0, respectively. In this same group, when either cabergoline was added to maximum dose LAO or LAO was added to maximum dose cabergoline, there was an additive but still only partial response with respect to normalizing serum IGF-I and ameliorating symptoms.
In summary, GH excess was present in 21% of the patients with MAS/MASV. In patients who have had PP, normal stature is an important presenting sign. Recognition and treatment of GH excess may be important to prevent vision and hearing loss, which is associated with CF FD in these patients. Furthermore, the data from this population extend our definition and understanding of gsp-mediated acromegaly. They allow us to conclude that in GH excess of this molecular origin, the tumors are more likely to be cosecretors of PRL and respond to TRH stimulation, and that the tumors tend to be smaller. Because the presentation of GH excess in MAS can be subtle, with typical signs obscured by the CF FD, and because the disease progressively worsens CF FD, all patients with MAS/MASV should be screened with an OGTT.
Acknowledgments
We thank Dr. Philip Gorden for his critical review of the manuscript; Dr. Monica Skarulis for her support, consultation, and sharing of clinical data; and Dr. John Butman for review of the sella MRI scans. We also thank Drs. Dennis Styne, Pamela Freda, Mirta Gryngarten, M. Eugenia Escobar, and Patrick Nolan for allowing us to study and contribute to the care of their patients. We appreciate the superior care provided by the NIH Interinstitute Endocrine Training Program Fellows and the Warren Grant Magnuson Clinical Center Endocrine Nurses of Units 8 and 9 West.
Footnotes
P.B. was supported by Telethon Foundation ONLUS Grant E1029.
Abbreviations: CF, Craniofacial; FD, fibrous dysplasia; LAO, long-acting octreotide; MAS, McCune-Albright syndrome; MASV, MAS variant; MRI, magnetic resonance image or imaging; OGTT, oral glucose tolerance test; PP, precocious puberty; PRL, prolactin.
Received December 17, 2001.
Accepted August 5, 2002.
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