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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 5 2107-2113
Copyright © 2004 by The Endocrine Society

Activating Gs{alpha} Mutations: Analysis of 113 Patients with Signs of McCune-Albright Syndrome—A European Collaborative Study

Serge Lumbroso, Françoise Paris and Charles Sultan

Service d’Hormonologie (S.L., F.P., C.S.), Hôpital Lapeyronie, Centre Hospitalier Universitaire (CHU) de Montpellier and Institut National de la Santé et de la Recherche Médicale, Montpellier, France 34295; and Unité d’Endocrinologie et Gynécologie Pédiatriques (F.P., C.S.), Service de Pédiatrie I, Hôpital Arnaud de Villeneuve, CHU de Montpellier, Montpellier, France 34295

Address all correspondence and requests for reprints to: Professor Charles Sultan, Unité d’Endocrinologie et Gynécologie Pédiatriques, Service de Pédiatrie I, Hôpital A. de Villeneuve, 34295 Montpellier, France. Email: chsultan{at}montp.inserm.fr.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
McCune-Albright syndrome (MAS) is a sporadic disorder characterized by the classic triad of polyostotic fibrous dysplasia, café-au-lait skin pigmentation, and peripheral precocious puberty. It is due to postzygotic activating mutations of arginine 201 in the guanine-nucleotide-binding protein (G protein) {alpha}-subunit (Gs{alpha}), leading to a mosaic distribution of cells bearing constitutively active adenylate cyclase. MAS is heterogeneous: beyond the classic triad, a number of atypical or partial presentations have been reported. We present here the results of a systematic search for Gs{alpha} mutations in patients presenting with at least one of the signs of MAS, using a PCR-based sensitive method. We studied 113 patients (98 girls and 15 boys), 24% presenting the classic triad, 33% with two signs, and 40% with only one classic sign. Overall, the mutation was identified in 43% of the patients. When an affected tissue was available, the mutation was found in more than 90% of the patients, whatever the number of signs. Skin was a noteworthy exception because only three of the 11 skin samples were positive. The mutation was detected in 46% of blood samples in patients presenting the classic triad, whereas this figure fell to 21% and 8% in patients with two and one sign, respectively. Our results highlight the frequency of partial forms of MAS and the usefulness of sensitive techniques to confirm the diagnosis at the molecular level. It should be emphasized that we found the mutation in 33% of the 39 cases of isolated peripheral precocious puberty. This study has further widened the definition of MAS. Affections as clinically different as monostotic fibrous dysplasia, isolated peripheral precocious puberty, neonatal liver cholestasis, and the classic MAS all appear to be components of a wide spectrum of diseases based on the same molecular defect.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
THE MCCUNE-ALBRIGHT syndrome (MAS) is a sporadic disease first described in 1936 by McCune (1) and separately by Albright (2). MAS is characterized by a triad of physical signs: café-au-lait pigmented skin lesions, polyostotic fibrous dysplasia (FD), and endocrine dysfunction, in particular, peripheral precocious puberty in girls. Other hyperfunctional endocrinopathies have been reported such as pituitary adenomas secreting GH and/or prolactin (PRL) (3), hyperthyroidism (4), autonomous adrenal hyperplasia (5), and hypophosphatemic osteomalacia (6). These endocrine disorders occur alone or in combination and encompass a wide range of severity. One of the main characteristics of these endocrinopathies is that they are autonomous: the metabolic disorders are not accompanied by elevated plasma concentration of the stimulating pituitary hormone or hypothalamic releasing factor. The endocrine glands that are hyperactive in MAS also have in common a response to extracellular signals by the adenylate cyclase (AC)-cAMP pathway. Indeed, laboratory investigations indicated that affected tissues present an elevated AC activity (7). In 1989, Landis et al. (8) and Lyons et al. (9) identified activating mutations in the guanine-nucleotide-binding protein (G protein) {alpha}-subunit (Gs{alpha}) that stimulates AC in a subset of pituitary and thyroid tumors, disorders that can be found in MAS. The sporadic occurrence of the syndrome, the variable involvement of endocrine glands, and the characteristic pattern of skin and bone lesions that follows lines of embryologic development all support the hypothesis of a mosaic distribution of abnormal cells (10). These data led to the hypothesis that MAS is due to postzygotic mutation of the Gs{alpha} subunit leading to a mosaicism distribution of cells bearing constitutively active AC activity. This was confirmed by the identification of somatic activating mutations of Gs{alpha} in MAS (11, 12).

Since the original papers, numerous cases have been reported in the literature (see reviews in Refs.13, 14, 15, 16, 17, 18, 19, 20). The mutation is nearly always a substitution of the residue arginine at position 201 by histidine or cysteine. Very infrequently, arginine is replaced by serine, glycine, or leucine (21, 22, 23). Over the past few years, it has become apparent that MAS is an extremely heterogeneous disease and that a number of atypical and partial forms exist beyond the classic MAS. We report here the results of a systematic search for the activating Gs{alpha} mutations in 113 patients presenting with signs of MAS, using a highly sensitive method.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Patients

Within the framework of a European collaborative project, we had the opportunity to study 113 children presenting with one or several signs of MAS. Informed consent was obtained from patients’ parents in accordance with institutional guidelines. The principal clinical characteristics of the patients and the tissues studied are presented in Table 1Go.


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  		TABLE 1. Main characteristics of patients and tissue types

 
This series confirmed the net predominance of girls affected by MAS because only 13% of our patients were boys (n = 15). Classic presentations with the triad of precocious puberty, skin lesions, and osteotic FD were seen in about one quarter of our cases (24%). One third of the children showed two of the three signs. Among these cases, skin lesion was the most frequent sign (32 of 37) associated either with precocious puberty (23 of 37) or bone lesion (19 of 37). Almost 40% (n = 47) had only one sign at the time of diagnosis; most showed precocious puberty (39 of 47), whereas seven had isolated FD and one child showed only skin lesions with the typical pattern of MAS.

Precocious puberty was the sign most often seen, and only in girls, because none of the 15 boys was affected. The percentage [91% (of girls); n = 89] is relatively higher than in the large series reported by Ringel et al. (15) and might be explained by the fact that we recruited mostly in pediatric endocrinology departments. Both skin and bone lesions were noted in about half of the children (n = 60 and 52, respectively). Other endocrine or nonendocrine signs were infrequent. Hyperthyroidism (n = 3), GH hyperproduction (n = 5), and hyperprolactinemia (n = 4) were less frequent than previously reported; hypercortisolism (n = 7) and liver cholestasis (n = 6) were more frequent than previously reported (15).

For the clinical characteristics of each patient, see Table 5GoGo.


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  		TABLE 5. Clinical characteristics and mutation analysis in PBL, ovary, skin, bone, liver, and other tissues studied from patients with MAS

 

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  		TABLE 5A. Continued

 
DNAs

The number of DNAs studied (174) was greater than the number of patients (113) because in several cases, different tissue samples were taken from the same patient. DNA was thus extracted from various tissues. Peripheral blood leukocytes (PBL) were most frequently studied because they are the easiest to obtain; in fact, they were the only cells analyzed in half the cases (n = 56). The ovary was the most accessible affected tissue, with ovarian tissue taken from ovariectomy and ovarian cyst tissue or fluid obtained from cystectomy or ovarian puncture. Skin and bone samples could be studied in only a small number of cases (11 of 60 and 11 of 52, respectively). More rarely, we were able to extract DNA from the liver, adrenals, muscle, testis (24), thyroid, or endometrium (25). In all, 174 tissue samples were analyzed (Table 1Go).

Methods

DNA extraction. DNA was obtained from PBL, fresh or frozen tissue, or tissue preserved in paraffin. Before extraction, tissues biopsies were submitted to proteinase K treatment. Although paraffin-embedded tissue did not always provide DNA in satisfactory quantity or quality, it had the advantage of providing access to archived samples and thus allowed retrospective study. Moreover, preliminary identification of the pathologic zones, even in a single tissue cut, increased the sensitivity of detection by limiting the search to abnormal cells.

Identification of the Arg201 mutation. We used a method, with some modifications, previously reported by Candeliere et al. (21) that enables selective enrichment of mutated DNA. The principle is based on the use of a modified primer to obtain a PCR product from normal DNA that can be digested by a restriction enzyme (EagI), whereas the PCR product obtained from mutated DNA is resistant to this enzyme. The performance of successive PCR steps and enzyme digestion result in an enrichment of the mutated allele. The sense and antisense primers were those described by Candeliere et al. (21). Amplifications were performed with DNA polymerase from Qiagen (Courtaboeuf, France) in a final volume of 50 µl using standard conditions. Before enzymatic digestion, the PCR product was purified using Qiaquick PCR columns (Qiagen). Two successive steps of PCR and digestion were used in this study to limit the risk of contamination due the nested PCR. After purification, the final PCR products were sequenced with the antisense primer. Sequencing reactions were repeated twice with at least two different PCR products.

All molecular investigations were performed in a single center in Montpellier, France.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
The main results are summarized in Tables 2–4GoGoGo. Detailed results for each tissue studied are given in Table 5GoGo.


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  		TABLE 2. Main patient results

 

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  		TABLE 3. Main results according to tissue studied

 

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  		TABLE 4. Percentage of patients with identified mutation, depending on the clinical presentation (number of classic signs of MAS: precocious puberty, skin lesions, FD) and the analyzed tissue

 
A mutation of arginine 201 in the Gs{alpha} protein was found in 49 of the 113 patients (43%), with a net preponderance of the substitution by histidine (n = 34) as opposed to cysteine (n = 15). No difference in severity or manifestations of the disease was noted between the two mutations. We did not find any of the rarely reported mutations of arginine 201 into serine, glycine, or leucine (21, 22, 23). In patients who had several tissue samples analyzed, the same mutation was always found. This supports the hypothesis of a somatic mutation appearing early in the course of development and yielding a monoclonal population of mutated cells.

These raw numbers were analyzed as a function of tissue and presentation of the syndrome. Overall, the abnormality was more often detected in those patients presenting the complete clinical picture (59%) than in those showing only one or two signs (46 and 34%, respectively). However, this was highly dependent on the tissue that was available for analysis. Disregarding the skin samples, which were infrequently positive (see Discussion), we were able to detect the mutation in about 90% of the patients from samples of affected tissue (i.e. ovary, bone, etc.), with no difference between patients presenting three (90%), two (94%), or one sign (89%) (Table 4Go).

Only 21% of the DNAs extracted from PBL were positive for the mutation. However, it is noteworthy that the mutation was detected in almost half of the PBL samples (46%, Table 4Go) in patients presenting the classic triad. This figure fell to 21% and 8% in patients with two and one sign, respectively.

The mutation was found in 10 of the 13 ovarian tissue samples (77%) of our series. We also had the opportunity to study DNA extracted from ovarian cystic fluids obtained either from cystic puncture or cystectomy. Of the 19 fluid samples analyzed, 13 were positive for the mutation (68%). This is important to keep in mind in cases of isolated precocious puberty, as discussed below. Unlike cystic fluid, ovarian cyst tissue itself showed relatively low positivity (38%).

Analysis of bone tissues revealed a very high proportion of positive samples (9 of 11; 82%). The two cases in which mutation was not detected corresponded to isolated FD.

The mutation was identified in only three of 11 skin lesion samples (27%). In patients with the classic triad, only one skin sample was positive among the seven that were available. It is interesting to note that in the patients from whom both blood and skin samples were taken, the mutation was found five times in blood but only twice in skin.

Other than the three classic tissues of MAS, ovary, bone, and skin, we analyzed only a few other tissues. These included four adrenal glands (two were positive), as well as single cases of other endocrine tissues (2B), some of which have already been reported (24, 25).

Only two nonendocrine tissues were studied. We found the mutation in five of six liver samples and in the single muscle tissue studied (Table 3Go).


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
In MAS, the postzygotic occurrence of the mutation leads to a mosaic distribution of mutant-bearing cells and to a constellation of abnormal tissues specific to each patient. The number of abnormal cells in a given tissue, and thus the quantity of mutated DNA, is quite variable and may be extremely low. The molecular diagnosis of MAS is therefore highly dependent on the sensitivity of the detection technique. We used a previously described, highly sensitive PCR-based technique that allows the selective enrichment of mutated DNA (21). However, in contrast to the several steps described by Candeliere et al. (21), we performed only two steps of digestion to limit the risk of contamination inherent to the nested PCR. We also applied several negative controls, and the results were repeated at least twice on separate assays. We believe that these procedures helped to maintain an optimal balance between specificity (no false positives) and sensitivity (the fewest possible false negatives). Other sensitive techniques have been used for the diagnosis of MAS, in particular PCR coupled with allele-specific oligonucleotide hybridization (11, 26). One of the most recently described methods is based on the use of a protein nucleic acid primer to block amplification of the normal allele (27).

Despite a highly sensitive detection method, some samples may remain negative. Mutated cells may be confined to only specific loci in the affected tissue, and some ovarian or bone samples will be negative if the biopsy has missed these loci. This highlights the interest of studying sections from paraffin-embedded tissues in which the pathological regions have been localized before DNA extraction, as was nicely shown by Weinstein et al. (11) on the ovary. We used this approach successfully in several cases when the initial studies on the whole tissue or biopsy were negative.

Our results confirmed, however, that the overall risk of not detecting the mutation in affected tissues is rare: only about 10% of these samples were negative (Table 4Go). The skin was a remarkable exception to this because we found only 27% of café-au-lait spot samples to be positive for the mutation. Even in patients with the classic triad, the mutation was detected in only one of seven skin tissues. These findings confirm previous reports showing the difficulty of detecting the mutation in skin (12), likely due to the low proportion of melanocytes, which are the cells potentially mutated in skin tissue.

We confirmed the high frequency of the mutation in bone using a sensitive technique (21, 26, 27). Three isolated FD samples were positive, confirming previous reports showing that Gs{alpha} mutation constitutes the same molecular basis for development of bone lesions in isolated FD and in classic MAS (21, 27).

Since the original description of MAS and the classic triad, numerous reports have shown that its clinical expression is in fact extremely heterogeneous. The first sign is variable, as well. Diagnostic efforts must thus be oriented toward these numerous atypical or partial forms.

We have now studied a total of 39 cases of girls presenting peripheral precocious puberty without other signs of MAS since our original report (28). Overall, we found the mutation in 13 cases (33%). Detailed individual results can be found in Table 5GoGo. Interestingly, among the 13 cystic fluids analyzed, nine were positive for the mutation (70%). The data available to date in the patients showing mutation indicate that, although precocious puberty has remained isolated in five, skin and/or bone lesions have appeared in the eight other patients since diagnosis. The major implications of identifying the mutation—for both disease progression and treatment—encourage us to urge physicians to study ovarian cystic fluid more systematically in girls with isolated precocious puberty and recurrent ovarian cyst.

Other than the ovaries, the adrenals were the most commonly affected endocrine gland in our series, with seven cases of autonomous hypercortisolism. Several cases of hypercortisolism associated with MAS have been reported (5, 15, 29, 30, 31, 32), but the neonatal occurrence seems rare (30, 33). We studied a case of severe neonatal Cushing’s syndrome in a girl in whom the mutation was identified first in blood and then in adrenal tissue after unilateral adrenalectomy (34).

Although mutation of Arg201 is most frequently found in endocrine organs (11), it has also been identified in nonendocrine tissues (35). In this respect, we previously reported in detail two cases of patients with MAS and liver cholestasis (36). We also recently studied a case in which the cholestasis occurred at 8 months of age and actually revealed the syndrome 5 yr before the precocious puberty. In cases of unexplained liver cholestasis in neonates or infants, MAS should thus be suspected.

In conclusion, the detection of the mutation is of particular interest in the partial and atypical forms of MAS. This will ensure early diagnosis and the proper management of children in whom the possibility of later completion of MAS certainly does exist, as was shown in isolated FD (37) and as we have shown here for precocious puberty.


   Acknowledgments
 
We thank Professor Cherif Beldjord (Institut Cochin de Génétique Moléculaire, Paris, France) for having introduced us to the molecular biology of Gs{alpha}. The technical assistance of Hanane Dib, Anne Licznar, Pascal Phillibert, Cécile Caubel, and Isabelle Ringeard was much appreciated, as was the participation of Dr. Claire Jeandel in the patient management.

We are deeply grateful to the following doctors and professors for having sent us MAS patients or the DNA from these patients: Alos (Narbonne), Attouche (Toulouse), Baechler-Sadoul (Nice), Barat (Bordeaux), Baron (Nantes), Bercovici (Brest), Bertrand (Besançon), Bost (Grenoble), Brauner (Paris), Bremond (Marseille), Carel (Paris), Cartigny (Lille), Charbonnel (Nantes), Chaussain (Paris), Colle (Bordeaux), Copelli (Buenos-Aires), Coutant (Angers), Czernichow (Paris), de Kerdanet (Rennes), de Muinck-Keizer (Rotterdam), Despert (Tours), Drop (Rotterdam), Dumas (Montpellier), Eiholzer (Zurich), Fauser (Rotterdam), Fellman (Besançon), Feron (Orleans), Garandeau (Montpellier), Gillerot (Brussels), Gottrand (Lille), Jouk (Saint-Etienne), HoorwegNijman (Amsterdam), Kacem (Monastir), L’Allemand (Zurich), Lauras (Saint-Etienne), Laven (Rotterdam), Lebouc (Paris), Leger (Paris), Leheup (Nancy), Limal (Angers), Mallet (Rouen), Malpuech (Clermont-Ferrand), Metz (Brest), Nemeth (Stockholm), Nicolino (Lyon), Nivot (Caen), Peterkova (Moscow), Petrus (Tarbes), Pienkowski (Toulouse), Pinto (Paris), Plauchu (Lyon), Puel (Bordeaux), Razafimahefa (Toulon), Richard (Lyon), Rifai (Lille), Semicheva (Moscow), Silva (Porto), Sokal (Brussels), Soskin (Strasbourg), Starzyk (Krakaw), Szarras-Czapnik (Warsaw), Tauber (Toulouse), Thibaud (Paris), Toublanc (Paris), Troller (La Rochelle), Tsaregorotsev (Moscow), Van den Ouweland (Rotterdam), and Weill (Lille).


   Footnotes
 
This work was presented in part as an oral communication at the 82nd Annual Meeting of The Endocrine Society in Toronto, Canada, in June, 2000.

Abbreviations: AC, Adenylate cyclase; FD, fibrous dysplasia; Gs{alpha}, guanine-nucleotide-binding protein (G protein) {alpha}-subunit; MAS, McCune-Albright syndrome; PBL, peripheral blood leukocytes; PRL, prolactin.

Received July 16, 2003.

Accepted January 23, 2004.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

  1. McCune DJ 1936 Osteitis fibrosa cystica; the case of a nine year old girl who also exhibits precocious puberty, multiple pigmentation of the skin and hyperthyroidism. Am J Dis Child 52:743–744
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