Activating or gain-of-function GNAS1 mutations in patients with the McCune-Albright syndrome are present in the mosaic state, resulting from a postzygotic somatic mutation appearing early in the course of development which yields a monoclonal population of mutated cells ... Activating or gain-of-function GNAS1 mutations in patients with the McCune-Albright syndrome are present in the mosaic state, resulting from a postzygotic somatic mutation appearing early in the course of development which yields a monoclonal population of mutated cells within variously affected tissues. The nonmosaic state for most activating mutations is presumably lethal to the embryo. The disorder is characterized clinically by the classic triad of polyostotic fibrous dysplasia (POFD), cafe-au-lait skin pigmentation, and peripheral precocious puberty. However, the disorder is clinically heterogeneous and can include various other endocrinologic anomalies such as thyrotoxicosis, pituitary gigantism, and Cushing syndrome (219080) (Lumbroso et al., 2004).
This disorder is called McCune-Albright syndrome or simply Albright syndrome, but should not be confused with pseudohypoparathyroidism (103580), which includes a constellation of features termed Albright hereditary osteodystrophy (AHO). The predominant features of MAS occur in 3 areas: ... This disorder is called McCune-Albright syndrome or simply Albright syndrome, but should not be confused with pseudohypoparathyroidism (103580), which includes a constellation of features termed Albright hereditary osteodystrophy (AHO). The predominant features of MAS occur in 3 areas: the bony skeleton, the skin, and the endocrine system. In all 3 systems, the extent of the abnormality and, in the case of the endocrine system, the nature of the abnormality, are highly variable from case to case, depending on the specific tissues involved in the mosaicism and the extent of involvement. - Skeletal No bone is spared. There is a strong tendency to asymmetry. Involvement of the skull and facial bones can be striking, and in the case of these bones also, asymmetry is the rule. Pathologic fracture or bone deformity may be presenting manifestations and pseudarthrosis occurs frequently. Deafness and blindness can result from impingement of the bony process on the cranial foramina. Shepherd's crook deformity of the proximal femur is particularly characteristic of the bony involvement. (The bone lesions of neurofibromatosis are usually less extensive than are those in polyostotic fibrous dysplasia, but may be difficult to distinguish on radiologic grounds alone.) Hypophosphatemic osteomalacia ('rickets') has been observed in some cases of polyostotic fibrous dysplasia. Dent and Gertner (1976) suggested that this may represent a situation comparable to 'tumor rickets' which is associated with mesenchymal tumors and regresses when the tumor is removed. McArthur et al. (1979) described 4 patients with Albright syndrome, hypophosphatemia, and inappropriately low renal tubular reabsorption of phosphate. Three of the patients had radiologic evidence of rickets. They postulated that a substance elaborated by the dysplastic bone interfered with phosphate reabsorption in the renal tubule. Kaplan et al. (1988) reported the case of a 31-year-old woman with this disorder in whom bone lesions progressed rapidly during pregnancy. A study of these lesions showed the presence of estrogen and progesterone receptors in osteogenic cells. Whether estrogen receptors are unique to the McCune-Albright syndrome or, alternatively, a property of any activated, dedifferentiated, or neoplastic bone cells is unclear. Viljoen et al. (1988) described a severely affected man, aged about 30, with massive craniofacial hyperostosis. They raised the question of whether this represents the severe end of the scale for polyostotic fibrous dysplasia, or whether it is a distinct entity. It seems likely that this was a severe expression of polyostotic fibrous dysplasia (McCune-Albright syndrome). McKusick (1988) studied a patient with severe craniofacial hyperostosis who had other, more characteristic features of polyostotic fibrous dysplasia, including cafe-au-lait pigmentation, which was absent in the case of Viljoen et al. (1988); this patient was later found by Schwindinger et al. (1992) to have a mutation in the GNAS1 gene (139320.0009). There are other definite cases of patients with very severe craniofacial involvement (Nager et al., 1982; Nager and Holliday, 1984). Such is also evident from inspection of the descriptions in the classic monograph of Albright and Reifenstein (1948). For example, they produced a picture (their Figure 145) of a skeleton thought by von Recklinghausen (1891) to represent hyperparathyroidism (osteitis fibrosa generalisata of von Recklinghausen). That this was severe Albright polyostotic fibrous dysplasia was suggested by the shepherd's crook deformity of the femora and the asymmetric bulge of the occipital area of the skull. Taconis (1988) reported 2 cases of osteosarcomatous transformation, 1 in the skull of a 25-year-old man and 1 in the iliac bone of a 38-year-old man. Taconis (1988) stated that the incidence of malignancy of the bone lesions may be lower than previously suggested. Malignant transformation occurs in both monostotic and polyostotic disease but is more common in the latter form. Although radiation therapy is often an inciting cause, this was not the case in either of these patients, who had received no radiation therapy. Candeliere et al. (1995) reported a 7-year-old boy with McCune-Albright syndrome in whom they identified high levels of expression of the FOS (164810) oncogene in bone lesions. Increased expression of the FOS oncogene was presumably a consequence of increased adenylate cyclase activity and may have been important in the pathogenesis of the bone lesions. Genetic analysis identified the R201H mutation in the GNAS1 gene (139320.0013). - Skin The involvement of the skin consists predominantly of large cafe-au-lait spots with irregular margins, giving them a 'coast of Maine' configuration as opposed to the more regularly outlined 'coast of California' cafe-au-lait spots of neurofibromatosis (162200). Like the bony lesions, the pigmentary lesions of the skin may be limited predominantly to one side and stop sharply at the midline. The nape of the neck is a commonly involved site. (The cafe-au-lait spots of neurofibromatosis are for the most part smaller, more regular, and more uniformly distributed, and are accompanied by axillary freckling and usually by skin tumors.) - Endocrine The leading endocrinologic feature is precocious puberty, which occurs in over half of female cases. Menstruation may occur in the first months of life. Precocious puberty has been reported also in males with this syndrome; testicular biopsy has revealed the full process of spermatogenesis with mature sperm in patients as young as 6 years (Benedict, 1966; Giovannelli et al., 1978). Probably the second most common endocrinopathy is hyperthyroidism (Lichtenstein and Jaffe, 1942; Hamilton and Maloof, 1973). Excessive secretion of growth hormone (GH1; 139250) with gigantism, hyperadrenocorticism with Cushing syndrome, and gynecomastia have been observed. In specific instances, it has been demonstrated that the Cushing syndrome is due to multinodular change in the adrenals and the hyperthyroidism to multinodular toxic goiter (Hamilton and Maloof, 1973). Falconer et al. (1942) reported pituitary gigantism in association with McCune-Albright syndrome. Wrong (1992) stated that he saw this patient, a boy born in Nottingham in 1930, in 1954; the patient was still alive, though severely disabled by bone disease, in the late 1960s at the age of almost 40. Premawardhana et al. (1992) described a 26-year-old woman with acromegaly due to a pituitary adenoma who developed secondary hypothyroidism and hypoadrenalism, in a setting of McCune-Albright syndrome. Cremonini et al. (1992) described acromegaly and hyperprolactinemia due to pituitary adenoma in a 35-year-old woman with McCune-Albright syndrome. Malchoff et al. (1994) reported a 27-year-old woman with McCune-Albright syndrome who had an unusual clinical course. She presented at the age of 3 years with vaginal bleeding, had breast development at age 4 years, and had a second episode of vaginal bleeding at age 5 years 7 months. She had no pigmentary skin lesions, and 2 sets of radiographs of the chest, pelvis, skull, and long bones were normal. She was treated for 24 months with medroxyprogesterone acetate, and precocity resolved. She progressed normally through puberty, starting at age 10 years, and had normal menses, starting at age 12 years. At age 25 years, she delivered a normal daughter. A chest x-ray at age 27 years after minor trauma identified a single lesion of fibrous dysplasia in the left seventh rib. Radiographs of other bones were normal. Studies of the GNAS1 gene showed an R201H mutation. Tinschert et al. (1999) reported a 37-year-old man with McCune-Albright syndrome causing gigantism and fibrous dysplasia with hypersecretion of growth hormone and prolactin (176760), with no evidence of pituitary tumor. The patient had an R201H mutation which ranged from 0% in buccal mucosa, blood, and skin melanocytes to 45% in a frozen section of the middle nasal concha. Coutant et al. (2001) reported a 3.8-year-old boy with McCune-Albright syndrome associated with abnormal prepubertal testis enlargement and no sexual precocity. Other endocrine tests showed excessive GH secretion and moderate adrenal androgen hypersecretion. These findings were consistent with the occurrence of an activating mutation of the GNAS1 gene mainly expressed in Sertoli cells and weakly expressed or absent in Leydig cells. Abnormal prepubertal testicular enlargement extends the clinical spectrum of MAS, suggesting that determination of serum inhibin B (see 147290) and anti-mullerian hormone (600957) should be considered in boys with this syndrome. DNA sequence analysis from bone and testis tissues detected the R201H mutation. Akintoye et al. (2002) estimated the prevalence of GH excess in MAS, characterized the clinical and endocrine manifestations, and described the response to treatment. Twelve patients (21%) had GH excess, based on failure to suppress serum GH on oral glucose tolerance test. Vision and hearing deficits were more common in patients with GH excess (33%) than in those without (4%). 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 (613879), 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. GH excess is common in MAS and results in a distinct clinical phenotype characterized by inappropriately normal stature, TRH responsiveness, prolactin (176760) cosecretion, small or absent pituitary tumors, a consistent but inadequate response to treatment with cabergoline, and an intermediate response to long-acting octreotide. Laven et al. (2001) presented the first longitudinal assessment of ovarian dysfunction in an adult patient with McCune-Albright syndrome. Their report provided evidence for persistent autonomous unilateral ovarian dysfunction during early adulthood in McCune-Albright syndrome not compatible with normal fertility. Laven et al. (2004) presented a case of an adult MAS patient with persistent unilateral autonomous ovarian activity whose ovarian and endometrial function was restored by removal of the affected ovary. Obuobie et al. (2001) studied the GH and insulin-like growth hormone I (IGF1; 147440) profiles in a patient with confirmed McCune-Albright syndrome and GH hypersecretion throughout a successful pregnancy and postpartum period. Prepregnancy, the IGF I level was 60.6 nmol/L (normal, 18.0-43.1) and the daytime GH profile measured using assay A was 9.6-14.0 mU/L. At 13 weeks' gestation there was a decline of IGF I to 33.9 nmol/L and in the daytime GH profile (assay A) to 5.4-6.8 mU/L. At 24 weeks, IGF I had risen to 51.6 nmol/L. At 36 weeks, IGF I was still elevated at 56.6 nmol/L, with a daytime GH profile of 16.6-17.7 mU/L using assay A. At 12 weeks postpartum, the daytime GH profile with assay B was 5.6-8.6 mU/L. The authors concluded that GH suppression during pregnancy in acromegaly associated with McCune-Albright syndrome is best shown with assay B, which discriminates between GH and human placental lactogen (HPL; 150200). They also stated that GH secretion in a pregnant acromegalic with the McCune-Albright syndrome may not be entirely autonomous, as seen in classic acromegaly, but may be associated with a degree of negative feedback control that could be exerted by a circulating factor of placental origin, probably HPL or placental GH (GH2; 139240). DiGeorge (1975) reviewed unusual features of the syndrome and the evidence that the endocrinopathy represents autonomous function of the endocrine glands. Two main hypotheses had been stated: (1) excessive secretion of the hypothalamic releasing hormones is involved in the endocrinopathy of this disorder (Hall and Warrick, 1972); and (2) this disorder represents multiple, circumscribed embryonic alterations in a variety of tissues resulting from clones of cells characterized by autonomous behavior, and perhaps aberrant behavior, toward otherwise normal stimuli. The latter hypothesis appeared to be the more compatible with the skeletal, cutaneous, and endocrinologic features and with the mosaic hypothesis of Happle (1986); its validity was proved by demonstration of mosaicism for mutations in the GNAS1 gene. Majzoub and Scully (1993) described a 6-year-old boy who had apocrine sweat, facial acne, Tanner stage 2 pubic hair, and midpubertal-sized testes and penis, all indicative of precocious puberty, in association with osseous changes of this disorder. A patient, aged 50 years, with McCune-Albright syndrome had a large syrinx (syringomyelia) causing neurologic manifestations in the arms and legs (McKusick, 1988). Because of a linear midline pigmentation in the high cervical area posteriorly, in the same area of the syrinx, the possibility can be raised that the syrinx, which extended from C2 to T11, was a primary manifestation of the syndrome. The patient also had extensive involvement of the base of the skull with Arnold-Chiari syndrome (i.e., extension of cerebellar tissue through the foramen magnum). He had had hyperthyroidism, as reported by Hamilton and Maloof (1973). (The same patient had severe craniofacial hyperostosis and was demonstrably mosaic for a specific GNAS1 mutation, i.e., arg201-to-his (139320.0009).) Abs et al. (1990) described a case of atypical McCune-Albright syndrome; a 36-year-old woman had acromegaly due to a pituitary adenoma, a toxic multinodular goiter that was associated with spontaneous normalization of thyroid function, and asymptomatic polyostotic fibrous dysplasia. There was no skin pigmentation and no sexual precocity. See 139320.0009 for discussion of the molecular basis of the association of pituitary tumor with McCune-Albright syndrome. Chanson et al. (1994) reported 5 patients with McCune-Albright syndrome and acromegaly. In all, acromegaly began before the age of 20 years and was recognized after the diagnosis of fibrous dysplasia, which was polyostotic in 3 and monostotic in 2. Bone fibrous dysplasia always involved the base of the skull and in 4 patients prevented surgical removal of the pituitary adenoma, which was visualized easily by MRI. Yoshimoto et al. (1991) described the extraordinary case of a female infant who at birth had cutaneous pigmentation, hyperthyroidism, and Cushing syndrome. Mastorakos et al. (1997) described a 6-year-old girl with MAS and hyperthyroidism and reviewed the previously reported 63 patients with MAS and thyroid disorders. Kirk et al. (1999) presented 5 children (4 girls) with features of McCune-Albright syndrome who had Cushing syndrome in the infantile period (under 6 months of age). In 2 children, spontaneous resolution occurred, but the remaining 3 required bilateral adrenalectomy. In addition, all 4 girls experienced precocious puberty, and 3 children demonstrated radiologic evidence of nephrocalcinosis. In 1 patient, laparotomy, performed at 7 weeks of age because of vomiting and abdominal distention, revealed multiloculated ovarian cysts. Bilateral adrenalectomy was performed at 3 months for nodular hyperplasia. Irregular vaginal bleeding in association with breast development occurred by 11 months of age. Thyrotoxicosis subsequently developed, and the patient had a number of pathologic fractures of both femurs through polyostotic lesions and had marked spinal deformity. Kirk et al. (1999) postulated that the hypercalcemia and hypercalciuria leading to renal stones are secondary to the effects of cortisol on bone turnover. Yang et al. (1999) reported a case of thyroid cancer in McCune-Albright syndrome. Collins et al. (2003) reported a second case and reviewed both cases, extending the phenotypic spectrum of the disorder. - Phenotypic Variation Cole et al. (1983) reported the case of a French-Canadian boy, of nonconsanguineous parents, who had unusual facial appearance (depressed nasal bridge, synophrys, and forehead hirsutism), 'coast of Maine' pigmented patches, myelofibrosis, recurrent femoral fractures and widespread fibrous dysplasia of bone leading to the suggested designation 'panostotic fibrous dysplasia.' Biochemical findings included elevated serum alkaline phosphatase (bone isozyme) and 1,25-(OH)2 vitamin D and low serum phosphorus levels. Increased turnover of bone was indicated by urinary excretion rates of hydroxyproline, glycylproline, and gamma-carboxyglutamic acid. Progressive cortical thinning and loss of bony trabeculae were demonstrated by serial x-rays and supported by bone biopsy. No precisely similar case was known. Candeliere et al. (1995) demonstrated that this patient, then a 14-year-old boy, had an arg201-to-cys mutation in the GNAS1 gene (139320.0008). Thus, this was an unusually severe form of McCune-Albright syndrome not fundamentally different from that disorder or perhaps from monostotic fibrous dysplasia. Cole (1996) pointed out that the patient with 'idiopathic hyperphosphatasia with dermal pigmentation' reported by Dohler et al. (1986) appears to have had the same disorder as the patient reported by Cole et al. (1983). De Sanctis et al. (1999) reported the diagnostic clinical features and their long-term evolution in 32 patients with McCune-Albright syndrome. Almost all patients had skin changes at birth. There was a 50% probability of bone dysplasia at 8 years of age and a 50% probability of precocious puberty in females at 4 years. Coutant et al. (2001) reported a 3.8-year-old boy with McCune-Albright syndrome associated with abnormal prepubertal testis enlargement and no sexual precocity. Physical examination showed cafe-au-lait skin lesions, enlarged testes, prepubertal sized penis, and no pubic or axillary hair. Skeletal radiography disclosed fibrous dysplasia. The serum testosterone level was 0.58 nmol/L and remained below 1.4 nmol/L during the 4-year follow-up. By contrast, serum inhibin B (see 147290) and anti-mullerian hormone (600957) concentrations were abnormally increased up to 255 pg/mL (childhood range, 35-180) and 792 pmol/L (childhood range, 309-566), respectively. The luteinizing hormone (LH; 152780) response to a gonadotropin-releasing hormone (GnRH; 152760) test was in the prepubertal range, whereas the follicle-stimulating hormone (FSH; 136530) response was blunted. This abnormal hormone concentration profile indicated autonomous hyperfunction of Sertoli cells, with no evidence of Leydig cell activation. Testicular histology showed tubules with marked Sertoli cell hyperplasia and very rare germinal cells, and interstitial tissue containing mesenchymal cells but no mature Leydig cells. DNA sequence analysis from bone and testis tissues detected the known activating mutation in MAS that results in the arg201-to-his mutation in the GNAS1 protein (139320.0009).
The mystery of the etiology and pathogenesis of polyostotic fibrous dysplasia appears to have been solved by the identification of activating mutations in the GNAS1 gene (139320) which render the gene functionally constitutive (Weinstein et al., 1991; Schwindinger ... The mystery of the etiology and pathogenesis of polyostotic fibrous dysplasia appears to have been solved by the identification of activating mutations in the GNAS1 gene (139320) which render the gene functionally constitutive (Weinstein et al., 1991; Schwindinger et al., 1992). Similar mutations leading to constitutive activation of this gene had been identified in some human growth hormone secreting pituitary tumors and human thyroid tumors. Furthermore, the demonstration of the mutation in peripheral blood leukocytes but not in DNA from biopsies of clinically normal skin supports the proposal of Happle (1986) that this is a disorder of mosaicism resulting from postzygotic somatic cell mutation. Kitoh et al. (1999) found a mutation in GNAS1 in endosteal, but not in periosteal, cells taken from a cystic lesion of the humerus of an 11-year-old boy with polyostotic fibrous dysplasia. Bianco et al. (1998) isolated progenitor cells from the stromal system of the bone marrow involved in fibrous dysplasia in patients with McCune-Albright syndrome and analyzed these cells in culture. Analysis of the GNAS1 gene from individual colonies provided direct evidence for the presence of 2 different genotypes within single fibrous dysplastic lesions: marrow stromal cells containing 2 normal GNAS1 alleles, and those containing a normal allele and an allele with an activating mutation. Transplantation of clonal populations of normal cells into the subcutis of immunocompromised mice resulted in normal ossicle formation. In contrast, transplantation of clonal populations of mutant cells always led to the loss of transplanted cells from the transplantation site and no ossicle formation. However, transplantation of a mixture of normal and mutant cells reproduced an abnormal ectopic ossicle recapitulating human fibrous dysplasia and providing an in vivo cellular model of this disease. The results provided experimental evidence for the need of both normal and mutant cells in the development of McCune-Albright syndrome fibrous dysplastic lesions in bone. This study confirmed the hypothesis of Happle (1986). It also confirmed the editorial comment of DiGeorge (1975) concluding with the remark that MAS is 'a rare disorder, yes; an unimportant one, never' (Olsen, 1998). Bianco et al. (2000) analyzed a series of 8 consecutive cases of isolated fibrous dysplasia without the classic features of McCune-Albright syndrome and identified arg201 mutations in the GNAS1 gene in all of them. Histologic findings in these cases were not distinguishable from those observed in MAS-related fibrous dysplasia and included subtle changes in cell shape and collagen texture putatively ascribed to excess endogenous cAMP. Unmineralized osteoid changes characteristic of osteomalacia were prominent in lesional fibrous dysplasia. Bianco et al. (2000) concluded that the findings support the view that fibrous dysplasia, MAS, and nonskeletal isolated endocrine lesions associated with GNAS1 mutations represent a spectrum of phenotypic expressions, probably reflecting different patterns of somatic mosaicism, of the same basic disorder. Akintoye et al. (2002) noted that the molecular etiology of MAS is postzygotic activating mutations of the GNAS1 gene product, the alpha subunit of the Gs protein. The term 'GSP oncogene' has been assigned to these mutations due to their association with certain neoplasms. Collins et al. (2003) performed molecular analysis of thyroid carcinomas from 2 McCune-Albright syndrome patients and demonstrated that foci of malignancy and adjacent areas of hyperplasia and, in 1 case, some areas of normal thyroid harbored an activating mutation of GNAS1 at the arg201 codon (139320.0008 and 139320.0009, respectively). The authors concluded that these 2 cases of thyroid carcinoma in MAS supported the hypothesis that activation of the G(s) signaling cascade alone is insufficient for malignant transformation of thyroid or other endocrine cells. Using a PCR-based sensitive method, Lumbroso et al. (2004) reported a systematic search for Gs-alpha arg201 mutations in patients presenting with at least 1 of the signs of MAS. They studied 113 patients (98 girls and 15 boys), 24% presenting the classic triad, 33% with 2 signs, and 40% with only 1 classic sign. Overall, mutation of the arg201 codon 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 3 of 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 2 and 1 sign, respectively. The authors concluded that 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.