Is periostin useful as a biomarker for fibrous dysplasia? / ¿Es útil periostina como biomarcador de displasia fibrosa?

Fibrous dysplasia (FD) is an infrequent non-hereditary bone disease caused by a somatic mutation of the GNAS gene. Periostin is a novel marker that increases during tissue healing and fibrous or inflammatory diseases. We conducted an exploratory case-control study to evaluate sensitivity of periostin as a biomarker of FD. The study comprised 15 patients with FD, and healthy age- and sex-matched subjects (controls). Serum periostin levels were assessed and comparisons were established between FD patients and controls, and between patients with the monostotic and the polyostotic form of FD. No statistically significant differences in serum periostin levels were observed between the cohort of FD patients studied here and the control group (FD: 51.1±10ng/ml vs. control: 44.2±15ng/ml; p=0.15), or between the clinical forms of FD (polyostotic: 51.8±9.1ng/ml vs. monostotic: 49.6±13 ng/ml; p=0.66). A sub-analysis performed to compare serum levels of periostin in FD patients with and without a history of fractures showed no statistically significant differences [fracture patients (n=4): 41.2±17ng/ml vs. non-fracture patients (n=11): 49.9±11 ng/ml; p=0.47].Lastly, sensitivity of periostin as a biomarker of FD was analyzed, and was found to have low sensitivity to estimate disease activity [ROC curve; cut-off points: 39.625(0.867-0.467)]. To conclude, in the cohort of FD patients studied here, periostin serum levels did not differ significantly from those of the control group or between the two forms of the disease, and showed low sensitivity as a biomarker of the disease. (AU)

La displasia fibrosa (DF) es una enfermedad infrecuente del hueso, no hereditaria producida por una mutación somática del gen GNAS. Periostina (Postn) es un novedoso marcador, cuyos niveles séricos se encuentran elevados en los procesos de reparación tisular, enfermedades fibrosas o inflamatorias. Llevamos a cabo un estudio exploratorio caso-control para evaluar la sensibilidad de Postn como biomarcador de DF. Se incluyeron en el estudio 15 pacientes con DF apareados por edad y género con sujetos sanos (controles) en los cuales se evaluó los niveles séricos de Postn en pacientes con DF y controles y según forma de presentación clínica. No observamos diferencias estadísticamente significativas en los niveles séricos de Postn y el grupo control (DF: 51.1±10ng/ml vs. control: 44.2±15ng/ml; p=0.15) como así tampoco por forma clínica de DF (poliostótica: 51.8±9.1ng/ml vs. monos-tótica: 49.6±13 ng/ml; p=0.66). Posteriormente realizamos un sub-análisis para evaluar los niveles séricos de Postn en los pacientes con DF y antecedentes de fracturas no observan-do diferencias estadísticamente significativas [fracturados (n=4): 41.2±17ng/ml vs. no frac-turados (n=11): 49.9±11 ng/ml; p=0.47]. Por último analizamos la sensibilidad Postn como biomarcador de DF, mostrando este poseer escasa sensibilidad para estimar actividad de la enfermedad [curva ROC; puntos de corte: 39.625 (0.867-0.467)]. En conclusión, los ni-veles séricos de Postn en nuestra cohorte de pacientes con DF no mostraron diferencias estadísticamente significativas comparadas con el grupo control o por forma clínica de presentación, mostrando una baja sensibilidad como biomarcador de enfermedad. (AU)

Serum periostin levels and severity of fibrous dysplasia of bone.

Fibrous dysplasia of bone (FD) is a rare congenital bone disease, characterized by a fibrous component in the bone marrow. Periostin has been extensively researched because of its implication in various fibrotic or inflammatory diseases. Periostin may be associated with the burden or the severity of FD. The case control PERIOSDYS study aimed at assessing serum periostin levels in FD patients. Sixty four patients with monostotic or polyostotic disease were included, in order to evaluate whether the concentrations were greater in patients than in 128 healthy age, BMI and sex-matched controls and if they were more elevated in patients with the more severe phenotypes. We found that periostin levels were greater in patients with FD compared to controls (mean = 1085 vs 958 pmol/l, p = 0.026), especially in those with a history of fracture (mean = 1475 vs 966 pmol/l, p = 0.0005), polyostotic forms (mean = 1214 vs 955 pmol/l, p = 0.004) or McCune-Albright syndrome (mean = 1585 vs 1023 pmol/l, p = 0.0048). In contrast, high pain levels were not associated with periostin levels (mean = 1137 vs 1036 pmol/l, p = 0.445). Furthermore, patients undergoing bisphosphonate therapy had significantly lower levels than treatment naïve patients (mean = 953 vs 1370 pmol/l, p = 0.002). In conclusion, periostin may be a biochemical marker indicative of the most severe forms of FD and could be used to monitor patients treated with bisphosphonates.

Clinical significance of increased serum levels of FGF-23 in fibrous dysplasia. / Significado clínico del aumento de los valores séricos de FGF-23 en la displasia fibrosa.

INTRODUCTION AND OBJECTIVE: Fibrous dysplasia (FD) can be associated with the development of hypophosphatemic osteomalacia, caused by the production of FGF-23 by dysplastic bone tissue. This study analysed FGF-23 levels in patients with FD, and their association with disease activity and serum phosphate values. PATIENTS AND METHODS: Twelve adult patients with FD were included in the study. Clinical history, disease extension and activity and treatments received were reviewed, and the relationship of those values with FGF-23 and serum P levels was analysed. RESULTS: FGF-23 was elevated in 6/12 patients (50%). Patients with high FGF-23 levels had similar age and disease activity and extension than those who did not. No differences were observed in serum phosphate values between both groups (increased FGF-23: 3.9±0.9 mg/dl vs. decreased FGF-23: 3.5±0.6 mg/dl). In fact, none of the patients with increased FGF-23 had low serum phosphate values. CONCLUSION: Adult FD patients frequently present elevated FGF-23 values with no serum phosphate level repercussion, suggesting an alteration in the processing of this protein in the dysplastic bone tissue for this pathology.

Displasia fibrosa ósea / Fibrous dysplasia of bone

La displasia fibrosa ósea es un trastorno no hereditario del desarrollo esquelético caracterizado por una proliferación anormal de fibroblastos y diferenciación deficiente de osteoblastos que conduce a un reemplazo del tejido óseo esponjoso por tejido conectivo fibroso. Es producida por una mutación somática activadora del gen GNAS1 que induce una activación y proliferación de células mesenquimales indiferenciadas con formación de tejido fibroso y trabéculas óseas anómalas. Existen formas monostóticas, poliostóticas y craneofaciales con diversos grados de dolor, deformidades y fracturas óseas, aunque muchos casos son asintomáticos. En ocasiones se producen quistes óseos aneurismáticos, hemorragias, compromisos neurológicos y raramente osteosarcomas. Algunos casos se asocian a síndrome de McCune-Albright, síndrome de Mazabraud y a osteomalacia por hipofosfatemia por pérdida tubular renal inducida por el FGF23 producido por el tejido displásico. Los hallazgos en las radiografías convencionales son característicos, aunque variables y de carácter evolutivo. La gammagrafía ósea es la técnica de imagen con mayor sensibilidad para determinar la extensión de la enfermedad. El diagnóstico diferencial incluye múltiples lesiones óseas de características similares y en raras ocasiones se requiere biopsia ósea o estudio genético para confirmarlo. No existe un consenso unánime acerca del abordaje terapéutico de estos pacientes, razón por la cual es necesario un enfoque multidisciplinario. La conducta puede ser expectante o quirúrgica según el tipo de lesiones y es importante el manejo del dolor y de las endocrinopatías asociadas. La mayor experiencia publicada se refiere al uso de bifosfonatos y, más recientemente, denosumab. Los tratamientos actuales son insuficientes para modificar el curso de la enfermedad y es necesario el desarrollo de nuevas moléculas que actúen específicamente en el gen GNAS1 o sobre las células mesenquimales afectadas. (AU)

Fibrous dysplasia of bone is a noninherited developmental anomaly of bone characterized by abnormal proliferation of fibroblasts and differentiation of osteoblasts that cause a replacement of trabeculous bone by fibrous connective tissue. It is caused by a somatic mutation in the GNAS1 gene, which induces an undifferentiated mesenquimal cells activation and proliferation with formation of fibrous tissue and abnormal osseous trabeculae. There are monostotic, polyostotic and craniofacial variants with different grades of bone pain, deformities and fractures, although many cases remain asymptomatic. Aneurysmal bone cysts, bleeding, neurological compromise and infrequently osteosarcoma are possible complications. Some cases are associated to McCune-Albright syndrome, Mazabraud syndrome or hypophosphatemia and osteomalacia due to to renal tubular loss induced by FGF23 produced by dysplastic tissue. The findings on conventional radiography are characteristic although variable and evlolve with time. Bone scintigraphy is the most sensitive technique to evaluate the extent of disease. Differential diagnosis include several osseous lesions of similar appearance and, in some cases, bone biopsy or genetic testing may be necessary. Today, there is no consensus regarding the therapeutic approach for these patients and it is necessary a multidisciplinary medical team. Watchful waiting or surgical interventions can be indicated, depending on the type of bone lesions. Bone pain and associated endocrinopathies management are very important. Most published experience refers to the use of bisphosphonates and, more recently, denosumab. Current treatments are insufficient to modify the natural curse of the disease and therefore, new molecules with specific action on GNAS1 gene or affected mesenchymal cells are necessary. (AU)

A randomized, double blind, placebo-controlled trial of alendronate treatment for fibrous dysplasia of bone.

CONTEXT: Fibrous dysplasia (FD) is a rare skeletal disorder, resulting in deformity, fracture, functional impairment, and pain. Bisphosphonates have been advocated as a potential treatment. OBJECTIVE: To determine the efficacy of alendronate for treatment of FD. DESIGN: Two-year randomized, double-blind, placebo-controlled trial. SETTING: Clinical research center. PATIENTS: Forty subjects with polyostotic FD (24 adults, 16 children). Subjects were randomized and stratified by age. INTERVENTIONS: Study drug was administered over a 24 month period in 6 month cycles (6 months on, 6 months off). Alendronate dosing was stratified: 40 mg daily for subjects >50 kg, 20 mg for 30-50 kg, 10 mg for 20-30 kg. MAIN OUTCOME MEASURES: Primary endpoints were bone turnover markers, including serum osteocalcin, and urinary NTX-telopeptides. Secondary endpoints included areal bone mineral density (aBMD), pain, skeletal disease burden score, and functional parameters including the 9-min walk test and manual muscle testing. RESULTS: Clinical data was collected on 35 subjects who completed the study. There was a decline in NTX-telopeptides in the alendronate group (P = .006), but no significant difference in osteocalcin between groups. The alendronate group had an increase in areal BMD in normal bone at the lumbar spine (P = .006), and in predetermined regions of FD (P < .001). There were no significant differences in pain scores, skeletal disease burden scores, or functional parameters between the groups. CONCLUSIONS: Alendronate treatment led to a reduction in the bone resorption marker NTX-telopeptides, and improvement in aBMD, but no significant effect on serum osteocalcin, pain, or functional parameters.

Rapid biochemical response to denosumab in fibrous dysplasia of bone: report of two cases.

We report on the clinical and biochemical outcomes in two adult patients with active polyostotic fibrous dysplasia (FD) treated with the RANK-L inhibitor, denosumab, following unsatisfactory responses to prior long-term bisphosphonate therapy. A 44-year-old female (case 1) who had received a cumulative dose of 20 mg zoledronic acid over 2.5 years and a 48-year-old male (case 2) who had received a cumulative dose of 45 mg zoledronic acid over 8 years both experienced minimal reductions in pain scores and markers of bone turnover. Following initiation of denosumab 60 mg sc, changes in bone pain, bone turnover [assessed by serum amino-terminal propeptide of type I collagen (PINP) and urinary deoxypyridinoline] were monitored over a period of 20 and 8 months, respectively. Following administration of denosumab, both patients demonstrated a rapid and pronounced biochemical response: Within 4-7 weeks, bone turnover markers fell to levels within the respective reference range, and one patient reported a reduction in pain. Treatment with denosumab was well tolerated. However, transient asymptomatic hypocalcaemia and/or hypophosphatemia associated with a transient two to threefold increase in serum PTH levels was observed in both patients. Dosing intervals for denosumab varied significantly between the two patients, depending on disease activity at baseline. Denosumab appears to be effective in reducing bone turnover in adult patients with active FD. However, caution should be exercised, and patients should be monitored carefully as significant fluctuations in biochemical and hormonal indices can occur.

A retrospective study on craniofacial fibrous dysplasia: preoperative serum alkaline phosphatase as a prognostic marker?

BACKGROUND: Craniofacial fibrous dysplasia (CFD) often requires surgery to correct facial deformity and prevent functional impairment. However, recurrence is common, and there is no reliable prognostic biomarker. The aim of this paper is to evaluate the possibility of using preoperative alkaline phosphatase (ALP) as a prognostic marker for CFD. MATERIAL AND METHODS: Forty-nine patients with CFD who underwent surgery from 2000 to 2011 were selected. The relationship between preoperative ALP and age, gender, lesion type and prognosis was investigated. RESULTS: The recurrence rate was 31.8% in patients who received conservative bone contouring. Patients with recurrence did not show significantly higher levels and abnormal rates of ALP than patients without recurrence. Young patients and those with polyostotic CFD showed higher ALP levels than adults and those with monostotic CPD (P < 0.05). Although CFD patients showed higher levels and abnormal rates of ALP than the control group, significant levels were not reached (P > 0.05). No correlation between age, gender, type, ALP and recurrence could be established using the logistic regression model. CONCLUSION: Preoperative ALP may not be a reliable prognostic marker of CFD based on the findings in this study. Close follow-up is recommended after conservative bone contouring.

Fibrous dysplasia of bone associated with primary hyperparathyroidism.

OBJECTIVE: Fibrous dysplasia of bone and primary hyperparathyroidism (PHPT) may occur in patients with McCune-Albright Syndrome. A small number of cases with both diagnoses that are not associated with the above-mentioned genetic disorder have been published in the literature. It is uncertain if these disorders are linked in some way. In the present study, we aimed to further explore a potential relationship between PHPT and fibrous dysplasia of bone. METHODS: We conducted a retrospective review of all cases seen at Mayo Clinic, Rochester, Minnesota, between 1976 and 2011 that were diagnosed with both PHPT and fibrous dysplasia of bone. RESULTS: We identified 10 patients who were diagnosed with both PHPT and fibrous dysplasia of bone. Fibrous dysplasia was polyostotic in 7 (70%) cases. It affected the lower extremities in 6 (60%) patients, the skull or facial bones in 4 (40%), and was localized to one rib in 1 patient (10%). In 4 patients, fibrous dysplasia was diagnosed first, between 9 to 50 years before being diagnosed with PHPT. Two cases of fibrous dysplasia were recognized between 2 and 5 years after the diagnosis of PHPT. The remaining 4 patients were diagnosed with both conditions at approximately the same time. CONCLUSION: It remains unclear if the association between fibrous dysplasia of bone and PHPT is more than coincidental, although the possibility of a rare familial genetic syndrome is not completely excluded.

[Fibroblast growth factor 23--a phosphate regulating hormone]. / Fibroblast growth factor 23--et fosfatregulerende hormon.

Fibroblast growth factor 23 (FGF23) is a recently identified phosphatonin. Its main physiological functions are to maintain serum phosphate within its reference range and to counter regulate the effects of vitamin D. Diseases correlated to high serum values of FGF23 are hypophosphatemic rickets, fibrous dysplasia, and tumour-induced osteomalacia. In contrast, hyperphosphatemic tumoral calcinosis is associated with accelerated degradation of FGF23. Measuring FGF23 serves as a differential diagnostic tool in elucidating conditions of long-lasting hypophosphatemia.

I can feel it in my bones--a case of deranged 'liver' function?

A 55-year-old Asian man was referred to a gastroenterology clinic by his general practitioner following an incidental finding of raised alkaline phosphatase (ALP) on routine blood testing. His ALP was found to be 198 (NR 35-129) with otherwise normal liver function tests. His past medical history consists of essential hypertension, type 2 diabetes and ischaemic heart disease. He was asymptomatic except for an intermittent ache over his left clavicle, which he had put down to angina. His gamma glutamyltransferase (GGT) was normal at 33 (NR 11-50) making bone the most likely source of his raised ALP. Imaging, including x-ray, CT and bone scan, showed an area of abnormality in the left clavicle. The appearances were consistent with fibrous dysplasia. We discuss the interpretation and investigation of deranged 'liver' function tests and suggest a rational and cost-effective diagnostic path to follow.

Expression of FGF23 is correlated with serum phosphate level in isolated fibrous dysplasia.

Fibrous dysplasia (FD) patients sometimes suffer from concomitant hypophosphatemic rickets/osteomalacia, resulting from renal phosphate wasting. It was recently reported that FD tissue in the patients with McCune-Albright syndrome (MAS) expressed fibroblast growth factor-23 (FGF-23), which is now known to be as a pathogenic phosphaturic factor in patients with oncogenic osteomalacia and X-linked hypophosphatemic rickets. Since it remains controversial whether serum phosphate levels are influenced by FGF23 expressions in FD tissue, isolated FD patients without MAS syndrome were examined for the relationship between FGF23 expressions, circulating levels of FGF-23 and phosphate to negate the effects of MAS-associated endocrine abnormalities on serum phosphate. Eighteen paraffin embedded FD tissues and 2 frozen tissues were obtained for the study. Sixteen of 18 isolated FD tissues were successfully analyzed GNAS gene, which exhibited activated mutations observed in MAS. Eight of 16 FD tissues, which exhibited GNAS mutations, revealed positive staining for FGF-23. These evidence indicate that postzygotic activated mutations of GNAS is necessary for the FD tissue formation by mosaic distribution of mutated osteogenic cell lineage, but is not sufficient to elevate FGF23 expression causing generalized osteomalacia with severe renal phosphate wasting. The expression level of FGF23 in isolated FD tissue with hypophosphatemic osteomalacia determined by real-time PCR was abundant close to the levels in OOM tumors. Osteoblasts/osteocytes in woven bone were predominant source of circulating FGF-23 in FD tissues by immunohistochemistry. A negative correlation of the intensity of FGF-23 staining with serum inorganic phosphate levels indicated that the expression of FGF23 in focal FD tissues could be a prominent determinant of serum phosphate levels in isolated FD patient. These data provide novel insights into the regulatory mechanism of serum inorganic phosphate levels in isolated FD patients and extend the notion that FGF-23 originating from FD tissue may cause hypophosphatemia not only in isolated FD patients but also in the patients with MAS syndrome.

Cherubism in siblings: a case report.

Cherubism is a non-neoplastic bone disease characterized by clinically evident bilateral, painless enlargements of the jaws that are said to give the patient a cherubic appearance. Cherubism may appear in solitary cases or in many members of the same family, often in multiple generations. On radiography, the lesions exhibit bilateral multilocular radiolucent areas. Histopathologic evaluation reveals proliferating fibrous connective tissue containing numerous multinucleated giant cells. Since the first description of this condition in 1933, almost 200 cases have been reported. We describe cherubism in 2 siblings and briefly review the literature on this subject.

Cushing's syndrome caused by nodular adrenal hyperplasia in children with McCune-Albright syndrome.

McCune-Albright syndrome consists of fibrous dysplasia of bone, café-au-lait skin pigmentation, and endocrine dysfunction (usually precocious puberty). Other endocrine abnormalities occur in a minority of patients, and of these, Cushing's syndrome is the least often recognized. We present 5 children (4 girls) with features of McCune-Albright syndrome who had Cushing's syndrome in the infantile period (<6 months). In 2 children spontaneous resolution occurred, but the remaining 3 required bilateral adrenalectomy. In addition, all 4 girls have experienced precocious puberty, and 3 children demonstrated radiologic evidence of nephrocalcinosis. Understanding of the underlying defect causing McCune-Albright syndrome emphasizes the importance of searching for other endocrine dysfunction in these children.

Parathyroid hormone and cardiovascular effects of dihydropyridines in chronic renal failure.

We studied the influence of parathyroid gland activity on cardiovascular response to dihydropyridines (nicardipine (NIC), 80 mg/day for 4 weeks) in 20 hypertensive patients with end-stage renal failure (ESRF). Before the treatment hyperparathyroidism (HPTH) was estimated on the basis of serum parathormone (PTH), and bone histomorphometry (osteoclastic resorption surfaces (ORS), and number of osteoclasts (NO]. NIC induced a significant decrease in systolic (SAP) and diastolic (DAP) arterial blood pressure, but did not significantly change the heart rate (HR) or the SAP X HR (myocardial oxygen consumption estimate). Changes in SAP and DAP were correlated to baseline serum PTH (P less than .001), to ORS (P less than .01) and to NO (P less than .01). Furthermore, a significant decrease in blood pressure was observed only in patients with histological signs of hyperparathyroidism (ORS greater than 1%). In this subset of patients NIC induced a significant decrease in SAP X HR (P less than .02) which was correlated to PTH and histomorphometric indexes of HPTH (P less than .01). The results of the present study show that blood pressure response to dihydropyridines in ESRF is associated with parathyroid activity as judged from serum PTH and bone histomorphometry.

Chronic idiopathic hyperphosphatasia and fibrous dysplasia in the same child.

A generalized skeletal dysplasia with features of chronic idiopathic hyperphosphatasia and fibrous dysplasia of the mandible were observed in a 6-year-old child. The abnormal development of the bones resulted from enhanced remodeling and the failure of mature bone to form. The occurrence of the two lesions in the same child and a review of the literature support the hypothesis that pathogenesis of fibrous dysplasia and idiopathic hyperphosphatasia reflect an underlying common defect in the control of bone cell activity.

Hypersecretion of growth hormone and prolactin in McCune-Albright syndrome.

Acromegaly and hyperprolactinemia have been reported in association with the McCune-Albright syndrome, but the pathophysiology of the GH and PRL hypersecretion that occurs in patients with this disorder has not been defined. We studied GH and PRL secretory dynamics in three patients with McCune-Albright syndrome and hypersecretion of these hormones. Each patient had excessive linear growth, glucose-non-suppressible plasma GH concentration, and GH responsiveness to TRH and GHRH. In response to exogenous GHRH, plasma GH concentrations rose approximately 2-fold in all three patients. Plasma GHRH levels were 20-40 ng/L (normal, less than 30). Study of the spontaneous GH secretory pattern in two patients indicated nocturnal augmentation of GH release. Bromocriptine therapy failed to reduce plasma GH in all patients; in one patient treatment with octreotide, a long-acting somatostatin analog, partially suppressed plasma GH and insulin-like growth factor I levels. These results suggest that hypersecretion of GH in the McCune-Albright syndrome is not due to ectopic GHRH production or autonomous somatotroph function. The results are similar to those described in classic acromegaly due to GH-secreting pituitary tumors. However, the lack of radiographic pituitary enlargement, the variable pituitary pathology reported in similar patients, and frequent concordance of GH and PRL excess suggest that the pathogenesis of this disorder may differ fundamentally from other forms of acromegaly or gigantism. The pathophysiology may reflect abnormal hypothalamic regulation and/or an embryological defect in pituitary cellular differentiation and function.

Precocious puberty in the McCune-Albright syndrome. Progression from gonadotrophin-independent to gonadotrophin-dependent puberty in a girl.

A 5-year-old girl with McCune-Albright syndrome, was observed over a 7-year period. She presented with gonadotrophin-independent puberty and later developed gonadotrophin-dependent puberty. Hormonal signs of central puberty remained unchanged over the last 2 years.

McCune-Albright syndrome with gigantism and hyperprolactinemia.

We describe the case of a 38-year-old man with typical Mc Cune-Albright syndrome and the unusual combination of both growth-hormone and prolactin hypersecretion. The patient was extremely tall, which is unusual in Mc Cune-Albright syndrome, suggesting that he did not have precocious fusion of the epiphysis, a common finding in this syndrome. Unfortunately the patient refused any treatment for his disease. A similar case has been previously described only in a 14-year-old boy.

Absence of pubertal gonadotropin secretion in girls with McCune-Albright syndrome.

Precocious puberty in girls with McCune-Albright syndrome has been attributed in some cases to early activation of the hypothalamic-pituitary-gonadal axis and in other cases to sex steroid secretion by apparently autonomous ovarian cysts. We evaluated serum gonadotropins and sex steroids in six girls (aged 1-9 yr) with McCune-Albright syndrome. The children had Tanner stage II-IV pubertal development. In five patients, nocturnal gonadotropin concentrations and the gonadotropin response to LHRH were within the normal range for prepubertal children. Thus, the precocious puberty in these patients could not be explained by activation of the hypothalamic-pituitary-ovarian axis. One child had high amplitude nocturnal pulses of serum LH and a LH-predominant response to LHRH. She was the oldest of the six girls and had a bone age of 13.5 yr which is within the range in which hypothalamic-pituitary-ovarian activation normally occurs. The children all had ovarian enlargement and ovarian cysts determined by ultrasound. It appears that precocious puberty in McCune-Albright syndrome may result from ovarian estrogen secretion in the absence of normal pubertal activation of the hypothalamic-pituitary-ovarian axis.