McCune-Albright Syndrome Patients Research Articles

THU235 Usefulness Of Digital Droplet Polymerase Chain Reaction (ddPCR) For Molecular Diagnosis Of McCune-Albright Syndrome In DNA From Peripheral Blood Leukocytes

Abstract Disclosure: A.G. de Faria: None. L.R. Montenegro: None. A.A. Jorge: None. R.S. Jallad: None. R.M. Martin: None. M.C. Fragoso: None. A.P. Canton: None. C.E. Seraphim: None. F.R. Tinano: None. N.C. Pinto: None. B.B. Mendonca: None. A. Latronico: None. V.N. Brito: None. Background: McCune-Albright Syndrome (MAS) is a rare congenital disorder caused by post-zygotic activating mutations in GNAS gene. Due to the mosaic pattern of this disease, mutation abundance is frequently low in several tissues, including blood cells. The emergence of digital droplet Polymerase Chain Reaction (ddPCR) is a breakthrough technology of quantitative PCR useful for a targeted detection and quantification of rare events. Objective: This study aims to identify the GNAS mutation in peripheral blood leukocytes of patients with MAS using ddPCR. Patients and Methods: Thirty-four patients (25 female and 9 male) with typical (classic triad) or atypical (one or two features) MAS were included. DNA was extracted from peripheral blood and was analyzed through ddPCR method. Two ddPCR mutation detection assays were used, each one targeting the p.R201C or p.R201H mutations. For each assay, the Taqman PCR system was used with two fluorescence probes: the first labeled with HEX, targeting de (WT allele), and the second labeled 6-FAM, targeting the (mutated allele). The mixture (reagents + DNA) was divided into 20,000 nanodrops, which was placed on a PCR plate and amplified by PCR. After amplification by PCR, the fluorescence of each droplet was read on the 200 Droplet Digital PCR system (Bio-Rad), being classified as positive (drop containing the target sequence) or negative. Results were analyzed using Quantasoft software (Bio-Rad) to determine the total amount of positive droplets in the original sample. The results were reported in fractional abundance (FA), corresponding to the percentage of mutated alleles within the total alleles. Results: Among all patients, the most common MAS feature was osteofibrous dysplasia (OFD) (73.5%), followed by peripheral precocious puberty (PPP) (64.7%), and café-au-lait skin spots (52.9%). Acromegaly or hyperthyroidism was diagnosed in 6 and 4 patients, respectively. Classical MAS triad, 2 clinical features, or 1 clinical feature (PPP or OFD) were present in 15, 9, and 10 patients, respectively. GNAS mutations were identified in 12/34 (35.3%) MAS patients: the p.R201C in 5 and the p.R201H in 7. Among them, 8 patients presented typical MAS and 4 patients with two MAS clinical features, respectively. Considering only typical MAS group, the positive molecular test rate was 53.3% (8/15). GNAS mutations were not identified in patients with only one MAS feature. There was a positive correlation between a positive molecular test and the number of MAS clinical features (p = 0.01). Median FA was 1.45%, ranged from 0.25% to 8.4%. There was no association between FA rate and the number of MAS clinical features (p=1.0). Conclusion: ddPCR representeds a more sensitive tool for identifying GNAS mutations in peripheral blood leukocytes, even with low abundance, in patients with classical and atypical MAS. Presentation: Thursday, June 15, 2023

Identification of pathogenic variants in three Chinese patients with McCune-Albright syndrome

To explore the genetic basis for three Chinese patients with McCune-Albright syndrome (MAS). Three children who had respectively presented at Shandong Provincial Hospital in April 2019 and Peking Union Medical College Hospital in August 2020 and May 2021 were selected as the research subjects. Peripheral blood samples of the probands and their family members were taken for the extraction of genomic DNA. Potential variants were screened by whole exome sequencing (WES), and candidate variants were validated by Sanger sequencing of the patients and their family members. The proband from family 1 was found to harbor a heterozygous c.601C>T (p.R201C) missense variant in exon 8 of the GNAS gene, whilst the probands from families 2 and 3 were both found to harbor a heterozygous c.602G>A (p.R201H) missense variant in exon 8 of the GNAS gene. Both variants were known to be pathogenic, and all probands were found to be mosaics for the corresponding variants but with various degrees. WES can effectively diagnose MAS and other somatic genetic disorders. In this study, the combined WES and Sanger sequencing have verified the degree of mosaicisms of pathogenic variants in the three MAS patients, albeit no apparent correlation was found between the degree of mosaicisms and the phenotype of patients. Above finding has provided a basis for genetic counseling and prenatal diagnosis for the affected families.

Prevalence of Polycystic Ovary Syndrome in Patients With McCune Albright Syndrome.

To identify polycystic ovarian syndrome (PCOS) in a population of female patients with McCune-Albright syndrome (MAS) by retrospective chart review. Retrospective study. Academic setting. All female patients with a prior diagnosis of MAS who were more than 12 years of age at the time of chart review. Only complete medical records from January 2009 to January 2020 were included in the analysis. None. Diagnosis of PCOS based on the Rotterdam 2003 criteria. Seventeen female patients with MAS were included in the analysis. PCOS appeared to be more prevalent in MAS patients than expected based on population estimates (exact binomial test=0.353; CI=0.142-0.617, P=.01). The average body mass index was not significantly different between MAS patients with and without PCOS (23.38 kg/m2 vs 23.44 kg/m2, 2-sample Wilcoxon rank-sum test with continuity correction, W=29, P=0.733). The majority of patients (71%) were treated with an aromatase inhibitor and/or a gonadotropin-releasing hormone (GnRH) agonist. The results of this study suggest that female individuals with MAS have a statistically higher prevalence of PCOS. These findings warrant further studies to determine whether the increased risk of PCOS may be associated with precocious puberty, treatment of precocious puberty, or other factors.

Craniofacial Fibrous Dysplasia Involvements of Mccune-Albright Syndrome: A Review with an Additional Case.

McCune-Albright Syndrome (MAS) is a genetic disorder with a triad of endocrine diseases, café-au-lait macules and fibrous dysplasias. Craniofacial fibrous dysplasia is a term that is used to describe the fibrous dysplasia, which was localized at the craniofacial skeleton and is common in MAS patients. The objective of this review is to determine the involvement frequency of cranial and facial bones in patients with MAS and CFD. Articles in PubMed was searched with the following details "(mccune[Title/Abstract] OR albright[Title/Abstract]) OR ("craniofacial fibrous dysplasia"[MeSH Terms] OR ("craniofacial"[ All Fields] AND "fibrous"[All Fields] AND "dysplasia"[All Fields]) OR "craniofacial fibrous dysplasia"[All Fields])". The articles in which the authors did not state the involved bones or did not add any radiographic images were excluded from the study. 26 cases in 25 articles met the inclusion criteria. Among the 26 cases and our case, sphenoid and frontal bones were involved in 17 cases, parietal and occipital bones were involved in 15 cases, mandible and ethmoid bone were involved in 14 cases, maxilla-zygoma-temporal and palate was involved in 13, 11, 6 and 3 cases, respectively. Palate was involved in cases where maxilla was also involved. Our case was the only case that was evaluated with CBCT. Routine follow-ups are important since new CFDs can occur in different cranial or facial bones. 2D imaging techniques may not be able to demonstrate early CFDs; thus, an advanced imaging technique should be used after MAS diagnosis.

McCune Albright Syndrome: Gastrointestinal Polyps and Platelet Dysfunction over 12 Years

Background and Objective: Gastrointestinal (GI) polyps with unknown malignant potential and a platelet storage pool deficiency that increases the risk of severe intraoperative and other types of bleeding have been identified in McCune-Albright syndrome (MAS). The natural course of these disorders has not been well characterized. The aim of this study was to report the follow-up of GI polyps and platelet dysfunction (PD) in a cohort of 28 patients with MAS. Methods: Twenty-eight patients with MAS (15 females) were included. Endoscopic screening for GI polyps was undertaken in 14 subjects and 19 were tested for PD. Results: Six subjects (5 males) were diagnosed with GI polyps at a median age of 23 (range 15–43) years, and were monitored for a median period of 8 (range 4.5–11.5) years. At endoscopic follow-up, the 4 patients with hamartomatous polyps at first endoscopy had either normal findings (n = 2), or duodenal gastric metaplasia (n = 2). Two patients with caecal polyps were identified. Of 8 subjects with a platelet storage pool deficiency, 5 required transfusions during surgery, and subsequent platelet cover in 2 markedly reduced intraoperative blood loss. Conclusions: New polyps with uncertain malignant potential are diagnosed after long term follow-up in MAS. Platelet cover reduces the need for red blood cell transfusion during orthopaedic surgery and may be useful to reduce non-operative bleeding events. We recommend regular upper and lower endoscopy and screening for PD in all MAS patients.

SUN-324 Should We Screen for Pancreatic Cancer in Patient with Mccune Albright Syndrome?

BACKGROUND: McCune-Albright syndrome (MAS) is a rare disorder defined by the classical association of polycystic fibrous dysplasia, precocious puberty and café au lait spots. MAS is also associated with an increased risk of various endocrine and non-endocrine neoplasms, such as thyroid adenoma, GH-secreting pituitary adenomas, adrenal Cushing’s and hepatobiliary and pancreatic tumors. MAS is caused by an autosomal dominant activating mutation of the G-protein alpha subunit gene (GNAS). CASE: 59-year-old male with McCune-Albright syndrome with multiple manifestations including polyostotic fibrous dysplasia, thyroid involvement, history of Leydig cell tumor, and cafe-au-lait spots presented with pancreatitis. The patient's history was significant for recurrent episodes of pancreatitis. The first one occurred in 2000.He recalls undergoing upper endoscopy which demonstrated pancreatic cysts. The patient denies any history of alcohol consumption or cholelithiasis. During the admission, liver function test ,lipase and amylase were normal. MRI and MRCP abdomen were performed and revealed dilatation of the extrahepatic common bile duct and pancreatic duct, with replacement of pancreatic parenchyma by pancreatic cyst. These findings are concerning for intraductal papillary mucinous neoplasm. Upper endoscopy with ultrasound of the pancreas was performed and multiple cysts were seen and biopsied. Pathology revealed IPMN. Patient underwent resection of the pancreatic mass. The patient was monitored yearly with pancreatic imaging. DISCUSSION: Somatic activating GNAS mutations have been reported in various hepatobiliary and pancreatic neoplasm such as hepatocellular adenoma, hepatocellular carcinoma and pancreatic IPMN. cAMP pathway is involved in the pathophysiology of this neoplasm. The true incidence of IPMN is not known but has been estimated to be only 25 per 100 000. IPMN have been described in patient with Carney complex due to inactivating mutations of PKAR1A, one of the main regulators of the cAMP signaling pathway. Idiopathic pancreatitis has been also described in patients with MAS and could possibly be explained by IPMN, since mild pancreatitis is a classic presentation of these neoplasms. In this particular case, the pancreatic cyst was found because he had multiple episodes of pancreatitis and imaging was performed. Sebastien G et al published a small observational study were they describe the new association between MAS and pancreatic neoplasm (IPMN) , liver adenomas and choledochal cyst. That study strongly suggested that cAMP pathway is involved in IPMN tumorigenesis. Given the long-term malignancy potential of IPMN, all MAS patients might be offered routine screening by MRI. If no lesion is found, surveillance MRI can be performed every 5 years. Our patient underwent surgical resection of the cysts and surveillance imaging will be performed every year.

The role of molecular genetic methods in the diagnosis of McCune—Albright syndrome

McCune-Albright syndrome (MAS) is a rare genetic disorder which is caused by somatic mutations in the GNAS gene. Clinical symptoms of MAS include café-au-lait skin pigmentation, fibrous dysplasia, and autonomous endocrine hyperfunction. Somatic character of the gene defects determines wide variety of syndrome manifestations, from mild forms with minimum presentation to severe conditions with aggressive course. Potential multicomponent form of the MAS syndrome necessitates the dynamic monitoring, including regular screening for possible components of the disease. Therefore, additional methods specifying the diagnosis of MAS syndrome, especially of its suppressed forms, should facilitate selection of patient management strategy and monitoring rate and/or complete exclusion of the diagnosis. Molecular genetic verification of the diagnosis may be one of these methods.
 Objective — the study was aimed at evaluating massive parallel sequencing (next generation sequencing, NGS) and real-time polymerase chain reaction using the TaqMan technique for detection of somatic mutations (competitive allele-specific TaqMan PCR, CAST-PCR) in the diagnosis of somatic mutations R201C and R201H in the GNAS gene based on DNA obtained from the peripheral blood.
 Material and methods. The study included patients diagnosed with and suspected for MAS syndrome. Molecular genetic testing of R201C and R201H mutations in the GNAS gene based on DNA extracted from peripheral blood leukocytes was carried out by Next generation sequencing (NGS) and real-time polymerase chain reaction methods using the TaqMan technique for detection of somatic mutations (competitive allele-specific TaqMan PCR, CAST-PCR). Based on clinical data, patients were divided into groups depending on the severity of the disease and the number of MAS manifestations. The results were evaluated by comparing the rate of detected molecular genetic defects in the formed groups of patients.
 Results. Molecular genetic study included 39 children with MAS syndrome and 6 children with suspected MAS. R201C and R201H mutations in GNAS gene were detected in 16 patients with severe to moderate MAS 16 (41%) 39. No mutations were detected in other MAS patients and patients with suspected MAS.
 Conclusion. NGS and CAST-PCR methods can detect the presence of mutant alleles R201C and R201H of GNAS gene in DNA samples obtained from the blood in the case of severe to moderate MAS syndrome, but they cannot be recommended for MAS diagnosis based on the peripheral blood samples in children with mild signs of the syndrome or suspected diagnosis.

Outcome of Long-Term Bisphosphonate Therapy in McCune-Albright Syndrome and Polyostotic Fibrous Dysplasia.

McCune-Albright syndrome (MAS) is a rare bone disorder characterized by fibrous dysplasia (FD), endocrinopathies, and café-au-lait patches. FD patients have been shown to respond favorably to treatment with bisphosphonates, but data are scarce in the more severe polyostotic form (PFD), including MAS, and factors determining treatment outcome are not known, particularly in the long-term. We evaluated the biochemical (bone turnover markers [BTMs]) and clinical (pain reduction) outcome of bisphosphonate therapy in 11 patients with MAS and 30 patients with PFD: median duration of treatment 6 years (range, 2 to 25 years). Prognostic factors for treatment outcome were identified in both groups. Patients with MAS were younger at diagnosis (p = 0.001), all had precocious puberty, and four (36%) had additional growth hormone (GH) excess associated with severe craniofacial FD. Extent of skeletal disease was more severe in MAS compared to PFD. MAS patients had higher serum alkaline phosphatase (ALP) concentrations (p = 0.005), higher skeletal burden scores (p < 0.001), and more fractures (p = 0.021). MAS patients had also higher levels of FGF-23 (p = 0.008) and higher prevalence of hypophosphatemia (p = 0.013). Twenty-four of 30 PFD patients (80%) demonstrated a complete clinical and biochemical response within a year of starting treatment (p = 0.015), compared to only four of 11 MAS patients (36%). There were no nonresponders. In the whole group, FGF-23, total ALP, P1NP, and CTX positively correlated with skeletal burden scores (all p ≤ 0.001), which was the only significant risk factor for an incomplete response to bisphosphonate therapy (p < 0.01). Our data suggest a beneficial and safe outcome of long-term bisphosphonate therapy in the majority of patients with PFD, although response to therapy was limited by the higher skeletal disease burden in MAS patients. In the PFD/MAS population studied, the only identified prognostic factor that influenced the outcome of bisphosphonate therapy was a high skeletal burden score. © 2016 American Society for Bone and Mineral Research.

Anesthetic Consideration of a Patient with McCune-Albright Syndrome: A Case Report

The McCune-Albright syndrome is rare disease diagnosed by the clinical triad, fibrous dysplasia, cafe-au lait skin pigmentations and endocrine hyperfunction. Those patients with bone issues could have various surgeries under general anesthesia. Airway abnormality and various endocrine abnormalities should be considered during general anesthesia for McCune-Albright syndrome patients. A 15-year-old male with McCune-Albright syndrome was admitted with complaint of right nasal obstruction originated from fibrous dysplasia. Endoscopic resection of nasal cavity lesion was scheduled under navigation system guidance. Difficult airway could be anticipated due to protrusion of maxilla and right nostril. Awake fiberoptic intubation was performed by spray-as-you-go technique. When an anesthesiologist expects to take care of the patient with the McCune-Albright syndrome, the most appropriate anesthetic induction and tracheal intubation technique should be selected, and multiple backup instruments such as supraglottic device, video laryngoscope and fiberoptic bronchoscopy should be prepared.

A Suspected Case and Literature Review of McCune-Albright Syndrome.

Dear Editor: The McCune-Albright syndrome (MAS) is typically characterized by fibrous dysplasia (FD), endocrine abnormalities, and cafe au lait macules (CALMs). However, in some cases, MAS consists of a wide spectrum of symptoms. A 15-year-old boy presented with an asymptomatic, brownish patch on the right cheek with facial asymmetry that had developed 100 days ago. On physical examination, a solitary, brown patch with an irregular border was seen covering the patient's right cheek and upper eyelid (Fig. 1A). He was otherwise healthy with no neurologic or visual defects. He had no significant medical or family history. Computed tomography (CT) scans of the brain showed polyostotic FD (Fig. 1B). The histopathologic features of the samples taken from the cheek and maxilla bone are shown in Fig. 2. On the basis of the findings, the boy was suspected of having MAS, accompanied with CALMs and polyostotic FD. Fig. 1 Solitary, brown patch with irregular border, throughout the patient's right cheek and upper eyelid with facial asymmetry. (B) Coronal computed tomography scan demonstrates heterogenous ground glass appearance at the right anterior skull, consistent with ... Fig. 2 (A) Hyperkeratosis, epidermal acanthosis, basal layer hyperpigmentation, and perivascular inflammatory infiltrates in the dermis (H&E, ×100). (B) Curvilinear trabeculae of woven bone admixed with fibrous tissue without nuclear atypia and ... MAS is classically defined by the clinical triad of FD, CALMs, and precocious puberty (PP). It was later found that other endocrinopathies, namely hyperthyroidism, excess growth hormone (GH) production, renal phosphate wasting, and Cushing's syndrome, occasionally develop along with the original triad1. Currently, a combination of any of these findings is referred to as MAS2. The involvement of a broad spectrum of tissues and the combined unpredictable manifestations of this disease are attributed to the molecular defects due to dominant mutations in the widely expressed signaling protein, Gsα, and to the fact that these mutations arise sporadically, often early in development, prior to gastrulation, and are distributed across many or few tissues2. FD is a genetic, non-inheritable disease, characterized by bone pain, bone deformity, and fracture. The histological hallmark of the disease is the accumulation of fibrous tissue, containing immature spindle fibroblast-like cells, within the bone marrow and expanding from the medullary cavity to the cortical bone3. Although a solitary, small CALM is common and considered a normal finding, some CALMs are considered a diagnostic criterion or a characteristic trait of various syndromes, such as neurofibromatosis, tuberous sclerosis, Turner and Noonan syndromes as well as MAS4. The CALMs seen in MAS patients are typically the first manifestations of the disease, usually appearing either at or shortly after birth. Therefore, this manifestation could be used as a clue to the early diagnosis of MAS. The symptoms associated with endocrinopathies of hyperfunction of the endocrine glands are PP, hyperthyroidism, excess production of GH, etc. Regarding PP, our patient showed no evidence of PP on physical examination; PP is very rare in boys affected with MAS. The timely diagnosis of hyperthyroidism in MAS patients is important to avoid exacerbation of osteoporosis. Non-suppressible serum GH secretion during oral glucose tolerance test (OGTT) is another characteristic feature of MAS. However, in subtle disease, the results of the OGTT can be equivocal, especially in the cases of young children; therefore, more detailed examination is required in such cases.

The Use of Real Time PCR Genotyping to Detect Activating GNAS Mutations in McCune-Albright Syndrome

Introduction: The McCune-Albright syndrome (MAS) is a genetic disease clinically characterized by the triad: bone fibrous dysplasia cafe-au-lait skin spots and endocrine hyperfunction, such as precocious puberty. MAS is due to activating mutations of GNAS, the gene encoding Gs alpha and mutations analysis of this gene could increase the definitive diagnosis of MAS and atypical and partial. Objectives: To identify the p.R201H and p. R201C GNAS activating mutations in multiple tissues derived from patients with MAS using real time PCR genotyping. Material and methods: Genomic DNA was isolated from blood from 31 patients (28 females) with typical and atypical forms of MAS. Skin, adrenal gland or bone tissue samples were also available from six different patients. Genotyping based on PCR real time assay using TaqMan probes was performed for identification of p.R201H and p. R201C GNAS mutations. Cloning and sequencing were used as assenting techniques. Results: Using real time PCR genotyping, no mutations in GNAS were identified in blood samples of MAS patients, only in bone sample of a patient with a previously identified p.R201H. Cloning and sequencing from blood of this same patient revealed that 5/150 clones harboring the p. R201H. Conclusion: The real time PCR genotyping proved to be efficient for the molecular diagnosis of MAS in affected patient's tissues. Advantages of this technique are rapidity, accuracy, it is generally easy to perform and could be used routinely. Nevertheless, optimization of GNAS detection mutation is still necessary to considerer this technique to earlier diagnosis of non-classical forms of MAS using peripheral blood.

Visual Field Improvement After Pituitary Tumor Surgery in Patients With McCune–Albright Syndrome

McCune-Albright syndrome (MAS) is a rare, sporadic congenital disorder, in which optic neuropathy may cause devastating visual consequences. Pituitary adenoma with overproduction of growth hormone (GH) is present in approximately two-thirds of MAS patients, and its role in the pathogenesis of MAS-associated optic neuropathy has not been studied. Three MAS patients with GH-secreting pituitary adenoma and optic chiasm compression diagnosed between January 2008 and November 2010 were included in this case series. Transsphenoidal pituitary resection was performed in all 3 patients. Neuro-ophthalmologic evaluation was performed at presentation and every 6 months during follow-up. Of the 3 patients, 2 were female and 1 was male; their ages ranged from 17 to 27 years. Visual acuity ranged from 20/20 to 20/200 before surgery and all had visual field loss. The patients were followed up for 6-18 months with substantial improvement in their visual fields. GH-secreting pituitary adenoma may contribute to optic nerve damage, at least partially, in MAS patients. Pituitary surgery may be important for visual recovery in some MAS patients in whom there is compression of the optic chiasm.

GNAS is not involved in gastrointestinal tumour formation in Peutz-Jeghers syndrome

Peutz-Jeghers syndrome (PJS), caused by germ-line mutations in LKB1, is characterized by the development of hamartomatous polyps in the gastrointestinal (GI) tract. McCune Albright syndrome (MAS), caused by somatic activating mutations in GNAS, presents with cutaneous, skeletal, and endocrine manifestations. Recently, hamartomatous GI polyps with histological features similar to those in PJS were observed in MAS patients, suggesting a role for GNAS in the pathogenesis of PJS. This study reports the first somatic GNAS mutation analysis in GI tumours of PJS patients. No mutations were observed, suggesting that GNAS is not involved in the pathogenesis of GI tumours in PJS.

Allergic manifestations and cutaneous histamine responses in patients with McCune Albright syndrome

Background McCune Albright syndrome (MAS) is a rare disorder characterized by precocious puberty, café-au-lait spots, and fibrous dysplasia. Its cause is an activating mutation in the GNAS gene, encoding a subunit of the stimulatory G protein, Gsalpha (Gsα). The action of any mediator that signals via Gsα and cyclic AMP can be up regulated in MAS. We had observed gastritis, gastroesophageal reflux, and anaphylaxis in McCune Albright patients.Objective As histamine is known to signal via histamine 1 (H1) and histamine 2 (H2) receptors, which couple with stimulatory G proteins, we attempted to mechanistically link histamine responsiveness to the activating GNAS mutation. We hypothesized that responsiveness to histamine skin testing would differ between MAS patients and healthy controls.Patients and methods After obtaining informed consent, we performed a systematic review of histamine responsiveness and allergic manifestations in 11 MAS patients and 11 sex-matched, Tanner-stage matched controls. We performed skin prick testing, quantifying the orthogonal diameters of wheals and erythema. We also quantitated G protein mRNA expression.Results The peak wheal and flare responses to histamine were significantly higher in MAS patients compared to controls.Conclusions This study suggests that MAS patients may be at risk for exaggerated histamine responsiveness compared to unaffected controls.

Transsphenoidal approach for pituitary adenomas in patients with McCune–Albright syndrome

The feasibility of transsphenoidal approach under a guidance of neuronavigation was explored to remove pituitary adenomas for patients with McCune-Albright syndrome (MAS). From August, 2008 to July, 2010, there were 5 patients diagnosed with MAS associated with a pituitary adenoma in our department of Peking Union Medical College Hospital. All the patients underwent transsphenoidal surgery for the removal of pituitary adenomas with the assistant of neuronavigation and all the procedures went uneventfully. Four of the five patients have got cured radiologically by imaging and 3 of them have got cured based on endocrinological criteria. Transsphenoidal approach under the neuronavigational guidance is a safe and effective management for the MAS patients with pituitary adenomas.

SomaticGNASMutation Causes Widespread and Diffuse Pituitary Disease in Acromegalic Patients with McCune-Albright Syndrome

Context:McCune-Albright syndrome (MAS) is caused by sporadic mutations of the GNAS. Patients exhibit features of acromegaly. In most patients, GH-secreting pituitary adenomas have been held responsible for this presentation. However, surgical adenomectomy rarely eliminates excess GH production.Objective:The aim of this study was to elucidate pituitary pathology in patients with MAS and to explain the basis of failure of adenomectomy to eliminate GH hypersecretion.Design and Setting:We conducted a case series at the National Institutes of Health.Intervention(s):Interventions included medical therapy and transsphenoidal surgery.Patients and Main Outcome Measures:We studied clinical and imaging features and the histology and molecular features of the pituitary of four acromegalic MAS patients.Results:We identified widespread and diffuse pituitary gland disease. The primary pathological changes were characterized by hyperplastic and neoplastic change, associated with overrepresentation of somatotroph cells in structurally intact tissue areas. Genetic analysis of multiple microdissected samples of any type of histological area consistently revealed identical GNAS mutations in individual patients. The only patient with remission after surgery received complete hypophysectomy in addition to removal of multiple GH-secreting tumors.Conclusions:These findings indicate developmental effects of GNAS mutation on the entire anterior pituitary gland. The pituitary of individual cases contains a spectrum of changes with regions of normal appearing gland, hyperplasia, and areas of fully developed adenoma formation, as well as transitional stages between these entities. The primary change underlying acromegaly in MAS patients is somatotroph hyperplasia involving the entire pituitary gland, with or without development of somatotroph adenoma. Thus, successful clinical management, whether it is medical, surgical, or via irradiation, must target the entire pituitary, not just the adenomas evident on imaging.

Clinical characteristics of McCune-Albright syndrome in Chinese patients

To present the ophthalmological characteristics of McCune-Albright syndrome (MAS). Case series study. Best corrected visual acuity (BCVA), visual field, color vision, retinal nerve fiber layer (RNFL) thickness, visual evoked potentials (VEP), fundus examination, computed tomography (CT) imaging of the optic canal, follow up results of multidisciplinary comprehensive treatments were analyzed. Of the 6 patients, three were male and three were female. Their age were between 4 to 43 years old (median, 16 years old). Based on CT imaging of the optic canal, encasement of the optic canal was found in all 6 patients (12 eyes); three patients (6 eyes) had circumferential encasement of the optic canal; the remaining 3 patients (6 eyes) had partial encasement of the optic canal. Two patients (3 eyes) with circumferential encasement of the optic canal had optic neuropathy versus none in the remaining 9 eyes with circumferential or partial optic canal encasement. In addition, lengthening of the optic nerve was found in all 4 patients (8 eyes). Optic canal encasement and lengthening of the optic nerve are common in MAS patients, which is worthy of attention in clinical practice.

Intragenic suppressor mutations of a constitutively active allele of Gs alpha

Heterotrimeric G‐proteins cycle between an active/GTP‐bound conformation and an inactive/GDP‐bound conformation. Reduction in GTP hydrolysis by the G‐protein alpha subunit results in constitutive activity of the protein. McCune‐Albright Syndrome (MAS) is a human genetic disorder caused by a mutation that constitutively activates the Gs alpha subunit by inhibiting GTP hydrolysis. Arginine 201 substitutions with histidine, serine, or cysteine have been reported in biopsies from MAS patients. Previous work in this laboratory modeled the MAS mutation in a yeast system, and identified an intragenic suppressor of the MAS mutation, which substituted two residues in the GTP‐binding site. The homologous mutations (F222P, D223V) in the human Gs alpha subunit also suppressed the constitutive activity of the MAS mutation when the protein was expressed in human cells. To extend these studies, F222 and D223 were mutated to a variety of other amino acids to determine the structural requirements for suppression of the MAS mutation. Basal and receptor‐stimulated cAMP levels were measured in HEK293 cells transfected with the different alleles of Gs alpha. While some single mutations at either F222 or D223 were able to suppress the MAS R201H mutation, a range of levels of suppression were observed.

Letrozole Treatment of Precocious Puberty in Girls With the McCune-Albright Syndrome: A Pilot Study

Young girls with McCune-Albright syndrome (MAS), a rare disorder characterized by precocious puberty, café- au-lait pigment, and polyostotic fibrous dysplasia (PFD), frequently present with precocious puberty and vaginal bleeding. In this setting, precocious puberty is independent of gonadotropins and is a result of estrogen secretion by large ovarian cysts. It does not respond to treatment with a gonadotropin-releasing hormone agonist, and short-acting aromatase inhibitors have limited efficacy. Adult stature often is markedly reduced in MAS patients with precocious puberty. This study evaluated a potent third-generation aromatase inhibitor, letrozole, for slowing pubertal development in 9 girls 3 to 8 years of age with gonadotropin-independent precocious puberty. They had presented at ages 1.3 to 6 years with breast development, vaginal bleeding or discharge, and suppressed gonadotropin levels. All the girls had advanced bone age, and all but one had significantly increased growth rate scores. In an open-label therapeutic trial, participants were followed for 1 to 3 years during and after a 6-month period during which they received letrozole orally in a daily dose of 1.5 to 2.0 mg/m2. Rates of growth slowed during treatment with letrozole, and the change in bone age versus change in chronological age declined. Estradiol levels fell in the only patient with detectable estradiol at the outset. Bleeding slowed or ceased during treatment. Breast stage and pubic hair stage decreased in some patients. After 6 months, mean ovarian volume and indices of bone metabolism both decreased, but tended to increase at 24 to 36 months. There was no change in uterine volume. Mean levels of serum markers of bone formation as well as a urinary marker of bone resorption decreased. Treatment resumed in 4 girls who had recurrent symptoms and signs of puberty after 6 months of letrozole therapy. The remaining patients were treated without interruption for as long as 3 years. One child had a ruptured ovarian cyst after 2 years of treatment and underwent laparoscopic surgery. PFD progressed during treatment in 2 patients with relatively advanced disease. These preliminary findings indicate that letrozole can be an effective initial treatment for girls with gonadotropin-independent precocious puberty. It also may prove useful for treating girls who fail to respond to estrogen blockers such as tamoxifen.

Pituitary pathology in patients with Carney Complex: growth-hormone producing hyperplasia or tumors and their association with other abnormalities

First described in the mid 80's, Carney Complex (CNC) is a rare, dominantly heritable disorder with features overlapping those of McCune-Albright syndrome (MAS) and other multiple endocrine neoplasia (MEN) syndromes like MEN type 1 (MEN 1). Pituitary tumors have been described in a number of patients with CNC; they present with elevated growth hormone (GH) levels and mild hyperprolactinemia. However, most patients with CNC have mild hypersomatomammotropinemia starting in adolescence; this is similar to the situation in MAS patients: in both disorders, pituitary hyperplasia appears to precede tumor development. Familial pituitary tumor syndromes such as CNC provide an important insight into the genetics and molecular pathology of pituitary and other endocrine tumors. Our understanding of these conditions is expanding rapidly due to the identification of the causative genes and the availability of murine disease models. The present report reviews the clinical findings related to pituitary tumor development among patients with CNC and provides an update on murine models of the complex.