[Research progress on the pathogenic mechanisms, diagnosis and treatment of McCune-Albright syndrome].

McCune-Albright syndrome is a rare chimeric disorder due to mutations in the postzygotic GNAS gene. It belongs to the group of guanine nucleotide-binding protein diseases, affecting a wide range of individuals. It is characterized by fibrous dysplasia, café-au-lait skin macules, and precocious puberty with other variable clinical manifestations. At present, there are difficulties in the molecular diagnosis of McCune-Albright syndrome, and there is a lack of effective clinical treatments to halt or reverse the course and regression of the disease. This article summarizes the clinical manifestations, diagnosis, pathogenic molecular mechanisms, treatment and relevant fertility guidelines of McCune-Albright syndrome, with a view to further research and therapy of McCune-Albright syndrome.

Choosing the Best Tissue and Technique to Detect Mosaicism in Fibrous Dysplasia/McCune-Albright Syndrome (FD/MAS).

GNAS-activating somatic mutations give rise to Fibrous Dysplasia/McCune-Albright syndrome (FD/MAS). The low specificity of extra-skeletal signs of MAS and the mosaic status of the mutations generate some difficulties for a proper diagnosis. We studied the clinical and molecular statuses of 40 patients referred with a clinical suspicion of FD/MAS to provide some clues. GNAS was sequenced using both Sanger and Next-Generation Sequencing (NGS). We were able to identify the pathogenic variants in 25% of the patients. Most of them were identified in the affected tissue, but not in blood. Additionally, NGS demonstrated the ability to detect more patients with mosaicism (8/34) than Sanger sequencing (4/39). Even if in some cases, the clinical information was not complete, we confirmed that, as in previous works, when the patients were young children with a single manifestation, such as hyperpigmented skin macules or precocious puberty, the molecular diagnosis was usually negative. In conclusion, as FD/MAS is caused by mosaic variants, it is essential to use sensitive techniques that allow for the detection of low percentages and to choose the right tissue to study. When not possible, and due to the low positive genetic rate, patients with FD/MAS should only be genetically tested when the clinical diagnosis is really uncertain.

[The enigma of Henry IV's disease: Did he suffer from McCune-Albright syndrome/fibrous dysplasia?] / El enigma de la enfermedad de Enrique IV, rey de Castilla: ¿padeció síndrome de McCune-Albright/displasia fibrosa?

BACKGROUND: Henry IV King of Castile, last king of the Trastámara dynasty, was the brother of Isabella the Catholic. He is known as "the impotent". Based on previous descriptions by historians and biographers, Gregorio Marañón in 1922 described him as "eunuchoid dysplastic with acromegalic reaction and clear schizoid features". METHODS: In 1946, a post-mortem inspection was carried out on the mummified corpse found in the Monastery of Guadalupe. A written document and some photographs were recorded. We have collected the signs and symptoms described and applied the international classification of diseases recommended by the World Health Organisation, ICD11-2023. We have relied on the coins issued in the money of Henry IV, on which we have identified enlargement of the thyroid gland. RESULTS: With the data available at this time, we suggest that Henry IV most probably suffered from: facial and polyostotic bone dysplasia, kyphosis, limb limping, multiple endocrine disorders, acromegaly with macrognatia, nodular thyroid disease, malodorous diaphoresis, erectile dysfunction, hypospadias, abnormal sexual development, "feminoid pelvis", abdominal colic, oligodontia and dental displacement. It is possible that he also suffered from: precocious puberty, renal lithiasis with debilitating phosphaturia, carpal tunnel, thrombopenia and growth hormone-producing pituitary hyperplasia or adenoma. CONCLUSION: We suggest that Henry IV may have suffered from McCune-Albrigth syndrome associated with fibrous dysplasia, a rare disease due to gain-of-function mutations in the GNAS gene.

Brain and eye involvement in McCune-Albright Syndrome: clinical and translational insights.

McCune-Albright Syndrome (MAS) is a rare mosaic (post-zygotic) genetic disorder presenting with a broad continuum clinical spectrum. MAS arises from somatic, activating mutations in the GNAS gene, which induces a dysregulated Gsα-protein signaling in several tissues and an increased production of intracellular cyclic adenosine monophosphate (cAMP). Overall, MAS is a rare disorder affecting less than 1/100,000 children and, for this reason, data establishing genotype-phenotype correlations remain limited. Affected individuals clinically present with a variable combination of fibrous dysplasia of bone (FD), extra-skeletal manifestations (including cafeí-au-lait spots) and precocious puberty which might also be associated to broad hyperfunctioning endocrinopathies, and also gastrointestinal and cardiological involvement. Central nervous system (CNS) and eye involvement in MAS are among the less frequently described complications and remain largely uncharacterized. These rare complications mainly include neurodevelopmental abnormalities (e.g., delayed motor development, cognitive and language impairment), CNS anomalies (e.g., Chiari malformation type I) and a wide array of ophthalmological abnormalities often associated with vision loss. The pathophysiological mechanisms underlying abnormal neurological development have not been yet fully elucidated. The proposed mechanisms include a deleterious impact of chronically dysregulated Gsα-protein signaling on neurological function, or a secondary (damaging) effect of (antenatal and/or early postnatal) hypercortisolism on early pre- and post-natal CNS development. In this Review, we summarize the main neurological and ophthalmological features eventually associated with the MAS spectrum, also providing a detailed overview of the potential pathophysiological mechanisms underlying these clinical complications.

Successful ART outcome in a woman with McCune-Albright syndrome: a case report and literature review.

McCune-Albright syndrome (MAS) is a rare genetic disease affecting multiple organs, including endocrine tissues. This endocrinopathy is sometimes responsible for infertility, as it may induce an independent functioning of the ovaries leading to anovulatory cycles. This case report describes the infertility journey of a 22-year-old female who had early puberty and irregular periods with high estrogen and progesterone levels, low FSH and LH (on day 3 of her menstrual cycle), and a multi-cystic right ovary. She received several infertility treatments: initially in vitro oocyte maturation (IVM) followed by cyst transvaginal ultrasound-guided aspiration, all unsuccessful. A right hemi-ovariectomy was performed that eventually restored regular cycles and made it possible to perform ovarian stimulation (OS) and in vitro fertilization (IVF). Live birth was obtained after the first embryo transfer.

McCune-Albright Syndrome: A Case Report and Review of Literature.

McCune-Albright syndrome (MAS) is a rare sporadic condition defined by the classic triad of fibrous dysplasia of bone, café au lait skin macules, and hyperfunctioning endocrinopathies. The molecular basis of MAS has been ascribed to the post-zygotic somatic gain-of-function mutations in the GNAS gene, which encodes the alpha subunit of G proteins, leading to constitutive activation of several G Protein-Coupled Receptors (GPCRs). The co-occurrence of two of the above-mentioned cardinal clinical manifestations sets the diagnosis at the clinical level. In this case report, we describe a 27-month-old girl who presented with gonadotropin-independent precocious puberty secondary to an estrogen-secreting ovarian cyst, a café au lait skin macule and growth hormone, and prolactin excess, and we provide an updated review of the scientific literature on the clinical features, diagnostic work-up, and therapeutic management of MAS.

Pharmacological Interventions Targeting Pain in Fibrous Dysplasia/McCune-Albright Syndrome.

Fibrous dysplasia (FD) is a rare, non-inherited bone disease occurring following a somatic gain-of-function R201 missense mutation of the guanine-nucleotide binding protein alpha subunit stimulating activity polypeptide 1 (GNAS) gene. The spectrum of the disease ranges from a single FD lesion to a combination with extraskeletal features; an amalgamation with café-au-lait skin hyperpigmentation, precocious puberty, and other endocrinopathies defines McCune-Albright Syndrome (MAS). Pain in FD/MAS represents one of the most prominent aspects of the disease and one of the most challenging to treat-an outcome driven by (i) the heterogeneous nature of FD/MAS, (ii) the variable presentation of pain phenotypes (i.e., craniofacial vs. musculoskeletal pain), (iii) a lack of studies probing pain mechanisms, and (iv) a lack of rigorously validated analgesic strategies in FD/MAS. At present, a range of pharmacotherapies are prescribed to patients with FD/MAS to mitigate skeletal disease activity, as well as pain. We analyze evidence guiding the current use of bisphosphonates, denosumab, and other therapies in FD/MAS, and also discuss the potential underlying pharmacological mechanisms by which pain relief may be achieved. Furthermore, we highlight the range of presentation of pain in individual cases of FD/MAS to further describe the difficulties associated with employing effective pain treatment in FD/MAS. Potential next steps toward identifying and validating effective pain treatments in FD/MAS are discussed, such as employing randomized control trials and probing new pain pathways in this rare bone disease.

Identification of GNAS Variants in Circulating Cell-Free DNA from Patients with Fibrous Dysplasia/McCune Albright Syndrome.

Fibrous dysplasia/McCune-Albright syndrome (FD/MAS) is a rare mosaic bone and endocrine disorder. Although most variants affect the GNAS R201 codon, obtaining a genetic diagnosis is difficult because not all cells harbor the variant, and an invasive biopsy may be required. We explored the presence of GNAS p.R201 variants in blood circulating cell free DNA (ccfDNA) using sensitive techniques of digital droplet polymerase chain reaction (PCR) (ddPCR) and competitive allele-specific TaqMan PCR (castPCR) in an effort to improve the genetic diagnosis of FD/MAS. We isolated ccfDNA from the plasma of 66 patients with a wide range of disease severity and performed both ddPCR and castPCR mutation analysis to search for GNAS p.R201H or R201C variants. We detected R201 variants in ccfDNA samples of 41 of 66 (62.1%) patients by either castPCR or ddPCR, and 45 of 66 (68.2%) of patients if the techniques were combined. Variant detection was more likely in patients with more severe disease. Skeletal disease burden score (SBS) was significantly higher in patients who had detectable variants, and SBS was a predictor of variant allele frequency. By ddPCR analysis, patients aged ≤30 years had higher detection rates, and higher variant allele frequencies, independent of disease burden. We detected variant DNA in only one patient with monostotic FD by ddPCR only. In summary, we have demonstrated that ccfDNA containing variant GNAS can be isolated from the plasma of patients with FD/MAS and that ddPCR and castPCR methods have similar variant detection rates. This methodology represents an important potential advancement in diagnosis for patients with FD/MAS, especially those younger than 30 years or with more severe disease. Published 2023. This article is a U.S. Government work and is in the public domain in the USA.

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

OBJECTIVE: To explore the genetic basis for three Chinese patients with McCune-Albright syndrome (MAS). METHODS: 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. RESULTS: 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. CONSLUSION: 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.

Identification of pathogenic variants in three Chinese patients with McCune-Albright syndrome / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for three Chinese patients with McCune-Albright syndrome (MAS).@*METHODS@#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.@*RESULTS@#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.@*CONSLUSION@#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.

Caracterización clínica de pacientes chilenos con displasia fibrosa/síndrome de McCune-Albright / Clinical features of Chilean patients with Fibrous Dysplasia/McCune-Albright Syndrome

BACKGROUND: Fibrous Dysplasia/McCune-Albright Syndrome (FD/MAS) is characterized by a spectrum of manifestations that may include fibrous dysplasia of bone and multiple endocrinopathies. AIM: To describe the clinical spectrum, the study and follow-up of patients with FD/MAS cared at our institution. MATERIAL AND METHODS: Review of medical records of 12 pediatric and adult patients (11 women) who met the clinical and genetic diagnostic criteria for FD/ MAS. RESULTS: The patients' mean age at diagnosis was 4.9 ± 5.5 years. The most common initial clinical manifestation was peripheral precocious puberty (PPP) in 67% of patients and 75% had café-au-lait spots. Fibrous dysplasia was present in 75% of patients and the mean age at diagnosis was 7.9 ± 4.7 years. Ten patients had a bone scintigraphy, with an age at the first examination that varied between 2 and 38 years of age. The most frequent location of dysplasia was craniofacial and appendicular. No patient had a recorded history of cholestasis, hepatitis, or pancreatitis. In four patients, a genetic study was performed that was positive for the pathogenic variant of guanine nucleotide binding protein, alpha stimulating (GNAS). CONCLUSIONS: These patients demonstrate the variable nature of the clinical presentation and study of FD/MAS. It is essential to increase the index of diagnostic suspicion and adherence to international recommendations.

Cushing syndrome as a failed cardiac screen in a patient with McCune-Albright syndrome: a case report.

BACKGROUND: McCune-Albright syndrome is a complex disorder encompassing multiple endocrinopathies. These manifestations are secondary to a mutation in the stimulatory G-protein alpha subunit. Cushing syndrome is due to autonomous secretory function of the adrenal gland and is present in 7.1% of patients with McCune-Albright syndrome. Cardiac newborn screenings assist in the identification of critical congenital heart disease. These screenings have become part of routine postnatal care nationwide. CASE REPORT: A 6-week-old Caucasian male presented to a cardiologist at the University of Tennessee Health Science Center with left ventricular hypertrophy and poor feeding after a failed cardiac newborn screen. He had been previously seen at 2 weeks by a cardiologist on follow-up for abnormal critical congenital heart disease screening. Electrocardiogram and echocardiographic studies identified hypertrophic cardiomyopathy. Other examination findings revealed multiple characteristic café-au-lait lesions along with hypotonia and rounded facies. Given his cardiac disease, he was admitted to the hospital, where an evaluation was done for Cushing syndrome, showing elevated cortisol by immunoassay of 38 µg/dL (1.7-14.0 µg/dL, Vitros 5600) after a dexamethasone suppression test and urinary cortisol elevated to 35 µg/dL/24 hours (reference range 3-9 µg/dL/24 hours) (Esoterix; Calabasas, CA). He was started on metyrapone therapy to block synthesis of cortisol. His cortisol improved and was suppressed less than 2 µg/dL. His hypertension and clinical features of Cushing syndrome improved. CONCLUSIONS: This case demonstrates a unique presentation of Cushing syndrome in a young infant. This is the first case to our knowledge showing significant left ventricular hypertrophy resulting from Cushing syndrome identified following a failure on a critical congenital heart disease screen. It highlights the importance of considering of McCune-Albright syndrome in patients with Cushing syndrome, especially if other clinical features are present. Medical therapy can be used to treat Cushing syndrome and can result in improvement in the cardiovascular pathology.

ACTH-independent Cushing's syndrome due to ectopic endocrinologically functional adrenal tissue caused by a GNAS heterozygous mutation: a rare case of McCune-Albright syndrome accompanied by central amenorrhea and hypothyroidism: a case report and literature review.

In a small number of cases, the development of ectopic residual adrenal lesions during embryogenesis causing Cushing's syndrome due to the production of excess cortisol has been reported. A 29-year-old woman was admitted to our hospital for fatigue and recent amenorrhea. Her plasma ACTH was <1.5 pg/mL, and her serum cortisol was 21.4 pg/mL after the 8 mg dexamethasone suppression test, revealing the presence of ACTH-independent Cushing's syndrome; however, her bilateral adrenal glands were atrophied. Abdominal CT revealed a 40-mm round tumor on the right renal hilum and remarkably accumulated 131I-labelled adosterol. CT and bone scintigraphy showed that 99mTc-methylene diphosphonate had accumulated in her dissymmetric skull at the right-frontoparietal region. The tumor on the right renal hilum was laparoscopically removed. Her cortisol levels rapidly decreased to below the normal range, and glucocorticoids were administered to rescue adrenal insufficiency. The resected tumor was yellowish in appearance and 4.5×3.0×2.8 cm in size. Immunohistochemical staining for SF-1, P450scc, CYP17A, CYP21A, and CYP11B1 indicated that this tumor produced cortisol. Exome sequencing analysis revealed that the GNAS heterozygous mutation (c.601C>T, p. Arg201Cys; accession number, NM_000516.5) was found in approximately 20% of the adrenal tumor sample. A mutation of GNAS, encoding the Gsα subunit that mediates GPCR signaling, causes the constitutive activation of adenylyl cyclase, resulting in hypersecretion of hormones regulated by the GPCR. GNAS mutation is one of the major genetic causes of cortisol-producing adrenal tumors independent of ACTH secretion. Considering the combination of GNAS mutation with one of the typical clinical triad characteristics, fibrous dysplasia of bone, we diagnosed this patient with McCune-Albright syndrome accompanied by ACTH-independent Cushing's syndrome caused by an ectopic residual adrenal tumor due to GNAS mutation. This case highlights that GNAS involves a previously unknown pathological mechanism in which inhibition of the natural elimination of remnant tissue leads to ectopic endocrine hypersecretion.

McCune-Albright Syndrome in Infant with Growth Hormone Excess.

BACKGROUND: McCune-Albright is a rare syndrome, caused by mutation of the GNAS1 gene, and is characterized by an appearance of multiple endocrinopathies, most commonly premature puberty, polyostotic fibrous dysplasia and skin changes called cafe au lait macules. CASE REPORT: We present the case of a patient who is, to the best of our knowledge and after extensive review of literature, the youngest McCune-Albright syndrome patient with growth hormone excess, diagnosed at 8.9 months of age. An extensive diagnostic procedure was done upon the diagnosis. Hormonal assessment was performed and all hormone levels were within reference range, and an additional oral glucose suppression that noted the presence of growth hormone excess. Magnetic resonance imaging of the pituitary gland did not detect a tumor process. The genetic analysis of the GNAS1 gene from skin punch biopsy came back negative. Octreotide was administered as therapy for growth hormone excess at 9.8 months. After the introduction of therapy, we noted a decrease in growth rate from 29.38 to 16.6 cm/year. CONCLUSION: This case report emphasizes the lack of available data on treatment of growth hormone excess and follow-up in pediatric population and the need for further research.

A rare pediatric case of McCune-Albright syndrome with acute visual disturbance: Case report.

RATIONALE: McCune-Albright syndrome (MAS) is a rare disorder characterized by clinical findings, which includes fibrous dysplasia (FD). FD is a benign tumor that leads to increased rates of bone fracture. In some MAS cases with FD, facial deformities, severe pain, and orbital neuropathies are complicated. Aneurysmal bone cyst (ABC) is a benign bone tumor and rare complication of FD. PATIENT CONCERNS: A 9-year-old boy was admitted to our hospital because of acute visual disturbance. DIAGNOSIS AND INTERVENTIONS: The patient was clinically diagnosed as ABC complicated with MAS, and he underwent surgery. OUTCOMES: After the surgery, his sight became normal. Recurrence of ABC and visual disturbance was not observed in 3 years. Genetic analysis of a tissue sample from the ABC lesion by next-generation sequencing revealed a somatic activating GNAS mutation. LESSONS: To the best of our knowledge, this is the first case report of MAS causing optic neuropathy complicated with ABC. ABC complicated with MAS is extremely rare, but it should be considered as a possible diagnosis in patients with acute visual loss and facial swelling. In addition, our case had OAS, which is an uncommon syndrome and a rare complication in ABC with MAS, and rapid decompression of the ABC was effective in improving the patient's eyesight.

Clinicopathological and genetic study of a rare occurrence: Malignant transformation of fibrous dysplasia of the jaws.

BACKGROUND: Malignant transformation of fibrous dysplasia (FD) is very rare and little is known about this occurrence. METHODS: We present the detailed clinical course of three cases of osteosarcoma arising from FD of the jaws and explore the genetic aberrations by Sanger sequencing, whole-exome sequencing (WES) and immunohistochemistry (IHC). A literature review of important topics related to this occurrence was also performed. RESULTS: It was observed that patients with secondary sarcoma from FD showed a wide range of ages, with most during the third decade. Female and males were equally affected. Craniofacial bones and femurs were the most affected sites. High-risk factors for this occurrence included polyostotic FD, McCune-Albright syndrome and excess growth hormone. Notably, a potential relationship between thyroid hormones and sarcoma development was suggested in one patient, who began to show malignant features after hypothyroidism correction. Sanger sequencing revealed GNAS mutations of FD retained in all malignant tissues. Additionally, abnormal TP53 was demonstrated in all three cases by WES and IHC. WES also revealed two other driver mutations, ROS1 and CHD8, and large amounts of somatic copy number alterations (CNAs) where various oncogenes and tumour suppressors are located. CONCLUSION: This study demonstrated and reviewed the clinical features and risk factors for a rare occurrence, secondary sarcoma from FD, and provided important new knowledge about its genetics.

[Clinical features of Chilean patients with Fibrous Dysplasia/McCune-Albright Syndrome]. / Caracterización clínica de pacientes chilenos con displasia fibrosa/síndrome de McCune-Albright.

BACKGROUND: Fibrous Dysplasia/McCune-Albright Syndrome (FD/MAS) is characterized by a spectrum of manifestations that may include fibrous dysplasia of bone and multiple endocrinopathies. AIM: To describe the clinical spectrum, the study and follow-up of patients with FD/MAS cared at our institution. MATERIAL AND METHODS: Review of medical records of 12 pediatric and adult patients (11 women) who met the clinical and genetic diagnostic criteria for FD/ MAS. RESULTS: The patients' mean age at diagnosis was 4.9 ± 5.5 years. The most common initial clinical manifestation was peripheral precocious puberty (PPP) in 67% of patients and 75% had café-au-lait spots. Fibrous dysplasia was present in 75% of patients and the mean age at diagnosis was 7.9 ± 4.7 years. Ten patients had a bone scintigraphy, with an age at the first examination that varied between 2 and 38 years of age. The most frequent location of dysplasia was craniofacial and appendicular. No patient had a recorded history of cholestasis, hepatitis, or pancreatitis. In four patients, a genetic study was performed that was positive for the pathogenic variant of guanine nucleotide binding protein, alpha stimulating (GNAS). CONCLUSIONS: These patients demonstrate the variable nature of the clinical presentation and study of FD/MAS. It is essential to increase the index of diagnostic suspicion and adherence to international recommendations.

Extent of Extraskeletal Manifestations of Fibrous Dysplasia/McCune-Albright Syndrome in Patients with Mazabraud's Syndrome.

Mazabraud's syndrome (MZB) is a rare condition in which fibrous dysplasia of bone/the McCune-Albright syndrome (FD/MAS) co-exists with intramuscular myxomas. Both FD and the myxomas harbor the GNAS-mutation. Recent studies have shown that extraskeletal, GNAS-related features are associated with a more severe phenotype of FD/MAS. However, patients with MZB are often only seen by orthopedic surgeons. We therefore evaluated MZB patients seen in tertiary referral centers from the Netherlands (LUMC), USA (National Institutes of Health) and France (INSERM UMR 1033 (Lyos), Hôpital Edouard Herriot). All FD/MAS patients known in these centers with an additional diagnosis of a myxoma were included. Demographic information and data on disease extent and extraskeletal manifestations of FD/MAS such as precocious puberty (PP) or café-au-lait patches (CAL) were retrieved from patient's medical records. Thirty MZB patients were included: 20 women (67%) and 10 men (33%). Patients received a diagnosis of MZB (median 42 years, range 16-19) significantly later than the diagnosis of FD/MAS (median 30 years, range 0-60), p < 0.01. Twenty-six patients were diagnosed with polyostotic disease (87%). In 97% the myxoma was located near the skeletal FD lesion. The combination of MZB and MAS was made in 13 patients in whom PP (n = 7), CAL (n = 7), GH-excess (n = 3) and hyperthyroidism (n = 3) were present. Other extraskeletal features were (multinodular) goiter (n = 2) and thyroid cysts (n = 1). Furthermore, in this cohort of patients with MZB several (pre-)malignant tumors were observed; ductal carcinoma in situ of the breast in 3 patients (10%), breast cancer in 1 patient (3.3%), intra pancreatic mucinous neoplasms in 3 patients (10%) and liver adenomas in 2 patients (6.6%). A total of 47% of patients with MZB had an additional extraskeletal feature such as an endocrinopathy. In MZB, 87% of patients suffer from polyostotic FD, 43% of patients have extraskeletal GNAS-features such as an hyperfunctioning endocrinopathy and 30% (pre-)malignant tumors. We therefore advocate that MZB patients should undergo a complete screening and long-term follow-up for extent of bone disease, but also extraskeletal GNAS features of FD/MAS.

Fertility in McCune Albright syndrome female: A case study focusing on AMH as a marker of ovarian dysfunction and a literature review.

BACKGROUND: The molecular basis of McCune Albright syndrome (MAS) is a recurrent GNAS Postzygotic gain of function sporadic mutation, resulting in a mosaic disease. Most of girls present precocious puberty, caused by the development of recurrent ovarian cysts with autonomous Hyperestrogenic stimulation. After menarche, the majority of patients with ovarian GNAS mutation have menstrual disturbances and infertility. OBJECTIVES: We wanted to focus on the fertility of MAS females and propose an appropriate management, by a detailed case report and an exhaustive review of the literature on fertility and pregnancy in MAS females. RESULTS: We present the case of a 29-year-old MAS female, who had previously undergone a unilateral ovariectomy and was managed by in vitro fertilization (IVF). Eight oocytes with many morphological abnormalities were retrieved. The GNAS mutation was found at a low frequency in follicular cells. The ovarian histopathological examination showed developing follicles of all stages, strongly expressing AMH by immunohistochemistry. In addition, AMH was high (45.5 pmol/L) and the AMH / AFC ratio (5.69 pmol/L per follicle) was much higher than in PCOS and control groups (2.16, and 1.34 respectively). CONCLUSIONS: Ovarian and endometrial involvement can be responsible for infertility in MAS women. IVF and oophorectomy may be useful in management. The genetic characterization of the different tissues may have a prognostic utility. Moreover, we suggest that the AMH could be a marker of the ovarian activity in MAS. Further studies are needed to clarify the potential oocyte abnormalities and the risk of miscarriages in order to guide genetic counseling.

Genotype-Phenotype Correlation in Fibrous Dysplasia/McCune-Albright Syndrome.

CONTEXT: Fibrous dysplasia/McCune-Albright syndrome (FD/MAS) is a rare bone and endocrine disorder resulting in fractures, pain, and disability. There are no targeted or effective therapies to alter the disease course. Disease arises from somatic gain-of-function variants at the R201 codon in GNAS, replacing arginine by either cysteine or histidine. The relative pathogenicity of these variants is not fully understood. OBJECTIVE: This work aimed 1) to determine whether the most common GNAS variants (R201C and R201H) are associated with a specific clinical phenotype, and 2) to determine the prevalence of the most common GNAS variants in a large patient cohort. METHODS: This retrospective cross-sectional analysis measured the correlation between genotype and phenotype characterized by clinical, biochemical, and radiographic data. RESULTS: Sixty-one individuals were genotyped using DNA extracted from tissue or circulating cell-free DNA. Twenty-two patients (36.1%) had the R201C variant, and 39 (63.9%) had the R201H variant. FD skeletal disease burden, hypophosphatemia prevalence, fracture incidence, and ambulation status were similar between the 2 groups. There was no difference in the prevalence of endocrinopathies, ultrasonographic gonadal or thyroid abnormalities, or pancreatic involvement. There was a nonsignificant association of cancer with the R201H variant. CONCLUSION: There is no clear genotype-phenotype correlation in patients with the most common FD/MAS pathogenic variants. The predominance of the R201H variant observed in our cohort and reported in the literature indicates it is likely responsible for a larger burden of disease in the overall population of patients with FD/MAS, which may have important implications for the future development of targeted therapies.