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McCune-Albright Syndrome

Recent research efforts aimed at curing McCune-Albright Syndrome.

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McCune-Albright Syndrome

Overview

McCune-Albright syndrome (MAS), often discussed together with fibrous dysplasia as FD/MAS, is a rare, non-inherited mosaic genetic disorder. A disease-causing change in the GNAS gene arises after conception, so only some cells carry it; this explains why the condition can affect the bones, skin, and hormone-producing organs in very different combinations and severities from one person to another. Typical features include weak fibrous-dysplasia bone lesions, café-au-lait skin patches, and hormone excess such as early puberty, hyperthyroidism, or excess growth hormone. GeneReviews: Fibrous Dysplasia/McCune-Albright Syndrome NIH overview (ncbi.nlm.nih.gov)

Prognosis depends largely on the amount and location of affected bone and on how well endocrine complications are controlled. Severe disease can cause pain, fractures, deformity, impaired mobility, vision or hearing complications, and reduced quality of life, while some people have relatively limited disease. There is currently no treatment that removes the underlying mosaic GNAS mutation or reliably reverses all established fibrous-dysplasia lesions. Standard care is therefore multidisciplinary and individualized: orthopedic management of fractures and deformity, treatment of hormone excess, phosphate and active-vitamin-D treatment when phosphate wasting is present, pain management, monitoring, and selected surgery. GeneReviews: management of FD/MAS International FD/MAS management guideline (ncbi.nlm.nih.gov)

Scope of Recent Research (2020–present)

Research since 2020 has been active but remains concentrated in a small number of specialist centers and focuses mainly on making fibrous-dysplasia lesions less active, preventing phosphate-wasting complications, and developing measurable biomarkers for trials. The field is not yet close to a whole-body genetic cure: no clinical gene-editing, gene-replacement, RNA-silencing, or cell-replacement therapy has entered clinical testing for MAS. The most consequential recent work instead tests targeted biologic drugs—especially RANKL inhibition with denosumab and FGF23 inhibition with burosumab—that may modify important downstream disease processes. GeneReviews: no established disease-modifying therapy RANKL inhibition study (ncbi.nlm.nih.gov)

Major Breakthroughs and Emerging Therapies

The strongest potential disease-modifying signal has come from denosumab, an antibody that blocks RANKL, a signaling protein that promotes bone-resorbing osteoclasts. In a 2024 translational study using biopsies from a phase 2 study alongside mouse and laboratory lesion models, RANKL inhibition reduced fibrous-dysplasia lesion cellularity and the detectable mutant Gαs signal, while increasing maturation of bone-forming cells and bone formation within lesions. This is important because it suggests denosumab may do more than reduce bone breakdown: it may interrupt harmful communication between osteoclasts and mutation-bearing bone progenitor cells. RANKL inhibition reduces lesion cellularity and mutant Gαs expression (pubmed.ncbi.nlm.nih.gov)

Imaging and small clinical studies support that biological rationale, but do not yet establish a cure. A 2021 study using sodium-fluoride PET/CT found that patients receiving denosumab had reduced lesion activity, lower bone-turnover markers, and improved pain measures; the imaging method also provided an objective way to quantify treatment response within affected bone. A 2026 single-center pediatric study of five patients likewise reported less pain, lower bone-turnover markers, and radiographic lesion regression after denosumab, but two children developed rebound hypercalcemia after treatment stopped. Denosumab PET/CT study Pediatric denosumab study (pubmed.ncbi.nlm.nih.gov)

A second emerging strategy targets excess fibroblast growth factor 23 (FGF23), a hormone produced by some extensive fibrous-dysplasia lesions that causes the kidneys to waste phosphate. Burosumab is an antibody that neutralizes FGF23. Published MAS case reports since 2021 have described rapid and sustained improvement in blood phosphate and bone biochemistry, with reported improvements in pain, strength, rickets, or mobility in some patients with severe phosphate wasting despite conventional phosphate and active-vitamin-D therapy. These reports address a serious complication of MAS rather than correcting the causative mutation or eliminating lesions. Burosumab case report, 2021 Burosumab pediatric MAS case report, 2023 Burosumab child case report, 2025 (pubmed.ncbi.nlm.nih.gov)

There are also important advances in diagnostics and trial readiness. Researchers have detected pathogenic GNAS variants in circulating cell-free DNA using highly sensitive assays, particularly in younger people and those with more extensive skeletal disease. This could eventually reduce reliance on affected-tissue biopsies and provide a biomarker for disease burden or treatment response, although it is not yet a curative treatment or a universal diagnostic test. Circulating cell-free DNA GNAS study (pubmed.ncbi.nlm.nih.gov)

Clinical Trials and Experimental Approaches

The U.S. National Institute of Dental and Craniofacial Research (NIDCR) conducted an open-label phase 2 denosumab study, NCT03571191, in skeletally mature adults with painful fibrous dysplasia. Participants received 120 mg denosumab every four weeks for six months after loading doses, with measurements including bone-turnover markers, pain, bone histology, imaging, mineral metabolism, and effects after discontinuation. Publications linked to the study reported reduced lesion activity and evidence of improved bone maturation, but they also documented clinically important mineral-metabolism disturbances that make supervised use essential. NCT03571191 Safety and efficacy report Mechanistic phase 2 analysis (clinicaltrials.gov)

For phosphate wasting, the NIDCR-sponsored phase 2 study NCT05509595 evaluated burosumab in 12 children and adults with FGF23-mediated hypophosphatemia from fibrous dysplasia, including FD/MAS. The registry records actual study completion in November 2024; it describes 48 weeks of treatment but does not list posted efficacy results in the available registry record. NCT05509595 (clinicaltrials.gov)

In Europe, Leiden University Medical Center is sponsoring the recruiting phase 4 DeFiD trial, NCT05966064, a randomized, double-blind, placebo-controlled study of denosumab in adults with FD/MAS. The planned enrollment is 82 participants, with primary completion estimated for December 2027; no outcomes have yet been posted. DeFiD trial (clinicaltrials.gov)

Methodologies and Scientific Approaches

Recent studies combine human lesion biopsies with mouse models, ex vivo lesion cultures, histology, RNA sequencing, and molecular assays that distinguish mutant from non-mutant cells. This approach has helped investigators move beyond symptom outcomes and test whether a therapy changes the cellular composition and developmental state of fibrous-dysplasia tissue itself. RANKL inhibition study (pubmed.ncbi.nlm.nih.gov)

Researchers are also improving outcome measures for small rare-disease trials. Sodium-fluoride PET/CT can quantify active fibrous-dysplasia lesion burden, while blood biomarkers such as alkaline phosphatase, P1NP, CTX, RANKL/OPG ratio, interleukin-6, phosphate, and FGF23 are being evaluated to monitor disease and predict treatment response. Circulating cell-free GNAS DNA adds a potential molecular biomarker. PET/CT response study Biomarker study Circulating cell-free DNA study (pubmed.ncbi.nlm.nih.gov)

Leading Institutions and Funding

The leading U.S. program is the NIH intramural FD/MAS effort at NIDCR in Bethesda, led by investigators including Alison Boyce and colleagues. NIDCR sponsors the denosumab phase 2 trial and the completed burosumab phase 2 trial, and its program integrates natural-history research, endocrine care, imaging, tissue studies, and clinical trials. NIDCR FD/MAS program NIDCR denosumab trial NIDCR burosumab trial (nidcr.nih.gov)

Leiden University Medical Center is a major European center for denosumab research and sponsors the DeFiD randomized trial. The FD/MAS Alliance maintains a patient registry, and patient organizations participate in international clinical-guideline development and research recruitment. Public records reviewed for this report identify institutional programs and trial sponsorship, but do not provide a comparable current dollar amount for a dedicated MAS cure-development program. DeFiD trial FD/MAS patient registry International FD/MAS guideline (clinicaltrials.gov)

Strengths, Limitations, and Challenges

The field’s principal strength is that it has identified actionable downstream mechanisms in a disorder once managed almost entirely with surgery and symptom control. Denosumab has shown lesion-level biological effects, and burosumab can directly address the phosphate wasting that worsens rickets, fractures, deformity, and pain. Sensitive molecular testing, standardized imaging, and rare-disease registries should make future trials more informative and less dependent on subjective outcomes alone. RANKL inhibition study Burosumab case report, 2021 Circulating cell-free DNA study (pubmed.ncbi.nlm.nih.gov)

The major limitations are biological and practical. MAS is mosaic, meaning that affected cells are scattered through different tissues; a curative genetic medicine would need to find, safely edit, silence, or replace mutant cells across bone and potentially endocrine organs without harming normal cells. Denosumab can cause severe rebound activation of bone turnover and disturbances in calcium and phosphate after discontinuation, especially in younger people or those with high skeletal burden, while burosumab evidence in FD/MAS remains limited mainly to case reports and a small completed trial without posted results. Neither drug has demonstrated that it can eradicate the underlying mutation or permanently cure MAS. GeneReviews: denosumab and burosumab limitations Pediatric denosumab study NCT05509595 (ncbi.nlm.nih.gov)

Outlook and Future Directions

As of August 8, 2026, a cure for McCune-Albright syndrome is not near-term, but the field has moved toward genuinely disease-modifying research for the skeletal component of the condition. The most important milestones to watch are publication of the completed burosumab phase 2 results, safety and efficacy results from the randomized DeFiD denosumab trial, confirmation that imaging and blood-based biomarkers predict meaningful clinical benefit, and early preclinical work capable of selectively targeting mutant GNAS cells. A durable cure will likely require a mutation-directed therapy that can be delivered safely to the many tissues involved in mosaic disease; current biologics are better understood as potentially valuable bridges toward that goal rather than curative treatments. NCT05509595 DeFiD trial RANKL inhibition study (clinicaltrials.gov)

References

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