Delayed Diagnosis of McCune-Albright Syndrome in Adulthood Revealed by Spinal Fibrous Dysplasia: Report of 2 Cases

Abstract

McCune-Albright syndrome (MAS) is a rare genetic disorder characterized by fibrous dysplasia of bone, café-au-lait skin pigmentation, and endocrine abnormalities. Adult presentation with spinal fibrous dysplasia, although previously reported, is uncommon and diagnostically challenging. We report 2 cases of MAS diagnosed in young women who initially presented with persistent back pain. Both patients underwent imaging studies that revealed multiple lytic lesions in the spine, raising concern for metastatic disease. Further evaluation confirmed the presence of polyostotic fibrous dysplasia without evidence of malignancy. Both patients had a history of precocious puberty, consistent with the syndrome's known manifestations. In 1 case, the diagnosis was supported by detection of a somatic GNAS variant using next-generation sequencing on DNA and RNA extracted from bone biopsy. The second patient declined genetic testing. These cases highlight the importance of considering MAS in the differential diagnosis of spinal lesions in young individuals, particularly when imaging reveals multifocal, expansile, and radiolucent bone lesions. Early recognition is essential for appropriate management, genetic counseling, and monitoring of potential endocrine complications.

Introduction

McCune-Albright syndrome (MAS) is a rare, sporadic disorder resulting from postzygotic activating mutations in the GNAS gene [1-3]. This leads to a triad of clinical features: polyostotic fibrous dysplasia, café-au-lait skin pigmentation, and endocrine abnormalities—most commonly precocious puberty in females [4, 5]. Although MAS typically presents in childhood, adult patients with mild or incomplete forms may be diagnosed later, often during evaluation of bone lesions or chronic pain [6]. This report presents 2 adult female patients who were diagnosed with MAS after presenting with persistent back pain and were found to have multiple spinal lesions, highlighting the importance of considering MAS in the differential diagnosis of multifocal skeletal abnormalities.

Case Presentation

Patient 1: A 38-year-old woman presented with worsening back pain lasting several months, with no history of trauma, fever, or weight loss. Physical examination revealed localized tenderness over the thoracic spine. No neurological deficits were noted. There was no known family history of endocrine or skeletal disorders.

Patient 2: A 20-year-old woman presented with progressive lower back pain and mild stiffness. There was no trauma or systemic symptoms. Examination showed lumbar tenderness and normal neurological function. Skin examination revealed a discreet café-au-lait spot on her shoulder.

Both patients had experienced precocious puberty during childhood but were not previously diagnosed with any genetic or skeletal disorder.

Diagnostic Assessment

Patient 1: Initial imaging with spinal computed tomography (CT) and magnetic resonance imaging revealed multiple lytic lesions with ground-glass matrix appearance and cortical thinning involving the L2 and L3 vertebral bodies, as well as a pathologic fracture of vertebra T5 (Figures 1 and 2). Multiple lesions and cortical thinning involving the iliac wings bilaterally, sacrum, and right proximal femur were also seen, demonstrating a polyostotic distribution (Figure 3).

Figure 1.

Sagittal computed tomography scan of the thoracolumbar spine in bone window reveals lytic lesions with soft-tissue density and sclerotic margins within the L2 and L3 vertebral bodies. A similar lesion is seen in the T5 vertebra, causing a pathologic fracture.

Figure 2.

Axial computed tomography scan in bone window showing a lytic lesion in the L2 vertebral body, pedicle, and left transverse process with cortical thinning.

Figure 3.

Coronal computed tomography scan in bone window showing cortical thinning and lesions in the left iliac bone and ischium. A similar lesion is seen in the right sacral bone. L2 and L3 lesions are also noted.

Patient 2: Imaging studies revealed lytic lesions involving the L2 and L4 vertebral bodies. The lesions exhibited a ground-glass appearance, cortical thinning, and mild reduction in vertebral height (Fig. 4). Coronal CT scan of the chest showing expansile lesions with ground-glass appearance and cortical thinning in multiple ribs bilaterally (Fig. 5).

Figure 4.

Sagittal computed tomography scan of the lumbar spine showing lytic lesions in L2 and L4 vertebral bodies with ground-glass appearance, cortical thinning, and mild height loss.

Figure 5.

Coronal computed tomography scan of the chest showing expansile lesions with ground-glass appearance and cortical thinning in multiple ribs bilaterally.

The differential diagnosis of vertebral bone lesions in patients younger than age 40 years is summarized in Table 1.

Table 1.

Key differential diagnosis of vertebral bone lesions in patients younger than age 40 years

Diagnosis	Lesion type	Typical Age range	Key Clinical features	Imaging characteristics
Hemangioma	Benign	Any	Usually asymptomatic	Vertical striations (“corduroy” sign), “polka-dot” pattern on axial CT
Osteoid osteoma	Benign	10-30 years	Nocturnal pain relieved by NSAIDs	Small nidus (<1.5 cm) with surrounding sclerosis on CT
Osteoblastoma	Benign	10-30 years	Persistent pain; less NSAID response	Expansile, lytic lesion, often in posterior vertebral elements
Fibrous dysplasia	Benign	<30 years	Often asymptomatic; deformity in polyostotic form	Ground-glass matrix with bony expansion
Ewing sarcoma	Malignant	10-30 years	Pain, fever, systemic symptoms	Aggressive lytic lesion ± soft tissue mass; onion-skin periosteal reaction
Osteosarcoma	Malignant	10-25 years	Pain, swelling	Mixed sclerotic/lytic lesion; sunburst or Codman triangle periosteal reaction
Primary bone lymphoma	Malignant	20-40 years	Bone pain; systemic “B” symptoms	Lytic lesion; may mimic infection or metastasis
Metastasis	Malignant	Pediatric-young adult	Bone pain, systemic signs	Lytic or infiltrative lesions; possible vertebral collapse
Schmorl's node	Traumatic/postural	Teens-30s	Often incidental or posttraumatic back pain	Endplate herniation of disc; round, well-defined vertical defect

Age ranges are approximate. Laboratory values are not applicable in this imaging-based differential diagnosis.

Abbreviations: CT, computed tomography; MRI, magnetic resonance imaging; NSAIDs, nonsteroidal anti-inflammatory drugs.

Laboratory tests including complete blood count, inflammatory markers, calcium, phosphate, parathyroid hormone, and vitamin D were within normal limits. Serum prolactin, cortisol, and thyroid function tests were unremarkable (Table 2).

Table 2.

Core metabolic and endocrine laboratory values

Parameter	Reference range	Patient 1	Patient 2
Calcium	2.15-2.55 mmol/L (8.6-10.2 mg/dL)	2.35 mmol/L (9.4 mg/dL)	2.42 mmol/L (9.7 mg/dL)
Phosphate	0.81-1.45 mmol/L (2.5-4.5 mg/dL)	0.90 mmol/L (2.8 mg/dL)	1.20 mmol/L (3.7 mg/dL)
Alkaline phosphatase	35-105 U/L (35-105 IU/L)	109 U/L (109 IU/L)	140 U/L (140 IU/L)
PTH	1.6-6.9 pmol/L (15-65 pg/mL)	2.5 pmol/L (24 pg/mL)	1.9 pmol/L (18 pg/mL)
25-Hydroxyvitamin D	50-125 nmol/L (20-50 ng/mL)	55 nmol/L (22 ng/mL)	80 nmol/L (32 ng/mL)
C-terminal telopeptide of type I collagen	0.162-0.436 µg/L (162-436 ng/L)	0.472 µg/L (472 ng/L)	0.780 µg/L (780 ng/L)
Procollagen type I N-terminal propeptide	41-73.7 µg/L (41-73.7 µg/L)a	42.7 µg/L (42.7 µg/L)	Not performed
TSH	0.4-4.0 mIU/L (0.4-4.0 µIU/mL)	1.6 mIU/L (1.6 µIU/mL)	3.3 mIU/L (3.3 µIU/mL)
Free T4	11.5-22.7 pmol/L (0.9-1.8 ng/dL)	15.7 pmol/L (1.2 ng/dL)	14.1 pmol/L (1.1 ng/dL)
Prolactin	<530 mIU/L (<25 ng/mL, female)	127 mIU/L (6 ng/mL)	148 mIU/L (7 ng/mL)
Urinary free cortisol (24 hours)	<138 nmol/24 hours (<50 µg/24 hours)	86 nmol/24 hours (31 µg/24 hours)	74 nmol/24 hours (27 µg/24 hours)
Serum cortisol after overnight 1 mg dexamethasone	<50 nmol/L (<1.8 µg/dL)	29 nmol/L (1.1 µg/dL)	32 nmol/L (1.2 µg/dL)
IGF-1	9.2-30.0 nmol/L (70-230 ng/mL)b	18.2 nmol/L (139 ng/mL)	20.4 nmol/L (156 ng/mL)
GH	<10 µg/L (<10 ng/mL, random)	1.02 µg/L (1.02 ng/mL)	2.04 µg/L (2.04 ng/mL)

^a Reported in µg/L; equivalent in SI and conventional systems.

^b Age- and sex-adjusted reference range.

Imaging alone was not diagnostic, and tissue biopsy was required for confirmation. In patient 1, CT-guided needle biopsy of the L3 vertebra revealed curvilinear woven bone trabeculae embedded in a fibrous stroma composed of bland spindle cells, findings compatible with fibrous dysplasia (Fig. 6A).

Figure 6.

(A) Hematoxylin and eosin-stained section of spinal bone lesion from patient 1 (magnification ×100). Irregular, curvilinear trabeculae of immature woven bone lacking osteoblastic rimming are embedded in a moderately cellular fibrous stroma—a histologic pattern typical of fibrous dysplasia. Scale bar = 0.1 mm. (B) Hematoxylin and eosin-stained section of spinal bone lesion from patient 2 (magnification ×100). Fragments show irregular woven bone trabeculae without osteoblastic rimming, set in a moderately cellular fibrous stroma findings consistent with fibrous dysplasia. Scale bar = 0.1 mm.

In patient 2, biopsy of the L4 vertebra showed a small focus of reactive woven bone trabeculae lacking osteoblastic rimming, embedded within a fibrous stroma. Although these findings may represent fibrous dysplasia, clinical and radiological correlation was recommended (Fig. 6B).

For patient 1, a comprehensive next-generation sequencing-based assay (Oncomine Comprehensive Assay) using the Ion GeneStudio S5 instrument, was performed on DNA and RNA extracted from formalin-fixed paraffin-embedded block of bone tissue. The tumor cell content was 50%, reported sensitivity of detection in affected tissue up to 99%. The GNAS c.601C > T p.Arg201Cys was detected at a 37.5% allele frequency. The variant was not detected in the blood.

Patient 2 declined genetic testing.

Treatment

Because of the severity of back pain and the extent of bone involvement, both patients were treated with a single 5-mg intravenous zoledronic acid. Pain management was supplemented with acetaminophen and physiotherapy. Both patients tolerated the treatment well, with no acute adverse effects.

Outcome and Follow-up

At follow-up (6 and 12 months), both patients reported significant improvement in back pain and functional mobility. Repeat imaging showed stable bone lesions without progression. Neither patient developed new endocrinopathies during a follow-up period of 18 months. Both remain under routine surveillance with endocrinology and orthopedic services for monitoring of skeletal integrity and endocrine status.

Discussion

These cases illustrate an uncommon adult presentation of MAS, where back pain was the primary complaint leading to diagnosis. Although MAS typically presents in childhood, a delayed or mild form may escape early detection, particularly in patients with subtle or isolated manifestations. Spinal involvement in fibrous dysplasia is less common than in long bones or craniofacial structures [7-9], and when present, may mimic metastatic disease or other skeletal pathologies on imaging [10].

Review of the literature shows that bisphosphonates, including zoledronic acid, have been used successfully to manage bone pain and stabilize fibrous dysplasia lesions. Although not curative, bisphosphonates may reduce bone turnover and alleviate symptoms [11-14]. Management of MAS requires a multidisciplinary approach tailored to the individual's skeletal and endocrine manifestations. Surveillance is necessary to detect evolving endocrinopathies or orthopedic complications such as fractures or scoliosis.

A limitation in these cases was the retrospective recognition of MAS features—specifically precocious puberty and café-au-lait macules—that had not previously prompted investigation. Although adult cases of MAS with spinal fibrous dysplasia have been reported, our cases underscore persistent diagnostic pitfalls, particularly when prior endocrine manifestations (eg, precocious puberty) are overlooked.

Learning Points

• McCune-Albright syndrome (MAS) may first present in adulthood with chronic pain resulting from undiagnosed polyostotic fibrous dysplasia.

• The presence of spinal lesions, café-au-lait spots, and a history of precocious puberty should prompt evaluation for MAS.

• Imaging and genetic testing for GNAS mutations are central to diagnosis.

• Bisphosphonate therapy (eg, zoledronic acid) can significantly improve bone pain in MAS-related fibrous dysplasia.

• Multidisciplinary, long-term follow-up is essential due to the progressive nature and multisystem involvement of the syndrome.

Contributors

All authors made individual contributions to authorship. V.R., Y.G., and E.S. were involved in the diagnosis and management of the patient and manuscript submission. N.R. was involved in orthopedic consultation and I.D. in the radiologic evaluation and preparation of images. M.Y. was responsible for the patient's genetic testing. All authors reviewed and approved the final draft.

Funding

No public or commercial funding.

Disclosures

The authors declare no conflicts of interest relevant to this case report.

Informed Patient Consent for Publication

Informed consent was obtained directly from both patients.

Data Availability Statement

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.