Melorheostosis, also known as Léri-Joanny syndrome, has fascinated physicians since it was first described in 1922. Its nickname in radiology circles, the dripping candle wax sign, comes from the way dense bone appears to ooze along the outer contours of affected bones, as if molten wax had been poured over them and hardened in place. The condition is a non-hereditary, congenital sclerotic bone dysplasia, meaning that bone tissue becomes abnormally thickened and dense. Although the disease was long understood only through its appearance on imaging, recent molecular work has finally revealed its biological roots: somatic activating mutations in the MAP2K1 gene, which encodes the MEK1 protein, drive constitutive activation of the MAPK/ERK signaling pathway. That pathway, when stuck in the on position, pushes osteoblasts—the cells responsible for building bone—into aberrant, uncontrolled activity, producing the dense sclerotic masses that define the disease.

The story of this particular case began on what clinicians call day zero, when the patient fell onto his left hand during recreational sports. He reported only mild wrist discomfort, and his initial examination at an orthopedics clinic the following day revealed localized tenderness over the thenar eminence, the fleshy pad at the base of the thumb. There was no redness, no deformity, no sensory deficit, and his wrist and finger joints moved through a full, painless range of motion. Radiographs ordered simply to rule out a fracture instead unveiled something unexpected: irregular, linear, hyperdense sclerosis involving the second metacarpal, the lunate and triquetrum of the wrist, and the distal ends of the radius and ulna.

Those first images displayed the hallmark ivory-like density and flowing pattern along the bone contours that immediately suggested the dripping candle wax appearance. Critically, there was no periosteal reaction—the aggressive bone-forming response often seen with tumors or infection—and no soft tissue swelling. To characterize the lesions further, the team turned to computed tomography, whose axial and coronal reformats provided exquisite osseous detail. The CT scans confirmed irregular endosteal and intracortical hyperdensity, meaning the dense bone was forming inside the medullary cavity and within the cortex itself. Cortical thickening and partial obliteration of the medullary cavity were evident, and the sclerotic areas blended seamlessly with the surrounding cortex, recreating the melted wax appearance in three dimensions while sparing the adjacent joints.

Magnetic resonance imaging then supplied the decisive piece of the diagnostic puzzle. On both T1-weighted and fat-suppressed T2-weighted sequences, the lesions showed homogeneous, markedly low signal intensity, matching that of cortical bone—exactly what dense, compact sclerotic bone should look like. Far more important was what the MRI did not show: there was no bone marrow edema, no soft tissue mass, and no joint effusion, and the surrounding marrow signal was entirely normal. In bone imaging, the absence of these features is often more informative than their presence, because marrow edema and soft tissue masses are the fingerprints of aggressive processes such as osteosarcoma or osteomyelitis.

Laboratory findings reinforced the benign interpretation. The patient’s complete blood count, C-reactive protein of 2 mg/L, and erythrocyte sedimentation rate of 3 mm/h all fell comfortably within reference ranges, as did serum alkaline phosphatase at 51 U/L and calcium at 9.0 mg/dL. Taken together, the normal inflammatory markers and metabolic panel argued strongly against infection or a metabolic bone disorder. With the classic radiographic wax-flow pattern, CT confirmation of cortical sclerosis, and a conspicuously quiet MRI, the clinicians established a definitive diagnosis of melorheostosis and classified it within the two major frameworks used in the literature. Under Freyschmidt’s radiological classification, the case fits the classic candle-wax subtype, and according to the system proposed by Yu and colleagues, it represents the endosteal type, defined by the direction in which the lesion spreads within the bone.

The rarity of this anatomical distribution deserves emphasis. In Freyschmidt’s review of 23 cases, only five involved the upper extremity, roughly 22 percent, and documented involvement of the lunate and triquetrum—two of the eight small carpal bones of the wrist—is exceedingly scarce. The authors contrasted their case with a recent pediatric report by Na and colleagues, in which a 9-year-old boy presented with multifocal melorheostosis of the entire right upper limb, spanning the scapular coracoid process, humeral head, distal humerus, ulnar head, wrist, and metacarpals. That child exhibited the same pathognomonic melting wax pattern and the same endosteal subtype, but required a biopsy for definitive diagnosis, with histopathology revealing irregular endosteal bone proliferation composed of densely arranged lamellar bone and enlarged, distorted Haversian canals. The adult patient in the new report, by contrast, avoided any invasive procedure altogether, illustrating how multimodal imaging can spare cooperative adult patients the risks and discomfort of surgical sampling.

The comparison also highlights the remarkable phenotypic spectrum of the disease. One patient was a child with multifocal disease throughout an entire limb; the other was an adult with localized involvement confined to the carpometacarpal region. Both remained asymptomatic over their respective follow-up periods—six months in the pediatric case and two years in the present one—reinforcing a consistent management principle: asymptomatic melorheostosis requires monitoring only. The authors acknowledge one limitation of their report, namely that no repeat imaging was performed during follow-up because the absence of symptoms did not justify additional radiation exposure. Still, a sustained, completely asymptomatic clinical course over two years strongly supports the interpretation of a benign, quiescent process.

The molecular dimension of the disease adds a forward-looking note to the discussion. Because MAP2K1 mutations arise somatically after fertilization, they produce post-zygotic mosaicism, which elegantly explains why the disease tends to affect localized, often linear distributions along a single limb rather than the entire skeleton. Genetic testing was not performed in this asymptomatic patient, consistent with current clinical practice in which diagnosis remains imaging-based, but the authors stress that recognizing these molecular underpinnings is crucial. Beyond explaining the disease’s localized nature, the identification of a specific druggable pathway—the MEK-ERK cascade—opens potential avenues for targeted therapies in symptomatic cases, a prospect that was unimaginable when the condition was first described a century ago.

Differentiating melorheostosis from its mimics remains the central diagnostic challenge, particularly when lesions are discovered incidentally in the wrist. The differential diagnosis in this case included osteosarcoma, chronic osteomyelitis, and osteopoikilosis, a related sclerotic bone dysplasia often associated with LEMD3 mutations that produces multiple small, round sclerotic foci but lacks the linear, flowing morphology of melorheostosis. Osteosarcoma, the most dangerous mimic, typically shows heterogeneous signal intensity on MRI, a soft tissue mass, and aggressive periosteal reaction—features conspicuously absent here. The authors caution that the absence of marrow edema alone cannot entirely exclude a low-grade malignancy, which is precisely why the diagnosis rested on the overall clinical and radiological constellation rather than any single imaging feature. Treatment, when needed at all, is reserved for complications such as nerve entrapment, progressive deformity, or intractable pain; this patient received only reassurance, education, and periodic clinical follow-up, with instructions to return if pain or functional limitation ever develops. At his two-year check, he remained entirely symptom-free—a quiet outcome that, for a disease once guaranteed to trigger invasive work-ups, represents a genuine victory for modern diagnostic imaging.

Subject of Research: Non-invasive multimodal imaging diagnosis of melorheostosis involving the carpal and metacarpal bones

Article Title: Melorheostosis Involving the Carpal and Metacarpal Bones: Diagnostic Insights From Multimodal Imaging

Article References: Zhang, Z., Deng, Z., Yang, W., Zou, A., Leng, P., & Peng, Y. (2026). Melorheostosis Involving the Carpal and Metacarpal Bones: Diagnostic Insights From Multimodal Imaging. Clinical Case Reports, 14(10), Article e73526. https://doi.org/10.1002/ccr3.73526

Image Credits: AI Generated

DOI: 10.1002/ccr3.73526

Keywords: melorheostosis, bone dysplasia, radiology, MRI, computed tomography, MAP2K1, MAPK/ERK pathway, wrist, candle wax sign, sclerotic bone lesions, differential diagnosis, case report

Hepatocellular carcinoma, or HCC, is one of the leading causes of cancer-related death worldwide, and its molecular landscape has been mapped in increasing detail over the past decade through large-scale sequencing efforts. Among the recurrent alterations identified in human HCC samples, mutations in CTNNB1 and in the TERT promoter stand out for their exceptionally high frequency. CTNNB1 mutations stabilize the β-catenin protein, allowing it to escape degradation, accumulate in the cell nucleus and drive the expression of proliferation-promoting genes. TERT promoter mutations, meanwhile, create binding sites for transcription factors that boost expression of telomerase reverse transcriptase, the enzyme that rebuilds chromosome ends and grants cells the replicative immortality that cancer demands. Despite the well-documented prevalence of both alterations, the functional consequences of their co-occurrence had remained poorly understood, leaving a significant gap in the mechanistic picture of how liver tumors arise.

To begin closing that gap, the research team first turned to publicly available data from The Cancer Genome Atlas, or TCGA, a comprehensive genomic database of human tumors. Their statistical analysis of HCC samples revealed a significant association between mutations in CTNNB1 and mutations in the TERT promoter, with a Fisher’s exact test yielding a P value below 0.01. In practical terms, this means that liver tumors carrying one of these alterations are significantly more likely than chance alone would predict to carry the other as well. Such non-random co-occurrence is a classic signature of cooperating cancer genes: when two alterations appear together more often than expected, it typically suggests that their combined effect confers a selective growth advantage that natural selection within the tumor favors strongly.

Association, however, is not causation. To test whether β-catenin and TERT genuinely cooperate in driving liver cancer, the researchers employed an elegant and rapid animal modeling technique known as hydrodynamic tail vein injection, or HTVI. This method involves injecting plasmid DNA into the bloodstream of mice in a way that delivers the genetic material directly into hepatocytes, the main functional cells of the liver, allowing researchers to express specific oncogenes in liver tissue and monitor tumor development over time. The team constructed plasmids encoding a constitutively active form of β-catenin, called Δ90 β-catenin, which carries a deletion that prevents its degradation, alongside plasmids encoding TERT itself.

The results of these experiments were striking. When Δ90 β-catenin and TERT were coexpressed in mouse livers, the animals developed hepatocellular carcinoma rapidly, with tumors emerging far sooner and more abundantly than in any of the control conditions. In contrast, expression of Δ90 β-catenin alone produced only minimal tumor formation, and expression of TERT alone produced essentially no tumors at all. This pattern is the hallmark of oncogenic synergy: neither alteration is sufficient on its own to transform liver tissue, but together they unleash a potent cancer-driving program. The finding provides a functional explanation for the genetic co-occurrence observed in human patient data, and it suggests that the two mutations are not merely passengers traveling together but active collaborators in hepatocarcinogenesis.

With the synergy established, the researchers turned their attention to the molecular mechanism underlying it. Using immunohistochemistry, a technique that detects specific proteins in tissue sections, they examined the tumors induced by combined β-catenin and TERT expression and looked for signs of activated signaling cascades. What they found was strong phosphorylation of ERK1/2, the terminal kinases of the MAPK/ERK pathway, a central signaling cascade that transmits growth-promoting signals from the cell surface to the nucleus. ERK1/2 phosphorylation is a well-established readout of MAPK/ERK pathway activation, and its robust presence in the β-catenin and TERT-driven tumors indicated that this pathway had been switched on in the tumor cells.

To determine whether this pathway activation was merely a byproduct of tumorigenesis or an essential driver of it, the researchers performed a genetic knockdown experiment targeting MEK1/2, the upstream kinases responsible for phosphorylating ERK1/2. When MEK1/2 expression was suppressed in the mouse livers receiving the β-catenin and TERT plasmids, tumor formation was markedly reduced. This loss-of-function experiment confirmed that MAPK/ERK signaling is not incidental but indispensable for the oncogenic cooperation between β-catenin and TERT. In other words, without the MAPK/ERK cascade, the two cancer genes lose their combined power to transform liver tissue, identifying the pathway as a critical dependency of this tumor subtype.

The clinical implications of these findings are considerable. The MAPK/ERK pathway is already a major focus of drug development across many cancer types, and a range of inhibitors targeting components of the cascade, including MEK inhibitors, have been developed and tested clinically. The new study suggests that patients whose liver tumors harbor both CTNNB1 and TERT promoter mutations may represent a molecular subtype that is particularly dependent on MAPK/ERK signaling, and therefore potentially responsive to therapies that target this cascade. Genomic testing for the co-occurrence of these two mutations could, in principle, help identify patients most likely to benefit from such an approach, although the researchers emphasize that their work is preclinical and that translating the findings into patient treatment will require further study.

Beyond its therapeutic implications, the study fills an important conceptual void in liver cancer biology. β-catenin is classically understood as a transcriptional co-activator in the Wnt signaling pathway, and TERT as a guardian of chromosome integrity, so the demonstration that their cooperation routes through MAPK/ERK activation reveals an unexpected layer of crosstalk between these canonical systems. The work was supported by grants from the National Research Foundation of Korea and approved by the Animal Policy and Welfare Committee of Kyung Hee University. As sequencing of liver tumors becomes increasingly routine in clinical practice, mechanistic studies like this one, which connect specific mutation combinations to druggable signaling dependencies, will become ever more essential to realizing the promise of precision oncology in hepatocellular carcinoma.

Subject of Research: Cooperation between TERT promoter mutations and β-catenin activation in hepatocellular carcinoma development via MAPK/ERK signaling

Article Title: Telomerase reverse transcriptase (TERT) accelerates β-catenin-driven hepatocarcinogenesis via MAPK/ERK pathway activation

Article References: Park, H., Lee, J., Moon, H., & Ro, S. W. (2026). Telomerase reverse transcriptase (TERT) accelerates β-catenin-driven hepatocarcinogenesis via MAPK/ERK pathway activation. Cancer Cell International. https://doi.org/10.1186/s12935-026-04329-9

Image Credits: AI Generated

DOI: 10.1186/s12935-026-04329-9

Keywords: TERT promoter, β-catenin, hepatocellular carcinoma, MAPK/ERK pathway, liver cancer, telomerase, CTNNB1, oncogenic synergy, hydrodynamic tail vein injection, ERK1/2 phosphorylation, MEK1/2, cancer genetics