MELORHEOSTOSIS
'Dripping Candle Wax' Sclerosing Bone Dysplasia | Sclerotomal Distribution | MAP2K1 Mutation
CLINICAL PATTERNS
Critical Must-Knows
- Dripping candle wax appearance - pathognomonic dense cortical hyperostosis flowing along bone cortex on radiographs
- Sclerotomal distribution - classically follows a single sclerotome (dermatomal equivalent for bone)
- MAP2K1 somatic mutation - identified in approximately 50% of cases, activates MAPK/ERK pathway
- Pain and stiffness - predominant symptoms; contractures from soft tissue involvement
- Surgery has high recurrence - limited surgical role; excision complicated by disease recurrence and joint stiffness
Examiner's Pearls
- "Describe the classic radiographic appearance: dense, irregular cortical hyperostosis resembling 'dripping candle wax' flowing down the bone
- "Know the differential diagnosis: osteopoikilosis (round lesions), osteopathia striata (linear striations), parosteal osteosarcoma, myositis ossificans
- "Understand management is primarily conservative: NSAIDs, physiotherapy, bisphosphonates trial; surgery reserved for severe contractures or deformity
- "Surgical complications include high recurrence, stiffness, and incomplete symptom relief
Critical Melorheostosis Exam Points
Pathognomonic Radiographic Sign
Dripping candle wax appearance - dense, flowing cortical hyperostosis along one side of the bone cortex. This is the hallmark imaging finding and is virtually diagnostic. No other condition produces this exact pattern.
Sclerotomal Distribution
Single sclerotome involvement - the disease classically affects bones, soft tissues, and skin derived from a single somite. This explains the linear, segmental distribution often confined to one limb.
MAP2K1 Mutation Discovery
Somatic mosaic mutation in MAP2K1 gene identified in ~50% of cases. This activates MEK1 and the MAPK/ERK signaling pathway, causing osteoblast hyperactivity. This is a post-zygotic mutation (not inherited).
Surgery Has Limited Role
High surgical recurrence rate - disease often recurs after excision. Joint contracture release complicated by recurrent stiffness. Bone excision and soft tissue releases have unpredictable outcomes. Conservative management is first-line.
Quick Decision Guide
| Clinical Scenario | Key Features | Management | Exam Pearl |
|---|---|---|---|
| Incidental finding, asymptomatic | Characteristic imaging, no symptoms | Observation, reassurance, no treatment | Many cases are discovered incidentally on imaging |
| Pain with preserved function | Symptomatic but functional | NSAIDs, physiotherapy, bisphosphonate trial | Conservative management is first-line for most cases |
| Severe contracture or deformity | Functional impairment, failed conservative Rx | Surgical release, osteotomy, or excision | Warn patient about high recurrence and stiffness risk |
CANDLEDiagnostic Features of Melorheostosis
Memory Hook:CANDLE - think of wax dripping down a candle! The dripping candle wax appearance is the key diagnostic feature.
STIFFClinical Features
Memory Hook:STIFF - the disease makes joints STIFF! Pain and contractures are the cardinal clinical features.
POMPDifferential Diagnosis
Memory Hook:POMP - think of the POMP and circumstance of diagnosis! These are the key differentials for sclerotic bone lesions.
Overview and Epidemiology
Clinical Significance
Melorheostosis (from Greek: melos = limb, rhein = flow, osteon = bone) is a rare, sporadic sclerosing bone dysplasia characterized by dense cortical hyperostosis with a pathognomonic dripping candle wax appearance on radiographs. First described by Leri and Joanny in 1922, it remains one of the rarest bone conditions, with fewer than 500 cases reported in the literature. The 2013 discovery of somatic MAP2K1 mutations has transformed understanding of its pathogenesis.
Demographics
- Incidence: Estimated 1 per 1,000,000 (extremely rare)
- Age: Any age; 50% present before age 20
- Gender: Equal male:female distribution
- Inheritance: Sporadic (somatic mosaic mutation)
- Laterality: Usually unilateral, confined to one limb
Natural History
- Onset: Childhood to adulthood, insidious
- Progression: Slowly progressive over decades
- Distribution: Follows sclerotomal pattern
- Symptoms: Pain (most common), stiffness, contractures
- Prognosis: Benign but disabling; no malignant transformation
Anatomic Distribution
Melorheostosis shows a characteristic pattern of involvement:
- Lower limb predominance: 70% of cases
- Upper limb: 20% of cases
- Axial skeleton: Rare (10%), usually in combination with limb disease
- Monostotic vs polyostotic: Equal distribution; polyostotic often in adjacent bones
- Sclerotomal pattern: Classically involves bones, muscles, fascia, and skin from a single embryonic somite
The sclerotomal distribution explains why the disease often follows a dermatomal pattern, with skin and soft tissue changes overlying the affected bones.
Pathophysiology and Molecular Genetics
MAP2K1 Somatic Mutation
Molecular Pathogenesis
The landmark 2013 discovery by Kang et al. identified somatic activating mutations in MAP2K1 (encoding MEK1) in approximately 50% of melorheostosis lesions. This explains the sporadic, non-inherited nature and mosaic distribution. The mutation activates the RAS-MAPK-ERK signaling pathway, leading to osteoblast hyperactivity and excessive bone formation. Importantly, mutations are found in affected tissue only (not blood), confirming somatic mosaicism.
Molecular Mechanism
- Gene: MAP2K1 (mitogen-activated protein kinase kinase 1)
- Protein: MEK1 (dual-specificity kinase)
- Mutation type: Activating, somatic, mosaic
- Pathway: RAS-RAF-MEK-ERK cascade
- Effect: Constitutive ERK activation in osteoblasts
Cellular Consequences
- Osteoblasts: Hyperactive bone formation
- Bone remodeling: Uncoupled, favoring formation
- Soft tissues: Fibroblast activation, fibrosis
- Vasculature: Vascular malformations in some cases
- Skin: Scleroderma-like changes over affected areas
Histopathology
Microscopic examination of affected bone reveals:
- Dense lamellar bone: Mature, well-organized lamellar bone (not woven)
- Haversian system preservation: Normal osteons within sclerotic bone
- Trabecular thickening: Increased trabecular bone mass
- Periosteal new bone: Layers of new bone on cortical surface
- Soft tissue fibrosis: Dense fibrous tissue in adjacent soft tissues
- No inflammatory infiltrate: Distinguishes from chronic osteomyelitis
- No nuclear atypia: Distinguishes from malignancy
Sclerotomal Theory
The classic theory explaining melorheostosis distribution is the sclerotomal hypothesis:
- Sclerotome: Embryonic somite derivative that forms vertebra and associated bones
- Single sclerotome: Disease affects structures from one embryonic segment
- Linear pattern: Explains why disease follows a limb in linear fashion
- Mosaic mutation: Fits with post-zygotic somatic mutation affecting single cell lineage
However, some cases do not fit this pattern, suggesting alternative mechanisms or earlier mutations affecting multiple lineages.
Clinical Presentation
Cardinal Features
Presenting Symptoms
The clinical presentation of melorheostosis is highly variable, ranging from incidental discovery to severe disability:
- Pain (50-80%): Dull, aching, often worse with activity
- Stiffness (60-80%): Joint contractures, reduced range of motion
- Deformity (40-60%): Limb length discrepancy, angular deformity
- Skin changes (20-40%): Scleroderma-like hardening over affected areas
- Limb swelling (30%): From bone enlargement and soft tissue involvement
Pain Characteristics
- Quality: Deep, aching, bone pain
- Pattern: Often worse with activity, may have night pain
- Location: Over affected bone segment
- Progression: Slowly worsening over years
- Response to NSAIDs: Variable, often partial relief
Contracture Patterns
- Joints: Adjacent to affected bones
- Mechanism: Soft tissue fibrosis, capsular involvement
- Common sites: Knee, elbow, ankle, fingers
- Severity: Mild limitation to severe fixed contracture
- Progression: Gradually worsening over time
Physical Examination
Inspection:
- Limb asymmetry (affected limb may be shorter or angular)
- Skin changes: thickening, induration, scleroderma-like appearance
- Visible bone enlargement in superficial locations
- Muscle wasting from disuse or direct involvement
Palpation:
- Hard, irregular bone masses along cortical surface
- Non-tender or mildly tender
- Skin may feel indurated, bound down
- Reduced soft tissue mobility over affected areas
Range of Motion:
- Joint contractures in adjacent joints
- Fixed flexion deformities common
- End-range pain with stretching
- May have limb length discrepancy
Age-Related Presentations
Childhood (under 10 years):
- Limb length discrepancy
- Angular deformity
- Delayed motor milestones
- May be mistaken for developmental conditions
Adolescence/Young Adult:
- Pain with increasing activity
- Joint stiffness affecting sports, activities
- Cosmetic concerns
- Peak time for diagnosis
Adult:
- Progressive pain and stiffness
- Occupational limitations
- May have been symptomatic for decades before diagnosis
- Osteoarthritis in affected joints
Imaging and Diagnosis
Radiographic Imaging - Diagnostic Standard
Pathognomonic Radiographic Finding
The dripping candle wax appearance is virtually pathognomonic for melorheostosis. This consists of dense, irregular, flowing cortical hyperostosis along one side of the bone, resembling wax that has dripped down and hardened along a candle. The sclerosis typically involves one cortex (eccentric) and may extend across joints to involve adjacent bones in the same sclerotome.
Key Radiographic Features:
- Dense cortical hyperostosis: Markedly increased bone density
- Flowing/dripping pattern: Irregular wavy margins like melted wax
- Eccentric distribution: Usually one side of bone cortex
- Crosses joints: May extend to adjacent bones
- No periosteal reaction: Distinguishes from infection/tumor
- Soft tissue calcification: May see adjacent soft tissue ossification
Radiographic Patterns
Dense cortical hyperostosis flowing along the bone cortex, typically along one side. The outer margin is irregular and wavy, while the inner margin may encroach on the medullary canal. This pattern is pathognomonic.
Focal sclerotic areas within the medullary cavity, resembling osteopoikilosis. May coexist with classic dripping wax pattern. This variant is called melorheostotic variant of mixed sclerosing bone dysplasia.
Linear striations of dense bone, similar to osteopathia striata. May represent overlap syndrome or variant pattern. Less common than classic presentation.
Soft tissue ossification extending from bone, mimicking myositis ossificans or parosteal osteosarcoma. Important to correlate with clinical history (no trauma history) and histology.
CT Imaging
CT provides superior assessment of:
- Cortical extent: Precise delineation of sclerotic bone
- Medullary involvement: Extension into medullary canal
- Joint involvement: Intra-articular extension, osteoarthritis
- Soft tissue ossification: Better detection than radiographs
- Surgical planning: 3D reconstruction for complex cases
MRI - Soft Tissue Assessment
MRI is valuable for evaluating:
- Soft tissue fibrosis: Low signal on T1 and T2
- Muscle involvement: Atrophy, fibrosis, fatty replacement
- Neurovascular compression: Important for surgical planning
- Joint involvement: Synovitis, capsular thickening
- Marrow changes: Usually normal signal in sclerotic areas
Imaging Modality Selection
| Modality | Indication | Key Findings |
|---|---|---|
| Plain radiograph | Initial diagnosis, surveillance | Dripping candle wax, cortical hyperostosis |
| CT scan | Surgical planning, cortical detail | Precise extent, 3D reconstruction |
| MRI | Soft tissue assessment, nerve evaluation | Fibrosis, muscle involvement, neurovascular |
Bone Scintigraphy
- Increased uptake: In affected areas on bone scan
- Extent assessment: May show involvement beyond radiographic findings
- Activity monitoring: Intensity may correlate with disease activity
- Limited specificity: Cannot distinguish from other sclerotic conditions
Differential Diagnosis
Other Sclerosing Bone Dysplasias
| Condition | Radiographic Pattern | Distribution | Key Distinguishing Feature |
|---|---|---|---|
| Melorheostosis | Dripping candle wax | Sclerotomal, unilateral | Flowing cortical hyperostosis along one cortex |
| Osteopoikilosis | Multiple round foci (spotted bones) | Bilateral, symmetric | Round/oval sclerotic foci near joints |
| Osteopathia striata | Linear striations | Bilateral, symmetric | Longitudinal dense lines in metaphyses |
| Progressive diaphyseal dysplasia | Fusiform cortical thickening | Bilateral, symmetric, diaphyseal | Camurati-Engelmann, inherited, systemic symptoms |
Key Differential Point
Osteopoikilosis (spotted bones) consists of multiple small, round, well-defined sclerotic foci clustered near joints - completely different from the flowing, linear dripping wax of melorheostosis. Osteopathia striata shows linear striations but is bilateral and symmetric, unlike the unilateral sclerotomal pattern of melorheostosis.
Mixed Sclerosing Bone Dysplasia
Some patients show features of multiple sclerosing dysplasias:
- Melorheostosis + osteopoikilosis
- Osteopathia striata + osteopoikilosis
- Overlap syndromes suggest common pathogenetic mechanism
This ends the comparison of sclerosing dysplasias.
Management
Conservative Management - First-Line Approach
Conservative is First-Line
Conservative management is the mainstay of treatment for melorheostosis. Surgery has unpredictable results with high recurrence rates. Most patients can be managed with a combination of analgesics, physiotherapy, and supportive measures. Surgery is reserved for severe contractures or deformity causing functional impairment.
Pain Management
- NSAIDs: First-line analgesics, often provide partial relief
- Paracetamol: Adjunct for mild pain
- Neuropathic agents: Gabapentin, pregabalin if nerve involvement
- Opioids: Reserved for severe, refractory pain
- Local measures: Heat, ice, TENS
Physiotherapy
- Goals: Maintain ROM, prevent contracture progression
- Stretching: Regular stretching of affected joints
- Strengthening: Maintain muscle function
- Hydrotherapy: May be beneficial for pain and mobility
- Orthotics: Splints to maintain position, AFOs for drop foot
Bisphosphonates
Rationale: Bisphosphonates inhibit osteoclast activity and reduce bone turnover. While melorheostosis is primarily an osteoblastic condition, there is some evidence for pain reduction with bisphosphonate therapy.
Evidence:
- Case reports and small series suggest benefit in some patients
- May reduce pain scores in subset of patients
- Effect on bone formation is limited
- Trial of therapy is reasonable for symptomatic patients
Regimen:
- Alendronate 70mg weekly or
- Zoledronic acid 5mg IV annually
- Trial for 6-12 months to assess response
Limited Evidence for Bisphosphonates
Evidence for bisphosphonate efficacy in melorheostosis is limited to case reports and small case series. Response is variable, with some patients experiencing significant pain relief and others showing no benefit. A therapeutic trial is reasonable but patients should be counseled about uncertain efficacy.
Other Medical Therapies
- Nifedipine: Calcium channel blocker, reported to reduce pain in isolated cases
- MEK inhibitors: Targeted therapy under investigation given MAP2K1 mutation
- Denosumab: RANKL inhibitor, theoretical benefit, case reports only
This section covers the conservative management of melorheostosis.
Evidence Base
MAP2K1 Mutations in Melorheostosis
- Somatic MAP2K1 mutations identified in 8 of 15 melorheostosis lesions (53%)
- Mutations activate MEK1 and downstream ERK signaling
- Mutations found only in affected tissue, not blood (somatic mosaicism)
- Osteoblasts from affected tissue show increased proliferation and differentiation
- Provides molecular target for potential future therapies
Clinical and Radiological Features of Melorheostosis
- Dripping candle wax appearance is pathognomonic radiographic finding
- Sclerotomal distribution is classic but not universal
- Soft tissue involvement occurs in 50% of cases
- Pain and stiffness are the predominant clinical features
- Differential diagnosis includes osteopoikilosis and parosteal osteosarcoma
Bisphosphonate Treatment for Melorheostosis
- Zoledronic acid provided significant pain relief in one patient
- Reduction in bone turnover markers observed
- No change in radiographic appearance
- Suggests bisphosphonates may have role in symptom management
- Limited evidence - case report only
Surgical Treatment Outcomes in Melorheostosis
- High recurrence rate after soft tissue releases
- Corrective osteotomies achievable but challenging
- Multiple procedures often required
- Aggressive postoperative physiotherapy essential
- Conservative management remains first-line
Australian Context
Epidemiology in Australia
Melorheostosis is extremely rare worldwide, with an estimated incidence of approximately 1 per million. In Australia, this translates to very few new cases diagnosed annually across the entire country. Most Australian orthopaedic surgeons will encounter only a handful of cases throughout their career, if any.
Healthcare Access and Management
Tertiary Referral Centers:
- Given the rarity of the condition, patients are best managed at major tertiary hospitals with multidisciplinary bone tumor or musculoskeletal oncology services
- Access to specialist rheumatology, radiology, and physiotherapy is essential
- Metropolitan centers in Sydney, Melbourne, Brisbane, Adelaide, and Perth have appropriate expertise
Rural and Remote Considerations:
- Telehealth consultations with specialists are appropriate for ongoing management
- Initial diagnosis may occur at regional centers with referral for specialist input
- Physiotherapy can be coordinated locally with specialist guidance
- Travel assistance may be available through Patient Assisted Travel Schemes (PATS)
PBS Considerations for Medications
Bisphosphonates:
- Oral bisphosphonates (alendronate) available on PBS for osteoporosis but use in melorheostosis would be off-label
- Zoledronic acid available on PBS for specified indications; off-label use may require Special Access Scheme or hospital funding
- Patients should be counseled regarding off-label use and uncertain efficacy
Analgesics:
- Standard analgesics (paracetamol, NSAIDs) readily available
- Gabapentin/pregabalin on PBS for neuropathic pain with appropriate indication
- Opioid prescribing follows standard Australian guidelines and PBS restrictions
Surgical Considerations
Given the rarity of the condition and high surgical complication rates:
- Surgery should be performed at centers with experience in complex musculoskeletal conditions
- Multidisciplinary tumor board or complex case discussion may be valuable
- Patient expectations should be carefully managed
- Access to intensive post-operative physiotherapy is essential for optimal outcomes
Viva Practice Scenarios
Practice these scenarios to excel in your viva examination
"A 28-year-old woman presents with a 5-year history of progressive right knee stiffness and pain. Radiographs show dense cortical hyperostosis along the medial femur and tibia with a 'dripping candle wax' appearance. How would you assess and manage this patient?"
"You are shown a radiograph demonstrating dense cortical sclerosis along one cortex of the femur. What is your differential diagnosis and how would you distinguish between these conditions?"
"A patient with melorheostosis affecting the knee has a 45-degree fixed flexion contracture despite 12 months of conservative management. They are requesting surgery. How would you counsel them?"
Melorheostosis
High-Yield Exam Summary
Definition and Key Facts
Molecular Pathogenesis
Clinical Presentation
Radiographic Features
Differential Diagnosis
Management
Exam Pearls
References
- Kang H, Jha S, Deng Z, et al. Somatic activating mutations in MAP2K1 cause melorheostosis. Nature Communications. 2018;9(1):1390.
- Freyschmidt J. Melorheostosis: a review of 23 cases. European Radiology. 2001;11(3):474-479.
- Hollick RJ, Black A, Reid DM. Melorheostosis and its treatment with bisphosphonates. Rheumatology. 2010;49(12):2304-2307.
- Smith GC, Grudziak JS, Guttmann DM, et al. Melorheostosis: clinical features, treatment, and outcome. Journal of Pediatric Orthopaedics. 2017;37(8):e512-e517.
- Hellemans J, Preobrazhenska O, Willaert A, et al. Loss-of-function mutations in LEMD3 result in osteopoikilosis, Buschke-Ollendorff syndrome and melorheostosis. Nature Genetics. 2004;36(11):1213-1218.
- Campbell CJ, Papademetriou T, Bonfiglio M. Melorheostosis. A report of the clinical, roentgenographic, and pathological findings in fourteen cases. Journal of Bone and Joint Surgery. 1968;50(7):1281-1304.
- Jha S, Fratzl-Zelman N, Engel O, et al. Distinct clinical and pathological features of melorheostosis associated with somatic MAP2K1 mutations. Journal of Bone and Mineral Research. 2019;34(1):145-156.
- Whyte MP, Murphy WA, Fallon MD, et al. Mixed-sclerosing-bone-dystrophy: report of a case and review of the literature. Skeletal Radiology. 1981;6(2):95-102.