Melorheostosis

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Mappings

MONDO

MONDO:0007970 melorheostosis

MONDO:0007970 carries OMIM:155950 and Orphanet:2485 as cross-references, which are the OMIM and Orphanet identifiers for this disease. The OMIM entry predates the somatic MAP2K1 finding and describes the condition under a Mendelian framing, which no longer matches the mechanism curated here.

NCIT

NCIT:C84887 Melorheostosis

NCIT:C84887 is the NCI Thesaurus concept for this disease and is cross-referenced from MONDO:0007970.

NCIT

NCIT:C84887 Melorheostosis

NCIT:C84887 is the NCI Thesaurus concept for this disease and is cross-referenced from MONDO:0007970.

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Subtypes

2

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Mechanistic Hypotheses

2

Somatic Mosaic Clone Determines the Segmental Distribution

somatic_mosaic_clone CANONICAL

Evidence balance 1 support

The distribution reflects the territory occupied by the descendants of a single mutated progenitor. This follows from the genetics rather than from anatomy, and it accounts for the sharp boundary, the restriction to one side of a limb, and the involvement of overlying skin.

Show evidence (1 reference)

PMID:30218789 SUPPORT Human Clinical

"We believe that the disease distribution can be explained by clonal proliferation of a mutated skeletal progenitor cell along the limb axis. Studies in mice models on clonal proliferation in limb buds mimic the patterns seen in melorheostosis."

The authors propose a clonal explanation in place of the sclerotome account, and cite limb-bud clonal proliferation in mice as producing comparable patterns.

Sclerotomal Distribution

sclerotome_hypothesis ⚠ DEPRECATED

⚠ Overturned model — shown for reference, not as current mechanism

DisMech records superseded hypotheses explicitly rather than deleting them, so that claims still circulating in reviews, textbooks and older diagnostic criteria can be checked against an assessment. This model is not part of the disease mechanism DisMech asserts.

Citation volume does not decide standing here. A hypothesis may retain more supporting than refuting citations simply because the supporting literature accumulated for decades before the refutation landed; where the two conflict, DisMech follows the more recent and more direct evidence. Supporting citations below are retained for the historical record.

Evidence balance 2 refute

The historical account, that lesions occupy the bone territory innervated by a single spinal nerve level. It was tested directly by whole body CT in thirty patients and largely failed: only 17% conformed to a single sclerotome. Retained here because it is still widely repeated, including in reviews published after the test.

Marked DEPRECATED rather than deleted because it is still stated as fact in the review literature, including PMID:28676968, which describes a sclerotomal distribution. A curator meeting that claim should be able to find the test that contradicts it.

Show evidence (2 references)

PMID:30218789 REFUTE Human Clinical

"We found that the disease distribution conformed to the distribution of a single sclerotome in only 5 patients (17%). In another 12 patients, the lesions spanned parts of contiguous sclerotomes but did not involve the entire extent of the sclerotomes."

Direct quantitative test of the hypothesis in thirty patients, with the great majority not conforming.

PMID:30218789 REFUTE Human Clinical

"Our findings raise concerns about the sclerotomal hypothesis being the definitive explanation for the pattern of anatomic distribution in MEL."

The authors' own conclusion against the hypothesis.

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Pathophysiology

8

Post-zygotic Somatic Mutation in Skeletal Tissue

The initiating lesion, and the reason this disease looks the way it does. The mutation arises after fertilisation and is confined to a clone of cells, so it is present in affected bone and absent from unaffected bone in the same patient. Mosaicism extends to the skin overlying the lesions in most patients tested, which is consistent with a progenitor mutated early enough to populate more than one tissue.

MAP2K1 hgnc:6840 SMAD3 hgnc:6769

Downstream

MEK1-ERK Pathway Hyperactivation An activating mutation in the MEK1 negative regulatory domain releases the kinase from autoinhibition.

TGF-beta-SMAD3 Pathway Hyperactivation An activating SMAD3 mutation raises signalling through the TGF-beta pathway in the alternative arm.

Show evidence (2 references)

PMID:29643386 SUPPORT Human Clinical

"Using whole exome sequencing, we identify somatic mosaic MAP2K1 mutations in affected, but not unaffected, bone of eight unrelated patients with melorheostosis."

The affected-versus-unaffected contrast within the same patient is what establishes somatic mosaicism rather than germline disease.

PMID:29643386 SUPPORT Human Clinical

"Mosaicism is also detected in the skin overlying bone lesions in four of five patients tested."

Extends the mosaic clone beyond bone into overlying skin, which bears on how early the mutation arose.

MEK1-ERK Pathway Hyperactivation

Constitutive ERK1/2 signalling in the mutant osteoblast clone, demonstrable as two populations of differing p-ERK level within the same bone.

osteoblast CL:0000062

ERK1 and ERK2 cascade GO:0070371 ↑ INCREASED

Downstream

Osteoblast Overproliferation with Impaired Mineralisation ERK activation raises proliferation while blocking BMP2-driven differentiation and mineralisation.

Skin Changes Overlying Affected Bone The same activated clone occupies the skin overlying the lesion, which is why the cutaneous finding is segmental and tracks the bone rather than appearing generally.

Show evidence (1 reference)

PMID:29643386 SUPPORT In Vitro

"Osteoblasts cultured from affected bone comprise two populations with distinct p-ERK1/2 levels by flow cytometry, enhanced ERK1/2 activation, and increased cell proliferation."

Two distinct populations in one culture is the cellular signature of mosaicism, measured directly.

TGF-beta-SMAD3 Pathway Hyperactivation

Constitutive TGF-beta/SMAD signalling in the alternative arm, with enhanced nuclear translocation and target gene expression.

osteoblast CL:0000062

transforming growth factor beta receptor signaling pathway GO:0007179 ↑ INCREASED

Downstream

Osteoblast Hypoproliferation with Enhanced Mineralisation SMAD3 activation suppresses proliferation while stimulating differentiation and mineralisation, the mirror image of the MAP2K1 arm.

Show evidence (1 reference)

PMID:32232430 SUPPORT In Vitro

"Transcriptome profiling displayed that TGF-β pathway activation and ossification-related processes were significantly influenced by the SMAD3 mutation."

Transcriptome-level confirmation that the pathway and ossification programmes are both affected.

Osteoblast Overproliferation with Impaired Mineralisation

More osteoblasts laying down more matrix that mineralises poorly, so affected bone contains markedly increased osteoid. The excess bone in this arm is therefore excess unmineralised matrix rather than excess mineral.

osteoblast CL:0000062

cell population proliferation GO:0008283 ↑ INCREASED biomineral tissue development GO:0031214 ↓ DECREASED

Downstream

Increased RANKL/OPG Ratio in Affected Bone The RANKL/OPG shift is measured in osteoblasts from affected bone in MAP2K1-positive patients, which is what places it downstream of this arm specifically rather than of the disease as a whole.

Segmental Cortical Hyperostosis The expanded, poorly mineralising clone builds excess cortical bone within its territory.

Show evidence (1 reference)

PMID:29643386 SUPPORT In Vitro

"However, these MAP2K1 mutations inhibit BMP2-mediated osteoblast mineralization and differentiation in vitro, underlying the markedly increased osteoid detected in affected bone histology."

Links the mineralisation defect directly to the osteoid excess seen histologically.

Osteoblast Hypoproliferation with Enhanced Mineralisation

Fewer, more differentiated osteoblasts producing more heavily mineralised bone. Affected bone is more mineralised than unaffected bone in this arm, which is the opposite of the MAP2K1 arm and the reason the two produce different radiographic patterns.

osteoblast CL:0000062

cell population proliferation GO:0008283 ↓ DECREASED biomineral tissue development GO:0031214 ↑ INCREASED osteoblast differentiation GO:0001649 ↑ INCREASED

Downstream

Segmental Cortical Hyperostosis Enhanced mineralisation within the mutant clone produces the endosteal pattern of excess bone.

Show evidence (2 references)

PMID:32232430 SUPPORT In Vitro

"Osteoblast differentiation and mineralization were stimulated by the SMAD3 mutation, consistent with higher mineralization in affected than in unaffected bone, but differing from MAP2K1 mutation-positive melorheostosis."

Establishes the enhanced mineralisation and contrasts it with the other arm.

PMID:32232430 SUPPORT In Vitro

"Conversely, osteoblast differentiation and mineralization were inhibited when osteogenesis of affected osteoblasts was driven in the presence of BMP2."

A context dependence worth carrying - the same mutation reverses direction when osteogenesis is BMP2-driven, so the cellular phenotype is not unconditional.

Increased RANKL/OPG Ratio in Affected Bone

Mechanism confidence: Hypothetical

Osteoblasts from affected bone carry a markedly increased ratio of RANKL to osteoprotegerin transcripts. RANKL drives osteoclast differentiation and bone resorption, so the shift predicts increased osteoclastic remodelling within the lesion and is the join point for any therapy acting on bone turnover. The direction of causation is not established: the source raises the alternative that the shift is compensatory for the dense bone rather than contributing to it, which is why mechanism_confidence is HYPOTHETICAL and why the alternative is recorded as its own evidence item rather than omitted.

osteoblast CL:0000062 osteoclast CL:0000092

regulation of bone resorption GO:0045124 ↑ INCREASED osteoclast differentiation GO:0030316 ↑ INCREASED

Downstream

Segmental Cortical Hyperostosis Whether the altered remodelling contributes to the hyperostosis or responds to it is not resolved in any cached source, so the direction is left UNKNOWN rather than asserted.

Show evidence (2 references)

PMID:31485554 SUPPORT Human Clinical

"The finding of markedly increased ratio of RANKL/OPG transcripts in osteoblasts from affected bone in patients with MAP2K1-positive melorheostosis raises the possibility of using RANKL inhibitors in these patients,"

Measures the transcript ratio in osteoblasts from affected bone and states the therapeutic corollary that follows from it.

PMID:31485554 SUPPORT Human Clinical

"although it is possible that the increased ratio of RANKL/OPG transcripts is actually a compensatory mechanism for the dense bone."

The source's own alternative reading, in which the ratio is a response to the dense bone rather than a contributor to it. Recorded because it is what keeps this node HYPOTHETICAL rather than established.

Segmental Cortical Hyperostosis

Excess bone confined to a segment of the skeleton, classically as irregular cortical thickening resembling wax dripping down a candle, and often with involvement of the adjacent soft tissue. The segmental boundary is a consequence of mosaicism, though the historical explanation for its precise shape does not survive testing.

ossification GO:0001503 ↑ INCREASED

Downstream

Pain, Deformity and Restricted Movement Excess bone and soft tissue involvement produce the symptoms that bring patients to attention.

Peripheral Nerve Compression Expanding cortical bone compresses an adjacent nerve mechanically.

Somatic Sensory Deficit Sensory loss follows from compression of the nerves running through the affected segment, so the intermediate is the nerve compression curated separately.

Localized Soft Tissue Swelling Swelling of the affected segment accompanies the bone lesion. The sources list it as a presenting feature without establishing whether it is soft tissue involvement by the clone, venous or lymphatic obstruction, or a consequence of the hypervascularity, so the intermediates are left unstated.

Hypervascularity of Affected Bone Increased vascularity accompanies the lesion, in the cortex and the soft tissue around it. No cached source establishes whether the vascularity drives the bone formation, follows it, or is a parallel effect of the same clone, so the intermediates are unstated.

Show evidence (2 references)

PMID:25343102 SUPPORT Human Clinical

"The characteristic radiographic appearance consists of irregular hyperostotic changes of the cortex resembling melted wax dripping down the side of a candle."

Describes the radiographic lesion that defines the disease.

PMID:30218789 SUPPORT Human Clinical

"The disease remains limited to medial or lateral side of the extremity with proximo-distal progression."

Characterises the segmental boundary, which is the feature the mosaic mechanism has to explain.

Pain, Deformity and Restricted Movement

The clinical disease. Because the lesion is fixed in one skeletal territory, morbidity is local: pain, limb deformity, stiffness and loss of joint motion, with soft tissue involvement contributing to contracture.

Downstream

Bone Pain Local pain from the hyperostotic lesion and surrounding soft tissue.

Limitation of Joint Mobility Stiffness and restricted motion at joints crossed by the lesion.

Flexion Contracture Soft tissue involvement adjacent to the bone lesion produces fixed joint contracture.

Abnormal Cortical Bone Morphology The cortical lesion itself as observed radiographically.

Skeletal Muscle Atrophy Restricted movement leads to disuse, and disuse to muscle atrophy. The intermediate is stated in the source rather than inferred, which is what distinguishes this from a primary myopathy.

Show evidence (1 reference)

PMID:25343102 SUPPORT Human Clinical

"Melorheostosis is an uncommon, non-genetic, non-developmental, sclerosing dysplasia of bone and adjacent soft tissues, with deformity of the extremity, pain, limb stiffness and limitation of motion."

States the clinical picture this node represents.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

10

Cardiovascular 2

Skin Changes Overlying Affected Bone FREQUENT Erythema HP:0010783

Show evidence (2 references)

PMID:31485554 SUPPORT Human Clinical

"Skin abnormalities overlying the affected bone lesions were identified in 16 of 30 patients (53%)."

Gives the denominator, 16 of 30, which is what places this in the FREQUENT band rather than resting on a qualitative term.

PMID:31485554 SUPPORT Human Clinical

"Of 16 patients, 9 (56%) patients’ skin findings manifested as vascular changes, most commonly irregular macular erythema without overlying surface change."

Identifies the commonest morphology, which is what the HP:0010783 binding represents; the other 7 of 16 had changes this term does not cover.

Hypervascularity of Affected Bone FREQUENT Abnormal vascular morphology HP:0025015

Show evidence (2 references)

PMID:31485554 SUPPORT Human Clinical

"Twelve (12) patients (50%) showed marked hypervascularity of the cortex and adjacent soft tissue."

Twelve of thirty, which is the denominator behind the FREQUENT band.

PMID:31485554 SUPPORT Human Clinical

"It is not known if the observed hypervascularity contributes to pain."

Records that the clinical significance is unresolved, which is why this is curated as a finding rather than placed on the pain pathway.

Limbs 1

Localized Soft Tissue Swelling FREQUENT Localized soft-tissue swelling on extremity HP:6000840

Show evidence (1 reference)

PMID:31485554 SUPPORT Human Clinical

"Patients present with pain, deformities, contractures, range of motion limitation(s), and limb swelling."

Lists limb swelling among the presenting features. This band rests on the qualitative framing rather than a denominator, since the cohort reports no count for it.

Musculoskeletal 4

Abnormal Cortical Bone Morphology OBLIGATE HP:0003103

Onset: CHILDHOOD

Show evidence (2 references)

PMID:25343102 SUPPORT Human Clinical

"The characteristic radiographic appearance consists of irregular hyperostotic changes of the cortex resembling melted wax dripping down the side of a candle."

Gives the characteristic cortical appearance.

PMID:38978887 SUPPORT Human Clinical

"Diagnosis typically relies on X-rays, although not all cases exhibit the classic candle wax appearance."

Qualifies the classic sign, which matters because its absence does not exclude the diagnosis.

Flexion Contracture HP:0001371

Show evidence (1 reference)

PMID:31485554 SUPPORT Human Clinical

"Patients present with pain, deformities, contractures, range of motion limitation(s), and limb swelling."

Enumerates the presenting features in a prospectively recruited cohort, which is stronger than the case-report literature this disease otherwise rests on.

Limitation of Joint Mobility FREQUENT HP:0001376

Show evidence (2 references)

PMID:31485554 SUPPORT Human Clinical

"Motor exam showed restriction of joint movement due to bony growth in 16 patients."

Sixteen of thirty on examination, which grounds the FREQUENT band on a denominator rather than on a qualitative description.

PMID:25343102 SUPPORT Human Clinical

"Melorheostosis is an uncommon, non-genetic, non-developmental, sclerosing dysplasia of bone and adjacent soft tissues, with deformity of the extremity, pain, limb stiffness and limitation of motion."

Names limb stiffness and limitation of motion.

Skeletal Muscle Atrophy OCCASIONAL HP:0003202

Show evidence (1 reference)

PMID:31485554 SUPPORT Human Clinical

"Eight patients had muscle atrophy from disuse."

Eight of the thirty-patient cohort, 27 percent, and the source attributes it to disuse, which is what determines where it sits in the graph.

Nervous System 2

Somatic Sensory Deficit FREQUENT Somatic sensory dysfunction HP:0003474

Show evidence (1 reference)

PMID:31485554 SUPPORT Human Clinical

"Neurological clinical evaluation showed all 30 patients reporting pain symptomology with 77% patients with confirmed sensory deficit in the distribution of melorheostosis on exam."

Gives both the proportion and the segmental distribution, on examination rather than by report.

Peripheral Nerve Compression OCCASIONAL HP:0003406

Show evidence (4 references)

PMID:31485554 SUPPORT Human Clinical

"Electrophysiological testing identified isolated neuropathy in 43% patients (12/28 patients tested, with six sensory neuropathies and six mixed motor neuropathies) in the distribution of melorheostosis"

An objective electrodiagnostic figure, 12 of 28 tested, alongside the five patients with imaging-confirmed entrapment. The two numbers measure different things, so the band stays on the entrapment figure and this is recorded as the wider neuropathy burden.

PMID:31485554 SUPPORT Human Clinical

"We found sensory deficits in approximately 77% of patients, with evidence of focal nerve entrapment in five patients."

Five of the thirty-patient cohort, which is 17 percent and therefore OCCASIONAL, one band below the sensory deficit it sits inside.

PMID:31485554 SUPPORT Human Clinical

"Three additional ultrasound studies showed either displacement or swelling of a nerve due to compression by the bone overgrowth."

Imaging confirmation of the compression mechanism rather than inference from the sensory findings.

+ 1 more reference

Constitutional 1

Bone Pain FREQUENT HP:0002653

Show evidence (1 reference)

PMID:38978887 SUPPORT Human Clinical

"It can often be an incidental discovery, with patients experiencing associated pain and deformities."

Names pain and deformity, and records that presentation may equally be incidental.

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Genetic Associations

4

MAP2K1 (Somatic Mosaic Activating Mutation)

Gene: MAP2K1 hgnc:6840 relationship_type: CAUSATIVE variant_origin: SOMATIC

Show evidence (4 references)

PMID:29643386 SUPPORT Human Clinical

"Using whole exome sequencing, we identify somatic mosaic MAP2K1 mutations in affected, but not unaffected, bone of eight unrelated patients with melorheostosis."

Establishes causation and the tissue-restricted distribution that dictates how testing must be done.

PMID:29643386 SUPPORT Human Clinical

"strongly support MAP2K1 somatic mutations as causing about half of cases of sporadic melorheostosis."

Supports causation while bounding it at about half of sporadic cases, which is what makes a negative MAP2K1 result uninformative rather than exclusionary.

PMID:32387835 SUPPORT Human Clinical

"Our observations confirm that mutations in MAP2K1 are a major cause of melorheostosis and also suggest further locus heterogeneity for this disorder."

An independent statement of locus heterogeneity, which together with the previous item is why the genetic notes now say a negative result does not exclude the diagnosis.

+ 1 more reference

SMAD3 (Somatic Activating Mutation in Endosteal Pattern Disease)

Gene: SMAD3 hgnc:6769 relationship_type: CAUSATIVE variant_origin: SOMATIC

Show evidence (2 references)

PMID:32232430 SUPPORT Human Clinical

"We now report somatic SMAD3 mutations in bone lesions of four unrelated patients with endosteal pattern melorheostosis."

Establishes the gene and its association with the endosteal pattern.

PMID:35874167 SUPPORT Human Clinical

"Bone histomorphometry revealed markedly reduced cortical thickness (-68 %), trabecular thickness (-32 %), bone formation rate (-50 %) and delayed mineralization."

The germline loss-of-function contrast. This is a different disease, cited to show that the same gene in the opposite direction gives thin, undermineralised bone rather than excess bone.

LEMD3 (Causes Osteopoikilosis and Buschke-Ollendorff Syndrome, Not Isolated Melorheostosis)

Gene: LEMD3 hgnc:28887 relationship_type: DISPUTED variant_origin: GERMLINE

Show evidence (2 references)

PMID:19438932 REFUTE Human Clinical

"The search for mutations in DNA extracted from the peripheral blood, as well as skin and bone biopsies of the patient with melorheostosis failed to identify any pathogenic change."

A direct negative in the right tissues, which is why this gene is recorded as disputed rather than causative.

PMID:28676968 REFUTE Human Clinical

"LEM domain-containing protein 3 (LEMD3) gene mutations have been demonstrated in several familial cases, but these have been more strongly correlated with other hereditary dysplasias, such as osteopoikilosis, and are not thought to be the causative gene for melorheostosis."

Review-level conclusion that this gene is not causative for melorheostosis.

KRAS (Somatic Activating Mutation in a Minority of Cases)

Gene: KRAS hgnc:6407 relationship_type: CAUSATIVE variant_origin: SOMATIC

Show evidence (2 references)

PMID:30989250 SUPPORT Human Clinical

"Recent studies of melorheostosis lesional tissue indicate that most cases arise from somatic MAP2K1 mutations although a small number may arise from other genes in related pathways, such as KRAS."

Establishes KRAS as an additional somatic gene and places it as a minority cause alongside MAP2K1.

PMID:30989250 SUPPORT Human Clinical

"Those cases associated with MAP2K1 mutations are more likely to have the classic "dripping candle wax" appearance on radiographs."

A genotype-phenotype correlation supporting the separation of arms by gene, which is how the subtypes in this entry are organised.

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Medical Actions

6

Surgical Management

Action: surgical procedure Ontology label: Surgical Procedure NCIT:C15329

Platform: Surgery

Excision of bone overgrowth, release of contracture, or decompression of an entrapped nerve. Recurrence after excision is a recognised problem, which is unsurprising given that the causative somatic clone remains in place.

Mechanism Target:

MODULATES Pain, Deformity and Restricted Movement — Addresses the mechanical consequences of the lesion without altering the somatic mutation that produces it.

Show evidence (1 reference)

PMID:30989250 SUPPORT Human Clinical

"Surgical intervention may be required for those with large bone growths, nerve entrapments, joint impingement syndromes or major limb deformities."

Names the four mechanical indications, each of which is a consequence of the lesion rather than of the mutation.

Show evidence (1 reference)

PMID:38978887 SUPPORT Human Clinical

"Management is generally aimed at symptom relief, either through conservative measures or surgical intervention."

Places surgery as one of two arms of symptomatic management, not as disease-modifying therapy.

Physical Therapy

Action: physical therapy Ontology label: Physical Therapy NCIT:C15302

Platform: Behavioral / lifestyle

Part of conventional management alongside surgery and bisphosphonates, aimed at range of motion and at the disuse that drives the muscle atrophy.

Mechanism Target:

MODULATES Pain, Deformity and Restricted Movement — Targets restricted movement and its downstream disuse consequences rather than the bone lesion.

Show evidence (1 reference)

PMID:28676968 SUPPORT Human Clinical

"Management in recent years has involved nitrogen-containing bisphosphonates in addition to traditional orthopedic surgical approaches and physical therapy."

Names physical therapy as part of traditional management alongside surgery.

Show evidence (1 reference)

PMID:30989250 SUPPORT Human Clinical

"physical therapy and psychological assessments."

Independent source listing physical therapy in the management set.

Bisphosphonate Therapy

Action: bisphosphonate therapy Ontology label: Bisphosphonate Therapy NCIT:C198585

Platform: Small molecule

Nitrogen-containing bisphosphonates have entered management in recent years, but the evidence base is thin and the sources say so. This is recorded as used-without-guidance rather than as established therapy.

Mechanism Target:

MODULATES Increased RANKL/OPG Ratio in Affected Bone — Nitrogen-containing bisphosphonates act on the osteoclast, which is the cell the RANKL/OPG shift recruits. That node is the mechanistic join point for this drug class. Whether acting there alters the lesion is not established, which is why the effect is MODULATES and not INHIBITS.

Show evidence (1 reference)

PMID:28676968 SUPPORT Human Clinical

"Management in recent years has involved nitrogen-containing bisphosphonates in addition to traditional orthopedic surgical approaches and physical therapy."

Establishes that bisphosphonates are used, without claiming an effect size.

Show evidence (1 reference)

PMID:30989250 SUPPORT Human Clinical

"Medical treatments include bisphosphonates, but definitive guidance on their use is lacking given the small number of patients that have been studied."

States the weakness of the evidence base explicitly, which is why this treatment is not presented as established.

MEK Inhibition

Action: pharmacotherapy Ontology label: Pharmacotherapy NCIT:C15986

Platform: Small molecule

A mechanistic rationale rather than a therapy. The MAP2K1 paper proposes inhibiting MEK1 on the strength of the somatic activating mutations, and MEK inhibitors exist for other MAPK-driven diseases. No cached source reports a patient treated this way, so this is recorded for the reasoning it represents and not as an option to offer.

Mechanism Target:

INHIBITS MEK1-ERK Pathway Hyperactivation — Acts on the activated kinase itself, which is the only point in this pathograph where a treatment would be disease-modifying rather than symptomatic. It would do nothing for the SMAD3 arm.

Show evidence (1 reference)

PMID:29643386 SUPPORT Human Clinical

"identification of somatic MAP2K1 mutations in melorheostosis raises the possibility of inhibiting MEK1 to treat melorheostotic bone lesions."

States the proposal and its basis. "Raises the possibility" is the strength of the claim, and no cached source takes it further.

Show evidence (1 reference)

PMID:29643386 SUPPORT Human Clinical

"Development of a diagnostic test is especially valuable because identification of somatic MAP2K1 mutations in melorheostosis raises the possibility of inhibiting MEK1 to treat melorheostotic bone lesions."

Ties the therapeutic proposal to the value of genetic testing, which is the practical reason the proposal matters even without trial evidence.

RANKL Inhibition

Action: biological therapy Ontology label: Biological Therapy NCIT:C15187

Agent: denosumab NCIT:C61313

Platform: Monoclonal antibody

Proposed on the strength of the increased RANKL/OPG transcript ratio in affected bone. As with MEK inhibition, no cached source reports a treated patient, and the same source raises the possibility that the ratio is compensatory, in which case inhibiting RANKL would be acting on a response rather than a cause.

Mechanism Target:

INHIBITS Increased RANKL/OPG Ratio in Affected Bone — Neutralises RANKL, the ligand whose excess relative to osteoprotegerin defines that node.

Show evidence (1 reference)

PMID:31485554 SUPPORT Human Clinical

"The finding of markedly increased ratio of RANKL/OPG transcripts in osteoblasts from affected bone in patients with MAP2K1-positive melorheostosis raises the possibility of using RANKL inhibitors in these patients,"

States the proposal and the measurement it rests on.

Show evidence (1 reference)

PMID:31485554 SUPPORT Human Clinical

"although it is possible that the increased ratio of RANKL/OPG transcripts is actually a compensatory mechanism for the dense bone."

The caveat that limits this proposal, from the same sentence that makes it. Recorded on the treatment so a reader does not encounter the proposal without it.

Neuropathic Pain Pharmacotherapy

Action: pharmacotherapy Ontology label: Pharmacotherapy NCIT:C15986

Agent: gabapentin CHEBI:42797 pregabalin CHEBI:64356

Platform: Small molecule

Gabapentinoids for the neuropathic component of the pain, proposed on the basis of how common nerve entrapment is in the cohort rather than on trial evidence in this disease. The source says may be considered, and that is the strength of the recommendation.

Mechanism Target:

MODULATES Peripheral Nerve Compression — Modifies neuropathic pain signalling arising from the compressed nerve. It does not relieve the compression itself, which is why surgery remains the option for that.

Show evidence (1 reference)

PMID:31485554 SUPPORT Human Clinical

"Given the high prevalence of nerve entrapment from melorheostotic bone expansion, drugs such as pregabalin and gabapentin may be considered for management of neuropathic pain."

Ties the recommendation directly to the entrapment prevalence, and its hedging is why the effect is MODULATES rather than a claim of benefit.

Show evidence (1 reference)

PMID:31485554 SUPPORT Human Clinical

"Evaluation by a neurologist can help in identifying a suitable analgesic regimen."

Places analgesic selection under neurological assessment rather than as routine prescribing.

🔬

Diagnosis

2

Radiographic diagnosis (PRESENT)

Diagnosis rests on imaging. There is no definitive histological feature, so biopsy resolves uncertainty rather than confirming the diagnosis, and genetic testing requires affected tissue rather than blood.

Show evidence (2 references)

PMID:38978887 SUPPORT Human Clinical

"A biopsy may be necessary in cases of uncertainty, as there is not a definitive histological feature."

States both the role of biopsy and the absence of a defining histological feature.

PMID:38978887 SUPPORT Human Clinical

"A new imaging sign known as the "dumpling on a plate sign" has been proposed for flat bones for both MRI and CT scans."

Records a newer sign for flat bones, where the candle wax appearance does not apply.

Normal bone biochemistry (ABSENT)

Bone turnover markers and mineral chemistry are normal. This is a negative finding recorded because it is diagnostically useful: it separates melorheostosis from the metabolic sclerosing bone diseases that produce a similar radiographic impression, and it fits a disease driven by a somatic clone confined to one segment rather than by a systemic derangement.

Show evidence (2 references)

PMID:31485554 SUPPORT Human Clinical

"However, we did not find any biochemical abnormalities characteristic of the disease."

The prospective cohort looked for biochemical abnormality and found none.

PMID:38978887 SUPPORT Human Clinical

"Additional support can be obtained through normal serum calcium, phosphorus, and alkaline phosphatase levels,"

States which normal values support the diagnosis, which is what makes the negative finding useful rather than merely unremarkable.

📊

Prevalence

1

Worldwide

Point Prevalence 0.09 per 100,000 <1 in 1,000,000

Estimated prevalence 0.9 per million.

Show evidence (1 reference)

PMID:41938408 SUPPORT Human Clinical

"Melorheostosis (Léri-Joanny syndrome) is a rare, nonhereditary, congenital sclerotic bone dysplasia with an estimated prevalence of 0.9 per million."

Gives the estimated population prevalence.

🌍

Epidemiology

2

Reported case count

About 400 cases had been reported in the century after its first description, almost all as single reports or small series, which is the main constraint on everything else known about it.

Show evidence (1 reference)

PMID:28676968 SUPPORT Human Clinical

"Since its first description in 1922, about 400 cases of melorheostosis have been reported, either as single reports or in small case series."

Gives the total reported experience and the study designs it rests on.

Skeletal distribution

The appendicular skeleton is affected more often than the axial, and lower limb deformity is the usual presentation.

Show evidence (1 reference)

PMID:28676968 SUPPORT Human Clinical

"Melorheostosis affects the appendicular skeleton more commonly than the axial skeleton and usually presents with lower limb deformity."

Gives the anatomical distribution and the typical presentation.

🔬

Clinical Trials

1

NCT02504879 UNKNOWN

The NIH natural history study of melorheostosis. The 30-patient cohort that supplies most of the frequency data in this entry is drawn from it, which is why it is recorded here rather than treated as an interventional trial.

Target Phenotypes: Bone pain HP:0002653 Somatic sensory dysfunction HP:0003474

Show evidence (2 references)

clinicaltrials:NCT02504879 SUPPORT Human Clinical

"To see what happens to people with melorheostosis over time and understand the causes of the disease."

States the natural history objective, which is what makes this the source of the prospective frequency data rather than a treatment trial.

PMID:31485554 SUPPORT Human Clinical

"gov NCT02504879) and conducted at the National Institutes of Health (NIH), Bethesda, MD, USA."

Links the cohort publication to this trial registration.

{ }

Source YAML

click to show

name: Melorheostosis
creation_date: '2026-09-08T17:00:00Z'
description: >-
  A rare sclerosing bone dysplasia in which excess cortical bone accumulates in a
  striking asymmetric, segmental pattern classically likened to wax dripping down
  a candle. It is not inherited. The cause is a post-zygotic somatic mutation
  present only in affected tissue, which is why the disease stops at a boundary
  on the limb and why blood testing is uninformative. Two genes are established
  and they produce different radiographic patterns by opposite cellular routes:
  activating MAP2K1 mutations drive ERK signalling, increase osteoblast
  proliferation and impair mineralisation, leaving abundant unmineralised osteoid;
  activating SMAD3 mutations drive TGF-beta signalling, inhibit proliferation and
  enhance mineralisation. Both converge on excess bone. The historical explanation
  for the segmental distribution, that lesions follow sclerotomes, has been tested
  directly and largely fails.
categories:
- Sclerosing Bone Dysplasia
- Somatic Mosaic Disorder
- Skeletal Overgrowth Disorder
parents:
- osteochondrodysplasia
synonyms:
- Leri disease
- melorheostosis, isolated, somatic mosaic
- mixed sclerosing bone dystrophy
epidemiology:
- name: Reported case count
  description: >-
    About 400 cases had been reported in the century after its first description,
    almost all as single reports or small series, which is the main constraint on
    everything else known about it.
  evidence:
  - reference: PMID:28676968
    reference_title: 'Melorheostosis: a Rare Sclerosing Bone Dysplasia.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Since its first description in 1922, about 400 cases of melorheostosis have been
      reported, either as single reports or in small case series.'
    explanation: Gives the total reported experience and the study designs it rests on.
- name: Skeletal distribution
  description: >-
    The appendicular skeleton is affected more often than the axial, and lower
    limb deformity is the usual presentation.
  evidence:
  - reference: PMID:28676968
    reference_title: 'Melorheostosis: a Rare Sclerosing Bone Dysplasia.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Melorheostosis affects the appendicular skeleton more commonly than the axial skeleton
      and usually presents with lower limb deformity.'
    explanation: Gives the anatomical distribution and the typical presentation.
prevalence:
- population: Worldwide
  measure_type: POINT_PREVALENCE
  prevalence_class: BELOW_1_IN_1000000
  rate_per_100000: 0.09
  notes: Estimated prevalence 0.9 per million.
  evidence:
  - reference: PMID:41938408
    reference_title: A case report and literature review of pediatric multifocal melorheostosis in a unilateral
      limb.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Melorheostosis (Léri-Joanny syndrome) is a rare, nonhereditary, congenital sclerotic
      bone dysplasia with an estimated prevalence of 0.9 per million.'
    explanation: Gives the estimated population prevalence.
has_subtypes:
- name: MAP2K1-related
  display_name: MAP2K1-related (classic dripping candle wax)
  description: >-
    Somatic activating mutations clustering in the MEK1 negative regulatory
    domain, producing the classic cortical dripping candle wax pattern.
  evidence:
  - reference: PMID:29643386
    reference_title: Somatic activating mutations in MAP2K1 cause melorheostosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'The activating mutations (Q56P, K57E and K57N) cluster tightly in the MEK1 negative
      regulatory domain.'
    explanation: Names the recurrent alleles and their shared location in the negative regulatory
      domain.
- name: SMAD3-related
  display_name: SMAD3-related (endosteal pattern)
  description: >-
    Somatic activating SMAD3 mutations producing an endosteal rather than cortical
    dripping pattern, and an opposite cellular phenotype.
  evidence:
  - reference: PMID:32232430
    reference_title: Somatic SMAD3-activating mutations cause melorheostosis by up-regulating the TGF-β/SMAD
      pathway.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'We now report somatic SMAD3 mutations in bone lesions of four unrelated patients
      with endosteal pattern melorheostosis.'
    explanation: Establishes the gene and ties it specifically to the endosteal radiographic
      pattern.
pathophysiology:
- name: Post-zygotic Somatic Mutation in Skeletal Tissue
  biological_scale: MOLECULAR
  description: >-
    The initiating lesion, and the reason this disease looks the way it does. The
    mutation arises after fertilisation and is confined to a clone of cells, so it
    is present in affected bone and absent from unaffected bone in the same
    patient. Mosaicism extends to the skin overlying the lesions in most patients
    tested, which is consistent with a progenitor mutated early enough to populate
    more than one tissue.
  genes:
  - preferred_term: MAP2K1
    term:
      id: hgnc:6840
      label: MAP2K1
  - preferred_term: SMAD3
    term:
      id: hgnc:6769
      label: SMAD3
  evidence:
  - reference: PMID:29643386
    reference_title: Somatic activating mutations in MAP2K1 cause melorheostosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Using whole exome sequencing, we identify somatic mosaic MAP2K1 mutations in affected,
      but not unaffected, bone of eight unrelated patients with melorheostosis.'
    explanation: The affected-versus-unaffected contrast within the same patient is what
      establishes somatic mosaicism rather than germline disease.
  - reference: PMID:29643386
    reference_title: Somatic activating mutations in MAP2K1 cause melorheostosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Mosaicism is also detected in the skin overlying bone lesions in four of five patients
      tested.'
    explanation: Extends the mosaic clone beyond bone into overlying skin, which bears on how
      early the mutation arose.
  downstream:
  - target: MEK1-ERK Pathway Hyperactivation
    causal_link_type: DIRECT
    description: An activating mutation in the MEK1 negative regulatory domain releases the kinase
      from autoinhibition.
    evidence:
    - reference: PMID:29643386
      reference_title: Somatic activating mutations in MAP2K1 cause melorheostosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'Affected bone displays a mosaic pattern of increased p-ERK1/2 in osteoblast
        immunohistochemistry.'
      explanation: Shows the pathway output raised in affected bone, and mosaically, matching the
        genetic finding.
  - target: TGF-beta-SMAD3 Pathway Hyperactivation
    causal_link_type: DIRECT
    description: An activating SMAD3 mutation raises signalling through the TGF-beta pathway in
      the alternative arm.
    evidence:
    - reference: PMID:32232430
      reference_title: Somatic SMAD3-activating mutations cause melorheostosis by up-regulating the TGF-β/SMAD
        pathway.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: 'In vitro, the SMAD3 mutations stimulated the TGF-β pathway in osteoblasts, enhanced
        nuclear translocation and target gene expression, and inhibited proliferation.'
      explanation: Demonstrates pathway activation and nuclear translocation for the mutant
        protein.
- name: MEK1-ERK Pathway Hyperactivation
  biological_scale: MOLECULAR
  subtypes:
  - MAP2K1-related
  description: >-
    Constitutive ERK1/2 signalling in the mutant osteoblast clone, demonstrable as
    two populations of differing p-ERK level within the same bone.
  biological_processes:
  - preferred_term: ERK1 and ERK2 cascade
    modifier: INCREASED
    term:
      id: GO:0070371
      label: ERK1 and ERK2 cascade
  cell_types:
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  evidence:
  - reference: PMID:29643386
    reference_title: Somatic activating mutations in MAP2K1 cause melorheostosis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: 'Osteoblasts cultured from affected bone comprise two populations with distinct
      p-ERK1/2 levels by flow cytometry, enhanced ERK1/2 activation, and increased cell
      proliferation.'
    explanation: Two distinct populations in one culture is the cellular signature of mosaicism,
      measured directly.
  downstream:
  - target: Osteoblast Overproliferation with Impaired Mineralisation
    causal_link_type: DIRECT
    description: ERK activation raises proliferation while blocking BMP2-driven differentiation
      and mineralisation.
    evidence:
    - reference: PMID:29643386
      reference_title: Somatic activating mutations in MAP2K1 cause melorheostosis.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: 'However, these MAP2K1 mutations inhibit BMP2-mediated osteoblast mineralization
        and differentiation in vitro, underlying the markedly increased osteoid detected in affected
        bone histology.'
      explanation: The authors' own "however" marks the paradox this edge carries - an activating
        oncogenic mutation that impairs rather than enhances mineralisation.
  - target: Skin Changes Overlying Affected Bone
    causal_link_type: DIRECT
    description: The same activated clone occupies the skin overlying the lesion, which is why
      the cutaneous finding is segmental and tracks the bone rather than appearing generally.
    evidence:
    - reference: PMID:31485554
      reference_title: Clinical Evaluation of Melorheostosis in the Context of a Natural History Clinical Study.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'Patients with MAP2K1‐positive melorheostosis have a distinct “candle‐wax”
        appearance on radiographs, characteristic erythematous macular changes on skin overlying
        melorheostotic bone, and increased unmineralized osteoid on bone histomorphometry.'
      explanation: Ties the erythematous skin change specifically to MAP2K1-positive disease,
        which is what places it downstream of this node rather than of the TGF-beta arm.
- name: TGF-beta-SMAD3 Pathway Hyperactivation
  biological_scale: MOLECULAR
  subtypes:
  - SMAD3-related
  description: >-
    Constitutive TGF-beta/SMAD signalling in the alternative arm, with enhanced
    nuclear translocation and target gene expression.
  biological_processes:
  - preferred_term: transforming growth factor beta receptor signaling pathway
    modifier: INCREASED
    term:
      id: GO:0007179
      label: transforming growth factor beta receptor signaling pathway
  cell_types:
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  evidence:
  - reference: PMID:32232430
    reference_title: Somatic SMAD3-activating mutations cause melorheostosis by up-regulating the TGF-β/SMAD
      pathway.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: 'Transcriptome profiling displayed that TGF-β pathway activation and ossification-related
      processes were significantly influenced by the SMAD3 mutation.'
    explanation: Transcriptome-level confirmation that the pathway and ossification programmes are
      both affected.
  downstream:
  - target: Osteoblast Hypoproliferation with Enhanced Mineralisation
    causal_link_type: DIRECT
    description: SMAD3 activation suppresses proliferation while stimulating differentiation and
      mineralisation, the mirror image of the MAP2K1 arm.
    evidence:
    - reference: PMID:32232430
      reference_title: Somatic SMAD3-activating mutations cause melorheostosis by up-regulating the TGF-β/SMAD
        pathway.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: 'Osteoblast differentiation and mineralization were stimulated by the SMAD3 mutation,
        consistent with higher mineralization in affected than in unaffected bone, but differing
        from MAP2K1 mutation-positive melorheostosis.'
      explanation: States the cellular phenotype and, explicitly, that it differs from the MAP2K1
        arm, which is the contrast this entry is built around.
- name: Osteoblast Overproliferation with Impaired Mineralisation
  biological_scale: CELLULAR
  subtypes:
  - MAP2K1-related
  description: >-
    More osteoblasts laying down more matrix that mineralises poorly, so affected
    bone contains markedly increased osteoid. The excess bone in this arm is
    therefore excess unmineralised matrix rather than excess mineral.
  cell_types:
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  biological_processes:
  - preferred_term: cell population proliferation
    modifier: INCREASED
    term:
      id: GO:0008283
      label: cell population proliferation
  - preferred_term: biomineral tissue development
    modifier: DECREASED
    term:
      id: GO:0031214
      label: biomineral tissue development
  evidence:
  - reference: PMID:29643386
    reference_title: Somatic activating mutations in MAP2K1 cause melorheostosis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: 'However, these MAP2K1 mutations inhibit BMP2-mediated osteoblast mineralization and
      differentiation in vitro, underlying the markedly increased osteoid detected in affected
      bone histology.'
    explanation: Links the mineralisation defect directly to the osteoid excess seen histologically.
  downstream:
  - target: Increased RANKL/OPG Ratio in Affected Bone
    causal_link_type: DIRECT
    description: The RANKL/OPG shift is measured in osteoblasts from affected bone in
      MAP2K1-positive patients, which is what places it downstream of this arm specifically rather
      than of the disease as a whole.
    evidence:
    - reference: PMID:31485554
      reference_title: Clinical Evaluation of Melorheostosis in the Context of a Natural History Clinical Study.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'The finding of markedly increased ratio of RANKL/OPG transcripts in osteoblasts
        from affected bone in patients with MAP2K1-positive melorheostosis raises the possibility
        of using RANKL inhibitors in these patients,'
      explanation: Localises the transcript measurement to osteoblasts from MAP2K1-positive
        affected bone.
  - target: Segmental Cortical Hyperostosis
    causal_link_type: DIRECT
    description: The expanded, poorly mineralising clone builds excess cortical bone within its
      territory.
    evidence:
    - reference: PMID:32387835
      reference_title: A multi-omics approach expands the mutational spectrum of MAP2K1-related melorheostosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'Melorheostosis is a very rare sclerosing bone dysplasia characterized by asymmetrical
        and progressive cortical hyperostosis, usually with involvement of soft tissues surrounding
        the lesions.'
      explanation: Names the cortical hyperostosis and its asymmetry, which is the tissue endpoint
        of this arm.
- name: Osteoblast Hypoproliferation with Enhanced Mineralisation
  biological_scale: CELLULAR
  subtypes:
  - SMAD3-related
  description: >-
    Fewer, more differentiated osteoblasts producing more heavily mineralised
    bone. Affected bone is more mineralised than unaffected bone in this arm,
    which is the opposite of the MAP2K1 arm and the reason the two produce
    different radiographic patterns.
  cell_types:
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  biological_processes:
  - preferred_term: cell population proliferation
    modifier: DECREASED
    term:
      id: GO:0008283
      label: cell population proliferation
  - preferred_term: biomineral tissue development
    modifier: INCREASED
    term:
      id: GO:0031214
      label: biomineral tissue development
  - preferred_term: osteoblast differentiation
    modifier: INCREASED
    term:
      id: GO:0001649
      label: osteoblast differentiation
  evidence:
  - reference: PMID:32232430
    reference_title: Somatic SMAD3-activating mutations cause melorheostosis by up-regulating the TGF-β/SMAD
      pathway.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: 'Osteoblast differentiation and mineralization were stimulated by the SMAD3 mutation,
      consistent with higher mineralization in affected than in unaffected bone, but differing
      from MAP2K1 mutation-positive melorheostosis.'
    explanation: Establishes the enhanced mineralisation and contrasts it with the other arm.
  - reference: PMID:32232430
    reference_title: Somatic SMAD3-activating mutations cause melorheostosis by up-regulating the TGF-β/SMAD
      pathway.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: 'Conversely, osteoblast differentiation and mineralization were inhibited when
      osteogenesis of affected osteoblasts was driven in the presence of BMP2.'
    explanation: A context dependence worth carrying - the same mutation reverses direction when
      osteogenesis is BMP2-driven, so the cellular phenotype is not unconditional.
  downstream:
  - target: Segmental Cortical Hyperostosis
    causal_link_type: DIRECT
    description: Enhanced mineralisation within the mutant clone produces the endosteal pattern of
      excess bone.
    evidence:
    - reference: PMID:32232430
      reference_title: Somatic SMAD3-activating mutations cause melorheostosis by up-regulating the TGF-β/SMAD
        pathway.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'Melorheostosis is a rare sclerosing dysostosis characterized by asymmetric exuberant
        bone formation.'
      explanation: Names the excess bone formation this arm terminates in.
- name: Increased RANKL/OPG Ratio in Affected Bone
  biological_scale: MOLECULAR
  subtypes:
  - MAP2K1-related
  mechanism_confidence: HYPOTHETICAL
  description: >-
    Osteoblasts from affected bone carry a markedly increased ratio of RANKL to
    osteoprotegerin transcripts. RANKL drives osteoclast differentiation and bone
    resorption, so the shift predicts increased osteoclastic remodelling within the
    lesion and is the join point for any therapy acting on bone turnover. The
    direction of causation is not established: the source raises the alternative
    that the shift is compensatory for the dense bone rather than contributing to
    it, which is why mechanism_confidence is HYPOTHETICAL and why the alternative
    is recorded as its own evidence item rather than omitted.
  cell_types:
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  - preferred_term: osteoclast
    term:
      id: CL:0000092
      label: osteoclast
  biological_processes:
  - preferred_term: regulation of bone resorption
    modifier: INCREASED
    term:
      id: GO:0045124
      label: regulation of bone resorption
  - preferred_term: osteoclast differentiation
    modifier: INCREASED
    term:
      id: GO:0030316
      label: osteoclast differentiation
  evidence:
  - reference: PMID:31485554
    reference_title: Clinical Evaluation of Melorheostosis in the Context of a Natural History Clinical Study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'The finding of markedly increased ratio of RANKL/OPG transcripts in osteoblasts
      from affected bone in patients with MAP2K1-positive melorheostosis raises the possibility
      of using RANKL inhibitors in these patients,'
    explanation: Measures the transcript ratio in osteoblasts from affected bone and states the
      therapeutic corollary that follows from it.
  - reference: PMID:31485554
    reference_title: Clinical Evaluation of Melorheostosis in the Context of a Natural History Clinical Study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'although it is possible that the increased ratio of RANKL/OPG transcripts is actually
      a compensatory mechanism for the dense bone.'
    explanation: The source's own alternative reading, in which the ratio is a response to the
      dense bone rather than a contributor to it. Recorded because it is what keeps this node
      HYPOTHETICAL rather than established.
  downstream:
  - target: Segmental Cortical Hyperostosis
    causal_link_type: UNKNOWN
    description: Whether the altered remodelling contributes to the hyperostosis or responds to it
      is not resolved in any cached source, so the direction is left UNKNOWN rather than asserted.
    evidence:
    - reference: PMID:31485554
      reference_title: Clinical Evaluation of Melorheostosis in the Context of a Natural History Clinical Study.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'although it is possible that the increased ratio of RANKL/OPG transcripts is
        actually a compensatory mechanism for the dense bone.'
      explanation: States the unresolved direction directly, which is the basis for the UNKNOWN
        link type.
- name: Segmental Cortical Hyperostosis
  biological_scale: TISSUE
  description: >-
    Excess bone confined to a segment of the skeleton, classically as irregular
    cortical thickening resembling wax dripping down a candle, and often with
    involvement of the adjacent soft tissue. The segmental boundary is a
    consequence of mosaicism, though the historical explanation for its precise
    shape does not survive testing.
  biological_processes:
  - preferred_term: ossification
    modifier: INCREASED
    term:
      id: GO:0001503
      label: ossification
  evidence:
  - reference: PMID:25343102
    reference_title: Melorheostosis and a review of the literature in China.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'The characteristic radiographic appearance consists of irregular hyperostotic changes
      of the cortex resembling melted wax dripping down the side of a candle.'
    explanation: Describes the radiographic lesion that defines the disease.
  - reference: PMID:30218789
    reference_title: CT analysis of anatomical distribution of melorheostosis challenges the sclerotome hypothesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'The disease remains limited to medial or lateral side of the extremity with proximo-distal
      progression.'
    explanation: Characterises the segmental boundary, which is the feature the mosaic mechanism
      has to explain.
  downstream:
  - target: Pain, Deformity and Restricted Movement
    causal_link_type: DIRECT
    description: Excess bone and soft tissue involvement produce the symptoms that bring patients
      to attention.
    evidence:
    - reference: PMID:25343102
      reference_title: Melorheostosis and a review of the literature in China.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'Melorheostosis is an uncommon, non-genetic, non-developmental, sclerosing dysplasia
        of bone and adjacent soft tissues, with deformity of the extremity, pain, limb stiffness
        and limitation of motion.'
      explanation: Enumerates the clinical consequences of the lesion.
  - target: Peripheral Nerve Compression
    causal_link_type: DIRECT
    description: Expanding cortical bone compresses an adjacent nerve mechanically.
    evidence:
    - reference: PMID:31485554
      reference_title: Clinical Evaluation of Melorheostosis in the Context of a Natural History Clinical Study.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'Three additional ultrasound studies showed either displacement or swelling of a
        nerve due to compression by the bone overgrowth.'
      explanation: Imaging shows the bone overgrowth compressing the nerve, which is the
        mechanical link this edge asserts.
  - target: Somatic Sensory Deficit
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Sensory loss follows from compression of the nerves running through the affected
      segment, so the intermediate is the nerve compression curated separately.
    evidence:
    - reference: PMID:31485554
      reference_title: Clinical Evaluation of Melorheostosis in the Context of a Natural History Clinical Study.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'We found sensory deficits in approximately 77% of patients, with evidence of focal
        nerve entrapment in five patients.'
      explanation: Reports the sensory deficit and the entrapment together, which is what makes
        the intermediate known rather than assumed.
  - target: Localized Soft Tissue Swelling
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Swelling of the affected segment accompanies the bone lesion. The sources list it
      as a presenting feature without establishing whether it is soft tissue involvement by the
      clone, venous or lymphatic obstruction, or a consequence of the hypervascularity, so the
      intermediates are left unstated.
    evidence:
    - reference: PMID:31485554
      reference_title: Clinical Evaluation of Melorheostosis in the Context of a Natural History Clinical Study.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'Patients present with pain, deformities, contractures, range of motion
        limitation(s), and limb swelling.'
      explanation: Lists limb swelling alongside the mechanical consequences of the lesion without
        specifying a mechanism for it.
  - target: Hypervascularity of Affected Bone
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Increased vascularity accompanies the lesion, in the cortex and the soft tissue
      around it. No cached source establishes whether the vascularity drives the bone formation,
      follows it, or is a parallel effect of the same clone, so the intermediates are unstated.
    evidence:
    - reference: PMID:31485554
      reference_title: Clinical Evaluation of Melorheostosis in the Context of a Natural History Clinical Study.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'Ultrasound imaging was also useful in detecting hypervascularity in and around the
        melorheostotic lesions, correlating with the hypervascularity noted on bone histology and
        further supported by 18F-NaF PET/CT imaging.'
      explanation: Establishes that the vascularity is localised to the lesion, on three modalities,
        without establishing a direction of causation.
- name: Pain, Deformity and Restricted Movement
  biological_scale: ORGANISM
  description: >-
    The clinical disease. Because the lesion is fixed in one skeletal territory,
    morbidity is local: pain, limb deformity, stiffness and loss of joint motion,
    with soft tissue involvement contributing to contracture.
  evidence:
  - reference: PMID:25343102
    reference_title: Melorheostosis and a review of the literature in China.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Melorheostosis is an uncommon, non-genetic, non-developmental, sclerosing dysplasia
      of bone and adjacent soft tissues, with deformity of the extremity, pain, limb stiffness
      and limitation of motion.'
    explanation: States the clinical picture this node represents.
  downstream:
  - target: Bone Pain
    causal_link_type: DIRECT
    description: Local pain from the hyperostotic lesion and surrounding soft tissue.
    evidence:
    - reference: PMID:25343102
      reference_title: Melorheostosis and a review of the literature in China.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'Melorheostosis is an uncommon, non-genetic, non-developmental, sclerosing dysplasia
        of bone and adjacent soft tissues, with deformity of the extremity, pain, limb stiffness
        and limitation of motion.'
      explanation: Names pain among the manifestations.
  - target: Limitation of Joint Mobility
    causal_link_type: DIRECT
    description: Stiffness and restricted motion at joints crossed by the lesion.
    evidence:
    - reference: PMID:25343102
      reference_title: Melorheostosis and a review of the literature in China.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'Melorheostosis is an uncommon, non-genetic, non-developmental, sclerosing dysplasia
        of bone and adjacent soft tissues, with deformity of the extremity, pain, limb stiffness
        and limitation of motion.'
      explanation: Names limb stiffness and limitation of motion among the manifestations.
  - target: Flexion Contracture
    causal_link_type: DIRECT
    description: Soft tissue involvement adjacent to the bone lesion produces fixed joint
      contracture.
    evidence:
    - reference: PMID:31485554
      reference_title: Clinical Evaluation of Melorheostosis in the Context of a Natural History Clinical
        Study.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'Patients present with pain, deformities, contractures, range of motion limitation(s),
        and limb swelling.'
      explanation: Records contractures among the presenting features produced by the lesion.
  - target: Abnormal Cortical Bone Morphology
    causal_link_type: DIRECT
    description: The cortical lesion itself as observed radiographically.
    evidence:
    - reference: PMID:25343102
      reference_title: Melorheostosis and a review of the literature in China.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'The characteristic radiographic appearance consists of irregular hyperostotic changes
        of the cortex resembling melted wax dripping down the side of a candle.'
      explanation: Describes the cortical abnormality recorded by this phenotype.
  - target: Skeletal Muscle Atrophy
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Restricted movement leads to disuse, and disuse to muscle atrophy. The
      intermediate is stated in the source rather than inferred, which is what distinguishes this
      from a primary myopathy.
    evidence:
    - reference: PMID:31485554
      reference_title: Clinical Evaluation of Melorheostosis in the Context of a Natural History Clinical Study.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'Eight patients had muscle atrophy from disuse.'
      explanation: Attributes the atrophy to disuse, which places it downstream of the restricted
        movement rather than beside it.
phenotypes:
- category: Skeletal
  name: Abnormal Cortical Bone Morphology
  frequency: OBLIGATE
  description: >-
    Irregular cortical hyperostosis, classically in the dripping candle wax
    pattern, though not every case shows it. This is the defining finding and the
    basis of diagnosis.
  phenotype_term:
    preferred_term: Abnormal cortical bone morphology
    term:
      id: HP:0003103
      label: Abnormal cortical bone morphology
    onset:
      onset_category: CHILDHOOD
      notes: Half of patients are diagnosed by age 20, so onset is recorded as childhood while
        noting that diagnosis in adulthood is common and that the somatic mutation is present
        from before birth. PMID:31485554 states that most patients present in childhood or
        adolescence, with 50 percent diagnosed by age 20 years.
  diagnostic: true
  evidence:
  - reference: PMID:25343102
    reference_title: Melorheostosis and a review of the literature in China.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'The characteristic radiographic appearance consists of irregular hyperostotic changes
      of the cortex resembling melted wax dripping down the side of a candle.'
    explanation: Gives the characteristic cortical appearance.
  - reference: PMID:38978887
    reference_title: "Melorheostosis (Leri's Disease): A Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Diagnosis typically relies on X-rays, although not all cases exhibit the classic
      candle wax appearance.'
    explanation: Qualifies the classic sign, which matters because its absence does not exclude
      the diagnosis.
- category: Skeletal
  name: Bone Pain
  frequency: FREQUENT
  description: >-
    Local pain, the commonest symptomatic complaint, though the disease is
    sometimes found incidentally.
  phenotype_term:
    preferred_term: Bone pain
    term:
      id: HP:0002653
      label: Bone pain
  evidence:
  - reference: PMID:38978887
    reference_title: "Melorheostosis (Leri's Disease): A Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'It can often be an incidental discovery, with patients experiencing associated pain
      and deformities.'
    explanation: Names pain and deformity, and records that presentation may equally be
      incidental.
- category: Musculoskeletal
  name: Flexion Contracture
  description: >-
    Joint contracture from the soft tissue component of the lesion, recorded
    prospectively in the natural history cohort alongside pain and restricted
    range of motion.
  phenotype_term:
    preferred_term: Flexion contracture
    term:
      id: HP:0001371
      label: Flexion contracture
  evidence:
  - reference: PMID:31485554
    reference_title: Clinical Evaluation of Melorheostosis in the Context of a Natural History Clinical Study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Patients present with pain, deformities, contractures, range of motion limitation(s),
      and limb swelling.'
    explanation: Enumerates the presenting features in a prospectively recruited cohort, which is
      stronger than the case-report literature this disease otherwise rests on.
- category: Musculoskeletal
  name: Limitation of Joint Mobility
  frequency: FREQUENT
  description: >-
    Restricted joint motion and limb stiffness where the lesion and its soft
    tissue component cross a joint.
  phenotype_term:
    preferred_term: Limitation of joint mobility
    term:
      id: HP:0001376
      label: Limitation of joint mobility
  evidence:
  - reference: PMID:31485554
    reference_title: Clinical Evaluation of Melorheostosis in the Context of a Natural History Clinical Study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Motor exam showed restriction of joint movement due to bony growth in 16 patients.'
    explanation: Sixteen of thirty on examination, which grounds the FREQUENT band on a
      denominator rather than on a qualitative description.
  - reference: PMID:25343102
    reference_title: Melorheostosis and a review of the literature in China.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Melorheostosis is an uncommon, non-genetic, non-developmental, sclerosing dysplasia
      of bone and adjacent soft tissues, with deformity of the extremity, pain, limb stiffness
      and limitation of motion.'
    explanation: Names limb stiffness and limitation of motion.
- category: Dermatologic
  name: Skin Changes Overlying Affected Bone
  frequency: FREQUENT
  description: >-
    Skin changes confined to the segment overlying the melorheostotic bone, most
    often irregular macular erythema without surface change. The segmental
    distribution is the informative part: the skin follows the same somatic clone
    as the bone, which is why the finding tracks the lesion rather than appearing
    generally.
  phenotype_term:
    preferred_term: Erythema
    term:
      id: HP:0010783
      label: Erythema
  evidence:
  - reference: PMID:31485554
    reference_title: Clinical Evaluation of Melorheostosis in the Context of a Natural History Clinical Study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Skin abnormalities overlying the affected bone lesions were identified in 16 of 30
      patients (53%).'
    explanation: Gives the denominator, 16 of 30, which is what places this in the FREQUENT band
      rather than resting on a qualitative term.
  - reference: PMID:31485554
    reference_title: Clinical Evaluation of Melorheostosis in the Context of a Natural History Clinical Study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Of 16 patients, 9 (56%) patients’ skin findings manifested as vascular changes, most
      commonly irregular macular erythema without overlying surface change.'
    explanation: Identifies the commonest morphology, which is what the HP:0010783 binding
      represents; the other 7 of 16 had changes this term does not cover.
- category: Neurologic
  name: Somatic Sensory Deficit
  frequency: FREQUENT
  description: >-
    Sensory deficit confined to the distribution of the melorheostotic segment,
    found on examination in most patients in the prospective cohort. Its
    segmental distribution is what distinguishes it from an incidental
    neuropathy.
  phenotype_term:
    preferred_term: Somatic sensory dysfunction
    term:
      id: HP:0003474
      label: Somatic sensory dysfunction
  evidence:
  - reference: PMID:31485554
    reference_title: Clinical Evaluation of Melorheostosis in the Context of a Natural History Clinical Study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Neurological clinical evaluation showed all 30 patients reporting pain symptomology
      with 77% patients with confirmed sensory deficit in the distribution of melorheostosis on
      exam.'
    explanation: Gives both the proportion and the segmental distribution, on examination rather
      than by report.
- category: Neurologic
  name: Peripheral Nerve Compression
  frequency: OCCASIONAL
  description: >-
    Focal nerve entrapment where expanding bone compresses an adjacent nerve,
    confirmed on nerve conduction study and ultrasound in the natural history
    cohort. This is the mechanical subset of the sensory deficit and is what makes
    some patients surgical candidates.
  phenotype_term:
    preferred_term: Peripheral nerve compression
    term:
      id: HP:0003406
      label: Peripheral nerve compression
  evidence:
  - reference: PMID:31485554
    reference_title: Clinical Evaluation of Melorheostosis in the Context of a Natural History Clinical Study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Electrophysiological testing identified isolated neuropathy in 43% patients (12/28
      patients tested, with six sensory neuropathies and six mixed motor neuropathies) in the
      distribution of melorheostosis'
    explanation: An objective electrodiagnostic figure, 12 of 28 tested, alongside the five
      patients with imaging-confirmed entrapment. The two numbers measure different things, so
      the band stays on the entrapment figure and this is recorded as the wider neuropathy
      burden.
  - reference: PMID:31485554
    reference_title: Clinical Evaluation of Melorheostosis in the Context of a Natural History Clinical Study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'We found sensory deficits in approximately 77% of patients, with evidence of focal
      nerve entrapment in five patients.'
    explanation: Five of the thirty-patient cohort, which is 17 percent and therefore OCCASIONAL,
      one band below the sensory deficit it sits inside.
  - reference: PMID:31485554
    reference_title: Clinical Evaluation of Melorheostosis in the Context of a Natural History Clinical Study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Three additional ultrasound studies showed either displacement or swelling of a nerve
      due to compression by the bone overgrowth.'
    explanation: Imaging confirmation of the compression mechanism rather than inference from the
      sensory findings.
  - reference: PMID:30989250
    reference_title: "Melorheostosis and Osteopoikilosis: A Review of Clinical Features and Pathogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Surgical intervention may be required for those with large bone growths, nerve
      entrapments, joint impingement syndromes or major limb deformities.'
    explanation: Independent source naming nerve entrapment as a surgical indication, which is why
      it is curated separately from the broader sensory deficit.
- category: Musculoskeletal
  name: Localized Soft Tissue Swelling
  frequency: FREQUENT
  description: >-
    Swelling of the affected limb segment, listed among the common presenting
    features. Recorded separately from the bone lesion because it involves the
    soft tissue envelope, which the somatic clone also affects.
  phenotype_term:
    preferred_term: Localized soft-tissue swelling on extremity
    term:
      id: HP:6000840
      label: Localized soft-tissue swelling on extremity
  evidence:
  - reference: PMID:31485554
    reference_title: Clinical Evaluation of Melorheostosis in the Context of a Natural History Clinical Study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Patients present with pain, deformities, contractures, range of motion limitation(s),
      and limb swelling.'
    explanation: Lists limb swelling among the presenting features. This band rests on the
      qualitative framing rather than a denominator, since the cohort reports no count for it.
- category: Musculoskeletal
  name: Skeletal Muscle Atrophy
  frequency: OCCASIONAL
  description: >-
    Muscle atrophy attributed to disuse rather than to a primary myopathy, which
    places it downstream of the restricted movement rather than beside it.
  phenotype_term:
    preferred_term: Skeletal muscle atrophy
    term:
      id: HP:0003202
      label: Skeletal muscle atrophy
  evidence:
  - reference: PMID:31485554
    reference_title: Clinical Evaluation of Melorheostosis in the Context of a Natural History Clinical Study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Eight patients had muscle atrophy from disuse.'
    explanation: Eight of the thirty-patient cohort, 27 percent, and the source attributes it to
      disuse, which is what determines where it sits in the graph.
- category: Cardiovascular
  name: Hypervascularity of Affected Bone
  frequency: FREQUENT
  description: >-
    Marked hypervascularity of the cortex and adjacent soft tissue in half the
    natural history cohort, seen on ultrasound, on bone histology and on
    18F-NaF PET/CT. HPO has no term for increased vascularity of bone, so this
    binds the general abnormal vascular morphology term with the site carried in
    the preferred term. Whether it contributes to the pain is explicitly unknown
    in the source.
  phenotype_term:
    preferred_term: Hypervascularity of bone cortex and adjacent soft tissue
    term:
      id: HP:0025015
      label: Abnormal vascular morphology
  evidence:
  - reference: PMID:31485554
    reference_title: Clinical Evaluation of Melorheostosis in the Context of a Natural History Clinical Study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Twelve (12) patients (50%) showed marked hypervascularity of the cortex and adjacent
      soft tissue.'
    explanation: Twelve of thirty, which is the denominator behind the FREQUENT band.
  - reference: PMID:31485554
    reference_title: Clinical Evaluation of Melorheostosis in the Context of a Natural History Clinical Study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'It is not known if the observed hypervascularity contributes to pain.'
    explanation: Records that the clinical significance is unresolved, which is why this is
      curated as a finding rather than placed on the pain pathway.
genetic:
- name: MAP2K1
  gene_term:
    preferred_term: MAP2K1
    term:
      id: hgnc:6840
      label: MAP2K1
  relationship_type: CAUSATIVE
  variant_origin: SOMATIC
  association: Somatic Mosaic Activating Mutation
  notes: >-
    Recurrent alleles Q56P, K57E and K57N cluster in the MEK1 negative regulatory
    domain, and a further variant in the catalytic domain, C121S, has since been
    reported. Testing must be on affected tissue: the variants are absent from
    unaffected bone in the same patient, so a blood sample will not find them.
    MAP2K1 accounts for about half of sporadic cases, and the sources state
    further locus heterogeneity, so a negative result on affected tissue does not
    exclude the diagnosis.
  evidence:
  - reference: PMID:29643386
    reference_title: Somatic activating mutations in MAP2K1 cause melorheostosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Using whole exome sequencing, we identify somatic mosaic MAP2K1 mutations in affected,
      but not unaffected, bone of eight unrelated patients with melorheostosis.'
    explanation: Establishes causation and the tissue-restricted distribution that dictates how
      testing must be done.
  - reference: PMID:29643386
    reference_title: Somatic activating mutations in MAP2K1 cause melorheostosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'strongly support MAP2K1 somatic mutations as causing about half of cases of sporadic
      melorheostosis.'
    explanation: Supports causation while bounding it at about half of sporadic cases, which is
      what makes a negative MAP2K1 result uninformative rather than exclusionary.
  - reference: PMID:32387835
    reference_title: A multi-omics approach expands the mutational spectrum of MAP2K1-related melorheostosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Our observations confirm that mutations in MAP2K1 are a major cause of melorheostosis
      and also suggest further locus heterogeneity for this disorder.'
    explanation: An independent statement of locus heterogeneity, which together with the previous
      item is why the genetic notes now say a negative result does not exclude the diagnosis.
  - reference: PMID:32387835
    reference_title: A multi-omics approach expands the mutational spectrum of MAP2K1-related melorheostosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'WGS and RNAseq analysis in a third patient demonstrated the presence of a novel variant
      (p.Cys121Ser) in the catalytic domain of MAP2K1.'
    explanation: Independent replication that also extends the mutational spectrum beyond the
      original hotspot.
- name: SMAD3
  gene_term:
    preferred_term: SMAD3
    term:
      id: hgnc:6769
      label: SMAD3
  relationship_type: CAUSATIVE
  variant_origin: SOMATIC
  association: Somatic Activating Mutation in Endosteal Pattern Disease
  notes: >-
    Worth contrasting with germline SMAD3 disease. Loss-of-function SMAD3
    mutations cause Loeys-Dietz syndrome type 3, in which bone is undermineralised
    and fragile. Somatic gain-of-function SMAD3 mutations here produce the
    opposite, overmineralised excess bone. The gene, the tissue and the direction
    of the mutation together determine the phenotype.
  evidence:
  - reference: PMID:32232430
    reference_title: Somatic SMAD3-activating mutations cause melorheostosis by up-regulating the TGF-β/SMAD
      pathway.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'We now report somatic SMAD3 mutations in bone lesions of four unrelated patients with
      endosteal pattern melorheostosis.'
    explanation: Establishes the gene and its association with the endosteal pattern.
  - reference: PMID:35874167
    reference_title: SMAD3 mutation in LDS3 causes bone fragility by impairing the TGF-β pathway and enhancing
      osteoclastogenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Bone histomorphometry revealed markedly reduced cortical thickness (-68 %), trabecular
      thickness (-32 %), bone formation rate (-50 %) and delayed mineralization.'
    explanation: The germline loss-of-function contrast. This is a different disease, cited to show
      that the same gene in the opposite direction gives thin, undermineralised bone rather than
      excess bone.
- name: LEMD3
  gene_term:
    preferred_term: LEMD3
    term:
      id: hgnc:28887
      label: LEMD3
  relationship_type: DISPUTED
  variant_origin: GERMLINE
  association: Causes Osteopoikilosis and Buschke-Ollendorff Syndrome, Not Isolated Melorheostosis
  notes: >-
    Recorded as a negative. LEMD3 was long implicated because melorheostosis-like
    lesions occur in Buschke-Ollendorff syndrome, but direct sequencing of blood,
    skin and bone from a patient with isolated melorheostosis found no pathogenic
    change, and reviews conclude it is not the causative gene for the sporadic
    disease. Buschke-Ollendorff syndrome is a distinct entity and is not curated
    here.
  evidence:
  - reference: PMID:19438932
    reference_title: Novel and recurrent germline LEMD3 mutations causing Buschke-Ollendorff syndrome and
      osteopoikilosis but not isolated melorheostosis.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: 'The search for mutations in DNA extracted from the peripheral blood, as well as skin
      and bone biopsies of the patient with melorheostosis failed to identify any pathogenic
      change.'
    explanation: A direct negative in the right tissues, which is why this gene is recorded as
      disputed rather than causative.
  - reference: PMID:28676968
    reference_title: 'Melorheostosis: a Rare Sclerosing Bone Dysplasia.'
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: 'LEM domain-containing protein 3 (LEMD3) gene mutations have been demonstrated in
      several familial cases, but these have been more strongly correlated with other hereditary
      dysplasias, such as osteopoikilosis, and are not thought to be the causative gene for
      melorheostosis.'
    explanation: Review-level conclusion that this gene is not causative for melorheostosis.
- name: KRAS
  gene_term:
    preferred_term: KRAS
    term:
      id: hgnc:6407
      label: KRAS
  relationship_type: CAUSATIVE
  variant_origin: SOMATIC
  association: Somatic Activating Mutation in a Minority of Cases
  notes: >-
    A third somatic gene in the same pathway family, reported in a small number of
    cases. Its existence supports the general model - a somatic activating
    mutation in a growth-signalling pathway within a skeletal clone - rather than
    any one gene being essential.
  evidence:
  - reference: PMID:30989250
    reference_title: 'Melorheostosis and Osteopoikilosis: A Review of Clinical Features and Pathogenesis.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Recent studies of melorheostosis lesional tissue indicate that most cases arise from
      somatic MAP2K1 mutations although a small number may arise from other genes in related
      pathways, such as KRAS.'
    explanation: Establishes KRAS as an additional somatic gene and places it as a minority cause
      alongside MAP2K1.
  - reference: PMID:30989250
    reference_title: 'Melorheostosis and Osteopoikilosis: A Review of Clinical Features and Pathogenesis.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Those cases associated with MAP2K1 mutations are more likely to have the classic
      "dripping candle wax" appearance on radiographs.'
    explanation: A genotype-phenotype correlation supporting the separation of arms by gene, which
      is how the subtypes in this entry are organised.
mechanistic_hypotheses:
- hypothesis_group_id: somatic_mosaic_clone
  hypothesis_label: Somatic Mosaic Clone Determines the Segmental Distribution
  status: CANONICAL
  description: >-
    The distribution reflects the territory occupied by the descendants of a
    single mutated progenitor. This follows from the genetics rather than from
    anatomy, and it accounts for the sharp boundary, the restriction to one side
    of a limb, and the involvement of overlying skin.
  evidence:
  - reference: PMID:30218789
    reference_title: CT analysis of anatomical distribution of melorheostosis challenges the sclerotome hypothesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'We believe that the disease distribution can be explained by clonal proliferation
      of a mutated skeletal progenitor cell along the limb axis. Studies in mice models on clonal
      proliferation in limb buds mimic the patterns seen in melorheostosis.'
    explanation: The authors propose a clonal explanation in place of the sclerotome account, and
      cite limb-bud clonal proliferation in mice as producing comparable patterns.
- hypothesis_group_id: sclerotome_hypothesis
  hypothesis_label: Sclerotomal Distribution
  status: DEPRECATED
  description: >-
    The historical account, that lesions occupy the bone territory innervated by a
    single spinal nerve level. It was tested directly by whole body CT in thirty
    patients and largely failed: only 17% conformed to a single sclerotome.
    Retained here because it is still widely repeated, including in reviews
    published after the test.
  evidence:
  - reference: PMID:30218789
    reference_title: CT analysis of anatomical distribution of melorheostosis challenges the sclerotome hypothesis.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: 'We found that the disease distribution conformed to the distribution of a single
      sclerotome in only 5 patients (17%). In another 12 patients, the lesions spanned parts of
      contiguous sclerotomes but did not involve the entire extent of the sclerotomes.'
    explanation: Direct quantitative test of the hypothesis in thirty patients, with the great
      majority not conforming.
  - reference: PMID:30218789
    reference_title: CT analysis of anatomical distribution of melorheostosis challenges the sclerotome hypothesis.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: 'Our findings raise concerns about the sclerotomal hypothesis being the definitive
      explanation for the pattern of anatomic distribution in MEL.'
    explanation: The authors' own conclusion against the hypothesis.
  notes: >-
    Marked DEPRECATED rather than deleted because it is still stated as fact in
    the review literature, including PMID:28676968, which describes a sclerotomal
    distribution. A curator meeting that claim should be able to find the test
    that contradicts it.
diagnosis:
- name: Radiographic diagnosis
  presence: PRESENT
  description: >-
    Diagnosis rests on imaging. There is no definitive histological feature, so
    biopsy resolves uncertainty rather than confirming the diagnosis, and genetic
    testing requires affected tissue rather than blood.
  evidence:
  - reference: PMID:38978887
    reference_title: "Melorheostosis (Leri's Disease): A Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'A biopsy may be necessary in cases of uncertainty, as there is not a definitive
      histological feature.'
    explanation: States both the role of biopsy and the absence of a defining histological
      feature.
  - reference: PMID:38978887
    reference_title: "Melorheostosis (Leri's Disease): A Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'A new imaging sign known as the "dumpling on a plate sign" has been proposed for flat
      bones for both MRI and CT scans.'
    explanation: Records a newer sign for flat bones, where the candle wax appearance does not
      apply.
- name: Normal bone biochemistry
  presence: ABSENT
  description: >-
    Bone turnover markers and mineral chemistry are normal. This is a negative
    finding recorded because it is diagnostically useful: it separates
    melorheostosis from the metabolic sclerosing bone diseases that produce a
    similar radiographic impression, and it fits a disease driven by a somatic
    clone confined to one segment rather than by a systemic derangement.
  evidence:
  - reference: PMID:31485554
    reference_title: Clinical Evaluation of Melorheostosis in the Context of a Natural History Clinical Study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'However, we did not find any biochemical abnormalities characteristic of the
      disease.'
    explanation: The prospective cohort looked for biochemical abnormality and found none.
  - reference: PMID:38978887
    reference_title: "Melorheostosis (Leri's Disease): A Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Additional support can be obtained through normal serum calcium, phosphorus, and
      alkaline phosphatase levels,'
    explanation: States which normal values support the diagnosis, which is what makes the
      negative finding useful rather than merely unremarkable.
treatments:
- name: Surgical Management
  therapeutic_modality: SURGERY
  description: >-
    Excision of bone overgrowth, release of contracture, or decompression of an
    entrapped nerve. Recurrence after excision is a recognised problem, which is
    unsurprising given that the causative somatic clone remains in place.
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_mechanisms:
  - target: Pain, Deformity and Restricted Movement
    treatment_effect: MODULATES
    description: Addresses the mechanical consequences of the lesion without altering the somatic
      mutation that produces it.
    evidence:
    - reference: PMID:30989250
      reference_title: "Melorheostosis and Osteopoikilosis: A Review of Clinical Features and Pathogenesis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'Surgical intervention may be required for those with large bone growths, nerve
        entrapments, joint impingement syndromes or major limb deformities.'
      explanation: Names the four mechanical indications, each of which is a consequence of the
        lesion rather than of the mutation.
  evidence:
  - reference: PMID:38978887
    reference_title: "Melorheostosis (Leri's Disease): A Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Management is generally aimed at symptom relief, either through conservative measures
      or surgical intervention.'
    explanation: Places surgery as one of two arms of symptomatic management, not as
      disease-modifying therapy.
- name: Physical Therapy
  therapeutic_modality: BEHAVIORAL
  description: >-
    Part of conventional management alongside surgery and bisphosphonates, aimed
    at range of motion and at the disuse that drives the muscle atrophy.
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  target_mechanisms:
  - target: Pain, Deformity and Restricted Movement
    treatment_effect: MODULATES
    description: Targets restricted movement and its downstream disuse consequences rather than
      the bone lesion.
    evidence:
    - reference: PMID:28676968
      reference_title: "Melorheostosis: a Rare Sclerosing Bone Dysplasia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'Management in recent years has involved nitrogen-containing bisphosphonates in
        addition to traditional orthopedic surgical approaches and physical therapy.'
      explanation: Names physical therapy as part of traditional management alongside surgery.
  evidence:
  - reference: PMID:30989250
    reference_title: "Melorheostosis and Osteopoikilosis: A Review of Clinical Features and Pathogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'physical therapy and psychological assessments.'
    explanation: Independent source listing physical therapy in the management set.
- name: Bisphosphonate Therapy
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Nitrogen-containing bisphosphonates have entered management in recent years,
    but the evidence base is thin and the sources say so. This is recorded as
    used-without-guidance rather than as established therapy.
  treatment_term:
    preferred_term: bisphosphonate therapy
    term:
      id: NCIT:C198585
      label: Bisphosphonate Therapy
  target_mechanisms:
  - target: Increased RANKL/OPG Ratio in Affected Bone
    treatment_effect: MODULATES
    description: Nitrogen-containing bisphosphonates act on the osteoclast, which is the cell the
      RANKL/OPG shift recruits. That node is the mechanistic join point for this drug class.
      Whether acting there alters the lesion is not established, which is why the effect is
      MODULATES and not INHIBITS.
    evidence:
    - reference: PMID:28676968
      reference_title: "Melorheostosis: a Rare Sclerosing Bone Dysplasia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'Management in recent years has involved nitrogen-containing bisphosphonates in
        addition to traditional orthopedic surgical approaches and physical therapy.'
      explanation: Establishes that bisphosphonates are used, without claiming an effect size.
  evidence:
  - reference: PMID:30989250
    reference_title: "Melorheostosis and Osteopoikilosis: A Review of Clinical Features and Pathogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Medical treatments include bisphosphonates, but definitive guidance on their use is
      lacking given the small number of patients that have been studied.'
    explanation: States the weakness of the evidence base explicitly, which is why this treatment
      is not presented as established.
- name: MEK Inhibition
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    A mechanistic rationale rather than a therapy. The MAP2K1 paper proposes
    inhibiting MEK1 on the strength of the somatic activating mutations, and MEK
    inhibitors exist for other MAPK-driven diseases. No cached source reports a
    patient treated this way, so this is recorded for the reasoning it represents
    and not as an option to offer.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: MEK1-ERK Pathway Hyperactivation
    treatment_effect: INHIBITS
    description: Acts on the activated kinase itself, which is the only point in this pathograph
      where a treatment would be disease-modifying rather than symptomatic. It would do nothing
      for the SMAD3 arm.
    evidence:
    - reference: PMID:29643386
      reference_title: Somatic activating mutations in MAP2K1 cause melorheostosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'identification of somatic MAP2K1 mutations in melorheostosis raises the possibility
        of inhibiting MEK1 to treat melorheostotic bone lesions.'
      explanation: States the proposal and its basis. "Raises the possibility" is the strength of
        the claim, and no cached source takes it further.
  evidence:
  - reference: PMID:29643386
    reference_title: Somatic activating mutations in MAP2K1 cause melorheostosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Development of a diagnostic test is especially valuable because identification of
      somatic MAP2K1 mutations in melorheostosis raises the possibility of inhibiting MEK1 to treat
      melorheostotic bone lesions.'
    explanation: Ties the therapeutic proposal to the value of genetic testing, which is the
      practical reason the proposal matters even without trial evidence.
- name: RANKL Inhibition
  therapeutic_modality: MONOCLONAL_ANTIBODY
  description: >-
    Proposed on the strength of the increased RANKL/OPG transcript ratio in
    affected bone. As with MEK inhibition, no cached source reports a treated
    patient, and the same source raises the possibility that the ratio is
    compensatory, in which case inhibiting RANKL would be acting on a response
    rather than a cause.
  treatment_term:
    preferred_term: biological therapy
    term:
      id: NCIT:C15187
      label: Biological Therapy
    therapeutic_agent:
    - preferred_term: denosumab
      term:
        id: NCIT:C61313
        label: Denosumab
  target_mechanisms:
  - target: Increased RANKL/OPG Ratio in Affected Bone
    treatment_effect: INHIBITS
    description: Neutralises RANKL, the ligand whose excess relative to osteoprotegerin defines
      that node.
    evidence:
    - reference: PMID:31485554
      reference_title: Clinical Evaluation of Melorheostosis in the Context of a Natural History Clinical Study.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'The finding of markedly increased ratio of RANKL/OPG transcripts in osteoblasts
        from affected bone in patients with MAP2K1-positive melorheostosis raises the possibility
        of using RANKL inhibitors in these patients,'
      explanation: States the proposal and the measurement it rests on.
  evidence:
  - reference: PMID:31485554
    reference_title: Clinical Evaluation of Melorheostosis in the Context of a Natural History Clinical Study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'although it is possible that the increased ratio of RANKL/OPG transcripts is actually
      a compensatory mechanism for the dense bone.'
    explanation: The caveat that limits this proposal, from the same sentence that makes it.
      Recorded on the treatment so a reader does not encounter the proposal without it.
- name: Neuropathic Pain Pharmacotherapy
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Gabapentinoids for the neuropathic component of the pain, proposed on the
    basis of how common nerve entrapment is in the cohort rather than on trial
    evidence in this disease. The source says may be considered, and that is the
    strength of the recommendation.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: gabapentin
      term:
        id: CHEBI:42797
        label: gabapentin
    - preferred_term: pregabalin
      term:
        id: CHEBI:64356
        label: pregabalin
  target_mechanisms:
  - target: Peripheral Nerve Compression
    treatment_effect: MODULATES
    description: Modifies neuropathic pain signalling arising from the compressed nerve. It does
      not relieve the compression itself, which is why surgery remains the option for that.
    evidence:
    - reference: PMID:31485554
      reference_title: Clinical Evaluation of Melorheostosis in the Context of a Natural History Clinical Study.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'Given the high prevalence of nerve entrapment from melorheostotic bone expansion,
        drugs such as pregabalin and gabapentin may be considered for management of neuropathic
        pain.'
      explanation: Ties the recommendation directly to the entrapment prevalence, and its hedging
        is why the effect is MODULATES rather than a claim of benefit.
  evidence:
  - reference: PMID:31485554
    reference_title: Clinical Evaluation of Melorheostosis in the Context of a Natural History Clinical Study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Evaluation by a neurologist can help in identifying a suitable analgesic regimen.'
    explanation: Places analgesic selection under neurological assessment rather than as routine
      prescribing.
clinical_trials:
- name: NCT02504879
  status: UNKNOWN
  description: >-
    The NIH natural history study of melorheostosis. The 30-patient cohort that
    supplies most of the frequency data in this entry is drawn from it, which is
    why it is recorded here rather than treated as an interventional trial.
  target_phenotypes:
  - preferred_term: Bone pain
    term:
      id: HP:0002653
      label: Bone pain
  - preferred_term: Somatic sensory dysfunction
    term:
      id: HP:0003474
      label: Somatic sensory dysfunction
  evidence:
  - reference: clinicaltrials:NCT02504879
    reference_title: Study of the Natural History, Pathogenesis and Outcome of Melorheostosis - a
      Rare Osteosclerotic Disease
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'To see what happens to people with melorheostosis over time and understand the causes
      of the disease.'
    explanation: States the natural history objective, which is what makes this the source of the
      prospective frequency data rather than a treatment trial.
  - reference: PMID:31485554
    reference_title: Clinical Evaluation of Melorheostosis in the Context of a Natural History Clinical Study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'gov NCT02504879) and conducted at the National Institutes of Health (NIH), Bethesda,
      MD, USA.'
    explanation: Links the cohort publication to this trial registration.
references:
- reference: PMID:19438932
  title: "Novel and recurrent germline LEMD3 mutations causing Buschke-Ollendorff syndrome and osteopoikilosis but not isolated melorheostosis."
- reference: PMID:25343102
  title: "Melorheostosis and a review of the literature in China."
- reference: PMID:28676968
  title: "Melorheostosis: a Rare Sclerosing Bone Dysplasia."
- reference: PMID:29643386
  title: "Somatic activating mutations in MAP2K1 cause melorheostosis."
- reference: PMID:30218789
  title: "CT analysis of anatomical distribution of melorheostosis challenges the sclerotome hypothesis."
- reference: PMID:30989250
  title: "Melorheostosis and Osteopoikilosis: A Review of Clinical Features and Pathogenesis."
- reference: PMID:31485554
  title: "Clinical Evaluation of Melorheostosis in the Context of a Natural History Clinical Study."
- reference: PMID:32232430
  title: "Somatic SMAD3-activating mutations cause melorheostosis by up-regulating the TGF-\u03b2/SMAD pathway."
- reference: PMID:32387835
  title: "A multi-omics approach expands the mutational spectrum of MAP2K1-related melorheostosis."
- reference: PMID:35874167
  title: "SMAD3 mutation in LDS3 causes bone fragility by impairing the TGF-\u03b2 pathway and enhancing osteoclastogenesis."
- reference: PMID:38978887
  title: "Melorheostosis (Leri's Disease): A Review."
- reference: PMID:41938408
  title: "A case report and literature review of pediatric multifocal melorheostosis in a unilateral limb."
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0007970
      label: melorheostosis
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      MONDO:0007970 carries OMIM:155950 and Orphanet:2485 as cross-references, which are the
      OMIM and Orphanet identifiers for this disease. The OMIM entry predates the somatic
      MAP2K1 finding and describes the condition under a Mendelian framing, which no longer
      matches the mechanism curated here.
  ncit_mappings:
  - term:
      id: NCIT:C84887
      label: Melorheostosis
    mapping_predicate: skos:exactMatch
    mapping_source: NCIT
    mapping_justification: >-
      NCIT:C84887 is the NCI Thesaurus concept for this disease and is cross-referenced from
      MONDO:0007970.
disease_term:
  preferred_term: melorheostosis
  term:
    id: MONDO:0007970
    label: melorheostosis
notes: >-
  Why two arms converge on one disease. MAP2K1 and SMAD3 both cause
  melorheostosis, but by opposite cellular routes. The MAP2K1 arm raises
  osteoblast proliferation and impairs mineralisation, so the excess bone is
  largely unmineralised osteoid. The SMAD3 arm suppresses proliferation and
  enhances mineralisation, so affected bone is more mineralised than unaffected
  bone. They also produce different radiographic patterns, cortical dripping
  versus endosteal. Modelling them as separate arms rather than a single
  "increased bone formation" node preserves that, and the subtypes slot on each
  node records which arm it belongs to.

  A recorded negative that matters clinically. LEMD3 is carried as DISPUTED with
  REFUTE evidence. It is genuinely causative for osteopoikilosis and
  Buschke-Ollendorff syndrome, and melorheostosis-like lesions occur in those
  conditions, which is why the association persists. But sequencing of blood,
  skin and bone from a patient with isolated melorheostosis found nothing, and
  reviews conclude it is not the causative gene. Buschke-Ollendorff syndrome is a
  separate entity, has an open curation issue assigned to another curator, and is
  deliberately not modelled here.

  A deprecated hypothesis retained on purpose. The sclerotome account of the
  segmental distribution was tested by whole body CT in thirty patients and only
  17% conformed to a single sclerotome. It is recorded with status DEPRECATED and
  REFUTE evidence rather than omitted, because reviews published after that test
  still state a sclerotomal distribution as fact, and a curator meeting that
  claim should be able to find the evidence against it from this entry.

  Testing implication of mosaicism. The mutations are present in affected bone
  and absent from unaffected bone in the same patient. A blood sample will
  therefore be negative, and this is a property of the disease rather than a
  limitation of any assay. It is stated in the genetic notes because it changes
  what a clinician should order.

  A correction made before submission. This entry initially recorded that no
  quotable prevalence figure existed. It does - an estimated 0.9 per million -
  and the deep-research job surfaced it from a paper the draft had not fetched.
  That is the third time in this series that a claim of "no figure available" has
  turned out to be a claim about my search rather than about the literature, so
  it is recorded here rather than quietly replaced.

  Review round 2 added the RANKL/OPG limb, which is the one piece of molecular
  biology in this entry that connects to a drug class already in use. Osteoblasts
  from affected bone carry a markedly increased RANKL to osteoprotegerin ratio,
  RANKL drives osteoclast differentiation, and bisphosphonates act on the
  osteoclast - so that node, not the hyperostosis, is where bisphosphonate therapy
  attaches. The node is HYPOTHETICAL and its downstream link is UNKNOWN, because
  the same sentence that reports the ratio raises the possibility that it is
  compensatory for the dense bone rather than contributing to it. That caveat is
  carried as its own evidence item on the node and again on the RANKL inhibition
  treatment, so a reader cannot meet the proposal without it.

  Review round 1, and the pattern it exposed. The reviewer found that the entry
  under-consumed references this branch had already cached, and was right about
  every item. The natural history cohort at PMID:31485554 was the worst case: one
  sentence was quoted from it three times while the same full text carried
  denominators for skin change (16 of 30), sensory deficit (77 percent), nerve
  entrapment (five patients) and muscle atrophy (eight patients), plus the
  diagnosis-by-age-20 figure, the normal-biochemistry finding, the neuropathic
  pain recommendation and the trial registration. All are now consumed. The
  previous paragraph here listed skin and soft tissue involvement as an
  "extension point", which is not a scoping rationale when the evidence is
  already in the repository; both are now curated phenotypes.

  The frequency bands added in this round rest on denominators from the cohort
  rather than on qualitative terms, with one exception. Limb swelling has no count
  in any cached source and is banded FREQUENT from the framing "patients present
  with", with that basis stated in its evidence explanation rather than left
  implicit.

  The bundled treatment node is split. It previously described "conservative
  measures or surgery" while carrying therapeutic_modality SURGERY, which made the
  tag contradict its own content. There are now four treatments: surgery,
  physical therapy, bisphosphonates and gabapentinoids for the neuropathic
  component. The bisphosphonate entry records that definitive guidance on its use
  is lacking, quoted from the source, because a treatment being used is not the
  same as a treatment being established.

  Normal bone biochemistry is recorded as a diagnosis entry with presence ABSENT.
  A negative finding is worth curating here because it separates melorheostosis
  from the metabolic sclerosing bone diseases that produce a similar radiographic
  impression, and because it is what a disease driven by a segmental somatic clone
  should look like.

  Malignant transformation, stated because the reassurance is as useful as the
  risk. Melorheostotic bone lesions do not metastasise, and conversion to
  osteosarcoma has been reported only rarely. The natural history cohort notes at
  least three case reports of malignancy but says it is not clear whether the
  osteosarcoma arose in the precise distribution of the melorheostosis in any of
  them. That is well under the threshold at which a phenotype would be curated,
  and it is recorded here rather than as a phenotype for that reason.

  Two treatments here are proposals rather than practice. MEK inhibition and
  RANKL inhibition are both curated because the reasoning behind them is part of
  what the molecular work bought, and because the RANKL proposal comes with its
  own caveat in the same sentence that makes it. Neither has a treated patient in
  any cached source, and both descriptions say so. Nifedipine appears in one
  cached source as having produced symptomatic improvement in pain and vasomotor
  function; it is not curated as a treatment because the mention carries no
  denominator, no outcome measure and no mechanism beyond vasoconstriction, and
  the same source says it would not alter disease progression.

  Known extension points: malignant fibrous histiocytoma, reported in association
  but not described in any cached source here; animal and iPSC models, which the
  review suggested but which no cached reference describes, so adding them would
  mean fetching PMIDs that appear only in the deep-research report; and
  Buschke-Ollendorff syndrome, which belongs in its own entry.

  Provenance. Curated from PubMed with a five-iteration OpenScientist
  deep-research job as a cross-check, recorded alongside this entry. Content_type
  was checked before writing, and after review round 1 the full texts were mined
  again rather than trusted to have been mined the first time.

📚

References & Deep Research

References

12

PMID:19438932

Novel and recurrent germline LEMD3 mutations causing Buschke-Ollendorff syndrome and osteopoikilosis but not isolated melorheostosis.

No top-level findings curated for this source.

PMID:25343102

Melorheostosis and a review of the literature in China.

No top-level findings curated for this source.

PMID:28676968

Melorheostosis: a Rare Sclerosing Bone Dysplasia.

No top-level findings curated for this source.

PMID:29643386

Somatic activating mutations in MAP2K1 cause melorheostosis.

No top-level findings curated for this source.

PMID:30218789

CT analysis of anatomical distribution of melorheostosis challenges the sclerotome hypothesis.

No top-level findings curated for this source.

PMID:30989250

Melorheostosis and Osteopoikilosis: A Review of Clinical Features and Pathogenesis.

No top-level findings curated for this source.

PMID:31485554

Clinical Evaluation of Melorheostosis in the Context of a Natural History Clinical Study.

No top-level findings curated for this source.

PMID:32232430

Somatic SMAD3-activating mutations cause melorheostosis by up-regulating the TGF-β/SMAD pathway.

No top-level findings curated for this source.

PMID:32387835

A multi-omics approach expands the mutational spectrum of MAP2K1-related melorheostosis.

No top-level findings curated for this source.

PMID:35874167

SMAD3 mutation in LDS3 causes bone fragility by impairing the TGF-β pathway and enhancing osteoclastogenesis.

No top-level findings curated for this source.

PMID:38978887

Melorheostosis (Leri's Disease): A Review.

No top-level findings curated for this source.

PMID:41938408

A case report and literature review of pediatric multifocal melorheostosis in a unilateral limb.

No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (3)

Record notes

Why two arms converge on one disease. MAP2K1 and SMAD3 both cause melorheostosis, but by opposite cellular routes. The MAP2K1 arm raises osteoblast proliferation and impairs mineralisation, so the excess bone is largely unmineralised osteoid. The SMAD3 arm suppresses proliferation and enhances mineralisation, so affected bone is more mineralised than unaffected bone. They also produce different radiographic patterns, cortical dripping versus endosteal. Modelling them as separate arms rather than a single "increased bone formation" node preserves that, and the subtypes slot on each node records which arm it belongs to. A recorded negative that matters clinically. LEMD3 is carried as DISPUTED with REFUTE evidence. It is genuinely causative for osteopoikilosis and Buschke-Ollendorff syndrome, and melorheostosis-like lesions occur in those conditions, which is why the association persists. But sequencing of blood, skin and bone from a patient with isolated melorheostosis found nothing, and reviews conclude it is not the causative gene. Buschke-Ollendorff syndrome is a separate entity, has an open curation issue assigned to another curator, and is deliberately not modelled here. A deprecated hypothesis retained on purpose. The sclerotome account of the segmental distribution was tested by whole body CT in thirty patients and only 17% conformed to a single sclerotome. It is recorded with status DEPRECATED and REFUTE evidence rather than omitted, because reviews published after that test still state a sclerotomal distribution as fact, and a curator meeting that claim should be able to find the evidence against it from this entry. Testing implication of mosaicism. The mutations are present in affected bone and absent from unaffected bone in the same patient. A blood sample will therefore be negative, and this is a property of the disease rather than a limitation of any assay. It is stated in the genetic notes because it changes what a clinician should order. A correction made before submission. This entry initially recorded that no quotable prevalence figure existed. It does - an estimated 0.9 per million - and the deep-research job surfaced it from a paper the draft had not fetched. That is the third time in this series that a claim of "no figure available" has turned out to be a claim about my search rather than about the literature, so it is recorded here rather than quietly replaced. Review round 2 added the RANKL/OPG limb, which is the one piece of molecular biology in this entry that connects to a drug class already in use. Osteoblasts from affected bone carry a markedly increased RANKL to osteoprotegerin ratio, RANKL drives osteoclast differentiation, and bisphosphonates act on the osteoclast - so that node, not the hyperostosis, is where bisphosphonate therapy attaches. The node is HYPOTHETICAL and its downstream link is UNKNOWN, because the same sentence that reports the ratio raises the possibility that it is compensatory for the dense bone rather than contributing to it. That caveat is carried as its own evidence item on the node and again on the RANKL inhibition treatment, so a reader cannot meet the proposal without it. Review round 1, and the pattern it exposed. The reviewer found that the entry under-consumed references this branch had already cached, and was right about every item. The natural history cohort at PMID:31485554 was the worst case: one sentence was quoted from it three times while the same full text carried denominators for skin change (16 of 30), sensory deficit (77 percent), nerve entrapment (five patients) and muscle atrophy (eight patients), plus the diagnosis-by-age-20 figure, the normal-biochemistry finding, the neuropathic pain recommendation and the trial registration. All are now consumed. The previous paragraph here listed skin and soft tissue involvement as an "extension point", which is not a scoping rationale when the evidence is already in the repository; both are now curated phenotypes. The frequency bands added in this round rest on denominators from the cohort rather than on qualitative terms, with one exception. Limb swelling has no count in any cached source and is banded FREQUENT from the framing "patients present with", with that basis stated in its evidence explanation rather than left implicit. The bundled treatment node is split. It previously described "conservative measures or surgery" while carrying therapeutic_modality SURGERY, which made the tag contradict its own content. There are now four treatments: surgery, physical therapy, bisphosphonates and gabapentinoids for the neuropathic component. The bisphosphonate entry records that definitive guidance on its use is lacking, quoted from the source, because a treatment being used is not the same as a treatment being established. Normal bone biochemistry is recorded as a diagnosis entry with presence ABSENT. A negative finding is worth curating here because it separates melorheostosis from the metabolic sclerosing bone diseases that produce a similar radiographic impression, and because it is what a disease driven by a segmental somatic clone should look like. Malignant transformation, stated because the reassurance is as useful as the risk. Melorheostotic bone lesions do not metastasise, and conversion to osteosarcoma has been reported only rarely. The natural history cohort notes at least three case reports of malignancy but says it is not clear whether the osteosarcoma arose in the precise distribution of the melorheostosis in any of them. That is well under the threshold at which a phenotype would be curated, and it is recorded here rather than as a phenotype for that reason. Two treatments here are proposals rather than practice. MEK inhibition and RANKL inhibition are both curated because the reasoning behind them is part of what the molecular work bought, and because the RANKL proposal comes with its own caveat in the same sentence that makes it. Neither has a treated patient in any cached source, and both descriptions say so. Nifedipine appears in one cached source as having produced symptomatic improvement in pain and vasomotor function; it is not curated as a treatment because the mention carries no denominator, no outcome measure and no mechanism beyond vasoconstriction, and the same source says it would not alter disease progression. Known extension points: malignant fibrous histiocytoma, reported in association but not described in any cached source here; animal and iPSC models, which the review suggested but which no cached reference describes, so adding them would mean fetching PMIDs that appear only in the deep-research report; and Buschke-Ollendorff syndrome, which belongs in its own entry. Provenance. Curated from PubMed with a five-iteration OpenScientist deep-research job as a cross-check, recorded alongside this entry. Content_type was checked before writing, and after review round 1 the full texts were mined again rather than trusted to have been mined the first time.

Review round 1: mine the cached natural history cohort for five phenotypes, split bundled treatment, add trial · 2026-09-09T18:56:06Z · View source

Review round 1 on PR #11467 requested changes on six findings, all of them under-consumption of references this branch had already cached. The reviewer was right about every item, and the diagnosis was sharper than the individual findings: the natural history cohort at PMID:31485554 was quoted once and that one sentence reused three times, while the same committed full text carried denominators for four unrecorded phenotypes, the diagnosis-by-age figure, the normal-biochemistry finding, the neuropathic pain recommendation and the trial registration. Five phenotypes added, four of them with denominators from the cohort rather than qualitative terms. Skin changes overlying affected bone bind HP:0010783 Erythema at FREQUENT, from 16 of 30 patients, with a second evidence item recording that only 9 of those 16 had the vascular erythematous morphology the term covers. Somatic sensory deficit binds HP:0003474 at FREQUENT from 77 percent on examination. Peripheral nerve compression binds HP:0003406 at OCCASIONAL from five of thirty, one band below the sensory deficit it sits inside, with ultrasound confirmation of the mechanism and an independent source naming it as a surgical indication. Skeletal muscle atrophy binds HP:0003202 at OCCASIONAL from eight of thirty, with the source attributing it to disuse, which is what determines where it sits in the graph. Localized soft tissue swelling binds HP:6000840, the only one of the five banded from a qualitative framing rather than a count, and its evidence explanation says so. All five are wired into the pathograph rather than left free-floating. Skin changes hang DIRECT off MEK1-ERK hyperactivation, because the source ties the erythematous change specifically to MAP2K1-positive disease and not to the TGF-beta arm. Nerve compression hangs DIRECT off segmental cortical hyperostosis; sensory deficit hangs off the same node as INDIRECT_KNOWN_INTERMEDIATES with the compression as the stated intermediate. Muscle atrophy hangs off pain, deformity and restricted movement as INDIRECT_KNOWN_INTERMEDIATES via disuse. Limb swelling hangs off the hyperostosis as INDIRECT_UNKNOWN_INTERMEDIATES, because the sources list it without establishing whether it is soft tissue involvement by the clone, venous or lymphatic obstruction, or a consequence of the hypervascularity. The bundled treatment node is split. It described conservative measures or surgery while carrying therapeutic_modality SURGERY, so the tag contradicted its own content. There are now four treatments: surgery, physical therapy, bisphosphonates and gabapentinoids. The bisphosphonate entry quotes the source saying definitive guidance on its use is lacking, because a treatment being used is not a treatment being established, and its mechanism link is MODULATES rather than INHIBITS for the same reason. The gabapentinoid entry targets the nerve compression node rather than the pain node, and its description states that it does not relieve the compression itself. NCT02504879 is added as a clinical trial. It is the NIH natural history study the cohort is drawn from, so recording it makes the provenance of most of this entry's frequency data explicit rather than implicit. Status is UNKNOWN because the cached trial record does not carry a recruitment status and guessing one would be fabrication. Normal bone biochemistry is added as a diagnosis entry with presence ABSENT. The negative finding is worth curating because it separates melorheostosis from the metabolic sclerosing bone diseases that produce a similar radiographic impression, and because it is what a disease driven by a segmental somatic clone should look like. Suggestions addressed: mappings for MONDO:0007970 and NCIT:C84887, with OMIM:155950 and Orphanet:2485 recorded in the justification and both verified against MONDO cross-references; onset recorded as CHILDHOOD on the obligate phenotype with the diagnosis-by-age-20 figure in its notes; neuropathic pain agents curated. Two suggestions not taken. No frequency is set on flexion contracture because no cached source gives a denominator for contracture specifically; the 53 percent figure the review may have had in mind is for restricted joint mobility, which is a different phenotype already banded FREQUENT and is now grounded on that quote. Animal and iPSC models are not added because no cached reference describes one, and adding them would mean fetching PMIDs that appear only in the deep-research report, which is exactly the hallucination risk the review flagged. The notes paragraph that listed skin and soft tissue involvement as an extension point is replaced. Naming something an extension point is not a scoping rationale when the evidence is already committed to the repository, and this is the second entry in this series where that phrasing concealed unmined cached full text. Validation: 69/69 snippets verified, up from 46/46. Term validation passes, all repository content gates pass, no mid-word truncations, no value/prose contradictions, one root, no orphan phenotypes, no dangling targets, weighted compliance 100.0 percent.

Create: Melorheostosis MONDO:0007970 · 2026-09-08T16:57:55Z · View source

Created from PubMed literature with a five-iteration OpenScientist deep-research job as a cross-check, launched before writing so it ran in parallel. The entry is built around a contrast. Two somatic genes cause melorheostosis and they reach the same tissue endpoint by opposite cellular routes. Activating MAP2K1 mutations drive ERK signalling, raise osteoblast proliferation and impair BMP2-mediated mineralisation, so the excess bone is largely unmineralised osteoid. Activating SMAD3 mutations drive TGF-beta signalling, suppress proliferation and enhance mineralisation, so affected bone is more mineralised than unaffected bone. They also produce different radiographic patterns, cortical dripping versus endosteal, and a review reports that MAP2K1 cases are more likely to show the classic dripping candle wax appearance. Modelling these as separate arms rather than collapsing them into one increased-bone-formation node preserves the contrast, and the subtypes slot on each node records which arm it belongs to. Three negatives are recorded deliberately. LEMD3 is carried as DISPUTED with REFUTE evidence: it genuinely causes osteopoikilosis and Buschke-Ollendorff syndrome, and melorheostosis-like lesions occur in those conditions, but sequencing of blood, skin and bone from a patient with isolated melorheostosis found nothing and reviews conclude it is not causative here. The sclerotome hypothesis is carried as a DEPRECATED mechanistic hypothesis with REFUTE evidence, because whole-body CT in thirty patients found only 17 percent conformed to a single sclerotome, yet reviews published after that test still state a sclerotomal distribution as fact. The deep-research report itself repeated the sclerotomal claim in its summary, which is direct evidence that keeping the deprecated hypothesis with its refutation is worth doing. And the somatic mosaicism has a testing consequence stated in the genetic notes: the mutations are absent from unaffected bone in the same patient, so a blood sample will be negative as a property of the disease rather than a limitation of the assay. The deep-research report contributed three things, each verified against its cited paper before use. A prevalence figure of 0.9 per million, which corrected a claim in the draft notes that no quotable prevalence existed. KRAS as a third somatic gene in a minority of cases, together with the genotype-phenotype correlation above. And a prospective NIH natural history cohort of thirty adults, which supplies contractures, range of motion limitation and limb swelling from a prospectively recruited population rather than from the case-report literature the disease otherwise rests on. The prevalence correction is the third instance in this series of a claim that no figure was available turning out to be a claim about my search rather than about the literature. It is recorded in the entry notes rather than quietly replaced. Process. Content_type was checked on every cache before writing; seven of ten were full text. Two YAML failures from unquoted colons in plain scalars were found by validation and fixed, and a systematic scan for that pattern was run rather than fixing them one at a time. The full check battery was run as the last step after the report was folded in, not midway. Validation: 46/46 snippets verified, term validation passes, qualifier terms pass, weighted compliance 100.0 percent, no truncations, no value/prose contradictions, one root, no orphan phenotypes, no dangling targets.

OpenScientist ▸

1. Disease Information

openscientist-autonomous 2026-09-08T12:51:05.244832

1. Disease Information

Overview. Melorheostosis is a rare, benign, progressive sclerosing bone dysplasia of mesodermal origin featuring exuberant cortical bone overgrowth, most often in a single limb, that flows along the bone like melted wax. It was first described by Léri and Joanny (1922). [review] "Melorheostosis is a rare bone disease characterized by abundant bone formation with a characteristic radiographic appearance that resembles 'dripping candle wax'" (PMID 39776616).

Key identifiers. - MONDO: MONDO:0007970 - OMIM: 155950 (Melorheostosis, isolated) - Orphanet: ORPHA:2485 - ICD-10: Q78.8 (Other specified osteochondrodysplasias); ICD-11: LD24.Y / FB80.Y (other specified osteopathies) — often coded under other specified osteochondrodysplasias - MeSH: D008586 (Melorheostosis; MeSH tree C05.116.099.708.410) - UMLS/SNOMED CT: Melorheostosis (disorder), SCTID 43994001

Synonyms / alternative names. Léri disease; Léri–Joanny syndrome; "flowing hyperostosis"; "candle wax bone disease"; rheostosis; osteosis eburnisans monomelica.

Source of information. Derived predominantly from aggregated disease-level resources (OMIM, Orphanet) and from individual-patient case reports/case series plus a single institution's prospective natural-history cohort (NIH; PMIDs 31485554, 35403375). There is no large EHR/registry dataset given the rarity.

2. Etiology

Primary causal factor: genetic (somatic mosaicism). Melorheostosis is caused by post-zygotic (somatic) mosaic activating mutations arising in mesenchymal/osteoblast-lineage precursors during development. There is no infectious, environmental, or dietary cause; it is not inherited.

Genetic risk factors (causal variants). - MAP2K1 (MEK1) — the major driver. Recurrent activating missense variants cluster in the MEK1 negative-regulatory domain: p.Gln56Pro (Q56P), p.Lys57Glu (K57E), p.Lys57Asn (K57N), and a catalytic-domain variant p.Cys121Ser (C121S) (PMIDs 29643386, 32387835). [human clinical / in vitro] "we identify somatic mosaic MAP2K1 mutations in affected, but not unaffected, bone of eight unrelated patients ... The activating mutations (Q56P, K57E and K57N) cluster tightly in the MEK1 negative regulatory domain" (PMID 29643386). - SMAD3 — somatic activating mutations in endosteal-pattern melorheostosis (PMID 32232430). - KRAS — somatic activating variants in a subset (osteopathia-striata-like pattern) (PMID 30989250). - LEMD3 (MAN1) — germline loss-of-function mutations cause osteopoikilosis (OPK) and Buschke–Ollendorff syndrome (BOS); they do not cause isolated sporadic melorheostosis (PMIDs 17087626, 19438932, 31129707).

Modifier genes. None firmly established. Because lesions are clonal and mosaic, disease extent likely reflects the developmental timing and location of the somatic mutation rather than trans-acting modifiers.

Environmental risk factors. None identified (toxins, occupation, radiation, age, sex, family history all non-contributory). Trauma is sometimes an incidental discovery trigger, not a cause (PMID 41938408).

Protective factors. None identified (genetic or environmental).

Gene–environment interactions. None documented; the disease is monogenic-somatic.

3. Phenotypes

Melorheostosis is highly variable ("variable severity, progressive/insidious course"). Core phenotypes with suggested HPO terms and frequency (from the 47-patient natural-history cohort and case series; PMIDs 31485554, 35403375, 39776616):

Phenotype	Type	HPO term	Onset	Severity/Course	Frequency
Bone/limb pain	Symptom	Bone pain HP:0002653	Childhood–adult	Chronic, progressive	Very frequent (presenting complaint)
Cortical hyperostosis / sclerosis	Physical sign (imaging)	Cortical thickening of long bones HP:0005791; Hyperostosis HP:0100774	Congenital lesion, symptoms later	Progressive	Defining feature (~100%)
Joint contracture	Clinical sign	Joint contracture HP:0034392	Childhood–adult	Progressive	Frequent
Limited range of motion	Clinical sign	Limitation of joint mobility HP:0001376	Variable	Progressive	Frequent
Limb deformity / length discrepancy	Physical	Limb deformity; Limb undergrowth	Childhood	Progressive	Frequent
Limb swelling / soft-tissue mass	Sign	Localized skin lesion; Soft tissue swelling	Variable	Stable/progressive	Common
Overlying skin changes (hyperpigmentation, sclerotic/nevoid skin, hemangioma)	Physical	Abnormality of the skin HP:0000951	Variable	Stable	Subset
Neurological compromise (nerve entrapment, myelopathy in spinal disease)	Sign	Peripheral neuropathy; Myelopathy	Variable	Progressive	Rare (axial disease)
Fatigue (general/physical)	Symptom	Fatigue HP:0012378	Adult	Chronic	Prominent functional burden

Laboratory abnormalities: characteristically absent — serum calcium, phosphate, alkaline phosphatase, ESR, CRP are normal (PMIDs 42559563, 41938408). Normal biochemistry is itself a diagnostic clue.

Age of onset. Lesions are congenital/developmental but frequently present in childhood or adulthood; late-onset monomelic presentations occur (PMID 42559563).

Quality-of-life impact. [human clinical] Substantial functional burden: high-demand leisure activities were the least retained and most often given up (27%); general and physical fatigue were the most limiting constructs, with physical fatigue moderately negatively correlated with activity engagement (r = −0.524, p < .001) (PMID 35403375).

4. Genetic / Molecular Information

Causal genes (gene symbol; HGNC; OMIM; locus). - MAP2K1 — HGNC:6840; NCBI Gene 5604; OMIM 176872; 15q22.31; encodes MEK1 (UniProt Q02750). Major driver. - SMAD3 — HGNC:6769; NCBI Gene 4088; OMIM 603109; 15q22.33. Endosteal subtype. - KRAS — HGNC:6407; NCBI Gene 3845; OMIM 190070; 12p12.1. Rare subset. - LEMD3 — HGNC:28887; NCBI Gene 23592; OMIM 607844; 12q14.3. Germline; OPK/BOS spectrum (not isolated MEL).

Pathogenic variants. - Type/class: missense, gain-of-function (activating). MAP2K1: Q56P, K57E, K57N (negative-regulatory domain, exon 2 hotspot); C121S (catalytic domain). - Classification: Pathogenic (activating) per functional evidence; these are established oncogenic hotspots (also seen in Langerhans-cell histiocytosis, arteriovenous malformations, and some cancers). - Somatic vs germline: Somatic/mosaic, present in affected bone and overlying skin but not in unaffected tissue or blood (PMID 29643386); mosaicism detected in overlying skin in 4/5 patients tested. Skin distribution of somatic variants was mapped in PMID 32791068. - Allele frequency: Absent from population databases (gnomAD/1000G) as constitutional variants — they are somatic and, as germline events, would be embryonic-lethal or oncogenic. - Functional consequence: Gain of function → constitutive MEK1 kinase activity → increased phospho-ERK1/2 (MAP2K1); enhanced TGF-β/SMAD transcriptional activity (SMAD3).

Modifier genes / epigenetics / chromosomal abnormalities. No established modifier genes, no recurrent epigenetic signature, and no chromosomal abnormalities (aneuploidy/translocation/CNV) are implicated. A subset of clinically classical cases has no identifiable mutation in MAP2K1/SMAD3/LEMD3/KRAS (PMID 32387835), indicating additional undiscovered drivers.

5. Environmental Information

Environmental factors: None implicated (no toxin, radiation, pollution, or occupational association).
Lifestyle factors: None (no smoking/diet/alcohol/exercise association).
Infectious agents: Not applicable — melorheostosis is not infectious.

This section is largely not applicable: melorheostosis is a somatic genetic disease with no known environmental contribution.

6. Mechanism / Pathophysiology

Ordered causal chain

MAPK branch (classical "dripping candle wax", MAP2K1): 1. A post-zygotic somatic MAP2K1 mutation arises in an osteoblast/mesenchymal precursor during development → leads to a mosaic clone of mutant cells confined to a sclerotome/limb segment. 2. The mutation (e.g., K57N) causes constitutive MEK1 kinase activity (loss of negative autoregulation). 3. Constitutive MEK1 results in increased phospho-ERK1/2 signaling, detectable as a mosaic pattern (two osteoblast populations with distinct p-ERK levels) (PMID 29643386). 4. ERK hyperactivation leads to increased osteoprogenitor proliferation via cell-cycle activation (elevated phospho-Rb, Ki-67, higher S-phase fraction; CDK4-dependent) (PMIDs 29643386, 41395834). 5. Mutant cells secrete increased VEGF, driving hypervascularity/angiogenesis; VEGF is sufficient alone to increase mineralization of osteogenic cultures (PMID 37737377). [in vitro] 6. In parallel, the mutation impairs BMP2-mediated terminal mineralization/differentiation, which results in accumulation of excess unmineralized osteoid alongside dense cortical/woven bone (PMID 29643386). 7. The net effect results in segmental cortical/medullary hyperostosis → clinically pain, deformity, contractures, limb swelling; paradoxically the bone is harder and mechanically stronger despite decreased mineral density (inferred from geometry/microstructure; PMID 31689526). [model organism]

TGF-β/SMAD branch (endosteal pattern, SMAD3): 1b. A somatic SMAD3-activating mutation → enhances TGF-β/SMAD nuclear translocation and target-gene expression in osteoblasts (PMID 32232430). 2b. This stimulates osteoblast differentiation and mineralization (antagonized by BMP2) → endosteal-pattern hyperostosis.

(KRAS-driven cases converge on RAS–MAPK activation, upstream of MEK1.)

Detail by category

Molecular pathways: RAS–MAPK/ERK cascade (KEGG hsa04010; Reactome R-HSA-5673001 "RAF/MAP kinase cascade"); TGF-β/SMAD signaling (KEGG hsa04350; Reactome R-HSA-170834). BMP signaling is antagonistic/dysregulated. GO: MAPK cascade GO:0000165; ERK1/ERK2 cascade GO:0070371; transforming growth factor beta receptor signaling pathway GO:0007179.
Cellular processes: increased cell proliferation (GO:0008284), dysregulated osteoblast differentiation (GO:0001649) and ossification (GO:0001503), angiogenesis (GO:0001525). Cell-cycle dysregulation (phospho-Rb/CDK4). No apoptosis or inflammation signature is prominent.
Protein dysfunction: Gain of function — constitutively active MEK1 kinase; hyperactive SMAD3 transcription factor. Not misfolding/aggregation.
Metabolic changes: No systemic metabolic derangement (normal Ca/PO4/ALP). Local: increased collagen I/IV secretion by mutant iMSCs (PMID 37737377).
Immune system involvement: Not a primary feature; co-expression clustering noted altered interferon signaling in SMAD3 lesions (PMID 32232430) — significance uncertain.
Tissue damage mechanisms: Mechanical (mass effect → contracture, nerve/cord compression), not oxidative/ischemic/fibronecrotic.
Molecular profiling: RNAseq/GSEA of lesional tissue shows upregulation of proliferative pathways (PMID 32387835) and TGF-β/ossification/ECM-organization programs (PMID 32232430). Proteomic: elevated VEGF and collagen secretion (PMID 37737377).
Functional genomics: iPSC→iMSC→osteoblast patient models and MEK1DD mouse (see §15).

Cell types (CL): osteoblast CL:0000062; osteoprogenitor/mesenchymal stem cell CL:0000134; fibroblast CL:0000057 (overlying skin carries the mutation). Chemical entities (CHEBI): zoledronic acid CHEBI:46557; palbociclib CHEBI:85993; trametinib CHEBI:75998 (MEK inhibitor class).

7. Anatomical Structures Affected

Organ level (primary): Bone (UBERON:0002481 bone tissue; UBERON:0001474 bone element), predominantly long bones of the limbs (appendicular skeleton). Lower-extremity long bones (femur, tibia, fibula) most common; upper extremity (humerus, radius, ulna, hand) frequent. Cohort: 30/47 lower extremity, 14/47 upper extremity, 1 both (PMID 35403375).
Secondary involvement / body systems: Musculoskeletal (joints — contracture; muscle/soft tissue — swelling, sclerosis, ossification), integumentary (overlying skin — hyperpigmentation, scleroderma-like/nevoid changes), nervous (peripheral nerve entrapment; spinal cord compression/myelopathy in rare axial disease, PMID 41852826), vascular (hemangioma/hypervascularity). Axial sites reported: spine (C-spine, PMID 41852826), pubis (PMID 42047352).
Tissue/cell level: cortical and endosteal bone (dense cortical, woven bone, hypervascular); connective tissue of skin (collagen/elastin). Target cells: osteoblasts (CL:0000062), osteoprogenitors/MSCs (CL:0000134).
Subcellular (GO cellular component): nucleus GO:0005634 (SMAD3 translocation), cytoplasm/plasma membrane (MEK1/ERK signaling GO:0005886), extracellular region/matrix GO:0005576 (osteoid, collagen).
Localization/UBERON: femur UBERON:0000981; tibia UBERON:0000979; fibula UBERON:0001446; humerus UBERON:0000976; radius UBERON:0001423; ulna UBERON:0001424; vertebral column UBERON:0001130.
Lateralization: Characteristically unilateral, asymmetric, monomelic, in a sclerotomal distribution; bilateral/multifocal is uncommon (PMIDs 41938408, 39776616).

8. Temporal Development

Onset: Congenital/developmental lesion (somatic mutation occurs in utero); clinical onset is typically insidious, presenting in childhood or adulthood; late-onset adult presentations occur.
Onset pattern: Chronic, insidious (not acute).
Progression: Slowly progressive, lifelong. Bone overgrowth and contractures accrue over years to decades (e.g., 20-year progressive history, PMID 42555496). No formal staging system exists.
Course pattern: Progressive/stable; not relapsing-remitting or episodic.
Duration: Chronic, lifelong (not self-limited).
Remission: No spontaneous remission of bone lesions; symptom control (pain) is achievable with treatment.
Critical periods: Developmental window (timing/location of the somatic mutation) determines lesion distribution/extent; there is no defined therapeutic "critical window," though early physiotherapy may limit contractures.

9. Inheritance and Population

Epidemiology — prevalence: ultra-rare, ~0.9 per million (i.e., ~0.00009 per 100,000); global prevalence < 1 per million (PMIDs 41938408, 42559563). Incidence not reliably estimated. [review/case series] "an estimated prevalence of 0.9 per million" (PMID 41938408).
Inheritance pattern: Sporadic, non-hereditary — driven by somatic mosaicism; not Mendelian. (Germline LEMD3 → autosomal dominant OPK/BOS is a separate, related entity.)
Penetrance/expressivity: Not applicable in the classical sense (somatic); lesion expressivity is highly variable.
Genetic anticipation / germline mosaicism / founder effects / consanguinity / carrier frequency: Not applicable — no vertical transmission, no carriers, no founder or consanguinity effect.
Population demographics: No ethnic or geographic predilection; reported worldwide. Sex ratio ~1:1 (no strong sex predilection). Age distribution: diagnosed across pediatric to older-adult ages.

10. Diagnostics

Diagnosis is primarily radiographic, supported by normal biochemistry and (non-specific) histology; molecular confirmation requires lesional tissue.

Imaging (cornerstone): Plain radiograph/CT — flowing cortical hyperostosis resembling "dripping/melting candle wax" in a sclerotomal distribution (pathognomonic). [review/case] "a pathognomonic imaging appearance of flowing hyperostosis resembling melted candle wax" (PMID 32994853). MRI delineates soft-tissue involvement/extent; Tc-99m-MDP bone scintigraphy shows increased uptake reflecting activity (PMID 42555496); FDG/PSMA PET may be positive incidentally (PMIDs 42313078, 42047352). RadLex: hyperostosis.
Laboratory tests/biomarkers: No diagnostic blood/urine biomarker; serum Ca, PO4, ALP, ESR, CRP normal (LOINC panels for these analytes). Normality helps exclude Paget disease and metabolic bone disease.
Biopsy/histopathology (supportive, non-specific): dense cortical bone (73.3%), woven bone (60%), hypervascularity/increased porosity (66.7%), prominent cement lines (33%) (PMID 31386640); hyalinized collagen with dystrophic calcification also described (PMID 42559563). Biopsy is often avoidable when imaging is classic.
Genetic testing: Sequencing of affected lesional tissue (bone and/or overlying skin), not blood, because variants are somatic/mosaic. WES, WGS, and RNAseq of affected-vs-unaffected tissue are the definitive research/clinical approach and identified MAP2K1/SMAD3/novel variants (PMIDs 29643386, 32232430, 32387835). Targeted single-gene/panel testing (MAP2K1, SMAD3, KRAS, LEMD3) on lesional DNA is reasonable. Karyotype/CMA/FISH/mtDNA/repeat testing: not indicated (no such abnormalities).
Omics-based diagnostics: RNAseq of lesion (proliferative-pathway upregulation) is research-grade; no validated clinical omics/liquid-biopsy assay exists.
Clinical criteria / differential diagnosis: No formal consensus criteria; diagnosis is clinicoradiologic. Differential: osteoma/osteoid osteoma, osteoblastoma (can mimic and recur — PMID 42004422), osteosarcoma/parosteal osteosarcoma, fibrous dysplasia, Paget disease of bone, osteopathia striata, osteopoikilosis, and mixed sclerosing bone dysplasia; distinguishing features are the flowing candle-wax pattern, sclerotomal distribution, normal labs, and benign non-aggressive behavior (PMIDs 32994853, 41214899).
Screening: No population/newborn/carrier screening is applicable (somatic, non-heritable).

11. Outcome / Prognosis

Survival/mortality: Benign disease; normal life expectancy; not directly life-limiting. No disease-specific mortality data (deaths are not attributable to melorheostosis itself). Malignant transformation is a theoretical concern but has not been clinically reported (PMID 41938408).
Morbidity/disability: Chief morbidity is chronic pain, deformity, contracture, and reduced mobility, producing disability and reduced participation in high-demand activities; fatigue is prominent (PMID 35403375). Rare severe morbidity: neurological deficit from nerve entrapment or spinal cord compression (PMIDs 41852826, 41717511).
Quality of life: Impaired via pain/fatigue/loss of leisure activities (natural-history cohort, PMID 35403375). No disease-specific validated QoL instrument; generic tools used (Activity Card Sort, Multidimensional Fatigue Inventory, Lower/Upper Extremity Functional scales).
Complications: contractures, limb-length discrepancy, joint dysfunction, soft-tissue ossification, fibrolipomatous/vascular masses, nerve/cord compression; rare fragility fracture at unaffected sites (PMID 32057643).
Recovery potential: Bone lesions do not regress; symptoms are manageable. Function may improve with physiotherapy/analgesia and appropriately timed surgery.
Prognostic factors: Lesion extent, axial (spinal) involvement (worse — neurological risk), degree of contracture, and pain severity. Prognostic biomarkers: none validated; MAP2K1 vs SMAD3 genotype correlates with radiographic subtype and may predict therapy response (predictive, not prognostic).

12. Treatment

No cure and no established guideline exist; management is multidisciplinary and symptom-directed (PMID 42273437). [review/case] "There are no established guidelines for its management, as it is not a curable condition. Treatment primarily focuses on symptom relief."

Pharmacotherapy:
NSAIDs (e.g., celecoxib) for pain — VAS pain reduced to 1/10 with celecoxib + physiotherapy (PMID 42559563). NCIT: Nonsteroidal Anti-inflammatory Agent.
Bisphosphonates — IV zoledronic acid and pamidronate reduce pain and disease severity (PMIDs 42273437, 34169026, 32057643). NCIT: Bisphosphonate; Zoledronic Acid (CHEBI:46557).
Pharmacogenomics: none specific.
Targeted / advanced therapeutics (experimental):
MEK inhibitors (trametinib/selumetinib class) — mechanistically rational (block MEK1→ERK); proposed by discovery authors as a treatment avenue (PMID 29643386). NCIT: MEK Inhibitor.
CDK4/6 inhibitor palbociclib — FDA-approved; reduced phospho-Rb, proliferation, and mineralization in MAP2K1-mutant patient iMSCs/osteoblasts, "opening a pathway to treatment" (PMID 41395834). [in vitro] NCIT: Cyclin-Dependent Kinase Inhibitor.
Gene/cell/RNA therapy: none in use.
Surgical/interventional: osteotomy/contracture release, excision of exostoses/soft-tissue masses, limb-lengthening/deformity correction, and decompression/fusion for spinal cord compression; reserved for severe deformity, refractory pain, or neurological compromise (PMIDs 41852826, 41938408). Recurrence after excision is common. NCIT: Orthopedic Surgery; Osteotomy.
Supportive/rehabilitative: Physical/occupational therapy for range of motion, contracture prevention, and function; pain management; splinting (PMIDs 35403375, 41717511). NCIT: Physical Therapy; Rehabilitation Therapy.
Experimental / clinical trials: An NIH natural-history study (NCT02504879) has characterized the disease; no approved disease-modifying drug trial has reported results. MEK/CDK4 inhibition remains preclinical.
Treatment outcomes/adverse events: Bisphosphonate response is variable (only ~9 zoledronate reports to date; PMID 42273437); adverse events per drug class (bisphosphonate: acute-phase reaction, osteonecrosis of the jaw; MEK inhibitors: rash, ocular/cardiac toxicity; CDK4/6i: cytopenias).
Personalized medicine: Genotype-guided targeting (MEK inhibitor for MAP2K1; potential TGF-β–directed approaches for SMAD3) is the emerging paradigm.

13. Prevention

Primary prevention: Not possible — the causal somatic mutation arises sporadically in utero; no modifiable risk factor exists.
Secondary prevention (early detection): Early radiographic recognition prevents misdiagnosis, unnecessary biopsy, and enables early physiotherapy to limit contractures (PMIDs 30647832, 34169026).
Tertiary prevention: Physiotherapy, analgesia, bisphosphonates, and timely surgery to prevent/limit contracture, deformity, and neurological complications.
Immunization / behavioral / public-health / environmental interventions: Not applicable.
Genetic counseling: Reassurance that the disease is sporadic and non-heritable, with negligible recurrence risk to offspring or siblings (the mutation is somatic, not germline). Prenatal/carrier/PGD testing not applicable.

14. Other Species / Natural Disease

Taxonomy / natural disease: Melorheostosis is essentially a human-specific clinical entity; a well-defined naturally occurring homolog in companion animals or wildlife is not established (no OMIA entry for a melorheostosis phenotype). Human: Homo sapiens NCBI:txid9606.
Orthologous genes: Map2k1 (mouse, NCBI Gene 26395; NCBI:txid10090), smad3 (mouse 17127), Kras (mouse 16653) — highly conserved.
Comparative biology / evolutionary conservation: The RAS–MAPK and TGF-β/SMAD pathways are deeply conserved across vertebrates; the disease mechanism is modeled in mouse (see §15). Zoonotic potential: none (not transmissible).

This section is largely not applicable as a naturally occurring cross-species disease; relevance is via engineered model organisms.

15. Model Organisms

Mammalian (mouse): MEK1DD conditional transgenic mouse expressing constitutively active MEK1 in osteoprogenitors postnatally. [model organism] Recapitulates "extra-cortical bone formation, abundant osteoid formation, decreased mineral density, and increased porosity," with paradoxically stronger bone due to altered geometry/microstructure (PMID 31689526). Model type: conditional/transgenic gain-of-function (Cre-driven in osteoprogenitors). Resources: MGI (Map2k1, MGI:1346866).
Limitations: does not reproduce the mosaic/segmental (sclerotomal) distribution, the overlying soft-tissue/skin involvement, or the natural somatic-mutation timing; expression is broader than the human clonal patch.
Human in vitro / iPSC models: Patient-derived iPSCs reprogrammed (Sendai) from MAP2K1-mutant skin fibroblasts, differentiated to induced MSCs → osteoblasts; retain the mutation, show elevated MEK1/ERK activity, increased VEGF, proliferation, collagen I/IV, and mineralization (PMIDs 37737377, 41395834). Isogenic unaffected fibroblasts serve as controls. Cellosaurus/ATCC: patient-specific lines (not standardized).
Applications: dissecting MAPK→proliferation/VEGF mechanisms, testing MEK and CDK4/6 inhibitors (palbociclib), and modeling the mineralization paradox.
Model databases: MGI (mouse), Alliance of Genome Resources.

Supported vs Refuted Hypotheses

Supported: - Somatic mosaic activating MAP2K1 mutations cause classical melorheostosis via MEK1→ERK hyperactivation (PMID 29643386). ✔ - Genetic heterogeneity: SMAD3/TGF-β drives the endosteal subtype; KRAS a rare subset (PMIDs 32232430, 30989250). ✔ - VEGF is a sufficient downstream driver of increased bone mineralization in mutant cells (PMID 37737377). ✔ - MEK1DD mouse recapitulates core skeletal features (PMID 31689526). ✔ - CDK4 inhibition (palbociclib) reduces mutant-cell proliferation/mineralization (PMID 41395834). ✔

Refuted / not supported: - Germline LEMD3 mutation causes isolated sporadic melorheostosis — refuted; LEMD3 underlies OPK/BOS but not isolated MEL (PMIDs 17087626, 19438932, 31129707). - Environmental/infectious/inherited causation — not supported; disease is sporadic-somatic.

Limitations and Future Directions

Evidence rests on small cohorts and case reports (ultra-rare disease); a subset of classical cases has no identified mutation, implying additional drivers to discover.
No controlled therapeutic trials; bisphosphonate and targeted-therapy evidence is anecdotal/preclinical. MEK- and CDK4/6-inhibitor efficacy/safety in patients is unproven.
Genotype–phenotype correlations (subtype-specific therapy) and single-cell/spatial characterization of the mosaic lesion are priority future work.

Key ontology annotations (summary)

MONDO: MONDO:0007970 · HPO: HP:0002653, HP:0100774, HP:0005791, HP:0034392, HP:0001376, HP:0012378
Genes (HGNC): MAP2K1 (HGNC:6840), SMAD3 (HGNC:6769), KRAS (HGNC:6407), LEMD3 (HGNC:28887)
GO: GO:0000165, GO:0070371, GO:0007179, GO:0001503, GO:0001649, GO:0008284, GO:0001525
CL: CL:0000062 (osteoblast), CL:0000134 (MSC), CL:0000057 (fibroblast)
UBERON: UBERON:0001474 (bone element), UBERON:0000981 (femur), UBERON:0000979 (tibia), UBERON:0001446 (fibula)
CHEBI: CHEBI:46557 (zoledronic acid), CHEBI:85993 (palbociclib), CHEBI:75998 (trametinib)
NCIT: Bisphosphonate Therapy, NSAID, MEK Inhibitor, CDK Inhibitor, Orthopedic Surgery, Physical Therapy

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Genetic Associations

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Epidemiology

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References

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2. Etiology

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4. Genetic / Molecular Information

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Key ontology annotations (summary)

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