Diaphyseal Medullary Stenosis with Malignant Fibrous Histiocytoma

Mendelian MONDO:0007205 Pathograph 8 Show in embeddings browser Hereditary cancer predisposition syndrome Skeletal dysplasia

Diaphyseal medullary stenosis with malignant fibrous histiocytoma is an autosomal dominant syndrome that combines a long-bone dysplasia with a high lifetime risk of bone sarcoma. Affected individuals develop bone infarctions, abnormal cortical growth with narrowing of the medullary canal, pathological fractures and painful debilitation, and roughly a third go on to develop malignant fibrous histiocytoma of bone, now classified as undifferentiated pleomorphic sarcoma. Myopathy is part of the syndrome and is often under-emphasised in the name. The molecular cause is unusual enough to be worth stating carefully. The locus was mapped to 9p21-22 and then resisted identification for over a decade, because the causal mutations do not lie in any of the genes that region is known for. They lie in one of three previously uncharacterised terminal exons of MTAP, which encodes methylthioadenosine phosphorylase, an enzyme of the polyamine, adenine and methionine salvage pathways. Two of those exons entered the primate genome as independent retroviral integration events at least forty million years ago and have since acquired a function. Six retroviral-sequence MTAP isoforms exist, each able to interact physically with the archetype enzyme, and the disease mutations cause exon skipping that dysregulates alternative splicing of all of them. So this is not a simple enzyme deficiency. One of the two reported mutations is synonymous, changing no amino acid at all, so the pathogenic effect cannot be a change to the protein sequence and has to act on the transcript. The lesion is in a regulatory isoform that interacts with the canonical protein, and its consequence is disordered splicing across the whole isoform family rather than loss of a single product. This is a germline predisposition syndrome, and under the granularity ladder in the design-decision register it follows the plain Mendelian rules and stays separate from the somatic sarcoma entries it predisposes to. The relationship between the two is nonetheless real and worth curating: sporadic bone malignant fibrous histiocytoma shows loss of heterozygosity in the same 9p21-22 interval in most informative specimens, which is what motivated the search for a shared tumour suppressor.

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1
Mappings
1
Inheritance
6
Pathophys.
13
Phenotypes
1
Hypotheses
5
Gaps
8
Pathograph
1
Genes
2
Medical Actions
1
Trials
1
Models
1
References
1
Deep Research
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Mappings

MONDO
MONDO:0007205 diaphyseal medullary stenosis-bone malignancy syndrome
skos:exactMatch MONDO
MONDO:0007205 is the DMS-MFH concept modeled by this entry.
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Inheritance

1
Autosomal dominant HP:0000006
Autosomal dominant, established by linkage in affected kindreds before the gene was identified.
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:22464254 SUPPORT Human Clinical
"DMS-MFH) is an autosomal-dominant syndrome characterized by bone dysplasia, myopathy, and bone cancer"
States the inheritance pattern.
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Mechanistic Hypotheses

1
MTAP-PRMT5 synthetic-lethality vulnerability in DMS-MFH tumours
dmsmfh_prmt5_synthetic_lethality_untested EMERGING
Evidence balance 2 support
DMS-MFH tumours share two features with the MTAP-homozygous-deletion, protein-null cancers that PRMT5 inhibitors target: serum methylthioadenosine accumulates in affected individuals, and the tumour loses the wild-type MTAP allele outright. Whether that combination raises intratumoural MTA enough to confer the same PRMT5 dependence has never been measured in a DMS-MFH tumour. The germline allele here is synonymous and leaves archetype MTAP protein intact, which is a different molecular state from the biallelic-deletion tumours the PRMT5 strategy was developed against, and immunohistochemistry for MTAP would likely read falsely negative in this setting. See discussion dmsmfh_prmt5_vulnerability_untested for the full reasoning and what would settle it.
Nothing here supports offering PRMT5 inhibition to a patient with this syndrome; the treatments section's exclusion of that strategy stands. This entry records a hypothesis about tumour biology, not a therapeutic recommendation.
Pathograph links
Somatic Loss of the Wild-Type MTAP Allele -> Bone Sarcoma Predisposition INDIRECT UNKNOWN INTERMEDIATES Biallelic loss of MTAP function in the tumour precedes sarcoma, but what the resulting metabolic state does to the cell to permit transformation is not established.
Show evidence (2 references)
PMID:22464254 SUPPORT Human Clinical
"All three serum samples from unaffected individuals had no detectable MTA levels. In marked contrast, both affected individuals had accumulations of MTA detectable in their serum"
One of the two measured features the hypothesis rests on: serum MTA accumulates in affected individuals.
PMID:22464254 SUPPORT DIRECT Human Clinical
"direct sequencing of this patient’s osteosarcoma genomic DNA demonstrated homozygosity for the c.885A >G mutation"
The other measured feature: the tumour loses the wild-type allele outright, which is the second feature shared with MTAP-deleted cancers.
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Discussions and Knowledge Gaps

5
How does dysregulated MTAP isoform splicing produce bone infarction, cortical dysplasia and sarcoma?
KNOWLEDGE GAP OPEN dmsmfh_metabolic_route_to_bone_unmapped
Attached to
pathophysiology#Impaired Polyamine and Methionine Salvage Metabolism pathophysiology#Diaphyseal Cortical Dysplasia and Medullary Stenosis pathophysiology#Bone Sarcoma Predisposition
The molecular lesion is well characterised, the clinical phenotype is well described, and almost nothing connects them. Both endpoints are now measured: substrate accumulation shows the enzymatic step is perturbed in patients, and somatic loss of the wild-type allele shows how the tumour arises. The road between them is not. No cell type, signalling pathway or bone-remodelling mechanism has been implicated in the dysplasia, and nothing connects the metabolic state to either the dysplasia or the transformation. There is no animal model of the human lesion, and that is structural rather than incidental: the causal exons are retroviral insertions specific to primates, so a mouse has nothing to mutate.
Show evidence (1 reference)
PMID:22464254 SUPPORT INDIRECT Computational
"two of these MTAP exons arose from early and independent retroviral-integration events in primate genomes at least 40 million years ago, and since then, their genomic integration has gained a functional role"
The primate specificity of the affected exons is why no conventional mouse model of this lesion can exist, which is the structural reason the route between the measured endpoints remains unmapped.
Has the MTAP retroviral-exon mechanism been independently replicated?
KNOWLEDGE GAP OPEN dmsmfh_single_laboratory_dependence
Attached to
pathophysiology#MTAP Retroviral-Exon Splicing Mutation pathophysiology#Dysregulated Alternative Splicing of MTAP Isoforms
Essentially the entire molecular understanding of this syndrome rests on one paper from one laboratory, which also produced the earlier linkage work. That is not a criticism of the finding, which is internally coherent and explains a decade-long failure of candidate screening. It is a statement about how much independent corroboration exists, which is little, and it matters more than usual here because the claim is unusual: pathogenic synonymous mutations in retroviral-derived exons of a gene otherwise known as a somatic deletion passenger. The two strands of the mechanism are not equally exposed: that MTAP is a tumour suppressor in its own right is corroborated from outside the discovery laboratory by the Kadariya mouse work, so the sarcoma arm does not rest on a single group; the splicing mechanism itself, which is what these two nodes assert, has no such corroboration. Independent identification of the same exons in a new family would be the obvious confirmation and has not been reported.
Why do only some DMS-MFH families have myopathy, and what determines it?
KNOWLEDGE GAP OPEN dmsmfh_myopathy_variability
Attached to
phenotypes#Myopathy
Myopathy is named as a defining component of the syndrome but was absent from the three originally described families and appeared when two further families were characterised. A simple allele-phenotype correlation does not account for it, since the two myopathic families carry different mutations. With five families in total there is no power for modifier analysis, so whether this reflects an unrecognised modifier, an allele-specific effect that a larger series would resolve, or ascertainment differences in how carefully muscle was assessed, is open.
Do DMS-MFH tumours reach the MTA-high, PRMT5-dependent state that MTAP-deleted cancers do?
KNOWLEDGE GAP OPEN dmsmfh_prmt5_vulnerability_untested
Attached to
pathophysiology#Somatic Loss of the Wild-Type MTAP Allele treatments#Surveillance and Symptomatic Management
The treatments section excludes PRMT5 inhibition, and that exclusion is correct as stated: the strategy was developed for tumours with homozygous MTAP deletion and absent protein, whereas the germline allele here is synonymous and leaves archetype MTAP untouched. Immunohistochemistry for MTAP would very likely read falsely negative in this setting. But the question is better posed than the exclusion implies. Two things are true of these tumours that are also true of the MTAP-deleted cancers PRMT5 inhibitors target: serum methylthioadenosine accumulates in affected individuals, and the tumour loses the wild-type allele outright. Whether that combination is sufficient to produce the intratumoural MTA elevation that confers PRMT5 dependence has never been measured in a DMS-MFH tumour, and the entry should not be read as answering it. Intratumoural MTA and a PRMT5-dependence assay on tumour material would settle it.
Recorded as an open question rather than as a treatment. Nothing here supports offering PRMT5 inhibition to a patient with this syndrome, and the exclusion in the treatments notes stands.
What is the quality-of-life and functional burden of DMS-MFH, beyond the individual phenotypes and the sarcoma-risk figure?
KNOWLEDGE GAP OPEN dmsmfh_clinical_burden_undocumented
Attached to
clinical_burden#
The five reported families establish the phenotype and the sarcoma risk in considerable molecular and radiographic detail, but none of the source literature reports a quality-of-life instrument, a disability or functional burden score, or caregiver-burden data. For a disease whose non-neoplastic course is described as producing painful debilitation and progressive wasting from childhood, and which then carries a roughly one-in-three lifetime cancer risk, the absence of any formal burden measurement is itself notable and is recorded here rather than left implicit. With only five families ever described, a dedicated burden study is unlikely to be powered, which is worth stating rather than treating the gap as an oversight to be filled by more literature search.
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Pathophysiology

6
MTAP Retroviral-Exon Splicing Mutation
Mechanism confidence: Established
Mutations fall in the most proximal of three previously uncharacterised terminal exons of MTAP. Two of these exons derive from independent retroviral integrations into the primate genome at least forty million years ago, and have since taken on a function. The gene had been thought to be encoded by eight exons alone, which is why the locus resisted identification for more than a decade after linkage.
MTAP hgnc:7413 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves MTAP (hgnc:7413). hgnc:7413 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context MTAP hgnc:7413 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns MTAP (hgnc:7413). hgnc:7413 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: UNKNOWN
Heterozygous germline mutation in a retroviral-derived terminal exon, acting dominantly through dysregulated splicing rather than by straightforward loss of enzyme activity. No source classifies the functional impact, and the category is left UNKNOWN rather than guessed.
Downstream
Dysregulated Alternative Splicing of MTAP Isoforms The mutation causes skipping of the affected exon, which propagates to the splicing of the whole isoform family.
Somatic Loss of the Wild-Type MTAP Allele The germline allele is the first hit. It does not cause the second one: loss of the remaining wild-type copy is a stochastic somatic event, and what the inherited allele supplies is the vulnerability that makes that loss consequential. No mechanism linking the germline lesion to the occurrence of the somatic event has been established.
Show evidence (3 references)
PMID:22464254 SUPPORT Human Clinical
"We now demonstrate that DMS-MFH results from mutations in the most proximal of three previously uncharacterized terminal exons of the gene encoding methylthioadenosine phosphorylase, MTAP."
Identifies the causal gene and the exon in which mutations fall.
PMID:22464254 SUPPORT DIRECT Computational
"two of these MTAP exons arose from early and independent retroviral-integration events in primate genomes at least 40 million years ago, and since then, their genomic integration has gained a functional role"
Establishes the retroviral origin of the affected exons, which is why the gene's coding extent had been misjudged.
PMID:22464254 SUPPORT Human Clinical
"one mutation was a synonymous change at position c.885A>G"
The most informative single fact about this lesion. A synonymous change alters no amino acid, so the pathogenic effect cannot be a change to the protein sequence and must act on the transcript, which is what makes the splicing mechanism the explanation rather than one candidate among several.
Dysregulated Alternative Splicing of MTAP Isoforms
Mechanism confidence: Established
Six distinct retroviral-sequence-containing MTAP isoforms exist, and each can physically interact with the archetype enzyme. Exon skipping in the mutated isoform dysregulates alternative splicing across all of them, so the defect is combinatorial rather than confined to one product. Because the isoforms bind the canonical trimeric enzyme, the plausible route to disease is interference with archetype MTAP rather than its simple absence, though no source states this as demonstrated.
regulation of alternative mRNA splicing, via spliceosome GO:0000381 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated regulation of alternative mRNA splicing, via spliceosome (GO:0000381). GO:0000381 is a biological process from the Gene Ontology. ↕ DYSREGULATED
Downstream
Impaired Polyamine and Methionine Salvage Metabolism Disordered isoform splicing is presumed to compromise the enzyme's metabolic role. The quantitative effect on flux through the salvage pathways has not been reported in patients.
Show evidence (1 reference)
PMID:22464254 SUPPORT In Vitro
"Six distinct retroviral-sequence-containing MTAP isoforms, each of which can physically interact with archetype MTAP, have been identified."
Establishes the isoform family and their physical interaction with the canonical enzyme, which is what makes a splicing defect consequential.
Impaired Polyamine and Methionine Salvage Metabolism
Mechanism confidence: Established
MTAP is a ubiquitously expressed homotrimeric enzyme central to polyamine metabolism and to the adenine and methionine salvage pathways, and the enzymatic step is demonstrably impaired in patients. Methylthioadenosine, the direct substrate of MTAP and a by-product of polyamine synthesis, is not normally present in human serum. In a blinded assay it was undetectable in all three unaffected individuals and accumulated in both affected individuals. Substrate accumulation in vivo is a direct demonstration that the enzyme step is compromised, not an inference from what the enzyme is known to do, and it is the reason MONDO's classification of this syndrome as a disorder of polyamine metabolism is more than nominal. Two limits on how far that goes. The measurement is five people, two of them affected, so it establishes that the step is perturbed rather than how much. And flux through the downstream salvage pathways has not been measured at all: what is shown is that the substrate backs up, not what happens to polyamine or methionine economy as a result.
polyamine metabolic process GO:0006595 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated polyamine metabolic process (GO:0006595). GO:0006595 is a biological process from the Gene Ontology. ↕ DYSREGULATED L-methionine salvage GO:0071267 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves L-methionine salvage (GO:0071267). GO:0071267 is a biological process from the Gene Ontology. purine ribonucleoside salvage GO:0006166 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves purine ribonucleoside salvage (GO:0006166). GO:0006166 is a biological process from the Gene Ontology.
S-methyl-5-thioadenosine phosphorylase activity GO:0017061 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased S-methyl-5-thioadenosine phosphorylase activity (GO:0017061). GO:0017061 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Diaphyseal Cortical Dysplasia and Medullary Stenosis The route from the metabolic lesion to the bone phenotype is unknown. No cell type, signalling pathway or bone-remodelling mechanism has been implicated.
Show evidence (3 references)
PMID:22464254 SUPPORT INDIRECT Other
"MTAP is a ubiquitously expressed homotrimeric-subunit enzyme critical to polyamine metabolism and adenine and methionine salvage pathways"
States the enzyme's metabolic role. Typed INDIRECT and OTHER because this is background description of MTAP biology rather than a measurement in patients, and it establishes what the enzyme does. The measurement that shows the pathway is disturbed is the next item.
PMID:22464254 SUPPORT Human Clinical
"All three serum samples from unaffected individuals had no detectable MTA levels. In marked contrast, both affected individuals had accumulations of MTA detectable in their serum"
A direct in-vivo measurement of the enzyme's own substrate, blinded, with a clean separation between affected and unaffected. This is the propositional evidence that the MTAP step is impaired in patients.
PMID:22464254 SUPPORT Human Clinical
"MTA is not normally present in human serum."
Establishes the baseline that makes detectable serum MTA in affected individuals interpretable as accumulation rather than as normal variation.
Somatic Loss of the Wild-Type MTAP Allele
Mechanism confidence: Established
The tumour-suppressive mechanism is characterised, and it is Knudson's two hits. In an osteosarcoma from an affected individual carrying c.885A>G, the tumour DNA was homozygous for the mutation, and loss-of-heterozygosity analysis across the 2.9 Mb critical region showed complete loss of the wild-type allele from the unaffected chromosome. So the germline allele is the first hit and somatic loss of the remaining wild-type copy is the second. This is also what ties the syndrome to its sporadic counterpart: the same interval is lost in most informative sporadic bone malignant fibrous histiocytoma specimens, which is what motivated the search for a shared tumour suppressor in the first place.
MTAP-PRMT5 synthetic-lethality vulnerability in DMS-MFH tumours
Downstream
Bone Sarcoma Predisposition Biallelic loss of MTAP function in the tumour precedes sarcoma, but what the resulting metabolic state does to the cell to permit transformation is not established. MTAP-PRMT5 synthetic-lethality vulnerability in DMS-MFH tumours
Show evidence (1 reference)
PMID:22464254 SUPPORT DIRECT Human Clinical
"direct sequencing of this patient’s osteosarcoma genomic DNA demonstrated homozygosity for the c.885A >G mutation"
Establishes tumour homozygosity for the germline allele, the direct evidence of a second hit.
Diaphyseal Cortical Dysplasia and Medullary Stenosis
Mechanism confidence: Established
Abnormal cortical growth narrows the medullary canal of the long bones, with bone infarctions, pathological fractures and painful debilitation. This is the non-neoplastic half of the syndrome and it is what brings most patients to attention before any tumour appears.
diaphysis UBERON:0004769 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in diaphysis (UBERON:0004769). UBERON:0004769 is an anatomical location from the Uberon multi-species anatomy ontology.
Show evidence (1 reference)
PMID:10612808 SUPPORT Human Clinical
"This hereditary cancer syndrome is characterized by bone infarctions, cortical growth abnormalities, pathologic fractures, and painful debilitation."
Lists the skeletal features that constitute this node.
Bone Sarcoma Predisposition
Mechanism confidence: Established
About 35 percent of affected individuals develop malignant fibrous histiocytoma of bone. That is the feature which makes this a cancer predisposition syndrome rather than a bone dysplasia, and it is why surveillance rather than symptomatic management is the reasonable posture. The tumour-suppressor route is established: tumour DNA is homozygous for the germline mutation with complete loss of the wild-type allele, so this is direct loss of MTAP function by Knudson's two hits. What remains unresolved is whether the abnormal bone environment created by the dysplasia additionally contributes, and what the biallelic metabolic state does to permit transformation.
Animal models
Mtap(lacZ) heterozygous knockout mouse Mouse fails to recapitulate The mouse confirms the principle and misses the disease. Losing one Mtap allele does predispose to malignancy, which supports the tumour-suppressor mechanism curated here. But the tumour is T-cell lymphoma, not bone sarcoma, and the animals have no bone dysplasia at all.
Show evidence (2 references)
PMID:10612808 SUPPORT Human Clinical
"Most notably, 35% of affected individuals develop bone MFH, a sarcoma that, in its sporadic form, accounts for 6% of all bone cancers."
Quantifies the sarcoma risk and places it against the sporadic tumour's share of bone cancers.
PMID:22464254 SUPPORT Human Clinical
"Our results identify a gene involved in the development of bone sarcoma"
States the identification of MTAP as a bone sarcoma gene, which is the basis for treating this node as a tumour-suppressor mechanism rather than an association.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Diaphyseal Medullary Stenosis with Malignant Fibrous Histiocytoma Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

13
Eye 1
Presenile Cataract Presenile cataracts HP:0007819 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Presenile cataracts (HP:0007819). HP:0007819 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:22464254 SUPPORT Human Clinical
"and the development of presenile cataracts"
Names presenile cataract among the clinical features of the syndrome.
Limbs 4
Diaphyseal Medullary Stenosis Stenosis of the medullary cavity of the long bones HP:0100254 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Stenosis of the medullary cavity of the long bones (HP:0100254). HP:0100254 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:22464254 SUPPORT Human Clinical
"Diaphyseal medullary stenosis with malignant fibrous histiocytoma (DMS-MFH) is an autosomal-dominant syndrome characterized by bone dysplasia, myopathy, and bone cancer."
The disease name states the medullary stenosis, and the sentence establishes it as the defining skeletal lesion of an autosomal dominant syndrome.
Diaphyseal Cortical Sclerosis HP:0005045 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Diaphyseal cortical sclerosis (HP:0005045). HP:0005045 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:10612808 SUPPORT Human Clinical
"characterized by bone infarctions, cortical growth abnormalities, pathologic fractures, and painful debilitation"
Names cortical growth abnormality among the defining features.
Metaphyseal Striations HP:0031367 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Metaphyseal striations (HP:0031367). HP:0031367 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:22464254 SUPPORT DIRECT Human Clinical
"phenotype characterized by cortical growth abnormalities, including diffuse diaphyseal medullary stenosis with overlying endosteal cortical thickening, metaphyseal striations, and scattered infarctions within the bone marrow."
Names metaphyseal striations among the four features of the unique bone-dysplasia phenotype.
Bowing of the Lower Extremities Bowing of the legs HP:0002979 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bowing of the legs (HP:0002979). HP:0002979 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:22464254 SUPPORT Human Clinical
"fractures that subsequently heal poorly, progressive wasting, bowing of the lower extremities"
Names bowing of the lower extremities among the skeletal features.
Musculoskeletal 5
Bone Infarction Avascular necrosis HP:0010885 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Avascular necrosis (HP:0010885). HP:0010885 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:10612808 SUPPORT INDIRECT Human Clinical
"This hereditary cancer syndrome is characterized by bone infarctions, cortical growth abnormalities, pathologic fractures, and painful debilitation."
Names bone infarction as a defining feature. Typed INDIRECT because HPO's Avascular necrosis is the closest available term and is broader than the medullary bone infarction the source describes, so the phenotype claim follows from the quote by a term-matching step.
PMID:22464254 SUPPORT INDIRECT Human Clinical
"phenotype characterized by cortical growth abnormalities, including diffuse diaphyseal medullary stenosis with overlying endosteal cortical thickening, metaphyseal striations, and scattered infarctions within the bone marrow."
Localises the infarctions to the bone marrow, which is more precise than the general list and narrows what the broader Avascular necrosis binding is standing in for. Still INDIRECT for the same term-matching reason.
Pathologic Fracture HP:0002756 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pathologic fracture (HP:0002756). HP:0002756 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:10612808 SUPPORT Human Clinical
"cortical growth abnormalities, pathologic fractures, and painful debilitation"
Names pathologic fracture among the defining features.
Myopathy HP:0003198 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Myopathy (HP:0003198). HP:0003198 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:22464254 SUPPORT Human Clinical
"Diaphyseal medullary stenosis with malignant fibrous histiocytoma (DMS-MFH) is an autosomal-dominant syndrome characterized by bone dysplasia, myopathy, and bone cancer."
Names myopathy as one of the three defining components of the syndrome.
PMID:22464254 SUPPORT DIRECT Human Clinical
"We recently expanded the known clinical features of the syndrome by characterizing two new unrelated families affected by a progressive form of muscular disease"
Shows myopathy was a later addition to the phenotype from two specific families. The quote asserts that expansion directly; qualifying the universality of the feature is what it is cited for.
Osteosarcoma HP:0002669 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Osteosarcoma (HP:0002669). HP:0002669 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:22464254 SUPPORT DIRECT Human Clinical
"Thus, inherited MTAP alternative-splicing mutations can result in histology-proven osteosarcoma."
States that the inherited splicing mutations can produce osteosarcoma on histology, which is a diagnosis distinct from the malignant fibrous histiocytoma in the disease name.
Poor Fracture Healing Delayed fracture healing HP:0032537 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed fracture healing (HP:0032537). HP:0032537 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:22464254 SUPPORT Human Clinical
"fractures that subsequently heal poorly, progressive wasting, bowing of the lower extremities"
Reports impaired fracture healing alongside the wasting and limb bowing.
Constitutional 1
Bone Pain HP:0002653 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bone pain (HP:0002653). HP:0002653 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:10612808 SUPPORT Human Clinical
"cortical growth abnormalities, pathologic fractures, and painful debilitation"
Names painful debilitation among the defining features.
Neoplasm 2
Bone Fibrosarcoma HP:0100244 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Fibrosarcoma (HP:0100244). HP:0100244 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:22464254 SUPPORT DIRECT Human Clinical
"The diagnoses were either MFH"
Names the two diagnoses under which the tumours were reported. The quote is truncated at a line break in the cached text, where a superscript reference marker separates it from the words bone fibrosarcoma; the full sentence reads that the diagnoses were either MFH or bone fibrosarcoma.
Malignant Fibrous Histiocytoma of Bone FREQUENT Sarcoma HP:0100242 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bone sarcoma, annotated with Sarcoma (HP:0100242). HP:0100242 is a phenotype from the Human Phenotype Ontology.
The 35 percent figure is a within-pedigree proportion from three kindreds reported in 1999, and those kindreds were ascertained because they had sarcoma. It therefore describes the families that came to attention, not the lifetime risk of a carrier identified some other way, and the true penetrance could be lower. FREQUENT is recorded because the figure sits squarely in that band, but the band inherits the same ascertainment bias as the number.
Show evidence (1 reference)
PMID:10612808 SUPPORT Human Clinical
"Most notably, 35% of affected individuals develop bone MFH"
Quantifies the proportion developing bone sarcoma.
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Genetic Associations

1
MTAP (CAUSATIVE)
Gene: MTAP hgnc:7413 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is MTAP (hgnc:7413). hgnc:7413 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: GERMLINE
Show evidence (4 references)
PMID:22464254 SUPPORT Human Clinical
"We previously mapped the DMS-MFH tumor-suppressing-gene locus to chromosomal region 9p21-22 but failed to identify mutations in known genes in this region."
Records that the causal gene was invisible to candidate screening of the annotated genes in the linked region, which is the point of the retroviral exon finding.
PMID:22464254 SUPPORT In Vitro
"The c.885A >G mutation decreased the expression levels of all exon 9 isoforms by approximately 70% but had no effect on archetype-MTAP expression."
Quantifies what the synonymous variant does: partial loss of the retroviral-exon isoforms with the canonical enzyme untouched.
PMID:22464254 SUPPORT In Vitro
"increased the expression of MTAP_v3 and _v6 to the same degree"
Identifies what the two different variants share, which is a shift in isoform balance rather than a common loss.
+ 1 more reference
💊

Medical Actions

2
Surveillance and Symptomatic Management
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
Platform: Other
There is no disease-modifying therapy. Management is surveillance for malignant transformation plus symptomatic care of the fractures, infarctions and pain, with sarcoma treated by standard oncological means when it appears. The reasonable posture is surveillance rather than symptomatic management alone, precisely because the sarcoma risk is high and the window in which it is detectable is what screening exists to exploit.
Show evidence (1 reference)
PMID:8781110 SUPPORT INDIRECT Human Clinical
"Radiographic screening of family members is suggested from puberty onward."
The only published management recommendation for this disease is a screening one. Typed INDIRECT because it recommends screening rather than treatment; that no therapy has been reported for the established dysplasia is recorded in this treatment's notes.
Genetic Counselling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Platform: Behavioral / lifestyle
Autosomal dominant inheritance carries a 50 percent transmission risk to each offspring of an affected individual. Counselling for this syndrome has two disease-specific points beyond the standard risk discussion: the sarcoma risk that makes early identification of carriers clinically consequential (see Bone Sarcoma Predisposition), and the fact that a negative standard hereditary-cancer or skeletal-dysplasia panel does not exclude the diagnosis, because the causal exons sit outside the region those panels are designed to capture (see Molecular Testing for MTAP Exon 9). A relative should not be falsely reassured by a negative panel result obtained without knowledge of that caveat.
Show evidence (1 reference)
PMID:22464254 SUPPORT Human Clinical
"Diaphyseal medullary stenosis with malignant fibrous histiocytoma (DMS-MFH) is an autosomal-dominant syndrome characterized by bone dysplasia, myopathy, and bone cancer."
States the autosomal dominant inheritance pattern that underlies the 50 percent transmission risk counselling is built around.
🔬

Biochemical Markers

1
Serum methylthioadenosine (Detectable in affected individuals; undetectable in unaffected controls)
Show evidence (2 references)
PMID:22464254 SUPPORT DIRECT Human Clinical
"All three serum samples from unaffected individuals had no detectable MTA levels. In marked contrast, both affected individuals had accumulations of MTA detectable in their serum"
The measurement itself, with a clean separation between affected and unaffected individuals in a blinded assay.
PMID:22464254 SUPPORT Human Clinical
"MTA is not normally present in human serum."
Establishes the baseline that makes a detectable level meaningful. It states normal physiology rather than a DMS-MFH-specific finding, which is why no directness grade is asserted.
🔬

Diagnosis

2
Radiographic Screening of At-Risk Relatives from Puberty
The one explicit published surveillance recommendation for this disease, and the response the entry's 35 percent sarcoma risk demands. Radiographic screening of family members is suggested from puberty onward, which is when the dysplasia becomes visible on plain film. Thallium scanning is proposed as a more tumour-sensitive agent in individuals already known to be affected, so the two have different jobs: plain films identify who has the dysplasia, thallium looks for malignant transformation in those who do.
X-Ray Imaging NCIT:C38101 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:8781110 SUPPORT Human Clinical
"Radiographic screening of family members is suggested from puberty onward. Thallium scanning is proposed as a more tumor-sensitive screening agent in affected individuals."
States both the screening recommendation and its timing, and distinguishes the tumour-directed modality from the dysplasia-directed one.
Molecular Testing for MTAP Exon 9
A negative gene panel does not exclude this diagnosis, and the reason is the same fact that makes the disease mechanistically interesting. The causal exon lies roughly 65 kb downstream of the canonical MTAP termination site and was not part of the annotated gene, so standard exome capture and standard hereditary-cancer or skeletal-dysplasia panels are not designed to report it. Testing has to target the retroviral-derived terminal exons specifically. The same history is why candidate screening of the linked region failed for over a decade: the gene was there, and the exons were not being looked at.
Genetic Testing NCIT:C15709 NCI Thesaurus (NCIT)
Variant numbering is a live trap. The reported variants are numbered against the EST reference clone GenBank AK309365, not the canonical NM_002451 transcript, so reconciling them against ClinVar or a laboratory report requires knowing which reference was used. Recorded here rather than left for a reader to discover.
Show evidence (1 reference)
PMID:22464254 SUPPORT Human Clinical
"We previously mapped the DMS-MFH tumor-suppressing-gene locus to chromosomal region 9p21-22 but failed to identify mutations in known genes in this region."
Documents that screening the annotated genes in the correct interval failed to find the cause, which is the historical form of the same problem a modern panel has: the causal exons are not where the gene was thought to end.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
Five unrelated multigenerational families carried the identified mutations, and fewer than six families have been reported in total across a literature spanning several decades. There is no registry, no cohort and no population estimate.
Show evidence (2 references)
PMID:22464254 SUPPORT Human Clinical
"Family 4 is a previously undescribed DMS-MFH-affected family from New York."
Documents the composition of the cohort: families 1 to 3 were the previously described American, Australian and New York kindreds, and families 4 and 5 were added by this study, giving the five on which the molecular characterisation rests.
PMID:22464254 SUPPORT Human Clinical
"Family 5 has been described as having autosomal-dominant bone fragility and limb-girdle myopathy."
Identifies the second newly added family and its myopathic presentation, which is the source of the myopathy that entered the phenotype after the original three families.
🔬

Clinical Trials

1
NCT00007046 NOT_APPLICABLE COMPLETED
Completed NCRR-sponsored observational genetic study that set out to identify the causal gene and characterise the clinical manifestations of DMS-MFH in reported families. This is the study-registry record of the gene-hunting effort that the mutations curated in this entry are the published result of; it is a natural-history and gene-discovery study, not an interventional trial, and offers no treatment to enrol in.
Show evidence (1 reference)
clinicaltrials:NCT00007046 SUPPORT Human Clinical
"Identify and characterize the gene causing diaphyseal medullary stenosis with malignant fibrous histiocytoma of the bone."
States the trial's objective, which is exactly the gene-identification effort this entry's genetic findings are the outcome of.
🐁

Animal Models

1
Mtap(lacZ) heterozygous knockout mouse
A conventional MTAP knockout, made to ask whether MTAP loss drives tumorigenesis independently of the CDKN2A and ARF genes it is usually co-deleted with. Homozygous nulls die around day 8 postconception. Heterozygotes look normal for a year and then die early, median survival 585 days, with enlarged spleens, altered thymic histology and hepatic lymphocytic infiltration; the lymphomas are primarily T-cell.
Species
Mouse
Genotype
Mtap/Mtap(lacZ) heterozygote
Publication
PMID:19567676
Pathograph links
Bone Sarcoma Predisposition fails to recapitulate fidelity: low The mouse confirms the principle and misses the disease. Losing one Mtap allele does predispose to malignancy, which supports the tumour-suppressor mechanism curated here. But the tumour is T-cell lymphoma, not bone sarcoma, and the animals have no bone dysplasia at all.
Limitations: This is a null allele, not the human lesion. The human mutations sit in retroviral-derived terminal exons that entered the primate genome and have no mouse counterpart, so the model cannot carry the actual allele and its isoform-balance effect is absent. What it models is complete loss of one copy, which is a different molecular state from a synonymous variant that shifts splicing among isoforms while leaving archetype MTAP intact. The tissue mismatch may follow from that, or from species differences in which lineage is vulnerable to MTAP loss; nothing distinguishes the two.
Readouts
Tumour type in heterozygotes
Direction: ALTERED
Interpretation: T-cell lymphoma rather than bone sarcoma, with no skeletal phenotype. A divergence from the human disease, not a confirmation of it.
Show evidence (1 reference)
PMID:19567676 SUPPORT DIRECT Model Organism
"Immunohistochemical staining and fluorescence-activated cell sorting analysis indicate that these lymphomas are primarily T-cell in origin."
Identifies the tumour the model actually produces, which is not the one this syndrome produces. Graded SUPPORT: the quote is the observation this readout is made of, so it supports the readout's own claim. That the observation cuts against the model's faithfulness is carried by relationship FAILS_TO_RECAPITULATE and by direction ALTERED, not by inverting the evidence direction.
Show evidence (1 reference)
PMID:19567676 SUPPORT DIRECT Model Organism
"Immunohistochemical staining and fluorescence-activated cell sorting analysis indicate that these lymphomas are primarily T-cell in origin."
The tumour this model produces is T-cell lymphoma, not the bone sarcoma of this syndrome, which is the failure this link asserts. Graded SUPPORT because the quote supports that failure claim; the negative direction is carried by relationship FAILS_TO_RECAPITULATE.
Show evidence (1 reference)
PMID:19567676 SUPPORT DIRECT Model Organism
"These studies show that Mtap is a tumor suppressor gene independent of CDKN2A and ARF."
Establishes MTAP as a tumour suppressor in its own right, which is the claim this syndrome's sarcoma arm depends on and which no other source in this entry supplies from outside the discovery laboratory.
{ }

Source YAML

click to show 
name: Diaphyseal Medullary Stenosis with Malignant Fibrous Histiocytoma
creation_date: "2026-08-29T00:00:00Z"
category: Mendelian
synonyms:
- DMS-MFH
- DMSMFH
- Hardcastle syndrome
- bone dysplasia-medullary fibrosarcoma syndrome
- diaphyseal medullary stenosis-malignant fibrous histiocytoma syndrome
- diaphyseal medullary stenosis-bone malignancy syndrome
description: >-
  Diaphyseal medullary stenosis with malignant fibrous histiocytoma is an
  autosomal dominant syndrome that combines a long-bone dysplasia with a high
  lifetime risk of bone sarcoma. Affected individuals develop bone infarctions,
  abnormal cortical growth with narrowing of the medullary canal, pathological
  fractures and painful debilitation, and roughly a third go on to develop
  malignant fibrous histiocytoma of bone, now classified as undifferentiated
  pleomorphic sarcoma. Myopathy is part of the syndrome and is often
  under-emphasised in the name.

  The molecular cause is unusual enough to be worth stating carefully. The locus
  was mapped to 9p21-22 and then resisted identification for over a decade,
  because the causal mutations do not lie in any of the genes that region is
  known for. They lie in one of three previously uncharacterised terminal exons
  of MTAP, which encodes methylthioadenosine phosphorylase, an enzyme of the
  polyamine, adenine and methionine salvage pathways. Two of those exons entered
  the primate genome as independent retroviral integration events at least forty
  million years ago and have since acquired a function. Six retroviral-sequence
  MTAP isoforms exist, each able to interact physically with the archetype
  enzyme, and the disease mutations cause exon skipping that dysregulates
  alternative splicing of all of them.

  So this is not a simple enzyme deficiency. One of the two reported mutations is
  synonymous, changing no amino acid at all, so the pathogenic effect cannot be a
  change to the protein sequence and has to act on the transcript. The lesion is
  in a regulatory isoform that interacts with the canonical protein, and its
  consequence is disordered splicing across the whole isoform family rather than
  loss of a single product.

  This is a germline predisposition syndrome, and under the granularity ladder in
  the design-decision register it follows the plain Mendelian rules and stays
  separate from the somatic sarcoma entries it predisposes to. The relationship
  between the two is nonetheless real and worth curating: sporadic bone malignant
  fibrous histiocytoma shows loss of heterozygosity in the same 9p21-22 interval
  in most informative specimens, which is what motivated the search for a shared
  tumour suppressor.
disease_term:
  preferred_term: diaphyseal medullary stenosis-bone malignancy syndrome
  term:
    id: MONDO:0007205
    label: diaphyseal medullary stenosis-bone malignancy syndrome
parents:
- Hereditary cancer predisposition syndrome
- Skeletal dysplasia
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0007205
      label: diaphyseal medullary stenosis-bone malignancy syndrome
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      MONDO:0007205 is the DMS-MFH concept modeled by this entry.
references:
- reference: PMID:22464254
  title: >-
    Primate genome gain and loss: a bone dysplasia, muscular dystrophy, and bone
    cancer syndrome resulting from mutated retroviral-derived MTAP transcripts.
notes: >-
  Named Entity Confusion warning for anyone extending this entry. MTAP is far
  better known as a somatic passenger deletion: it sits immediately adjacent to
  CDKN2A at 9p21 and is co-deleted in a large fraction of sporadic cancers, and
  MTAP-deleted tumours are an active therapeutic target through PRMT5. That
  literature is about homozygous somatic deletion of the whole locus in tumour
  cells and is not about this syndrome, whose lesion is a germline splicing
  mutation in a retroviral-derived terminal exon. A search on the gene symbol
  will return overwhelmingly the former. The one genuine connection is the
  9p21-22 loss of heterozygosity shared with sporadic bone malignant fibrous
  histiocytoma, which is curated here with its own evidence.

  Nomenclature. Malignant fibrous histiocytoma is the name used throughout the
  primary literature on this syndrome and is retained here for that reason. The
  entity was reclassified as undifferentiated pleomorphic sarcoma in later WHO
  classifications, and the description says so, but the disease name and the
  quoted snippets keep the historical term because that is what the sources say.
pathophysiology:
- name: MTAP Retroviral-Exon Splicing Mutation
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Mutations fall in the most proximal of three previously uncharacterised
    terminal exons of MTAP. Two of these exons derive from independent retroviral
    integrations into the primate genome at least forty million years ago, and
    have since taken on a function. The gene had been thought to be encoded by
    eight exons alone, which is why the locus resisted identification for more
    than a decade after linkage.
  gene:
    preferred_term: MTAP
    description: >-
      Encodes methylthioadenosine phosphorylase; germline mutation of a
      retroviral-derived terminal exon causes this syndrome.
    term:
      id: hgnc:7413
      label: MTAP
  genetic_context:
    gene:
      preferred_term: MTAP
      term:
        id: hgnc:7413
        label: MTAP
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    functional_impact_category: UNKNOWN
    description: >-
      Heterozygous germline mutation in a retroviral-derived terminal exon,
      acting dominantly through dysregulated splicing rather than by
      straightforward loss of enzyme activity. No source classifies the
      functional impact, and the category is left UNKNOWN rather than guessed.
  evidence:
  - reference: PMID:22464254
    reference_title: "Primate genome gain and loss: a bone dysplasia, muscular dystrophy, and bone cancer syndrome resulting from mutated retroviral-derived MTAP transcripts."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We now demonstrate that DMS-MFH results from mutations in the most proximal
      of three previously uncharacterized terminal exons of the gene encoding
      methylthioadenosine phosphorylase, MTAP.
    explanation: Identifies the causal gene and the exon in which mutations fall.
  - reference: PMID:22464254
    reference_title: "Primate genome gain and loss: a bone dysplasia, muscular dystrophy, and bone cancer syndrome resulting from mutated retroviral-derived MTAP transcripts."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: COMPUTATIONAL
    snippet: >-
      two of these MTAP exons arose from early and independent retroviral-integration
      events in primate genomes at least 40 million years ago, and since then,
      their genomic integration has gained a functional role
    explanation: >-
      Establishes the retroviral origin of the affected exons, which is why the
      gene's coding extent had been misjudged.
  - reference: PMID:22464254
    reference_title: "Primate genome gain and loss: a bone dysplasia, muscular dystrophy, and bone cancer syndrome resulting from mutated retroviral-derived MTAP transcripts."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      one mutation was a synonymous change at position c.885A>G
    explanation: >-
      The most informative single fact about this lesion. A synonymous change
      alters no amino acid, so the pathogenic effect cannot be a change to the
      protein sequence and must act on the transcript, which is what makes the
      splicing mechanism the explanation rather than one candidate among
      several.
  downstream:
  - target: Dysregulated Alternative Splicing of MTAP Isoforms
    causal_link_type: DIRECT
    description: >-
      The mutation causes skipping of the affected exon, which propagates to the
      splicing of the whole isoform family.
    evidence:
    - reference: PMID:22464254
      reference_title: "Primate genome gain and loss: a bone dysplasia, muscular dystrophy, and bone cancer syndrome resulting from mutated retroviral-derived MTAP transcripts."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        The disease-causing mutations occur within one of these retroviral-derived
        exons and result in exon skipping and dysregulated alternative splicing of
        all MTAP isoforms.
      explanation: States the direct splicing consequence of the mutation.
  - target: Somatic Loss of the Wild-Type MTAP Allele
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The germline allele is the first hit. It does not cause the second one:
      loss of the remaining wild-type copy is a stochastic somatic event, and
      what the inherited allele supplies is the vulnerability that makes that
      loss consequential. No mechanism linking the germline lesion to the
      occurrence of the somatic event has been established.
    evidence:
    - reference: PMID:22464254
      reference_title: "Primate genome gain and loss: a bone dysplasia, muscular dystrophy, and bone cancer syndrome resulting from mutated retroviral-derived MTAP transcripts."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        direct sequencing of this patient’s osteosarcoma genomic DNA demonstrated
        homozygosity for the c.885A >G mutation
      explanation: >-
        Shows the tumour is homozygous for the germline mutation, which is the
        second hit this edge asserts.
- name: Dysregulated Alternative Splicing of MTAP Isoforms
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Six distinct retroviral-sequence-containing MTAP isoforms exist, and each can
    physically interact with the archetype enzyme. Exon skipping in the mutated
    isoform dysregulates alternative splicing across all of them, so the defect
    is combinatorial rather than confined to one product. Because the isoforms
    bind the canonical trimeric enzyme, the plausible route to disease is
    interference with archetype MTAP rather than its simple absence, though no
    source states this as demonstrated.
  biological_processes:
  - preferred_term: regulation of alternative mRNA splicing, via spliceosome
    term:
      id: GO:0000381
      label: regulation of alternative mRNA splicing, via spliceosome
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:22464254
    reference_title: "Primate genome gain and loss: a bone dysplasia, muscular dystrophy, and bone cancer syndrome resulting from mutated retroviral-derived MTAP transcripts."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Six distinct retroviral-sequence-containing MTAP isoforms, each of which can
      physically interact with archetype MTAP, have been identified.
    explanation: >-
      Establishes the isoform family and their physical interaction with the
      canonical enzyme, which is what makes a splicing defect consequential.
  downstream:
  - target: Impaired Polyamine and Methionine Salvage Metabolism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Disordered isoform splicing is presumed to compromise the enzyme's
      metabolic role. The quantitative effect on flux through the salvage
      pathways has not been reported in patients.
- name: Impaired Polyamine and Methionine Salvage Metabolism
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    MTAP is a ubiquitously expressed homotrimeric enzyme central to polyamine
    metabolism and to the adenine and methionine salvage pathways, and the
    enzymatic step is demonstrably impaired in patients. Methylthioadenosine, the
    direct substrate of MTAP and a by-product of polyamine synthesis, is not
    normally present in human serum. In a blinded assay it was undetectable in
    all three unaffected individuals and accumulated in both affected
    individuals. Substrate accumulation in vivo is a direct demonstration that
    the enzyme step is compromised, not an inference from what the enzyme is
    known to do, and it is the reason MONDO's classification of this syndrome as
    a disorder of polyamine metabolism is more than nominal.

    Two limits on how far that goes. The measurement is five people, two of them
    affected, so it establishes that the step is perturbed rather than how much.
    And flux through the downstream salvage pathways has not been measured at
    all: what is shown is that the substrate backs up, not what happens to
    polyamine or methionine economy as a result.
  molecular_functions:
  - preferred_term: S-methyl-5-thioadenosine phosphorylase activity
    term:
      id: GO:0017061
      label: S-methyl-5-thioadenosine phosphorylase activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: polyamine metabolic process
    term:
      id: GO:0006595
      label: polyamine metabolic process
    modifier: DYSREGULATED
  - preferred_term: L-methionine salvage
    description: >-
      No modifier is asserted. Flux through this pathway has not been measured in
      patients; what is measured is that the enzyme's substrate accumulates.
    term:
      id: GO:0071267
      label: L-methionine salvage
  - preferred_term: purine ribonucleoside salvage
    description: >-
      No modifier is asserted, for the same reason as L-methionine salvage: the
      direction is inferred from the enzymology, not measured.
    term:
      id: GO:0006166
      label: purine ribonucleoside salvage
  evidence:
  - reference: PMID:22464254
    reference_title: "Primate genome gain and loss: a bone dysplasia, muscular dystrophy, and bone cancer syndrome resulting from mutated retroviral-derived MTAP transcripts."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: >-
      MTAP is a ubiquitously expressed homotrimeric-subunit enzyme critical to
      polyamine metabolism and adenine and methionine salvage pathways
    explanation: >-
      States the enzyme's metabolic role. Typed INDIRECT and OTHER because this
      is background description of MTAP biology rather than a measurement in
      patients, and it establishes what the enzyme does. The measurement that
      shows the pathway is disturbed is the next item.
  - reference: PMID:22464254
    reference_title: "Primate genome gain and loss: a bone dysplasia, muscular dystrophy, and bone cancer syndrome resulting from mutated retroviral-derived MTAP transcripts."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All three serum samples from unaffected individuals had no detectable MTA
      levels. In marked contrast, both affected individuals had accumulations of
      MTA detectable in their serum
    explanation: >-
      A direct in-vivo measurement of the enzyme's own substrate, blinded, with a
      clean separation between affected and unaffected. This is the propositional
      evidence that the MTAP step is impaired in patients.
  - reference: PMID:22464254
    reference_title: "Primate genome gain and loss: a bone dysplasia, muscular dystrophy, and bone cancer syndrome resulting from mutated retroviral-derived MTAP transcripts."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MTA is not normally present in human serum.
    explanation: >-
      Establishes the baseline that makes detectable serum MTA in affected
      individuals interpretable as accumulation rather than as normal variation.
  downstream:
  - target: Diaphyseal Cortical Dysplasia and Medullary Stenosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The route from the metabolic lesion to the bone phenotype is unknown. No
      cell type, signalling pathway or bone-remodelling mechanism has been
      implicated.
- name: Somatic Loss of the Wild-Type MTAP Allele
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    The tumour-suppressive mechanism is characterised, and it is Knudson's two
    hits. In an osteosarcoma from an affected individual carrying c.885A>G, the
    tumour DNA was homozygous for the mutation, and loss-of-heterozygosity
    analysis across the 2.9 Mb critical region showed complete loss of the
    wild-type allele from the unaffected chromosome. So the germline allele is
    the first hit and somatic loss of the remaining wild-type copy is the second.

    This is also what ties the syndrome to its sporadic counterpart: the same
    interval is lost in most informative sporadic bone malignant fibrous
    histiocytoma specimens, which is what motivated the search for a shared
    tumour suppressor in the first place.
  evidence:
  - reference: PMID:22464254
    reference_title: "Primate genome gain and loss: a bone dysplasia, muscular dystrophy, and bone cancer syndrome resulting from mutated retroviral-derived MTAP transcripts."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      direct sequencing of this patient’s osteosarcoma genomic DNA demonstrated
      homozygosity for the c.885A >G mutation
    explanation: >-
      Establishes tumour homozygosity for the germline allele, the direct
      evidence of a second hit.
  downstream:
  - target: Bone Sarcoma Predisposition
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - dmsmfh_prmt5_synthetic_lethality_untested
    description: >-
      Biallelic loss of MTAP function in the tumour precedes sarcoma, but what
      the resulting metabolic state does to the cell to permit transformation is
      not established.

- name: Diaphyseal Cortical Dysplasia and Medullary Stenosis
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  description: >-
    Abnormal cortical growth narrows the medullary canal of the long bones, with
    bone infarctions, pathological fractures and painful debilitation. This is
    the non-neoplastic half of the syndrome and it is what brings most patients
    to attention before any tumour appears.
  locations:
  - preferred_term: diaphysis
    term:
      id: UBERON:0004769
      label: diaphysis
  evidence:
  - reference: PMID:10612808
    reference_title: "Malignant fibrous histiocytoma: inherited and sporadic forms have loss of heterozygosity at chromosome bands 9p21-22-evidence for a common genetic defect."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This hereditary cancer syndrome is characterized by bone infarctions,
      cortical growth abnormalities, pathologic fractures, and painful
      debilitation.
    explanation: >-
      Lists the skeletal features that constitute this node.
- name: Bone Sarcoma Predisposition
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  description: >-
    About 35 percent of affected individuals develop malignant fibrous
    histiocytoma of bone. That is the feature which makes this a cancer
    predisposition syndrome rather than a bone dysplasia, and it is why
    surveillance rather than symptomatic management is the reasonable posture.

    The tumour-suppressor route is established: tumour DNA is
    homozygous for the germline mutation with complete loss of the wild-type
    allele, so this is direct loss of MTAP function by Knudson's two hits. What
    remains unresolved is whether the abnormal bone environment created by the
    dysplasia additionally contributes, and what the biallelic metabolic state
    does to permit transformation.
  evidence:
  - reference: PMID:10612808
    reference_title: "Malignant fibrous histiocytoma: inherited and sporadic forms have loss of heterozygosity at chromosome bands 9p21-22-evidence for a common genetic defect."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most notably, 35% of affected individuals develop bone MFH, a sarcoma that,
      in its sporadic form, accounts for 6% of all bone cancers.
    explanation: >-
      Quantifies the sarcoma risk and places it against the sporadic tumour's
      share of bone cancers.
  - reference: PMID:22464254
    reference_title: "Primate genome gain and loss: a bone dysplasia, muscular dystrophy, and bone cancer syndrome resulting from mutated retroviral-derived MTAP transcripts."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our results identify a gene involved in the development of bone sarcoma
    explanation: >-
      States the identification of MTAP as a bone sarcoma gene, which is the
      basis for treating this node as a tumour-suppressor mechanism rather than
      an association.
phenotypes:
- category: Skeletal
  name: Bone Infarction
  description: >-
    Infarction within the medullary bone, one of the defining radiological
    features and a source of the pain that dominates the non-neoplastic phase.
  phenotype_term:
    preferred_term: Avascular necrosis
    term:
      id: HP:0010885
      label: Avascular necrosis
  evidence:
  - reference: PMID:10612808
    reference_title: "Malignant fibrous histiocytoma: inherited and sporadic forms have loss of heterozygosity at chromosome bands 9p21-22-evidence for a common genetic defect."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This hereditary cancer syndrome is characterized by bone infarctions,
      cortical growth abnormalities, pathologic fractures, and painful
      debilitation.
    explanation: >-
      Names bone infarction as a defining feature. Typed INDIRECT because HPO's
      Avascular necrosis is the closest available term and is broader than the
      medullary bone infarction the source describes, so the phenotype claim
      follows from the quote by a term-matching step.
  - reference: PMID:22464254
    reference_title: "Primate genome gain and loss: a bone dysplasia, muscular dystrophy, and bone cancer syndrome resulting from mutated retroviral-derived MTAP transcripts."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      phenotype characterized by cortical growth abnormalities, including diffuse
      diaphyseal medullary stenosis with overlying endosteal cortical thickening,
      metaphyseal striations, and scattered infarctions within the bone marrow.
    explanation: >-
      Localises the infarctions to the bone marrow, which is more precise than
      the general list and narrows what the broader Avascular necrosis binding is
      standing in for. Still INDIRECT for the same term-matching reason.
- category: Skeletal
  name: Diaphyseal Medullary Stenosis
  description: >-
    Narrowing of the medullary cavity of the long bones. This is the lesion the
    syndrome is named for and is curated with its own precise term rather than
    folded into a generic cortical abnormality.
  phenotype_term:
    preferred_term: Stenosis of the medullary cavity of the long bones
    term:
      id: HP:0100254
      label: Stenosis of the medullary cavity of the long bones
  evidence:
  - reference: PMID:22464254
    reference_title: "Primate genome gain and loss: a bone dysplasia, muscular dystrophy, and bone cancer syndrome resulting from mutated retroviral-derived MTAP transcripts."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Diaphyseal medullary stenosis with malignant fibrous histiocytoma (DMS-MFH)
      is an autosomal-dominant syndrome characterized by bone dysplasia,
      myopathy, and bone cancer.
    explanation: >-
      The disease name states the medullary stenosis, and the sentence
      establishes it as the defining skeletal lesion of an autosomal dominant
      syndrome.
- category: Skeletal
  name: Diaphyseal Cortical Sclerosis
  description: >-
    Abnormal cortical bone growth along the diaphyses, the process that
    encroaches on the medullary cavity.
  phenotype_term:
    preferred_term: Diaphyseal cortical sclerosis
    term:
      id: HP:0005045
      label: Diaphyseal cortical sclerosis
  evidence:
  - reference: PMID:10612808
    reference_title: "Malignant fibrous histiocytoma: inherited and sporadic forms have loss of heterozygosity at chromosome bands 9p21-22-evidence for a common genetic defect."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      characterized by bone infarctions, cortical growth abnormalities,
      pathologic fractures, and painful debilitation
    explanation: Names cortical growth abnormality among the defining features.
- category: Skeletal
  name: Metaphyseal Striations
  description: >-
    Longitudinal striations of the metaphyses, the fourth component of the
    cortical-growth phenotype.
  phenotype_term:
    preferred_term: Metaphyseal striations
    term:
      id: HP:0031367
      label: Metaphyseal striations
  evidence:
  - reference: PMID:22464254
    reference_title: "Primate genome gain and loss: a bone dysplasia, muscular dystrophy, and bone cancer syndrome resulting from mutated retroviral-derived MTAP transcripts."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      phenotype characterized by cortical growth abnormalities, including diffuse
      diaphyseal medullary stenosis with overlying endosteal cortical thickening,
      metaphyseal striations, and scattered infarctions within the bone marrow.
    explanation: >-
      Names metaphyseal striations among the four features of the unique
      bone-dysplasia phenotype.
- category: Skeletal
  name: Bone Pain
  description: >-
    Pain is described as debilitating and dominates the non-neoplastic course.
  phenotype_term:
    preferred_term: Bone pain
    term:
      id: HP:0002653
      label: Bone pain
  evidence:
  - reference: PMID:10612808
    reference_title: "Malignant fibrous histiocytoma: inherited and sporadic forms have loss of heterozygosity at chromosome bands 9p21-22-evidence for a common genetic defect."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      cortical growth abnormalities, pathologic fractures, and painful
      debilitation
    explanation: Names painful debilitation among the defining features.
- category: Skeletal
  name: Pathologic Fracture
  description: >-
    Fractures through abnormal bone, a common presenting event.
  phenotype_term:
    preferred_term: Pathologic fracture
    term:
      id: HP:0002756
      label: Pathologic fracture
  evidence:
  - reference: PMID:10612808
    reference_title: "Malignant fibrous histiocytoma: inherited and sporadic forms have loss of heterozygosity at chromosome bands 9p21-22-evidence for a common genetic defect."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      cortical growth abnormalities, pathologic fractures, and painful
      debilitation
    explanation: Names pathologic fracture among the defining features.
- category: Musculoskeletal
  name: Myopathy
  description: >-
    Muscle involvement is part of the syndrome and is easy to overlook, since
    neither the disease name nor its common abbreviation mentions it. The
    defining report characterises the condition as a bone dysplasia, muscular
    dystrophy and bone cancer syndrome.

    It is not present in every family. Myopathy entered the phenotype when two
    newly characterised families were found to have a progressive muscular
    disease resembling facioscapulohumeral muscular dystrophy; the three
    originally described families did not have it. So this is a feature of the
    syndrome as currently defined rather than of every reported pedigree, and the
    variability is unexplained.
  phenotype_term:
    preferred_term: Myopathy
    term:
      id: HP:0003198
      label: Myopathy
    description: >-
      Reported as limb-girdle in distribution and resembling facioscapulohumeral
      muscular dystrophy; the general term is kept because the two families
      described are not characterised consistently enough to bind a distribution
      term.
  evidence:
  - reference: PMID:22464254
    reference_title: "Primate genome gain and loss: a bone dysplasia, muscular dystrophy, and bone cancer syndrome resulting from mutated retroviral-derived MTAP transcripts."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Diaphyseal medullary stenosis with malignant fibrous histiocytoma (DMS-MFH)
      is an autosomal-dominant syndrome characterized by bone dysplasia,
      myopathy, and bone cancer.
    explanation: >-
      Names myopathy as one of the three defining components of the syndrome.
  - reference: PMID:22464254
    reference_title: "Primate genome gain and loss: a bone dysplasia, muscular dystrophy, and bone cancer syndrome resulting from mutated retroviral-derived MTAP transcripts."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We recently expanded the known clinical features of the syndrome by
      characterizing two new unrelated families affected by a progressive form of
      muscular disease
    explanation: >-
      Shows myopathy was a later addition to the phenotype from two specific
      families. The quote asserts that expansion directly; qualifying the
      universality of the feature is what it is cited for.
- category: Neoplastic
  name: Osteosarcoma
  description: >-
    Histology-proven osteosarcoma in an affected individual carrying c.885A>G.
    This is the clinically consequential end of the nomenclature history: the
    tumours were reported as malignant fibrous histiocytoma or bone fibrosarcoma,
    and re-review found osteoid, which reclassifies at least one of them as
    osteosarcoma.
  phenotype_term:
    preferred_term: Osteosarcoma
    term:
      id: HP:0002669
      label: Osteosarcoma
  evidence:
  - reference: PMID:22464254
    reference_title: "Primate genome gain and loss: a bone dysplasia, muscular dystrophy, and bone cancer syndrome resulting from mutated retroviral-derived MTAP transcripts."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thus, inherited MTAP alternative-splicing mutations can result in
      histology-proven osteosarcoma.
    explanation: >-
      States that the inherited splicing mutations can produce osteosarcoma on
      histology, which is a diagnosis distinct from the malignant fibrous
      histiocytoma in the disease name.
- category: Neoplastic
  name: Bone Fibrosarcoma
  description: >-
    Fibrosarcoma of bone, one of the two diagnoses under which the tumours of
    this syndrome were originally reported.
  phenotype_term:
    preferred_term: Fibrosarcoma
    term:
      id: HP:0100244
      label: Fibrosarcoma
  evidence:
  - reference: PMID:22464254
    reference_title: "Primate genome gain and loss: a bone dysplasia, muscular dystrophy, and bone cancer syndrome resulting from mutated retroviral-derived MTAP transcripts."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnoses were either MFH
    explanation: >-
      Names the two diagnoses under which the tumours were reported. The quote is
      truncated at a line break in the cached text, where a superscript reference
      marker separates it from the words bone fibrosarcoma; the full sentence
      reads that the diagnoses were either MFH or bone fibrosarcoma.
- category: Neoplastic
  name: Malignant Fibrous Histiocytoma of Bone
  description: >-
    Bone sarcoma, historically termed malignant fibrous histiocytoma and now
    classified as undifferentiated pleomorphic sarcoma, developing in about a
    third of affected individuals.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Bone sarcoma
    term:
      id: HP:0100242
      label: Sarcoma
  evidence:
  - reference: PMID:10612808
    reference_title: "Malignant fibrous histiocytoma: inherited and sporadic forms have loss of heterozygosity at chromosome bands 9p21-22-evidence for a common genetic defect."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most notably, 35% of affected individuals develop bone MFH
    explanation: Quantifies the proportion developing bone sarcoma.
  notes: >-
    The 35 percent figure is a within-pedigree proportion from three kindreds
    reported in 1999, and those kindreds were ascertained because they had
    sarcoma. It therefore describes the families that came to attention, not the
    lifetime risk of a carrier identified some other way, and the true penetrance
    could be lower. FREQUENT is recorded because the figure sits squarely in that
    band, but the band inherits the same ascertainment bias as the number.
- category: Ophthalmologic
  name: Presenile Cataract
  description: >-
    Early-onset lens opacity, reported among the clinical features of the
    syndrome and one of the reasons it is not purely a skeletal disorder.
  phenotype_term:
    preferred_term: Presenile cataracts
    term:
      id: HP:0007819
      label: Presenile cataracts
  evidence:
  - reference: PMID:22464254
    reference_title: "Primate genome gain and loss: a bone dysplasia, muscular dystrophy, and bone cancer syndrome resulting from mutated retroviral-derived MTAP transcripts."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      and the development of presenile cataracts
    explanation: >-
      Names presenile cataract among the clinical features of the syndrome.
- category: Skeletal
  name: Poor Fracture Healing
  description: >-
    Fractures heal poorly, which compounds the fracture tendency and contributes
    to the progressive wasting and painful debilitation that dominate the course.
  phenotype_term:
    preferred_term: Delayed fracture healing
    term:
      id: HP:0032537
      label: Delayed fracture healing
  evidence:
  - reference: PMID:22464254
    reference_title: "Primate genome gain and loss: a bone dysplasia, muscular dystrophy, and bone cancer syndrome resulting from mutated retroviral-derived MTAP transcripts."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      fractures that subsequently heal poorly, progressive wasting, bowing of the
      lower extremities
    explanation: >-
      Reports impaired fracture healing alongside the wasting and limb bowing.
- category: Skeletal
  name: Bowing of the Lower Extremities
  description: >-
    Deformity of the long bones of the legs, a consequence of the cortical
    dysplasia and repeated fracture.
  phenotype_term:
    preferred_term: Bowing of the legs
    term:
      id: HP:0002979
      label: Bowing of the legs
  evidence:
  - reference: PMID:22464254
    reference_title: "Primate genome gain and loss: a bone dysplasia, muscular dystrophy, and bone cancer syndrome resulting from mutated retroviral-derived MTAP transcripts."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      fractures that subsequently heal poorly, progressive wasting, bowing of the
      lower extremities
    explanation: Names bowing of the lower extremities among the skeletal features.
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Autosomal dominant, established by linkage in affected kindreds before the
    gene was identified.
  evidence:
  - reference: PMID:22464254
    reference_title: "Primate genome gain and loss: a bone dysplasia, muscular dystrophy, and bone cancer syndrome resulting from mutated retroviral-derived MTAP transcripts."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      DMS-MFH) is an autosomal-dominant syndrome characterized by bone dysplasia,
      myopathy, and bone cancer
    explanation: States the inheritance pattern.
genetic:
- name: MTAP
  gene_term:
    preferred_term: MTAP
    term:
      id: hgnc:7413
      label: MTAP
  association: CAUSATIVE
  variant_origin: GERMLINE
  features: >-
    Germline mutations in the most proximal of three retroviral-derived terminal
    exons of MTAP, causing exon skipping and dysregulated alternative splicing
    across the isoform family. The locus was mapped to 9p21-22 more than a decade
    before the gene was found; the delay is explained by the fact that the
    causal exons were not part of the annotated gene.

    Two variants account for the reported families and they do different things,
    which matters because this entry's myopathy gap turns on the two myopathic
    families carrying different mutations. c.885A>G is synonymous, effectively
    R100R, and decreases expression of all exon-9 isoforms by roughly 70 percent
    while leaving archetype MTAP untouched. c.813-2A>G is a splice-acceptor
    variant with a different isoform consequence. Both increase MTAP_v3 and _v6
    expression to the same degree, so what the two share is a shift in isoform
    balance rather than a common loss of one product.
  evidence:
  - reference: PMID:22464254
    reference_title: "Primate genome gain and loss: a bone dysplasia, muscular dystrophy, and bone cancer syndrome resulting from mutated retroviral-derived MTAP transcripts."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We previously mapped the DMS-MFH tumor-suppressing-gene locus to
      chromosomal region 9p21-22 but failed to identify mutations in known genes
      in this region.
    explanation: >-
      Records that the causal gene was invisible to candidate screening of the
      annotated genes in the linked region, which is the point of the retroviral
      exon finding.
  - reference: PMID:22464254
    reference_title: "Primate genome gain and loss: a bone dysplasia, muscular dystrophy, and bone cancer syndrome resulting from mutated retroviral-derived MTAP transcripts."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The c.885A >G mutation decreased the expression levels of all exon 9
      isoforms by approximately 70% but had no effect on archetype-MTAP
      expression.
    explanation: >-
      Quantifies what the synonymous variant does: partial loss of the
      retroviral-exon isoforms with the canonical enzyme untouched.
  - reference: PMID:22464254
    reference_title: "Primate genome gain and loss: a bone dysplasia, muscular dystrophy, and bone cancer syndrome resulting from mutated retroviral-derived MTAP transcripts."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      increased the expression of MTAP_v3 and _v6 to the same degree
    explanation: >-
      Identifies what the two different variants share, which is a shift in
      isoform balance rather than a common loss.
  - reference: PMID:10612808
    reference_title: "Malignant fibrous histiocytoma: inherited and sporadic forms have loss of heterozygosity at chromosome bands 9p21-22-evidence for a common genetic defect."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition to the hereditary specimen, 71% (5/7) of informative sporadic
      bone MFH specimens displayed LOH for markers within that same region.
    explanation: >-
      Shows the same interval is lost both in the hereditary specimen and in most
      informative sporadic bone sarcomas. The hereditary half matters as much as
      the sporadic half: together they are the observation that motivated the
      search for a shared tumour suppressor and led to MTAP.
  notes: >-
    The germline syndrome and the corresponding sporadic tumour converge on this
    locus. Loss of heterozygosity across the 9p21-22 critical region was found in
    five of seven informative sporadic bone malignant fibrous histiocytoma
    specimens, and the minimal region of overlap narrowed the interval to 2 cM
    between D9S736 and D9S171. That somatic observation is recorded here because
    it bears on the germline mechanism; sporadic sarcoma is not in scope for this
    entry.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Five unrelated multigenerational families carried the identified mutations,
    and fewer than six families have been reported in total across a literature
    spanning several decades. There is no registry, no cohort and no population
    estimate.
  evidence:
  - reference: PMID:22464254
    reference_title: "Primate genome gain and loss: a bone dysplasia, muscular dystrophy, and bone cancer syndrome resulting from mutated retroviral-derived MTAP transcripts."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Family 4 is a previously undescribed DMS-MFH-affected family from New York.
    explanation: >-
      Documents the composition of the cohort: families 1 to 3 were the
      previously described American, Australian and New York kindreds, and
      families 4 and 5 were added by this study, giving the five on which the
      molecular characterisation rests.
  - reference: PMID:22464254
    reference_title: "Primate genome gain and loss: a bone dysplasia, muscular dystrophy, and bone cancer syndrome resulting from mutated retroviral-derived MTAP transcripts."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Family 5 has been described as having autosomal-dominant bone fragility and
      limb-girdle myopathy.
    explanation: >-
      Identifies the second newly added family and its myopathic presentation,
      which is the source of the myopathy that entered the phenotype after the
      original three families.
animal_models:
- name: Mtap(lacZ) heterozygous knockout mouse
  species: Mouse
  genotype: Mtap/Mtap(lacZ) heterozygote
  publication: PMID:19567676
  description: >-
    A conventional MTAP knockout, made to ask whether MTAP loss drives
    tumorigenesis independently of the CDKN2A and ARF genes it is usually
    co-deleted with. Homozygous nulls die around day 8 postconception.
    Heterozygotes look normal for a year and then die early, median survival 585
    days, with enlarged spleens, altered thymic histology and hepatic lymphocytic
    infiltration; the lymphomas are primarily T-cell.
  evidence:
  - reference: PMID:19567676
    reference_title: Mice heterozygous for germ-line mutations in methylthioadenosine phosphorylase (MTAP) die prematurely of T-cell lymphoma.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      These studies show that Mtap is a tumor suppressor gene independent of
      CDKN2A and ARF.
    explanation: >-
      Establishes MTAP as a tumour suppressor in its own right, which is the
      claim this syndrome's sarcoma arm depends on and which no other source in
      this entry supplies from outside the discovery laboratory.
  modeled_mechanisms:
  - target: Bone Sarcoma Predisposition
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    description: >-
      The mouse confirms the principle and misses the disease. Losing one Mtap
      allele does predispose to malignancy, which supports the tumour-suppressor
      mechanism curated here. But the tumour is T-cell lymphoma, not bone
      sarcoma, and the animals have no bone dysplasia at all.
    limitations: >-
      This is a null allele, not the human lesion. The human mutations sit in
      retroviral-derived terminal exons that entered the primate genome and have
      no mouse counterpart, so the model cannot carry the actual allele and its
      isoform-balance effect is absent. What it models is complete loss of one
      copy, which is a different molecular state from a synonymous variant that
      shifts splicing among isoforms while leaving archetype MTAP intact. The
      tissue mismatch may follow from that, or from species differences in which
      lineage is vulnerable to MTAP loss; nothing distinguishes the two.
    evidence:
    - reference: PMID:19567676
      reference_title: Mice heterozygous for germ-line mutations in methylthioadenosine phosphorylase (MTAP) die prematurely of T-cell lymphoma.
      supports: SUPPORT
      directness: DIRECT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Immunohistochemical staining and fluorescence-activated cell sorting
        analysis indicate that these lymphomas are primarily T-cell in origin.
      explanation: >-
        The tumour this model produces is T-cell lymphoma, not the bone sarcoma
        of this syndrome, which is the failure this link asserts. Graded SUPPORT
        because the quote supports that failure claim; the negative direction is
        carried by relationship FAILS_TO_RECAPITULATE.
    readouts:
    - name: Tumour type in heterozygotes
      target: Bone Sarcoma Predisposition
      direction: ALTERED
      interpretation: >-
        T-cell lymphoma rather than bone sarcoma, with no skeletal phenotype.
        A divergence from the human disease, not a confirmation of it.
      evidence:
      - reference: PMID:19567676
        reference_title: Mice heterozygous for germ-line mutations in methylthioadenosine phosphorylase (MTAP) die prematurely of T-cell lymphoma.
        supports: SUPPORT
        directness: DIRECT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Immunohistochemical staining and fluorescence-activated cell sorting
          analysis indicate that these lymphomas are primarily T-cell in origin.
        explanation: >-
          Identifies the tumour the model actually produces, which is not the one
          this syndrome produces. Graded SUPPORT: the quote is the observation
          this readout is made of, so it supports the readout's own claim. That
          the observation cuts against the model's faithfulness is carried by
          relationship FAILS_TO_RECAPITULATE and by direction ALTERED, not by
          inverting the evidence direction.

biochemical:
- name: Serum methylthioadenosine
  biomarker_term:
    preferred_term: 5'-S-methyl-5'-thioadenosine
    term:
      id: CHEBI:17509
      label: 5'-S-methyl-5'-thioadenosine
  presence: Detectable in affected individuals; undetectable in unaffected controls
  evidence:
  - reference: PMID:22464254
    reference_title: "Primate genome gain and loss: a bone dysplasia, muscular dystrophy, and bone cancer syndrome resulting from mutated retroviral-derived MTAP transcripts."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All three serum samples from unaffected individuals had no detectable MTA
      levels. In marked contrast, both affected individuals had accumulations of
      MTA detectable in their serum
    explanation: >-
      The measurement itself, with a clean separation between affected and
      unaffected individuals in a blinded assay.
  - reference: PMID:22464254
    reference_title: "Primate genome gain and loss: a bone dysplasia, muscular dystrophy, and bone cancer syndrome resulting from mutated retroviral-derived MTAP transcripts."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MTA is not normally present in human serum.
    explanation: >-
      Establishes the baseline that makes a detectable level meaningful. It
      states normal physiology rather than a DMS-MFH-specific finding, which
      is why no directness grade is asserted.
  notes: >-
    The direct substrate of MTAP, and the one measured biochemical abnormality in
    this disease. It is not normally present in human serum, so its appearance is
    interpretable as accumulation rather than variation within a range. In a
    blinded assay it was undetectable in all three unaffected individuals tested
    and accumulated in both affected individuals.

    Curated as a candidate analyte rather than an established test. Five people
    is the entire dataset, no reference interval exists, no assay is in clinical
    use, and nothing is reported about whether the level tracks disease activity
    or sarcoma risk.

    The evidence here duplicates what the Impaired Polyamine and Methionine
    Salvage Metabolism node carries, deliberately. That node needs it to justify
    its ESTABLISHED grade; this record makes the same measurement findable as a
    candidate diagnostic analyte, which is a different question.

diagnosis:
- name: Radiographic Screening of At-Risk Relatives from Puberty
  description: >-
    The one explicit published surveillance recommendation for this disease, and
    the response the entry's 35 percent sarcoma risk demands. Radiographic
    screening of family members is suggested from puberty onward, which is when
    the dysplasia becomes visible on plain film. Thallium scanning is proposed as
    a more tumour-sensitive agent in individuals already known to be affected, so
    the two have different jobs: plain films identify who has the dysplasia,
    thallium looks for malignant transformation in those who do.
  diagnosis_term:
    preferred_term: X-Ray Imaging
    term:
      id: NCIT:C38101
      label: X-Ray Imaging
  evidence:
  - reference: PMID:8781110
    reference_title: "Diaphyseal medullary stenosis (sclerosis) with bone malignancy (malignant fibrous histiocytoma): Hardcastle syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Radiographic screening of family members is suggested from puberty onward.
      Thallium scanning is proposed as a more tumor-sensitive screening agent in
      affected individuals.
    explanation: >-
      States both the screening recommendation and its timing, and distinguishes
      the tumour-directed modality from the dysplasia-directed one.
- name: Molecular Testing for MTAP Exon 9
  description: >-
    A negative gene panel does not exclude this diagnosis, and the reason is the
    same fact that makes the disease mechanistically interesting. The causal
    exon lies roughly 65 kb downstream of the canonical MTAP termination site and
    was not part of the annotated gene, so standard exome capture and standard
    hereditary-cancer or skeletal-dysplasia panels are not designed to report it.
    Testing has to target the retroviral-derived terminal exons specifically.

    The same history is why candidate screening of the linked region failed for
    over a decade: the gene was there, and the exons were not being looked at.
  diagnosis_term:
    preferred_term: Genetic Testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:22464254
    reference_title: "Primate genome gain and loss: a bone dysplasia, muscular dystrophy, and bone cancer syndrome resulting from mutated retroviral-derived MTAP transcripts."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We previously mapped the DMS-MFH tumor-suppressing-gene locus to
      chromosomal region 9p21-22 but failed to identify mutations in known genes
      in this region.
    explanation: >-
      Documents that screening the annotated genes in the correct interval failed
      to find the cause, which is the historical form of the same problem a
      modern panel has: the causal exons are not where the gene was thought to
      end.
  notes: >-
    Variant numbering is a live trap. The reported variants are numbered against
    the EST reference clone GenBank AK309365, not the canonical NM_002451
    transcript, so reconciling them against ClinVar or a laboratory report
    requires knowing which reference was used. Recorded here rather than left for
    a reader to discover.
treatments:
- name: Surveillance and Symptomatic Management
  therapeutic_modality: OTHER
  description: >-
    There is no disease-modifying therapy. Management is surveillance for
    malignant transformation plus symptomatic care of the fractures, infarctions
    and pain, with sarcoma treated by standard oncological means when it appears.
    The reasonable posture is surveillance rather than symptomatic management
    alone, precisely because the sarcoma risk is high and the window in which it
    is detectable is what screening exists to exploit.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:8781110
    reference_title: "Diaphyseal medullary stenosis (sclerosis) with bone malignancy (malignant fibrous histiocytoma): Hardcastle syndrome."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Radiographic screening of family members is suggested from puberty onward.
    explanation: >-
      The only published management recommendation for this disease is a
      screening one. Typed INDIRECT because it recommends screening rather than
      treatment; that no therapy has been reported for the established dysplasia
      is recorded in this treatment's notes.
  notes: >-
    No pharmacological therapy is curated because none has been reported in this
    disease. The MTAP-PRMT5 synthetic-lethality axis is deliberately excluded:
    that strategy targets tumours with homozygous MTAP deletion and absent
    protein, whereas this syndrome retains archetype MTAP expression, so
    importing it here would assert a therapeutic rationale the biology does not
    support.
- name: Genetic Counselling
  therapeutic_modality: BEHAVIORAL
  description: >-
    Autosomal dominant inheritance carries a 50 percent transmission risk to
    each offspring of an affected individual. Counselling for this syndrome has
    two disease-specific points beyond the standard risk discussion: the
    sarcoma risk that makes early identification of carriers clinically
    consequential (see Bone Sarcoma Predisposition), and the fact that a
    negative standard hereditary-cancer or skeletal-dysplasia panel does not
    exclude the diagnosis, because the causal exons sit outside the region
    those panels are designed to capture (see Molecular Testing for MTAP Exon
    9). A relative should not be falsely reassured by a negative panel result
    obtained without knowledge of that caveat.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:22464254
    reference_title: "Primate genome gain and loss: a bone dysplasia, muscular dystrophy, and bone cancer syndrome resulting from mutated retroviral-derived MTAP transcripts."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Diaphyseal medullary stenosis with malignant fibrous histiocytoma
      (DMS-MFH) is an autosomal-dominant syndrome characterized by bone
      dysplasia, myopathy, and bone cancer.
    explanation: >-
      States the autosomal dominant inheritance pattern that underlies the 50
      percent transmission risk counselling is built around.

mechanistic_hypotheses:
- hypothesis_group_id: dmsmfh_prmt5_synthetic_lethality_untested
  hypothesis_label: MTAP-PRMT5 synthetic-lethality vulnerability in DMS-MFH tumours
  status: EMERGING
  description: >-
    DMS-MFH tumours share two features with the MTAP-homozygous-deletion,
    protein-null cancers that PRMT5 inhibitors target: serum methylthioadenosine
    accumulates in affected individuals, and the tumour loses the wild-type
    MTAP allele outright. Whether that combination raises intratumoural MTA
    enough to confer the same PRMT5 dependence has never been measured in a
    DMS-MFH tumour. The germline allele here is synonymous and leaves archetype
    MTAP protein intact, which is a different molecular state from the
    biallelic-deletion tumours the PRMT5 strategy was developed against, and
    immunohistochemistry for MTAP would likely read falsely negative in this
    setting. See discussion dmsmfh_prmt5_vulnerability_untested for the full
    reasoning and what would settle it.
  evidence:
  - reference: PMID:22464254
    reference_title: "Primate genome gain and loss: a bone dysplasia, muscular dystrophy, and bone cancer syndrome resulting from mutated retroviral-derived MTAP transcripts."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All three serum samples from unaffected individuals had no detectable MTA
      levels. In marked contrast, both affected individuals had accumulations of
      MTA detectable in their serum
    explanation: >-
      One of the two measured features the hypothesis rests on: serum MTA
      accumulates in affected individuals.
  - reference: PMID:22464254
    reference_title: "Primate genome gain and loss: a bone dysplasia, muscular dystrophy, and bone cancer syndrome resulting from mutated retroviral-derived MTAP transcripts."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      direct sequencing of this patient’s osteosarcoma genomic DNA demonstrated
      homozygosity for the c.885A >G mutation
    explanation: >-
      The other measured feature: the tumour loses the wild-type allele
      outright, which is the second feature shared with MTAP-deleted cancers.
  notes: >-
    Nothing here supports offering PRMT5 inhibition to a patient with this
    syndrome; the treatments section's exclusion of that strategy stands. This
    entry records a hypothesis about tumour biology, not a therapeutic
    recommendation.

clinical_trials:
- name: NCT00007046
  phase: NOT_APPLICABLE
  status: COMPLETED
  description: >-
    Completed NCRR-sponsored observational genetic study that set out to
    identify the causal gene and characterise the clinical manifestations of
    DMS-MFH in reported families. This is the study-registry record of the
    gene-hunting effort that the mutations curated in this entry are the
    published result of; it is a natural-history and gene-discovery study,
    not an interventional trial, and offers no treatment to enrol in.
  evidence:
  - reference: clinicaltrials:NCT00007046
    reference_title: "Genetic Study of Patients and Families With Diaphyseal Medullary Stenosis With Malignant Fibrous Histiocytoma of the Bone"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Identify and characterize the gene causing diaphyseal medullary
      stenosis with malignant fibrous histiocytoma of the bone.
    explanation: >-
      States the trial's objective, which is exactly the gene-identification
      effort this entry's genetic findings are the outcome of.

discussions:
- discussion_id: dmsmfh_metabolic_route_to_bone_unmapped
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    How does dysregulated MTAP isoform splicing produce bone infarction, cortical
    dysplasia and sarcoma?
  attaches_to:
  - pathophysiology#Impaired Polyamine and Methionine Salvage Metabolism
  - pathophysiology#Diaphyseal Cortical Dysplasia and Medullary Stenosis
  - pathophysiology#Bone Sarcoma Predisposition
  rationale: >-
    The molecular lesion is well characterised, the clinical phenotype is well
    described, and almost nothing connects them. Both endpoints are now measured:
    substrate accumulation shows the enzymatic step is perturbed in patients, and
    somatic loss of the wild-type allele shows how the tumour arises. The road
    between them is not. No cell type, signalling pathway or bone-remodelling
    mechanism has been implicated in the dysplasia, and nothing connects the
    metabolic state to either the dysplasia or the transformation.

    There is no animal model of the human lesion, and that is structural rather
    than incidental: the causal exons are retroviral insertions specific to
    primates, so a mouse has nothing to mutate.
  evidence:
  - reference: PMID:22464254
    reference_title: "Primate genome gain and loss: a bone dysplasia, muscular dystrophy, and bone cancer syndrome resulting from mutated retroviral-derived MTAP transcripts."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: COMPUTATIONAL
    snippet: >-
      two of these MTAP exons arose from early and independent retroviral-integration
      events in primate genomes at least 40 million years ago, and since then,
      their genomic integration has gained a functional role
    explanation: >-
      The primate specificity of the affected exons is why no conventional mouse
      model of this lesion can exist, which is the structural reason the route
      between the measured endpoints remains unmapped.
- discussion_id: dmsmfh_single_laboratory_dependence
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Has the MTAP retroviral-exon mechanism been independently replicated?
  attaches_to:
  - pathophysiology#MTAP Retroviral-Exon Splicing Mutation
  - pathophysiology#Dysregulated Alternative Splicing of MTAP Isoforms
  rationale: >-
    Essentially the entire molecular understanding of this syndrome rests on one
    paper from one laboratory, which also produced the earlier linkage work. That
    is not a criticism of the finding, which is internally coherent and explains
    a decade-long failure of candidate screening. It is a statement about how
    much independent corroboration exists, which is little, and it matters more
    than usual here because the claim is unusual: pathogenic synonymous mutations
    in retroviral-derived exons of a gene otherwise known as a somatic deletion
    passenger. The two strands of the mechanism are not equally exposed: that
    MTAP is a tumour suppressor in its own right is corroborated from outside the
    discovery laboratory by the Kadariya mouse work, so the sarcoma arm does not
    rest on a single group; the splicing mechanism itself, which is what these
    two nodes assert, has no such corroboration. Independent identification of
    the same exons in a new family would be the obvious confirmation and has not
    been reported.
- discussion_id: dmsmfh_myopathy_variability
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Why do only some DMS-MFH families have myopathy, and what determines it?
  attaches_to:
  - phenotypes#Myopathy
  rationale: >-
    Myopathy is named as a defining component of the syndrome but was absent from
    the three originally described families and appeared when two further
    families were characterised. A simple allele-phenotype correlation does not
    account for it, since the two myopathic families carry different mutations.
    With five families in total there is no power for modifier analysis, so
    whether this reflects an unrecognised modifier, an allele-specific effect
    that a larger series would resolve, or ascertainment differences in how
    carefully muscle was assessed, is open.
- discussion_id: dmsmfh_prmt5_vulnerability_untested
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Do DMS-MFH tumours reach the MTA-high, PRMT5-dependent state that
    MTAP-deleted cancers do?
  attaches_to:
  - pathophysiology#Somatic Loss of the Wild-Type MTAP Allele
  - treatments#Surveillance and Symptomatic Management
  rationale: >-
    The treatments section excludes PRMT5 inhibition, and that exclusion is
    correct as stated: the strategy was developed for tumours with homozygous
    MTAP deletion and absent protein, whereas the germline allele here is
    synonymous and leaves archetype MTAP untouched. Immunohistochemistry for
    MTAP would very likely read falsely negative in this setting.

    But the question is better posed than the exclusion implies. Two things are
    true of these tumours that are also true of the MTAP-deleted cancers PRMT5
    inhibitors target: serum methylthioadenosine accumulates in affected
    individuals, and the tumour loses the wild-type allele outright. Whether
    that combination is sufficient to produce the intratumoural MTA elevation
    that confers PRMT5 dependence has never been measured in a DMS-MFH tumour,
    and the entry should not be read as answering it. Intratumoural MTA and a
    PRMT5-dependence assay on tumour material would settle it.
  notes: >-
    Recorded as an open question rather than as a treatment. Nothing here
    supports offering PRMT5 inhibition to a patient with this syndrome, and the
    exclusion in the treatments notes stands.
- discussion_id: dmsmfh_clinical_burden_undocumented
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    What is the quality-of-life and functional burden of DMS-MFH, beyond the
    individual phenotypes and the sarcoma-risk figure?
  attaches_to:
  - clinical_burden#
  rationale: >-
    The five reported families establish the phenotype and the sarcoma risk in
    considerable molecular and radiographic detail, but none of the source
    literature reports a quality-of-life instrument, a disability or functional
    burden score, or caregiver-burden data. For a disease whose non-neoplastic
    course is described as producing painful debilitation and progressive
    wasting from childhood, and which then carries a roughly one-in-three
    lifetime cancer risk, the absence of any formal burden measurement is
    itself notable and is recorded here rather than left implicit. With only
    five families ever described, a dedicated burden study is unlikely to be
    powered, which is worth stating rather than treating the gap as an
    oversight to be filled by more literature search.
📚

References & Deep Research

References

1
PMID:22464254
Primate genome gain and loss: a bone dysplasia, muscular dystrophy, and bone cancer syndrome resulting from mutated retroviral-derived MTAP transcripts.
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 (1)

Create: Diaphyseal_Medullary_Stenosis_With_Malignant_Fibrous_Histiocytoma · 2026-08-29T05:25:17Z · View source

Created kb/disorders/Diaphyseal_Medullary_Stenosis_With_Malignant_Fibrous_Histiocytoma.yaml (MONDO:0007205, MTAP). Deep research was requested from falcon, which is not configured here, so the run used --fallback and claude_code produced the report. It was clean: 19 of 19 references verified, 0.0 confabulation rate, both checked quotes valid, no not-found and no obsolete terms. Its four flagged label mismatches are artifacts of source names and prose appearing in the label column of the report's own tables rather than wrong bindings. The entry was drafted from primary literature first and the report then contributed real content. It supplied the pedigree-level distribution of myopathy, presenile cataracts, and the observation that fewer than six families have been reported, each of which was then verified against the primary full text before use. Two facts from the full text materially changed the entry and neither was in the abstract. First, one of the two reported mutations is synonymous, c.885A>G, changing no amino acid. That is the most informative single fact about this lesion: a synonymous change cannot act by altering the protein sequence, so the splicing mechanism is the explanation rather than one candidate among several, and the entry now says so in the description and cites it. Second, myopathy was not present in the three originally described families and entered the phenotype when two further families with facioscapulohumeral-like muscular disease were characterised. The phenotype is retained, since the defining report names it as one of three components, but its description and a knowledge gap now record that it is a feature of the syndrome as defined rather than of every pedigree, and that the two myopathic families carry different mutations so a simple allele correlation does not explain it. A Named Entity Confusion warning is recorded in the entry notes. MTAP is far better known as a somatic passenger deletion adjacent to CDKN2A at 9p21, and MTAP-deleted tumours are an active PRMT5 target; that literature concerns homozygous somatic deletion in tumour cells and is not about this syndrome, whose lesion is a germline splicing mutation in a retroviral-derived exon. A gene-symbol search returns overwhelmingly the former. The one genuine connection, loss of heterozygosity across the same 9p21-22 interval in five of seven informative sporadic bone malignant fibrous histiocytoma specimens, is curated with its own evidence in the genetic block. Per the granularity ladder in the design-decision register this is a germline predisposition syndrome and follows the plain Mendelian rules, staying separate from the somatic sarcoma entries it predisposes to. Three knowledge gaps are recorded: the entirely unmapped route from the splicing defect to bone infarction, cortical dysplasia and sarcoma, including the structural reason no conventional mouse model can exist since the causal exons are primate-specific retroviral insertions; the dependence of the whole molecular understanding on a single laboratory, which matters more than usual for a claim this unusual; and the unexplained variability of myopathy across families. Nomenclature is deliberately historical. Malignant fibrous histiocytoma is the term used throughout the primary literature and is retained in the disease name and quoted snippets; the description notes the entity was later reclassified as undifferentiated pleomorphic sarcoma. One snippet begins mid-sentence because the preceding word in the cached PDF text is set with an fi ligature, which no exact-substring quote can span; the explanation records why. Validated with just validate-disorders, just validate-terms, just count-verified-snippets (23/23), just check-entity-refs, just check-duplicate-keys and just check-folded-hyphens. Compliance 91.2 percent.

Claude Code ▸
1. Disease Information
claude-haiku-4-5-20251001, claude-opus-5[1m] 37 citations 2026-08-29T01:19:30.071281

1. Disease Information

1.1 Overview

DMS‑MFH is a rare, autosomal‑dominant syndrome combining a distinctive long‑bone dysplasia with a high lifetime risk of high‑grade bone sarcoma. The skeletal lesion is diaphyseal medullary stenosis — progressive narrowing/obliteration of the medullary cavity of the long‑bone shafts by overlying endosteal cortical thickening — accompanied by scattered bone‑marrow infarctions, metaphyseal striations, pathologic fractures that heal poorly, progressive bowing of the lower limbs, and painful debilitation. Approximately one third of affected individuals develop a high‑grade bone sarcoma, historically diagnosed as malignant fibrous histiocytoma (MFH) or bone fibrosarcoma and, on modern review of at least one case, as osteosarcoma.

Two of the five known families additionally show a progressive limb‑girdle / facioscapulohumeral‑like myopathy, and features reported in individual pedigrees include presenile cataracts, thin skin, easy bruising, and premature graying.

Verbatim (Martignetti et al. 1999, PMID:10053015 abstract):

"Diaphyseal medullary stenosis with malignant fibrous histiocytoma (DMS-MFH) is an autosomal dominant bone dysplasia/cancer syndrome of unknown etiology. This rare hereditary cancer syndrome is characterized by bone infarctions, cortical growth abnormalities, pathological fractures, and eventual painful debilitation. Notably, 35% of individuals with DMS develop MFH, a highly malignant bone sarcoma."

Verbatim (Camacho‑Vanegas et al. 2012, PMID:22464254 abstract):

"Diaphyseal medullary stenosis with malignant fibrous histiocytoma (DMS-MFH) is an autosomal-dominant syndrome characterized by bone dysplasia, myopathy, and bone cancer."

Verbatim (Norton et al. 1996, PMID:8781110 abstract):

"Hardcastle syndrome is a rare, autosomally dominant inherited skeletal dysplasia, characterized by diaphyseal sclerosis, medullary stenosis, pathological fractures, bony infarction, and malignant transformation."

1.2 Identifiers (all verified)

Resource Identifier Notes
MONDO MONDO:0007205 diaphyseal medullary stenosis-bone malignancy syndrome — use as disease_term
OMIM 112250 (#) DIAPHYSEAL MEDULLARY STENOSIS WITH MALIGNANT FIBROUS HISTIOCYTOMA; DMSMFH
Orphanet ORPHA:85182 Diaphyseal medullary stenosis-bone malignancy syndrome
Disease Ontology DOID:0080664
UMLS C1862177 exact map (Orphanet)
MedGen UID 350613 / CUI C1862177
MeSH C536169 supplementary concept record; exact map
GARD 10072 exact map
ICD‑10 M89.8 Other specified disorders of bone — Orphanet flags DMS‑MFH as narrower than the ICD‑10 code
ICD‑11 LD24.1Y narrower than the targeted code
Causal gene MTAP — hgnc:7413, NCBI Gene 4507, OMIM 156540, UniProt Q13126, locus 9p21.3
Related OMIM entry 609940 — Myopathy, limb‑girdle, with bone fragility (now regarded as allelic/the same disorder; family 5)

Cross-reference block validated against Orphadata: api.orphadata.com ORPHA 85182 (CC‑BY‑4.0).

1.3 Synonyms and alternative names

  • Hardcastle syndrome (most common eponym)
  • Diaphyseal medullary stenosis–malignant fibrous histiocytoma syndrome
  • Bone dysplasia–medullary fibrosarcoma syndrome
  • Bone dysplasia with malignant fibrous histiocytoma
  • BDMF (OMIM/GTR gene‑test abbreviation)
  • DMSMFH / DMS‑MFH
  • Hereditary bone dysplasia with malignant change / with sarcomatous degeneration (historical, Arnold 1973; Hardcastle 1986)
  • Myopathy, limb‑girdle, with bone fragility (MedGen lists this as a synonym; formerly separate at MIM 609940)

Nomenclature note (important for curation). "Malignant fibrous histiocytoma" was retired as a diagnostic term in the 2013 WHO soft‑tissue classification and replaced by undifferentiated pleomorphic sarcoma (UPS); the 2020 WHO classification confirms UPS as "the correct designation for the storiform and pleomorphic variant of MFH." The disease name retains "MFH" for historical continuity, but the tumor should be curated as undifferentiated pleomorphic sarcoma of bone (UPSB) and/or osteosarcoma, per the 2012 re‑review of a family‑4 tumor.

1.4 Provenance of information

Aggregated, disease‑level, pedigree‑derived. There is no EHR cohort, no registry, and no population dataset for DMS‑MFH. All clinical data derive from five published multigenerational pedigrees (case series with radiographic and, latterly, molecular characterization). No dataset exists in GEO/dbGaP/SRA specific to this disease. This should be reflected in dismech prevalence.measure_type: CASES_IN_LITERATURE.

2. Etiology

2.1 Primary causal factor

Germline heterozygous mutation in a non‑canonical terminal exon (exon 9) of MTAP (9p21.3), acting through dysregulated alternative splicing of MTAP isoforms. Inheritance is Mendelian autosomal dominant; there is no known environmental or infectious contribution.

Verbatim (PMID:22464254):

"We now demonstrate that DMS-MFH results from mutations in the most proximal of three previously uncharacterized terminal exons of the gene encoding methylthioadenosine phosphorylase, MTAP."

2.2 Genetic risk factors

  • Causal variants (2 known, see §4.2): c.885A>G (p.(=), synonymous R100R) and c.813-2A>G, both in/adjacent to the retroviral‑derived MTAP exon 9.
  • Being a first‑degree relative of an affected individual is the only meaningful "risk factor" — 50% transmission risk per offspring.
  • Somatic second hit: loss of the wild‑type allele (LOH at 9p21) is the tumor‑initiating event (§4.2, §6.1).
  • No modifier genes identified. The variable myopathy across families (present in families 4 and 5, absent from the three original families) is unexplained; it is compatible with either an unrecognized modifier or with allele‑specific effects (the myopathic families 4 and 5 carry different mutations — family 4 c.885A>G, family 5 c.813-2A>G — so a simple allele–myopathy correlation is not supported).
  • Susceptibility loci: No GWAS exists for DMS‑MFH (impossible at n≈5 families). The neighbouring 9p21 CAD/MI GWAS locus is discussed by the authors as a speculative overlap (§2.4).

2.3 Environmental risk and protective factors

None identified. No toxic, occupational, dietary, infectious, or radiation exposure has been associated with DMS‑MFH onset, bone phenotype severity, or sarcoma risk. CTD/TOXNET contain no DMS‑MFH entries. Mechanical loading is a plausible but unstudied modifier of the fracture phenotype.

No protective genetic or environmental factors are described. No protective alleles, no dietary or lifestyle intervention has been shown to reduce sarcoma risk.

Curation note: the environmental: section should be left empty or, if a curator has searched, carry the repo's uncited‑exposure waiver pattern (review_notes beginning "Left deliberately uncited." plus a record of the searches run), rather than manufacturing an exposure.

2.4 Gene–environment interaction

None documented. One speculative gene–environment/comorbidity thread from the primary paper is worth recording as a hypothesis rather than a finding — a possible MTAP contribution to coronary artery disease:

Verbatim (PMID:22464254, Discussion):

"First, in DMS-MFH-affected family 1, two male family members died of heart disease in their early forties without other known risk factors. A third family member has been recently diagnosed with early CAD (J.A.M., unpublished data). As such, CAD might represent a previously unrecognized aspect of the disease phenotype in this syndrome."

This is explicitly flagged by the authors as unpublished/anecdotal and should be curated as a KNOWLEDGE_GAP discussion, not as a phenotype.

3. Phenotypes

3.1 Core skeletal phenotypes

All HPO IDs below were verified against the HPO release in this repository via OAK (sqlite:obo:hp).

Phenotype HPO term Category Onset Course Frequency
Stenosis of the medullary cavity of the long bones HP:0100254 Skeletal / radiographic Childhood–adolescence (radiographically detectable) Progressive Obligate; defining feature
Diaphyseal cortical sclerosis HP:0005045 Skeletal / radiographic Childhood–adolescence Progressive Obligate; defining feature
Metaphyseal striations HP:0031367 Skeletal / radiographic Childhood Stable/progressive Frequent
Patchy osteosclerosis HP:0005686 Skeletal / radiographic Childhood–adult Progressive Frequent
Pathologic fracture HP:0002756 Clinical sign Childhood to adult (mean ~24 yr in family 5) Recurrent Very frequent
Recurrent long bone fractures HP:0003084 Clinical sign as above Recurrent Very frequent
Bowing of the legs HP:0002979 Physical manifestation Progressive, post‑fracture Progressive Frequent
Osteopenia HP:0000938 Radiographic/lab Adult Progressive Reported
Osteomyelitis (leading to amputation from slow‑healing fractures) HP:0005010 (specific) / HP:0002754 (general) Complication Adult Episodic Occasional
Bone pain HP:0002653 Symptom Adult Progressive, debilitating Very frequent

The bone‑marrow infarction component ("scattered infarctions within the bone marrow", PMID:22464254) has no precise HPO term; the closest ontology anchor is via UBERON UBERON:0002371 (bone marrow) plus a curated pathophysiology node. This is a genuine ontology gap worth noting.

3.2 Neoplastic phenotypes

Phenotype HPO term Onset Frequency
Histiocytoma (MFH → UPS) HP:0012315 2nd–5th decade ~35% of affected individuals
Osteosarcoma HP:0002669 2nd–5th decade Confirmed in ≥1 family‑4 tumor on modern histopathology
Fibrosarcoma (of bone) HP:0100244 2nd–5th decade Original Arnold 1973 designation; 3 of 6 siblings

Verbatim (PMID:22464254):

"Approximately one-third of affected individuals within our families developed bone sarcomas arising between the second and fifth decades of life. The diagnoses were either MFH or bone fibrosarcoma." "…given the presence of osteoid, the histopathological analysis of a tumor from a DMS-MFH-affected individual (III-3 from family 4; c.885A>G) is consistent with the diagnosis of osteosarcoma. Thus, inherited MTAP alternative-splicing mutations can result in histology-proven osteosarcoma."

Frequency caveat. The "35%" figure derives from three pedigrees in 1999 and was restated as "approximately one-third" in 2012. It is a within‑pedigree proportion, not an age‑adjusted penetrance estimate, and is subject to severe ascertainment bias (families were identified because of sarcoma). Curate as FrequencyEnum band with a note; do not present as a validated lifetime risk.

3.3 Neuromuscular phenotypes (families 4 and 5 only)

Phenotype HPO term Onset Course
Myopathy HP:0003198 Mean ~31 yr (family 5) Progressive
Limb-girdle muscle weakness HP:0003325 Adult Progressive
Proximal muscle weakness HP:0003701 Adult Progressive
Skeletal muscle atrophy HP:0003202 Adult Progressive

Verbatim (PMID:22464254, Introduction):

"We recently expanded the known clinical features of the syndrome by characterizing two new unrelated families affected by a progressive form of muscular disease consistent with facioscapulohumeral muscular dystrophy (FSHD [MIM 158900])."

Note the internal tension in the literature: the 2012 paper describes the myopathy as FSHD‑like in the Introduction and as "features overlapping the symptoms of facioscapulohumeral muscular dystrophy and limb-girdle muscular dystrophy" in the Discussion; Watts/Mehta (2005/2006) describe family 5 as limb‑girdle. Curate as limb‑girdle with an explicit note about the FSHD‑overlap description. FSHD1/2 (D4Z4) and LGMD genes were not, to my knowledge, formally excluded in these families.

3.4 Ocular, integumentary and connective-tissue phenotypes

Phenotype HPO term Notes
Presenile cataracts HP:0007819 Listed as a core feature in the 2012 Introduction
Thin skin HP:0000963 Family 5 (Mehta 2006)
Soft skin HP:0000977 MedGen/GARD list
Bruising susceptibility HP:0000978 Family 5; GARD flags as occasional
Premature graying of hair HP:0002216 Family 5 (Mehta 2006)

Verbatim (PMID:22464254, Introduction):

"Affected individuals endure pathologic fractures that subsequently heal poorly, progressive wasting, bowing of the lower extremities, painful debilitation, and the development of presenile cataracts."

Mehta et al. 2006 (PMID:16419137) additionally report "premature graying with thin hair, thin skin, hernias" and clotting abnormalities in family 5 — features that have not been confirmed in the three original DMS‑MFH families and should be curated with a subtype/family qualifier rather than as disease‑wide.

3.5 Inheritance annotation

  • Autosomal dominant inheritance — HP:0000006

3.6 Quality-of-life impact

No formal QoL instrument (EQ‑5D, SF‑36, PROMIS, TESS, MSTS) has ever been applied to a DMS‑MFH cohort. Reported impact is qualitative and severe:

  • Repeated pathologic fractures with poor healing → prolonged immobilization, chronic pain ("eventual painful debilitation", PMID:10053015).
  • Progressive lower‑limb bowing → gait impairment, reduced ambulation.
  • Osteomyelitis complicating slow‑healing fractures has led to amputation (HP:0005010).
  • Superimposed limb‑girdle myopathy in two families compounds mobility loss.
  • Sarcoma diagnosis in the 2nd–5th decade brings the full burden of neoadjuvant/adjuvant chemotherapy plus limb‑salvage surgery or amputation.
  • The tumor‑predisposition status imposes lifelong surveillance and reproductive/genetic‑counselling burden.

This is a legitimate KNOWLEDGE_GAP for the dismech entry: clinical_burden# with no quantitative instrument available.

4. Genetic / Molecular Information

4.1 Causal gene

MTAP — S‑methyl‑5′‑thioadenosine phosphorylase (methylthioadenosine phosphorylase).

Attribute Value
HGNC hgnc:7413 (lowercase prefix per repo convention)
NCBI Gene 4507
Ensembl ENSG00000099810
UniProt Q13126
OMIM 156540
Cytoband 9p21.3, immediately telomeric to / adjacent to CDKN2A–CDKN2B
EC 2.4.2.28
Quaternary structure Homotrimer
PDB 1CG6 (trimer + MTA sulfate), 1CB0 (apoprotein) — structure at 1.7 Å (PMID:10404592)

Verbatim (PMID:22464254):

"MTAP is a ubiquitously expressed homotrimeric-subunit enzyme critical to polyamine metabolism and adenine and methionine salvage pathways and was believed to be encoded as a single transcript from the eight previously described exons."

The key structural discovery is that MTAP is not an eight‑exon gene. Three additional terminal exons exist:

  • Exon 9 — a 192 bp ORF (GenBank AF216650), located 65 kb downstream of the previously annotated MTAP termination site; derived from a MER50I retroviral element.
  • Exon 10 — derived from a THE1A element.
  • Exon 11 — third terminal exon.

Verbatim:

"Intriguingly, two of these MTAP exons arose from early and independent retroviral-integration events in primate genomes at least 40 million years ago, and since then, their genomic integration has gained a functional role."

Exon 9 integrated "into the primate genome at some point in evolution between the divergence of the ring-tailed lemur and the common woolly monkey approximately 40 million years ago" — i.e., after prosimian and New World monkey divergence. The authors describe this as exaptation and state:

"However, we are unaware of any other example wherein the loss of a co-opted gene and/or protein domain results in a disease phenotype."

4.2 Pathogenic variants

Two germline variants, both in/adjacent to exon 9, both splicing‑altering with no predicted amino‑acid change. Numbering is relative to the EST reference clone GenBank AK309365, not the canonical NM_002451 transcript — an important caveat for anyone reconciling these to ClinVar.

Variant Type Families Effect
c.885A>G (p.(=), "effectively R100R") Exonic synonymous; abolishes a predicted exonic splicing enhancer (ESE) 1, 3, 4 Reduces exon‑9‑containing isoform expression by ~70%; no effect on archetype MTAP
c.813-2A>G Intronic; destroys the canonical splice acceptor site 2, 5 Ablates all exon‑9‑containing isoforms; significantly increases archetype MTAP expression

Verbatim:

"one mutation was a synonymous change at position c.885A>G (p.(=)), effectively R100R, and was present in affected families 1, 3, and 4. The second mutation, c.813-2A>G, was an intronic change present in affected family 2."

Segregation and population evidence:

"The sequence changes segregated appropriately with the disease phenotype within all respective family members in each family… Neither mutation was identified in 1,000 chromosomes from 500 unaffected control individuals. Similarly, the mutations were not present in dbSNP build 131."

ACMG/AMP classification. Neither variant has, to my knowledge, been formally re‑classified under ACMG/AMP 2015 criteria. Under those criteria the evidence would be roughly: PS3 (well‑established functional studies — minigene splicing assays), PS4_moderate/PM (absent from 1,000 control chromosomes), PP1_strong (co‑segregation across five multigenerational pedigrees), PS3 supporting from the elevated serum MTA — but counterweighted by BS1‑type concerns from the ClinGen dosage curation and the fact that the reference transcript is non‑canonical. Best current summary: "reported pathogenic in the primary literature; not independently classified; ClinGen gene-level evidence rated as limited."

ClinVar status is confusing and must be handled carefully. Searching ClinVar for "Diaphyseal medullary stenosis-bone malignancy syndrome" returns records that are not the two published variants: e.g. NM_002451.4:c.*2837T>A (RCV000310131, VUS, 1‑star, Illumina Clinical Services, submitter note "No publications were found"), c.*2968T>C (RCV000332282), c.566G>T p.Trp189Leu (RCV000317123), c.315C>T p.Gly105= (RCV000330004). These are incidental submissions tagged to the condition, not disease‑causing alleles. The OMIM‑derived allelic variant record for c.885A>G is RCV000022659. Do not cite the 3′‑UTR VUS records as evidence for DMS‑MFH.

Somatic vs germline / two‑hit:

"Moreover, and in agreement with Knudson's two-hit hypothesis for a tumor-suppressing gene, direct sequencing of this patient's osteosarcoma genomic DNA demonstrated homozygosity for the c.885A>G mutation. LOH analysis with microsatellite markers spanning the originally defined 2.9 Mb DMS-MFH critical region revealed complete loss of the WT allele from the unaffected chromosome."

Functional consequence class. This is best modeled in dismech as functional_impact_category: LOSS_OF_FUNCTION for the exon‑9‑containing isoforms (v1, v2, v4, v5), with a simultaneous gain in v3/v6 — an unusual dual effect the authors explicitly flag:

"Given our findings that the DMS-MFH mutations also result in overexpression of two splice variants, MTAP_v3 and _v6, the possibility that at least two of the MTAP isoforms could represent oncogenic variants must also be considered at this time."

4.3 The six retroviral‑derived MTAP isoforms

Identified by 3′ RACE from control and patient fibroblast, lymphoblast and patient‑derived tumor cell lines. None contain wild‑type terminal exon 8; all alter the C‑terminus.

Isoform Exon composition Contains exon 7? MTAP enzymatic activity
MTAP_v1 1–7 + 9S–11 Yes Active
MTAP_v2 1–7 + 9L Yes Active
MTAP_v3 1–7 + 10 + 11 Yes Active
MTAP_v4 1–6 + 9S–11 No Not detectable
MTAP_v5 1–6 + 9L No Not detectable
MTAP_v6 1–6 + 10 + 11 No Not detectable

(9S = short 103 nt form of exon 9; 9L = long 192 nt form.) v4–v6 had "appreciably shorter half-lives"; activity remained undetectable even under proteasome inhibition with MG132.

All six isoforms "can physically interact with archetype MTAP" (co‑immunoprecipitation), supporting a heterotrimer / dominant‑negative‑like model at the subunit interface — the structural basis for dominant inheritance despite MTAP being a classic recessive‑style metabolic enzyme.

4.4 Linkage history

Study Finding
Martignetti 1999 (PMID:10053015) Genome scan, 3 families → ~3 cM on 9p21‑22, max two‑point LOD 5.49 at D9S171 (θ=0.05)
Watts 2005 (PMID:16244874) Family 5 (AD limb‑girdle myopathy + bone fragility) → 9p21‑p22, LOD 3.74, 15 Mb interval
Camacho‑Vanegas 2012 All 5 families, max combined location score 4.27 at D9SB3; critical region narrowed to ~1.2–1.3 Mb between AL882 and D9S976
Sporadic MFH LOH (ref. 14 of the 2012 paper) Smallest region of overlap 2.9 Mb between D9S736 and D9S171 — links hereditary and sporadic MFH

Candidate genes excluded by direct sequencing before exon 9 was found: CDKN2A (p16), p14‑ARF, CDKN2B (p15), the IFN gene cluster, and the eight canonical exons of MTAP.

4.5 Modifier genes, epigenetics, chromosomal abnormalities

  • Modifier genes: none identified.
  • Epigenetics: no DNA‑methylation, histone‑modification, or chromatin study has been performed in DMS‑MFH tissue. However, the mechanism is intrinsically epigenetic downstream (see §6.1): MTA accumulation inhibits PRMT5, reducing symmetric dimethylarginine marks including H4R3me2s and H3R8me2s. No ENCODE/Roadmap/DiseaseMeth dataset for this disease.
  • Chromosomal abnormalities: none constitutional. Somatically, 9p21 deletion/LOH is the second hit; 9p21 is "one of the most frequently deleted and/or translocated chromosomal regions in human cancer" (gliomas, melanoma, NSCLC, acute leukemias, osteosarcomas). The 2012 authors raise a methodological warning worth curating:

"The facts that MTAP is more complex than previously recognized and that its terminal coding exon lies within 25 kb of the p15/p16 locus has immediate significance to LOH mapping and copy number variation (CNV) studies in human cancer. Deletions including the p15/p16 locus will more than likely also include the 3′ region of MTAP and therefore might affect MTAP biochemical activity. Thus, the interpretation of many of these studies with regard to the genes being affected should be reevaluated."

5. Environmental Information

Not applicable. DMS‑MFH is a purely Mendelian disorder with no established environmental, lifestyle, or infectious contribution.

  • Environmental factors: none identified. No CTD entries.
  • Lifestyle factors: none identified. Weight‑bearing/mechanical loading is a theoretical modifier of fracture frequency but is unstudied.
  • Infectious agents: none. The retroviral element in exon 9 is an endogenous retroviral (ERV) remnant fixed in the primate germline 40 Mya, not an active infection. This distinction must be preserved in any curated text — MER50I and THE1A are exapted genomic sequence, not pathogens, and there is no NCBITaxon organism to annotate.

6. Mechanism / Pathophysiology

6.1 The causal chain (upstream → downstream)

Step 1 (MOLECULAR) — Germline exon‑9 splicing mutation. c.885A>G abolishes an ESE; c.813-2A>G destroys the splice acceptor. Both are heterozygous and germline. GO:0000380 (alternative mRNA splicing, via spliceosome)

Step 2 (MOLECULAR) — Dysregulated MTAP isoform stoichiometry. Verbatim: "c.813-2A>G and c.885A>G resulted in markedly decreased [expression]… the c.813-2A>G mutation ablated expression of all isoforms containing exon 9 and significantly increased the [archetype MTAP]… The c.885A>G mutation decreased the expression levels of all exon 9 isoforms by approximately 70% but had no [effect on archetype]." Loss of the enzymatically active exon‑9‑containing isoforms v1/v2 and the inactive v4/v5; overexpression of v3/v6.

Step 3 (MOLECULAR) — Perturbed MTAP holoenzyme assembly. All six isoforms co‑immunoprecipitate with archetype MTAP; molecular modelling on PDB 1CG6/1CB0 shows the splice‑variant insertion points (after K271 for v1‑type, after A230 for v4‑type) sit at the trimer subunit interface, adjacent to the exon‑6/exon‑7‑encoded substrate‑binding site (only L279 comes from exon 8). Verbatim: "The trimeric subunit interface of MTAP does appear to be affected by the alternate splicing events or, possibly, the MTA active site." GO:0017061 (S-methyl-5-thioadenosine phosphorylase activity), modifier DECREASED

Step 4 (ORGANISM/MOLECULAR) — Systemic MTA accumulation. ← the key human in‑vivo evidence MTAP normally phosphorolyses MTA (CHEBI:17509) to adenine (CHEBI:16708) + 5‑methylthioribose‑1‑phosphate, which is recycled to L‑methionine (CHEBI:16643). MTA is the by‑product of polyamine (spermidine CHEBI:16610, spermine) synthesis from SAM (CHEBI:15414). GO:0071267 (L-methionine salvage), GO:0043101 (purine-containing compound salvage), GO:0006595 (polyamine metabolic process)

Verbatim:

"MTA is not normally present in human serum. Cells lacking MTAP activity are unable to metabolize MTA, and functional inhibition or dysregulation of MTAP activity would therefore be expected to result in intracellular MTA accumulation and secretion… All three serum samples from unaffected individuals had no detectable MTA levels. In marked contrast, both affected individuals had accumulations of MTA detectable in their serum."

Serum donor MTA (pmol/100 µL)
F4 III‑1 (affected) 11.5
F4 IV‑2 (affected) 4.3
F4 IV‑3 (unaffected relative) not detected
Control 1 not detected
Control 2 not detected

This is a biomarker‑grade finding (n=2 affected vs 3 unaffected, blinded assay) and the single strongest piece of human in‑vivo mechanistic evidence for the disease. It is also, at n=5, a fragile one.

Step 5 (MOLECULAR, inferred) — PRMT5 hypomethylation. Not demonstrated in DMS‑MFH tissue, but established for MTAP‑null cancer generally: accumulated MTA is a SAM‑competitive inhibitor of PRMT5 with >100‑fold selectivity over other PRMT family members, reducing symmetric arginine dimethylation of histone and non‑histone substrates. GO:0019918 (peptidyl-arginine methylation, to symmetrical-dimethyl arginine), GO:0032259 (methylation) Curate as a MECHANISTIC_HYPOTHESIS / EMERGING hypothesis group with cancer‑biology (not DMS‑MFH) evidence.

Step 6a (CELLULAR/TISSUE) — Bone dysplasia arm. How MTAP dysfunction produces endosteal cortical thickening, medullary obliteration, marrow infarction, and impaired fracture healing is genuinely unknown. The only mechanistic thread the authors offer is polyamine‑dependent angiogenesis:

"Third, defects in polyamine metabolism have been associated with defects in angiogenesis and altered myocyte function, whereas a nearly pathognomonic feature of DMS-MFH bone dysplasia is the presence of scattered infarctions throughout the medullary cavity."

This is the highest‑value knowledge gap in the entry. Cell types implicated by the phenotype (not by direct evidence): osteoblast CL:0000062, osteocyte CL:0000137, osteoclast CL:0000092, bone‑marrow mesenchymal stem cell CL:2000079/CL:0000134, and marrow microvascular endothelium. GO:0001649 (osteoblast differentiation), GO:0001503 (ossification), GO:0030282 (bone mineralization)

Step 6b (TISSUE) — Sarcomagenesis arm. Germline heterozygous MTAP defect → somatic LOH/loss of the WT 9p21 allele (Knudson two‑hit) → biallelic MTAP dysfunction in a mesenchymal progenitor → high‑grade sarcoma (UPS/osteosarcoma) in the 2nd–5th decade. The 2012 authors present this as the first in‑vivo human demonstration of MTAP tumour suppression:

"…the identification of the MTAP splice variants and the fact that their genetic loss results in DMS-MFH provide a possible in vivo demonstration that MTAP can act as a tumor suppressor."

Supporting in vitro precedent: "Reintroduction of MTAP expression into the MCF7 breast adenocarcinoma cell line, which lacks endogenous MTAP gene expression and enzymatic activity, inhibits the cells' ability to grow both in vitro and in vivo."

Step 6c (TISSUE) — Myopathy arm (families 4, 5). Mechanism unknown. Only linkage cited: "defects in polyamine metabolism have been associated with… altered myocyte function." Cell type: skeletal muscle fiber CL:0008002.

6.2 Protein dysfunction

Not misfolding or aggregation. The defect is isoform stoichiometry within an obligate homotrimer: wild‑type‑length archetype MTAP retains catalytic competence, but the normal complement of C‑terminally variant subunits that co‑assemble with it is lost or skewed. Predicted (unvalidated) structural detail: "Secondary-structure and disulfide-bond prediction analyses predict the generation of a disulfide bond between cysteine residues in exons 9 and 10; these prediction analyses require future biochemical analysis for validation."

6.3 Metabolic changes

  • Methionine salvage — impaired (MTA→methylthioribose‑1‑P→methionine).
  • Adenine salvage — impaired; MTAP phosphorolysis "is the principle source of free adenine in human cells."
  • Polyamine metabolism — MTA, the by‑product of spermidine/spermine synthesis, is not cleared.
  • Methylation potential — MTA:SAM ratio rises, biasing SAM‑dependent methyltransferases (PRMT5 most sensitively).

6.4 Immune involvement

None in the human syndrome. In the mouse, however, Mtap heterozygosity produces a lymphoid phenotype (§15) — an interesting species divergence and a candidate HUMAN_MODEL_MISMATCH.

6.5 Tissue damage mechanisms

  • Ischemia/infarction: medullary bone infarcts are near‑pathognomonic; presumed vascular (polyamine–angiogenesis link, unproven).
  • Impaired repair: fractures "heal poorly"; slow union permits osteomyelitis and, in some cases, amputation.
  • Mechanical: stenosed medulla + thickened cortex alters bone biomechanics, predisposing to pathologic fracture and progressive bowing.

6.6 Molecular profiling — what exists and what does not

Modality Status for DMS‑MFH
Transcriptomics None. No GEO/ArrayExpress dataset. 3′ RACE and RT‑PCR on patient fibroblast/lymphoblast/tumor lines is the only transcript‑level work.
Proteomics None in PRIDE/ProteomeXchange. Co‑IP and immunoblot only.
Metabolomics Only the targeted serum MTA assay (n=5). No untargeted metabolomics; nothing in MetaboLights or Metabolomics Workbench.
Lipidomics None.
Single‑cell / spatial None.
Multi‑omics None.
Functional genomics (CRISPR/RNAi) None for the syndrome. Extensive DepMap MTAP‑dependency data exists for MTAP‑deleted cancer — relevant to §12 but not to the germline syndrome.
Genomic structural features UCSC/RepeatMasker/Retrosearch analysis of exons 9 (MER50I) and 10 (THE1A); primate genomic DNA PCR panel establishing ~40 Mya integration.

7. Anatomical Structures Affected

7.1 Organ level

Primary: the skeleton, specifically the long tubular bones. - Long bone — UBERON:0002495 - Diaphysis — UBERON:0004769 (the defining site) - Metaphysis — UBERON:0001438 (striations) - Femur UBERON:0000981, tibia UBERON:0000979, fibula UBERON:0001446, humerus UBERON:0000976 (diaphysis of humerus UBERON:0004652); the 1996 Norton report's MeSH indexing names femur, fibula and tibia specifically.

Secondary / additional systems: - Musculoskeletal (muscle): skeletal muscle, limb‑girdle distribution (families 4, 5). - Ocular: lens — UBERON:0000965 (presenile cataracts). - Integumentary: skin (thin/soft), hair (premature graying). - Hematologic/vascular: bone‑marrow vasculature (infarction); reported clotting abnormality in family 5. - Cardiovascular: speculative early CAD in family 1 (unpublished, do not curate as phenotype).

Body systems: skeletal (primary), muscular, ocular, integumentary, hematopoietic/marrow.

7.2 Tissue and cell level

Structure Term
Compact (cortical) bone tissue — thickened endosteally UBERON:0001439
Endosteum — site of pathological apposition UBERON:0009859
Bone marrow — site of infarction UBERON:0002371
Bone marrow cavity — stenosed/obliterated UBERON:0002484
Skeletal muscle tissue — limb girdle (use limb‑specific children as appropriate)
Cell population Term Basis
Osteoblast CL:0000062 Inferred from endosteal cortical thickening
Osteocyte CL:0000137 Inferred
Osteoclast CL:0000092 Inferred from failed medullary resorption
Mesenchymal stem cell (bone marrow) CL:2000079 / CL:0000134 Presumed sarcoma cell of origin — UPS is now attributed to mesenchymal stem cells rather than histiocytes
Fibroblast CL:0000057 Tumor histology: "malignant spindle (fibroblastic) cells of bone MFH"; also the patient cell line used for RACE
Skeletal muscle fiber CL:0008002 Myopathy arm

Curation warning: every cell‑type assignment above except fibroblast is inferred from tissue phenotype, not demonstrated. There is no cell‑type‑resolved study of DMS‑MFH. Bind these with descriptions that make the inference explicit, or leave them out.

7.3 Subcellular level

MTAP is cytosolic. Relevant GO cellular components: cytosol (GO:0005829), with nuclear relevance downstream via PRMT5 substrate methylation. No organellar pathology (mitochondrial, ER, lysosomal) is described.

7.4 Localization and lateralization

  • Bilateral and symmetric. The dysplasia is described as symmetric diaphyseal medullary stenosis of the long bones. Radiographic screening therefore uses bilateral long‑bone films.
  • Distribution: long tubular bones of the limbs; the 2012 description emphasizes "diffuse diaphyseal medullary stenosis with overlying endosteal cortical thickening" — i.e. length‑wise diffuse rather than focal.
  • Tumors arise focally and are not symmetric; extremity location predominates (consistent with UPSB generally).

8. Temporal Development

8.1 Onset

Manifestation Typical onset
Radiographic dysplasia Detectable from puberty — the basis for the screening recommendation
Pathologic fractures Childhood through adulthood; mean ~24 years in family 5 (Mehta 2006)
Limb‑girdle myopathy Mean ~31 years in family 5
Presenile cataracts Adult, premature relative to population norms
Bone sarcoma 2nd–5th decade (approximately ages 10–50)

Onset pattern: insidious and chronic for the dysplasia; acute for each fracture event; subacute for tumor presentation (pain, mass, or pathologic fracture through tumor).

Note the developmental sequencing this implies: the skeletal dysplasia is essentially congenital/constitutional in genotype but adolescent in radiographic expression, and the malignancy is a late, stochastic, second‑hit event.

8.2 Progression

Stages (not formally defined — proposed for curation from the natural history): 1. Latent / radiographic-only — childhood to puberty; asymptomatic, dysplasia visible on plain film. 2. Fracture phase — adolescence through adulthood; recurrent pathologic fractures with poor union; progressive bowing. 3. Debilitation phase — adult; chronic pain, deformity, infarction burden, superimposed myopathy in some families; osteomyelitis/amputation risk. 4. Malignant transformation — 2nd–5th decade; ~1 in 3 affected individuals; converts prognosis from chronic disability to life‑threatening.

Progression rate: slow and steady for the dysplasia (decades); the myopathy is explicitly "progressive"; sarcoma behaves as a high‑grade, rapidly progressive malignancy.

Course pattern: chronic progressive with superimposed episodic events (fractures, infarcts, tumor). Not relapsing‑remitting.

Duration: lifelong. There is no self‑limited form.

8.3 Patterns

  • Remission: none for the skeletal dysplasia — it is structural and irreversible. Tumor remission is treatment‑induced only (see §11, §12).
  • Critical periods:
  • Puberty — the radiographic screening window opens (Norton 1996 recommendation).
  • 2nd–5th decades — the sarcoma surveillance window; this is the period where surveillance could plausibly change outcome.
  • Peri‑fracture — the intervention window for preventing malunion and osteomyelitis.

9. Inheritance and Population

9.1 Epidemiology

  • Prevalence: not documented. Neither Orphanet nor GARD publishes a prevalence estimate. Orphanet describes the disorder only as "very rare."
  • Total reported cases: five families worldwide (as of the 2012 gene‑discovery paper and, to my knowledge, still the case in 2026). Family origins: American (Vermont/New York), Australian, English, and two New York families — one of which (family 5) is the 1958 Canadian Henry kindred with AD bone fragility and limb‑girdle myopathy.
  • Incidence: not documented. No registry, no national surveillance, no SEER capture (SEER codes the tumor, not the syndrome).

dismech prevalence record shape:

prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Five unrelated multigenerational families reported worldwide (Arnold 1973
    American kindred; Hardcastle 1986 English and Australian families; Norton
    1996 New York family; a second New York family and the 1958 Henry Canadian
    kindred added by Camacho-Vanegas 2012). No prevalence estimate is published
    by Orphanet or GARD.

9.2 Genetic parameters

Parameter Status
Inheritance pattern Autosomal dominant — confirmed across five multigenerational pedigrees, with male‑to‑male transmission excluding X‑linkage. HPO HP:0000006.
Penetrance Appears high to complete for the radiographic bone dysplasia (the trait segregated cleanly for linkage analysis, LOD 5.49). Incomplete/probabilistic for the sarcoma (~35%). No formal age‑adjusted penetrance study exists.
Expressivity Variable — most strikingly, myopathy is present in families 4 and 5 and absent from families 1–3; cataracts, skin and hair features are reported unevenly. Even within families, sarcoma occurs in only a subset.
Anticipation Not reported and not expected — this is not a repeat‑expansion disorder.
Germline mosaicism Not reported. No de novo case has been described; all reported probands come from affected kindreds. This is itself notable — an unascertained sporadic/de novo case population may exist.
Founder effect None. The two mutations are distributed across geographically unrelated families (c.885A>G in the American, New York, and second New York families; c.813-2A>G in the Australian and Canadian families) with no reported shared haplotype.
Consanguinity Not a factor — dominant inheritance.
Carrier frequency Not applicable (dominant); the causal alleles were absent from 1,000 control chromosomes and from dbSNP build 131. Note the tension with the ClinGen observation that MTAP LoF variants are "frequent in gnomAD" — those are canonical‑exon LoF variants, not exon‑9 splicing alleles, and the two observations are not contradictory but are easily conflated.

9.3 Population demographics

  • Affected populations: all reported families are of European/European-diaspora ancestry (United States, England, Australia, Canada). This almost certainly reflects ascertainment, not biology — the disorder has only ever been studied by centres in the US, UK and Australia. Do not curate as an ancestry association.
  • Geographic distribution: North America (US, Canada), United Kingdom, Australia. No endemic focus.
  • Variant geography: no meaningful pattern at n=2 variants / 5 families.
  • Sex ratio: 1:1 expected and consistent with reports — autosomal dominant, "males and females equally affected with 50% transmission risk per child" (MedGen). No sex bias in bone or tumor phenotype has been reported.
  • Age distribution of affected individuals: all ages; clinical burden concentrates in the 2nd–5th decades.

10. Diagnostics

10.1 Imaging — the diagnostic cornerstone

Plain radiography of the long bones is the primary diagnostic modality. Characteristic findings: - Symmetric diaphyseal medullary stenosis with endosteal cortical thickening (HP:0100254, HP:0005045) - Metaphyseal striations (HP:0031367) - Patchy osteosclerosis (HP:0005686) - Scattered medullary infarcts — serpiginous sclerotic rims - Healed/healing pathologic fractures, bowing deformity

MRI characterizes marrow infarction and is essential for tumor staging and local extent (used in the Norton 1996 report).

Thallium‑201 scintigraphy — proposed specifically for this syndrome as a tumor‑sensitive screen, because ordinary bone scintigraphy is confounded by the diffusely abnormal, infarcted, remodelling skeleton:

"Thallium scanning is proposed as a more tumor-sensitive screening agent in affected individuals." (PMID:8781110)

CT for cortical detail; FDG‑PET/CT is now standard for sarcoma staging generally, though it has not been specifically validated in DMS‑MFH and would be expected to have reduced specificity against a background of bone infarction and remodelling — a real and under‑discussed diagnostic problem in this disease.

10.2 Laboratory tests and biomarkers

  • Serum MTA (5′‑deoxy‑5′‑methylthioadenosine, CHEBI:17509) — the only disease‑specific biochemical marker. MTA is undetectable in normal serum; affected individuals had 11.5 and 4.3 pmol/100 µL. This is a research assay, not a clinical test — it has been performed in a single study on two affected individuals and three controls, has no validated reference interval, no established cutoff, no LOINC code, and is not offered by any clinical laboratory. Curate as an association/biomarker with validation_status language making this explicit, not as a diagnostic test.
  • Routine bone chemistry (calcium, phosphate, ALP, PTH, 25‑OH‑D) is used to exclude metabolic bone disease; no characteristic abnormality is reported.
  • CK is appropriate in the myopathic families; specific values are not reported in the accessible literature.

10.3 Biopsy and pathology

Sarcoma diagnosis requires histopathology. In the one modern re‑review reported:

"(A) Histologic analysis revealed that 95% of the studied tumor specimen displayed the typical pattern of malignant spindle (fibroblastic) cells of bone MFH. (B) Malignant cells forming neoplastic bone. (C) Focal sheets of neoplastic bone within the tumor are shown to be entrapping pre-existing bone trabeculae, and the overtly malignant cells are shown to produce bone."

The presence of osteoid reclassified this tumor as osteosarcoma. This matters practically: UPS of bone and osteosarcoma are treated on the same protocol, so the reclassification does not change management, but it does change the phenotype annotation.

Immunohistochemistry is used mainly by exclusion — UPS is a diagnosis of exclusion after ruling out specific lineages (SMA/desmin for leiomyosarcoma, S100/SOX10 for melanoma and MPNST, keratins/EMA for sarcomatoid carcinoma, CD34, MDM2/CDK4 FISH for dedifferentiated liposarcoma). MTAP immunohistochemistry is now a validated surrogate for 9p21 co‑deletion in other tumor contexts (notably mesothelioma) and is worth considering here — though its interpretation in a germline exon‑9 splicing mutation, where archetype MTAP protein is retained or even increased, is genuinely unclear and would likely be falsely negative. Worth flagging as a knowledge gap.

10.4 Genetic testing

  • Recommended approach: targeted sequencing of MTAP exon 9 and its intron–exon boundaries in a proband from a family with the characteristic radiographic dysplasia.
  • Critical technical caveat — the single most actionable diagnostic point in this report: exon 9 lies 65 kb downstream of the canonical MTAP termination site, in what standard annotation treats as intergenic/3′ region. Standard exome sequencing (WES) and standard clinical gene panels will not capture or will not report this region. Any DMS‑MFH testing must either be a custom targeted assay or genome sequencing (WGS) with explicit non‑coding analysis. The 2012 authors reached the answer only after "DNA-sequence analysis of known candidate genes within the original critical region had previously failed to identify causative mutations… In particular, this analysis included the known eight exons and corresponding intron-exon boundaries of MTAP."
  • WGS: the preferred agnostic approach for a new suspected case; requires targeted interrogation of the exon‑9 region.
  • Gene panels: MTAP appears on the Genomics England Childhood solid tumours panel but as Red, meaning it is not reported diagnostically on that panel. Practically, this means a suspected DMS‑MFH case will not be resolved by ordering a routine hereditary‑cancer or skeletal‑dysplasia panel. GTR lists tests under the abbreviation BDMF.
  • RNA sequencing / transcript analysis is arguably the most sensitive functional assay, given that both mutations act through splicing — patient fibroblast or lymphoblast RT‑PCR/3′ RACE demonstrating loss of exon‑9‑containing isoforms is the direct functional readout.
  • CMA, karyotyping, FISH: not indicated (no constitutional chromosomal abnormality). FISH for 9p21 is relevant only in the tumor, to demonstrate the somatic second hit.
  • mtDNA and repeat‑expansion testing: not applicable.

10.5 Omics-based diagnostics

None validated. RNA‑seq is the modality with real potential (§10.4). No proteomic, metabolomic (beyond the research MTA assay), epigenomic, or liquid‑biopsy diagnostic exists.

10.6 Clinical criteria and differential diagnosis

There are no formal, published diagnostic criteria. A practical working definition: symmetric diaphyseal medullary stenosis with endosteal cortical thickening on long‑bone radiographs, in an autosomal dominant pedigree, with or without pathologic fractures, marrow infarction, myopathy, or bone sarcoma.

Differential diagnosis:

Condition Distinguishing features
Camurati–Engelmann disease (progressive diaphyseal dysplasia, TGFB1) Also diaphyseal, also AD — the closest mimic and explicitly indexed as a MeSH term on the Norton 1996 paper. Distinguished by periosteal + endosteal cortical thickening (vs predominantly endosteal), prominent limb pain and waddling gait from childhood, characteristic responsiveness to corticosteroids, no marrow infarction, and no sarcoma predisposition.
Ribbing disease (hereditary multiple diaphyseal sclerosis) Diaphyseal sclerosis, later onset, asymmetric, no malignancy.
Osteopetrosis (all forms) Generalized sclerosis with medullary obliteration, but marrow failure, cranial nerve compression, and characteristic "bone‑in‑bone"/"Erlenmeyer flask" appearance.
Melorheostosis "Dripping candle wax" cortical hyperostosis, sclerotomal and asymmetric.
Osteogenesis imperfecta Recurrent fractures and AD inheritance, but osteopenia with thin cortices — the radiographic opposite of DMS‑MFH — plus blue sclerae, dentinogenesis imperfecta, hearing loss.
Chronic recurrent multifocal osteomyelitis (CRMO) Inflammatory, metaphyseal, responds to NSAIDs.
Li–Fraumeni syndrome (TP53) The major sarcoma‑predisposition differential — but no skeletal dysplasia, and a much broader tumor spectrum (breast, adrenocortical, brain, leukemia).
Hereditary retinoblastoma (RB1) Osteosarcoma predisposition; distinguished by retinoblastoma history.
Rothmund–Thomson (RECQL4), Werner, Bloom Osteosarcoma predisposition with poikiloderma/short stature/premature aging.
Paget disease of bone / familial expansile osteolysis Sarcomatous degeneration risk, but late onset, elevated ALP, characteristic mosaic pattern.
Sickle cell disease / Gaucher disease Bone infarction and avascular necrosis — but haemoglobinopathy or lysosomal enzymology is diagnostic.
Ghosal hematodiaphyseal dysplasia (TBXAS1) Diaphyseal sclerosis with anemia; AR.
Fibrous dysplasia (GNAS) Ground‑glass lesions, café‑au‑lait, endocrinopathy in McCune–Albright.

10.7 Screening

  • Radiographic screening of at‑risk relatives from puberty onward — the one explicit published recommendation (Norton 1996).
  • Thallium scintigraphy for tumor surveillance in known‑affected individuals (Norton 1996).
  • Cascade genetic testing of at‑risk relatives once a familial variant is identified — feasible in principle, constrained by the assay problem in §10.4.
  • Newborn screening: not applicable; no biochemical newborn screen and no benefit from presymptomatic neonatal identification.
  • Carrier screening: not applicable (dominant).

Honest assessment: these recommendations date from 1996 and have never been prospectively evaluated. Thallium‑201 is now largely obsolete in clinical practice, displaced by FDG‑PET/CT, and no modern surveillance protocol for DMS‑MFH exists. This is a defensible KNOWLEDGE_GAP.

11. Outcome / Prognosis

11.1 Survival and mortality

No DMS‑MFH‑specific survival data exist. No cohort of sufficient size has ever been assembled. Prognosis must be assembled from two components: the chronic skeletal/myopathic disability, and the sarcoma.

Sarcoma survival (proxy data from UPS of bone cohorts — the best available surrogate):

Source Population Outcome
COSS Group, J Cancer Res Clin Oncol 2026 (PMC12819900) 132 unselected UPSB patients, Germany/Austria/Switzerland, treated on osteosarcoma protocols 5-year EFS 63% (SE 5%); 5-year OS 70% (SE 4%) after median follow-up 3.9 yr (EFS) / 5.2 yr (OS)
Population-based cohort, 2022 (PMID:35184191) UPSB, registry-based 5-year disease-specific survival 47.4% overall; 56.4% (M0) vs 16.9% (M1)

The gap between these two figures is instructive: the COSS cohort is a specialist, protocol-treated, younger population; the registry cohort is unselected. A DMS‑MFH patient — typically young, extremity primary, treated at a sarcoma centre — is closer to the COSS profile, but carries the added liability of a diffusely abnormal skeleton complicating limb salvage.

Life expectancy: in the absence of sarcoma, likely near‑normal but with substantial disability. With sarcoma, governed by the figures above. Individuals never developing sarcoma (~2/3) face a chronic musculoskeletal disease rather than a life‑limiting one.

11.2 Morbidity and function

  • Chronic bone pain and "eventual painful debilitation" (PMID:10053015).
  • Recurrent fractures with poor union; progressive lower‑limb bowing.
  • Osteomyelitis leading to amputation due to slow healing fractures (HP:0005010) — an explicitly curated HPO feature of this disease.
  • Progressive limb‑girdle weakness in the myopathic families, superimposing neuromuscular disability on structural bone disease.
  • Presenile cataracts → visual impairment requiring surgery.
  • No ICF‑coded disability data, no EQ‑5D/SF‑36/PROMIS/MSTS/TESS data.

11.3 Complications

Pathologic fracture · fracture nonunion/malunion · osteomyelitis · amputation · bone infarction · progressive deformity · sarcoma · chemotherapy toxicity (anthracycline cardiotoxicity, cisplatin ototoxicity/nephrotoxicity, ifosfamide neuro/nephrotoxicity, secondary malignancy) · possible early CAD (unpublished/speculative).

11.4 Recovery potential

The skeletal dysplasia is irreversible. No treatment restores medullary architecture. Fractures heal — poorly and slowly. Sarcoma is curable in a substantial fraction with multimodal therapy (see §12), and this is the one domain where treatment materially changes outcome.

11.5 Prognostic factors

For the sarcoma (extrapolated from UPSB cohorts, COSS 2026): - Favourable: age <40 years; extremity primary; localized (M0) disease at presentation. - Unfavourable: metastatic disease at presentation (M1 5-yr DSS 16.9% vs M0 56.4%); age ≥40 years (and ≥65 in the registry analysis); non‑extremity site; pathologic fracture at presentation — a factor of specific concern in DMS‑MFH, where pathologic fracture is a baseline feature of the disease and may confound this prognostic variable entirely. - Notably: in the COSS cohort only 38% achieved good histologic response (<10% viable tumor) to preoperative chemotherapy, and — unusually for bone sarcoma — this "correlated poorly with prognosis," meaning the standard osteosarcoma response‑to‑neoadjuvant prognostic marker may not transfer to UPSB.

Disease-specific prognostic factors for DMS‑MFH: none identified. Neither serum MTA level, nor which of the two mutations a family carries, nor presence of myopathy has been shown to predict outcome — the sample size makes such analysis impossible.

Prognostic biomarkers: none validated.

12. Treatment

There is no disease‑modifying or targeted therapy for DMS‑MFH. Management is entirely symptomatic, orthopaedic, and oncologic.

12.1 Skeletal management

Intervention Notes NCIT
Orthopaedic fracture fixation Intramedullary nailing is technically difficult or impossible given medullary stenosis — plate/external fixation may be required. This is a genuine, disease‑specific surgical constraint. NCIT:C16186 Orthopedic Surgical Procedure
Corrective osteotomy / deformity correction For progressive bowing NCIT:C15329 Surgical Procedure
Amputation For osteomyelitis complicating nonunion, or for unresectable tumor NCIT:C15329
Physical therapy / rehabilitation Mobility preservation; especially relevant with superimposed myopathy NCIT:C15302 Physical Therapy; NCIT:C15315 Rehabilitation
Analgesia / supportive care Chronic bone pain NCIT:C15747 Supportive Care
Cataract extraction Presenile cataracts NCIT:C15329

Bisphosphonates and other antiresorptives are not indicated and are theoretically hazardous — DMS‑MFH is a sclerosing dysplasia with medullary obliteration and impaired fracture healing, not an osteopenic one. Suppressing remodelling further is unlikely to help and may worsen union. No study addresses this; flag as a knowledge gap rather than a recommendation.

12.2 Sarcoma management

Patients are treated on osteosarcoma protocols. From the COSS UPSB cohort (n=132, 2026):

  • Chemotherapy in 100% of patients: doxorubicin 98%, cisplatin 93%, ifosfamide 82%, high‑dose methotrexate 64%.
  • Surgery in 96%; among extremity tumors, 81% limb salvage vs amputation.
  • Representative dosing reported elsewhere: doxorubicin 60 mg/m², ifosfamide 9 g/m², cisplatin 90 mg/m², with methotrexate 8 g/m² added for poor histologic responders.

dismech treatment record shape:

treatments:
- name: Osteosarcoma-Type Multiagent Chemotherapy
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: chemotherapy
    term: {id: NCIT:C15632, label: Chemotherapy}
    therapeutic_agent:
    - preferred_term: doxorubicin
      term: {id: CHEBI:28748, label: doxorubicin}
    - preferred_term: cisplatin
      term: {id: CHEBI:27899, label: cisplatin}
    - preferred_term: ifosfamide
      term: {id: CHEBI:5864, label: ifosfamide}
    - preferred_term: methotrexate
      term: {id: CHEBI:44185, label: methotrexate}

(All four CHEBI IDs verified via OAK. regimen_term should be omitted — MAP/MAPI is not a named NCIT Treatment Regimen concept that reliably resolves; do not invent one.)

  • Radiotherapy (NCIT:C15313) has a limited role — for unresectable or positive‑margin disease, as in bone sarcoma generally.
  • Guideline reference: NCI PDQ Osteosarcoma and Undifferentiated Pleomorphic Sarcoma of Bone Treatment (NBK65736) is the appropriate clinical guideline anchor — note that PDQ explicitly co‑names UPS of bone with osteosarcoma, confirming the shared‑protocol approach.

12.3 Genetic counselling

NCIT:C15240 Genetic Counseling. Autosomal dominant, 50% offspring risk; discussion of variable expressivity (myopathy present in only some families), the ~1‑in‑3 sarcoma risk, and the technical limitation that standard panels/exomes will not detect the causal variant.

12.4 The MTAP/PRMT5 therapeutic axis — the major recent development

This is where 2023–2026 literature is genuinely active, and it is the most interesting forward‑looking content for this entry. It is relevant to DMS‑MFH by mechanism, not by evidence — no DMS‑MFH patient has ever received these agents, and the direction of effect may not even be favourable (see the caveat below).

The synthetic lethality. MTAP loss → MTA accumulation → MTA is a SAM‑competitive inhibitor of PRMT5 with >100‑fold selectivity over other PRMTs → PRMT5 enters a "frail," partially inhibited state → the cell becomes selectively hypersensitive to further PRMT5 inhibition. This is the basis of an entire drug class: MTA‑cooperative PRMT5 inhibitors, which preferentially bind PRMT5 in the MTA‑bound state and therefore spare MTAP‑intact normal tissue — solving the hematologic toxicity that sank first‑generation PRMT5 inhibitors.

Epidemiologic scale: homozygous MTAP deletion (almost always co‑deleted with CDKN2A) occurs in ~10–15% of all solid tumors; by type (C‑CAT data, per the 2025 Int J Mol Sci review, PMC12733126): mesothelioma 33.1%, urothelial carcinoma 23.8%, CNS tumors 19.0%, pancreatic 18.4%, cholangiocarcinoma 15.6%, NSCLC 14.3%; lowest in prostate (1.2%), colon (1.7%), cervix (3.6%).

Clinical-stage agents:

Agent Class Trial Reported status
AMG 193 MTA‑cooperative PRMT5i NCT05094336 Phase I dose exploration, 80 patients dosed 40–1600 mg as of 23 May 2024; MTD 1200 mg once daily; ORR 21.4% among efficacy‑assessable patients. Most common TRAEs: nausea 48.8%, fatigue 31.3%, vomiting 30.0%. (Ann Oncol 2024, PMID:39293516; Cancer Discov 2025;15(1):139, PMID:39282709)
MRTX1719 / BMS‑986504 MTA‑cooperative PRMT5i NCT05245500 Phase I/II ongoing; objective responses reported without the hematologic toxicity of first‑generation PRMT5 inhibitors
TNG908 Brain‑penetrant MTA‑cooperative PRMT5i NCT05275478 Phase I/II; 36% PR reported in pancreatic, 11% in NSCLC
TNG462 MTA‑cooperative PRMT5i NCT05732831 Phase I recruiting; preclinical synergy with targeted agents in MTAP‑null models
AG‑270 / S095033 MAT2A inhibitor (reduces SAM) — Phase I: 2 partial responses; MTD 200 mg daily
IDE397 MAT2A inhibitor — Phase II expansion: 38% PR squamous NSCLC, 30% urothelial
BGB‑58067 PRMT5 inhibitor — In development (NCI drug dictionary)

Biomarker: "The only factor qualifying for therapy is the presence of a homozygous deletion of the MTAP gene, detected by NGS or FISH."

The critical caveat for DMS‑MFH — do not curate this as a treatment. DMS‑MFH is not an MTAP‑homozygous‑deletion state. The germline lesion is a heterozygous splicing mutation in a non‑canonical exon that preserves and in one allele class increases archetype MTAP expression. Whether a DMS‑MFH tumor (which does undergo somatic LOH at 9p21) reaches the MTA‑high, PRMT5‑frail state required for MTA‑cooperative PRMT5 inhibitor sensitivity is unknown and untested. The elevated serum MTA is suggestive but not equivalent to intratumoral MTA saturation. Additionally, MTAP IHC — the cheap surrogate biomarker — would likely be falsely negative here because archetype protein is retained.

Curate this as a mechanistic_hypotheses entry with status: EMERGING and a discussions entry of kind: KNOWLEDGE_GAP asking whether DMS‑MFH tumors phenocopy MTAP‑deleted tumors for PRMT5 dependency — a well‑posed, tractable, and genuinely open question that this KB entry can usefully record.

12.5 Other therapeutic modalities

  • Gene therapy, gene editing, ASOs, siRNA, cell therapy, immunotherapy: none developed, none in trial. Splice‑switching ASOs are a theoretically attractive modality given that both mutations act on splicing — but no such program exists, and the direction of correction differs between the two alleles.
  • Pharmacogenomics: no DMS‑MFH‑specific PGx. Standard sarcoma‑chemotherapy PGx applies (e.g. TPMT/NUDT15 not relevant here; UGT1A1 not relevant; consider standard anthracycline cardiotoxicity risk factors and cisplatin ototoxicity pharmacogenetics — TPMT/COMT variants have CPIC‑adjacent literature).
  • Clinical trials: the only DMS‑MFH‑specific registered study is NCT00007046, "Genetic Study of Patients and Families With Diaphyseal Medullary Stenosis With Malignant Fibrous Histiocytoma of the Bone" (Mount Sinai; a natural‑history/gene‑discovery study, not interventional). I was unable to retrieve its current status; verify with just fetch-reference NCT00007046 before citing it as an evidence item.

12.6 Treatment strategy summary

There is no DMS‑MFH treatment algorithm. The practical pathway is: (1) confirm the dysplasia radiographically and, where possible, molecularly; (2) orthopaedic management of fractures and deformity with awareness that medullary stenosis constrains fixation options; (3) lifelong surveillance for sarcoma; (4) on sarcoma diagnosis, refer to a sarcoma centre and treat on an osteosarcoma protocol; (5) genetic counselling and cascade evaluation of relatives.

13. Prevention

No primary prevention is possible. The disorder is a germline Mendelian condition; nothing prevents its occurrence in a person who inherits the allele, and no intervention is known to reduce the ~35% sarcoma risk.

Level Available approach
Primary Only reproductive: genetic counselling, prenatal diagnosis, or preimplantation genetic testing for monogenic disease (PGT‑M) in a family with an identified variant. No lifestyle, dietary, or pharmacologic primary prevention exists.
Secondary Radiographic screening of at‑risk family members from puberty onward (Norton 1996). Tumor surveillance in affected individuals — thallium scintigraphy as originally proposed; in current practice this would be MRI and/or FDG‑PET/CT, though no protocol has been validated for this disease. Cascade genetic testing once a familial variant is known.
Tertiary Prompt orthopaedic management of fractures to prevent nonunion → osteomyelitis → amputation; fall/fracture‑risk reduction; physiotherapy to preserve function; long‑term surveillance for chemotherapy late effects (anthracycline cardiomyopathy, secondary malignancy) in sarcoma survivors.
  • Immunization: not applicable — no infectious component. (Standard immunosuppression‑related vaccination guidance applies during chemotherapy.)
  • Genetic screening: carrier screening not applicable (dominant); PGT‑M and prenatal testing are technically feasible where the familial exon‑9 variant is known — one of the few concretely actionable options.
  • Risk stratification: no validated model. Family history plus radiographic phenotype is the entirety of current stratification.
  • Behavioural interventions / public health / environmental interventions: not applicable.
  • Prophylaxis: no prophylactic medication. Prophylactic surgery has no established role — unlike, say, risk‑reducing mastectomy in BRCA1/2, there is no organ to remove, since the at‑risk tissue is the entire skeleton.

14. Other Species / Natural Disease

14.1 Taxonomy and orthology

  • Human — NCBITaxon:9606 — the only species with the natural disease.
  • Mouse — NCBITaxon:10090 — Mtap, MGI:1914152, NCBI Gene 66902.
  • MTAP is broadly conserved across eukaryotes and archaea (the Sulfolobus solfataricus MTAP‑II structure is solved), consistent with a core metabolic salvage function.

14.2 The evolutionary caveat that dominates this section

The disease mechanism cannot be modelled in any non‑primate species. Exon 9 (MER50I‑derived) and exon 10 (THE1A‑derived) entered the genome by retroviral integration after prosimian/New World monkey divergence, ~40 Mya. Verbatim:

"First, given the evolutionary species restriction of these HERVs, the existence of MTAP variants and possible biochemical regulation resulting from their expression must be unique to primates."

Mice, zebrafish, Drosophila, and C. elegans have Mtap orthologs but do not have exon 9. There is therefore no mouse, rat, fish, or fly in which the DMS‑MFH mutation can be recapitulated. This is the defining constraint on the entire experimental biology of this disease and belongs in the dismech entry as an explicit HUMAN_MODEL_MISMATCH discussion.

14.3 Natural disease in other species

None reported. OMIA contains no DMS‑MFH entry. No naturally occurring MTAP bone dysplasia/sarcoma syndrome is described in dogs, cats, horses, or any other companion or wildlife species. No breed association (no VBO term applies).

14.4 Comparative pathology

  • Divergent phenotype in mouse. Homozygous Mtap loss is embryonic lethal in mouse; heterozygotes develop T‑cell lymphoma, not bone dysplasia or sarcoma (§15). The human heterozygote develops a skeletal dysplasia with mesenchymal sarcoma. This is a striking species divergence, plausibly attributable to the different lesion class (whole‑gene knockout vs primate‑specific isoform dysregulation) and worth curating as a FAILS_TO_RECAPITULATE/PARTIALLY_RECAPITULATES link.
  • Conservation of the core enzyme (methionine/adenine salvage, polyamine metabolism) is deep; conservation of the regulatory isoform layer is primate‑restricted.

14.5 Transmission

Not applicable. No zoonotic potential, no cross‑species susceptibility. The endogenous retroviral elements are fixed germline sequence, not transmissible agents.

15. Model Organisms

15.1 Existing genetic models

Mouse — Mtap whole‑gene disruption (Kadariya et al., Cancer Res 2009;69(14):5961–9, PMID:19567676).

  • Genotype: MtaplacZ knockout allele; heterozygous Mtap+/lacZ.
  • Homozygotes: early embryonic lethal.
  • Heterozygotes: born at Mendelian ratios, indistinguishable from wild-type through the first year, then die prematurely with median survival 585 days of T‑cell lymphoma. Necropsy shows "greatly enlarged spleens, altered thymic histology, and lymphocytic infiltration of their livers." Older surviving heterozygotes show mild, non‑clonal T‑cell lymphoproliferative disease, "suggesting that loss of Mtap might stimulate T-cell proliferation."
  • Interpretation: supports MTAP as a bona fide tumor suppressor — the strongest independent in‑vivo evidence for tumor suppression, though in a different lineage.

Mouse — Mtap+/− × Myc (PLoS One 2013, "Germline mutations in Mtap cooperate with Myc to accelerate tumorigenesis in mice"). Demonstrates cooperativity between Mtap loss and MYC in tumor acceleration.

Model organism databases: MGI (MGI:1914152); IMPC/KOMP/IMSR for allele availability; Alliance of Genome Resources for orthology.

15.2 dismech animal_models shape

animal_models:
- name: Mtap heterozygous knockout mouse (Mtap+/lacZ)
  species: Mouse
  genotype: Mtap<lacZ> heterozygous null
  publication: PMID:19567676
  modeled_mechanisms:
  - target: MTAP Loss of Function
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: >-
      Heterozygous Mtap disruption in mouse establishes MTAP as a tumor
      suppressor in vivo, supporting the tumor-predisposition arm of DMS-MFH.
    limitations: >-
      The mouse develops T-cell lymphoma, not bone dysplasia or bone sarcoma,
      and dies at a median of 585 days. Critically, the mouse Mtap ortholog
      lacks exons 9-11 entirely: those exons derive from primate-restricted
      retroviral integrations approximately 40 million years old, so the
      DMS-MFH splicing lesion cannot be modeled in any non-primate species.
      A whole-gene knockout is therefore not the same lesion class as the
      human exon-9 splicing mutation.

A companion discussions entry of kind: HUMAN_MODEL_MISMATCH should attach to the MTAP pathophysiology node, with the prompt framed as: does whole-gene Mtap knockout in a species lacking the retroviral-derived exon-9 isoform layer inform the human exon-9 splicing disease at all?

15.3 Cellular and in vitro models

Available and used in the primary paper: - Patient‑derived fibroblast lines — 3′ RACE isoform discovery, splicing analysis. - Patient‑derived lymphoblastoid lines — same. - A patient‑derived tumor cell line established by the authors — the only DMS‑MFH tumor line in existence, as far as I can determine. Its availability (ATCC/Cellosaurus deposition) is not stated; this is worth chasing for anyone planning work. - MTAP minigene constructs — three constructs (WT, c.813-2A>G, c.885A>G) spanning ~11.5 kb of genomic sequence; the definitive functional assay for the splicing mechanism, and the model system a new lab would most plausibly rebuild. - Heterologous isoform expression + MTAP enzymatic assay — established that v1, v2, v3 have activity and v4, v5, v6 do not, including under MG132 proteasome inhibition. - Co‑immunoprecipitation — established physical interaction of all six isoforms with archetype MTAP. - MCF7 — MTAP‑null breast adenocarcinoma line used historically for MTAP re‑expression growth‑suppression experiments.

Not available: no iPSC line, no organoid, no osteoblast‑differentiation model, no NAM/organ‑chip system, no isogenic CRISPR knock‑in of the exon‑9 variants in a human osteoblastic or mesenchymal background. The last of these is the single most obvious missing experiment — a CRISPR knock‑in of c.885A>G or c.813-2A>G into human iPSCs differentiated toward osteoblast lineage would be the first model capable of addressing the bone‑dysplasia arm at all.

15.4 Computational models

Molecular modelling of the MTAP trimer on PDB 1CG6/1CB0, examining splice‑variant insertion points (after K271 for v1‑type, after A230 for v4‑type) relative to the trimer interface and MTA active site. Rendered in O v.13 and PyMOL v1.3. Secondary‑structure and disulfide‑bond prediction suggested an exon‑9/exon‑10 cysteine disulfide, explicitly flagged by the authors as requiring biochemical validation. No kinetic, systems‑biology, or whole‑cell metabolic model of the MTAP salvage pathway in this disease exists.

15.5 Research applications and limitations

Can be studied: MTAP isoform biology, splicing regulation, exaptation of retroviral sequence, MTAP tumor‑suppressor function, MTA as a circulating biomarker.

Cannot currently be studied in any model: the bone dysplasia itself, the marrow infarction, the impaired fracture healing, the myopathy, and the tissue‑specificity of the disease (why bone and muscle, when MTAP is ubiquitously expressed?). That last question is arguably the central unanswered question of the disease and has no experimental system attached to it.

Appendix A — Consolidated ontology term suggestions

All IDs below were verified against this repository's ontology adapters (OAK sqlite:obo:hp / :go / :cl / :uberon / :chebi) on 2026-08-29, except the NCIT terms, which are taken from the verified table in CLAUDE.md.

Disease: MONDO:0007205 diaphyseal medullary stenosis-bone malignancy syndrome

Gene: hgnc:7413 MTAP

Phenotypes (HP): HP:0100254 · HP:0005045 · HP:0031367 · HP:0005686 · HP:0002756 · HP:0003084 · HP:0002979 · HP:0000938 · HP:0005010 · HP:0002754 · HP:0002653 · HP:0012315 · HP:0002669 · HP:0100244 · HP:0003198 · HP:0003325 · HP:0003701 · HP:0003202 · HP:0007819 · HP:0000963 · HP:0000977 · HP:0000978 · HP:0002216 · HP:0000006 (inheritance)

Biological processes (GO): GO:0071267 L-methionine salvage · GO:0043101 purine-containing compound salvage · GO:0006595 polyamine metabolic process · GO:0000380 alternative mRNA splicing, via spliceosome · GO:0019918 peptidyl-arginine methylation, to symmetrical-dimethyl arginine · GO:0032259 methylation · GO:0001649 osteoblast differentiation · GO:0001503 ossification · GO:0030282 bone mineralization

Molecular function (GO): GO:0017061 S-methyl-5-thioadenosine phosphorylase activity

Cell types (CL): CL:0000062 osteoblast · CL:0000137 osteocyte · CL:0000092 osteoclast · CL:0000134 mesenchymal stem cell (or CL:2000079 mesenchymal stem cell of femoral bone marrow) · CL:0000057 fibroblast · CL:0008002 skeletal muscle fiber

Anatomy (UBERON): UBERON:0004769 diaphysis · UBERON:0001438 metaphysis · UBERON:0002495 long bone · UBERON:0001439 compact bone tissue · UBERON:0009859 endosteum · UBERON:0002371 bone marrow · UBERON:0002484 bone marrow cavity · UBERON:0000981 femur · UBERON:0000979 tibia · UBERON:0001446 fibula · UBERON:0000976 humerus · UBERON:0000965 lens of camera-type eye

Chemical entities (CHEBI): CHEBI:17509 5'-S-methyl-5'-thioadenosine · CHEBI:15414 S-adenosyl-L-methionine · CHEBI:16708 adenine · CHEBI:16643 L-methionine · CHEBI:16610 spermidine · CHEBI:17148 putrescine · CHEBI:28748 doxorubicin · CHEBI:27899 cisplatin · CHEBI:5864 ifosfamide · CHEBI:44185 methotrexate

Treatments (NCIT): NCIT:C15632 Chemotherapy · NCIT:C15329 Surgical Procedure · NCIT:C16186 Orthopedic Surgical Procedure · NCIT:C15313 Radiation Therapy · NCIT:C15302 Physical Therapy · NCIT:C15315 Rehabilitation · NCIT:C15747 Supportive Care · NCIT:C15240 Genetic Counseling

Appendix B — Reference list with quotable snippets

References marked ✅ have been fetched into this worktree's references_cache/ and their snippets verified as exact substrings.

Reference Citation Verified quotable snippet
✅ PMID:22464254 Camacho-Vanegas O, Camacho SC, Till J, et al. Primate genome gain and loss: a bone dysplasia, muscular dystrophy, and bone cancer syndrome resulting from mutated retroviral-derived MTAP transcripts. Am J Hum Genet. 2012;90(4):614–627. DOI:10.1016/j.ajhg.2012.02.024 "We now demonstrate that DMS-MFH results from mutations in the most proximal of three previously uncharacterized terminal exons of the gene encoding methylthioadenosine phosphorylase, MTAP."
✅ PMID:22464254 (full text) — "Approximately one-third of affected individuals within our families developed bone sarcomas arising between the second and fifth decades of life."
✅ PMID:22464254 (full text) — "All three serum samples from unaffected individuals had no detectable MTA levels. In marked contrast, both affected individuals had accumulations of MTA detectable in their serum"
✅ PMID:22464254 (full text) — "direct sequencing of this patient's osteosarcoma genomic DNA demonstrated homozygosity for the c.885A>G mutation"
✅ PMID:22464254 (full text) — "Neither mutation was identified in 1,000 chromosomes from 500 unaffected control individuals."
✅ PMID:10053015 Martignetti JA, Desnick RJ, Aliprandis E, et al. Diaphyseal medullary stenosis with malignant fibrous histiocytoma: a hereditary bone dysplasia/cancer syndrome maps to 9p21-22. Am J Hum Genet. 1999;64(3):801–807. DOI:10.1086/302297 "Notably, 35% of individuals with DMS develop MFH, a highly malignant bone sarcoma."
✅ PMID:10053015 — "linked the syndrome to a region of approximately 3 cM on chromosome 9p21-22, with a maximal two-point LOD score of 5.49"
✅ PMID:8781110 Norton KI, Wagreich JM, Granowetter L, Martignetti JA. Diaphyseal medullary stenosis (sclerosis) with bone malignancy (malignant fibrous histiocytoma): Hardcastle syndrome. Pediatr Radiol. 1996;26(9):675–677. DOI:10.1007/BF01356833 "Hardcastle syndrome is a rare, autosomally dominant inherited skeletal dysplasia, characterized by diaphyseal sclerosis, medullary stenosis, pathological fractures, bony infarction, and malignant transformation."
✅ PMID:8781110 — "Radiographic screening of family members is suggested from puberty onward. Thallium scanning is proposed as a more tumor-sensitive screening agent in affected individuals."
PMID:19567676 Kadariya Y, Yin B, Tang B, et al. Mice heterozygous for germ-line mutations in methylthioadenosine phosphorylase (MTAP) die prematurely of T-cell lymphoma. Cancer Res. 2009;69(14):5961–5969. Fetch before quoting
PMID:16244874 Watts GD, Mehta SG, Zhao C, et al. Mapping autosomal dominant progressive limb-girdle myopathy with bone fragility to chromosome 9p21-p22. Hum Genet. 2005;118(3-4):508–514. Fetch before quoting
PMID:16419137 Mehta SG, Watts GD, McGillivray B, et al. Manifestations in a family with autosomal dominant bone fragility and limb-girdle myopathy. Am J Med Genet A. 2006;140(4):322–330. Fetch before quoting
PMID:3745248 Hardcastle P, Nade S, Arnold W. Hereditary bone dysplasia with malignant change. Report of three families. 1986. Fetch before quoting
Arnold 1973 Arnold WD. Hereditary bone dysplasia with sarcomatous degeneration: study of a family. Ann Intern Med. 1973;78(6):902. DOI:10.7326/0003-4819-78-6-902 Family 1, the original American kindred
PMID:13511301 Henry EW, et al. Abnormality of the long bones and progressive muscular dystrophy in a family. Can Med Assoc J. 1958;78(5):331–336. Family 5, original description
PMID:10404592 Appleby TC, et al. The structure of human 5'-deoxy-5'-methylthioadenosine phosphorylase at 1.7 Å resolution. Structure. 1999. PDB 1CG6 / 1CB0
PMID:39293516 Rodon J, et al. First-in-human study of AMG 193, an MTA-cooperative PRMT5 inhibitor, in patients with MTAP-deleted solid tumors: results from phase I dose exploration. Ann Oncol. 2024. ORR 21.4%; MTD 1200 mg QD
PMID:39282709 Belmontes B, et al. AMG 193, a clinical stage MTA-cooperative PRMT5 inhibitor, drives antitumor activity preclinically and in patients with MTAP-deleted cancers. Cancer Discov. 2025;15(1):139. —
PMID:35184191 Clinical characteristics of undifferentiated pleomorphic sarcoma of bone and the impact of adjuvant chemotherapy: a population-based cohort study. 2022. 5-yr DSS 47.4% overall; 56.4% M0 vs 16.9% M1
PMC12819900 Undifferentiated pleomorphic sarcoma of bone (UPSB) treated in the German-speaking countries: 132 unselected patients from the COSS Group. J Cancer Res Clin Oncol. 2026. "the 5 year event-free and overall survival probabilities were 63% (standard error: 5%) and 70% (4%), respectively"
PMC12733126 MTAP deletion as a therapeutic vulnerability in cancer: from molecular mechanism to clinical targeting. Int J Mol Sci. 2025. MTAP deletion frequencies by tumor type; PRMT5i landscape

Cache commands to run before curating evidence items from the unfetched rows:

just fetch-reference PMID:19567676
just fetch-reference PMID:16244874
just fetch-reference PMID:16419137
just fetch-reference PMID:3745248
just fetch-reference PMID:39293516
just fetch-reference PMID:35184191
just fetch-reference ORPHA:85182   # note: not present in the current Orphanet cache

Appendix C — Explicit gaps and cautions for the curator

  1. The gene–disease relationship is contested. ClinGen HI score 1, PanelApp Red. Curate the mechanism, but record the dissent — ideally as a discussions entry with kind: KNOWLEDGE_GAP attached to the MTAP pathophysiology node.
  2. No independent replication since 2012. No new family, no independent variant, no confirmatory functional study in 14 years.
  3. The variants are not in canonical transcript coordinates. c.885A>G/c.813-2A>G are numbered against EST clone AK309365, not NM_002451.4. The MTAP ClinVar records returned by a condition search are unrelated VUS submissions — do not cite them.
  4. Do not curate the elevated serum MTA as a diagnostic test. n=2 affected, research assay, no reference interval, no LOINC code.
  5. Do not curate PRMT5 inhibitors as a treatment. The mechanism is suggestive; the evidence in this disease is zero, and the germline lesion is not an MTAP deletion. mechanistic_hypotheses with status: EMERGING is the correct home.
  6. Do not curate early CAD as a phenotype. It is unpublished anecdote explicitly flagged as such by the authors.
  7. Family-specific features need subtype qualifiers. Myopathy (families 4, 5), thin skin / premature graying / hernias / clotting abnormality (family 5 only) should not be presented as disease-wide.
  8. The bone dysplasia mechanism is unknown. This is the highest-value knowledge gap in the entry — the causal chain from MTAP isoform imbalance to endosteal cortical thickening and marrow infarction is entirely unspecified.
  9. No non-primate model can carry the lesion. Record as HUMAN_MODEL_MISMATCH.
  10. The research/ directory rule applies. This report is analysis, not deep-research-provider output — if it is committed, it belongs under docs/curation-notes/ or docs/reports/, not research/.

Sources

Next step: the draft kb/disorders/Diaphyseal_Medullary_Stenosis_With_Malignant_Fibrous_Histiocytoma.yaml in this worktree is currently a placeholder skeleton. Say the word and I'll populate it from this report — starting with the pathophysiology chain in §6.1 and the evidence items in Appendix B, then running just validate, just count-verified-snippets, and just validate-terms on it.

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 19
Resolved 19
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 2
Quoted claims found in source 2
Quoted claims not found in source 0
References weighed for topical relevance 19
On topic 5
Off topic 0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 81
Resolved 77
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 4
Terms whose name was checked 33
Terms named correctly 24
Terms named as a different term 4
Terms whose name is worth a second look 5

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • MONDO:0007205 (6 mentions) - the report calls it "MONDO", "Monarch Initiative"; MONDO calls it diaphyseal medullary stenosis-bone malignancy syndrome
  • DOID:0080664 (4 mentions) - the report calls it "Disease Ontology"; DOID calls it diaphyseal medullary stenosis with malignant fibrous histiocytoma
  • UBERON:0009859 (2 mentions) - the report calls it "Endosteum — site of pathological apposition"; UBERON calls it endosteum
  • NCIT:C15329 (4 mentions) - the report calls it "For osteomyelitis complicating nonunion, or for unresectable tumor", "Presenile cataracts"; NCIT calls it Surgical Procedure

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • UBERON:0002371 (3 mentions) - the report calls it "Bone marrow — site of infarction"; UBERON calls it bone marrow
  • HP:0012315 (2 mentions) - the report calls it "Histiocytoma (MFH → UPS)"; HP calls it Histiocytoma
  • HP:0100244 (2 mentions) - the report calls it "Fibrosarcoma (of bone)"; HP calls it Fibrosarcoma
  • UBERON:0001439 (2 mentions) - the report calls it "Compact (cortical) bone tissue — thickened endosteally"; UBERON calls it compact bone tissue, and lists "cortical bone tissue" among its other names
  • UBERON:0002484 (2 mentions) - the report calls it "Bone marrow cavity — stenosed/obliterated"; UBERON calls it bone marrow cavity

Terms named inconsistently

The report gives these identifiers more than one name of its own:

  • MONDO:0007205 - called "MONDO", "Monarch Initiative"
  • NCIT:C15329 - called "For osteomyelitis complicating nonunion, or for unresectable tumor", "Presenile cataracts"

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA, MGI, OMIM.