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Entry
- #155950 - MELORHEOSTOSIS, ISOLATED; MEL
- OMIM
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<span class="h4">#155950</span>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="/clinicalSynopsis/155950"><strong>Clinical Synopsis</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#history">History</a>
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<strong>ORPHA:</strong> 2485<br />
<strong>DO:</strong> 4253<br />
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155950
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MELORHEOSTOSIS, ISOLATED; MEL
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Gene/Locus <br /> MIM number
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<a href="/geneMap/15/310?start=-3&limit=10&highlight=310">
15q22.31
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Melorheostosis, isolated, somatic mosaic
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<a href="/entry/155950"> 155950 </a>
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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MAP2K1
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<a href="/entry/176872"> 176872 </a>
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<strong> INHERITANCE </strong>
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- Isolated cases <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1853237&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1853237</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003745" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003745</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003745" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003745</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/398241000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">398241000</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/413769002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">413769002</a>]</span><br />
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<strong> SKELETAL </strong>
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- Contractures over affected bones <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3805729&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3805729</a>]</span><br /> -
Flexion deformities over affected bones <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3805730&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3805730</a>]</span><br /> -
Melorheostosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/44697002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">44697002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0025239&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0025239</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:6000817" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:6000817</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:6000817" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:6000817</a>]</span><br /> -
Flowing hyperostosis of bone cortex <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3805731&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3805731</a>]</span><br /> -
Osteosclerosis (lesions mainly affect diaphyses of long bones, hands, feet, and pelvis although epiphyses may also be affected) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3805732&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3805732</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/49347007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">49347007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q78.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q78.2</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0011001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0011001</a>]</span><br />
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<span class="h5 mim-font">
<strong> SKIN, NAILS, & HAIR </strong>
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<span class="h5 mim-font">
<em> Skin </em>
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<span class="mim-font">
- Skin atrophy over affected bones <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3277087&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3277087</a>]</span><br /> -
Sclerotic soft tissue over affected bones <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3277088&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3277088</a>]</span><br />
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<strong> MISCELLANEOUS </strong>
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- Onset in childhood<br /> -
Progressive disorder <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1864985&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1864985</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003676" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003676</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003676" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003676</a>]</span><br /> -
Segmental distribution often affecting 1 limb<br />
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<p>A number sign (#) is used with this entry because of evidence that isolated melorheostosis (MEL) is caused by somatic mutation in the MAP2K1 gene (<a href="/entry/176872">176872</a>) on chromosome 15q22.</p>
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<p>Melorheostosis (MEL) is characterized by 'flowing' hyperostosis of the cortex of tubular bones. The lesions are usually asymmetric and involve only 1 limb or correspond to a particular sclerotome. They may be accompanied by abnormalities of adjacent soft tissue, including joint contractures, sclerodermatous skin lesions, muscle atrophy, or hemangiomas (review by <a href="#7" class="mim-tip-reference" title="Hellemans, J., Preobrazhenska, O., Willaert, A., Debeer, P., Verdonk, P. C. M., Costa, T., Janssens, K., Menten, B., Van Roy, N., Vermeulen, S. J. T., Savarirayan, R., Van Hul, W., and 9 others. &lt;strong&gt;Loss-of-function mutations in LEMD3 result in osteopoikilosis, Buschke-Ollendorff syndrome and melorheostosis.&lt;/strong&gt; Nature Genet. 36: 1213-1218, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15489854/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15489854&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng1453&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15489854">Hellemans et al., 2004</a>). The designation combines root words meaning 'limb,' 'flow,' and 'bone.' <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15489854" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Melorheostosis may sometimes be a feature of Buschke-Ollendorff syndrome (BOS; <a href="/entry/166700">166700</a>), a benign disorder which is caused by mutation in the LEMD3 gene (<a href="/entry/607844">607844</a>). Although germline or somatic LEMD3 mutations had been postulated to cause isolated melorheostosis (<a href="#1" class="mim-tip-reference" title="Butkus, C. E., Michels, V. V., Lindor, N. M., Cooney, W. P., III. &lt;strong&gt;Melorheostosis in a patient with familial osteopoikilosis.&lt;/strong&gt; Am. J. Med. Genet. 72: 43-46, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9295073/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9295073&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/(sici)1096-8628(19971003)72:1&lt;43::aid-ajmg9&gt;3.0.co;2-w&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9295073">Butkus et al., 1997</a>; <a href="#2" class="mim-tip-reference" title="Debeer, P., Pykels, E., Lammens, J., Devriendt, K., Fryns, J.-P. &lt;strong&gt;Melorheostosis in a family with autosomal dominant osteopoikilosis: report of a third family.&lt;/strong&gt; Am. J. Med. Genet. 119A: 188-193, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12749062/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12749062&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.20072&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12749062">Debeer et al., 2003</a>; <a href="#6" class="mim-tip-reference" title="Happle, R. &lt;strong&gt;Melorheostosis may originate as a type 2 segmental manifestation of osteopoikilosis.&lt;/strong&gt; Am. J. Med. Genet. 125A: 221-223, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14994228/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14994228&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.20454&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="14994228">Happle, 2004</a>; <a href="#7" class="mim-tip-reference" title="Hellemans, J., Preobrazhenska, O., Willaert, A., Debeer, P., Verdonk, P. C. M., Costa, T., Janssens, K., Menten, B., Van Roy, N., Vermeulen, S. J. T., Savarirayan, R., Van Hul, W., and 9 others. &lt;strong&gt;Loss-of-function mutations in LEMD3 result in osteopoikilosis, Buschke-Ollendorff syndrome and melorheostosis.&lt;/strong&gt; Nature Genet. 36: 1213-1218, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15489854/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15489854&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng1453&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15489854">Hellemans et al., 2004</a>), several studies have not been able to prove this (<a href="#7" class="mim-tip-reference" title="Hellemans, J., Preobrazhenska, O., Willaert, A., Debeer, P., Verdonk, P. C. M., Costa, T., Janssens, K., Menten, B., Van Roy, N., Vermeulen, S. J. T., Savarirayan, R., Van Hul, W., and 9 others. &lt;strong&gt;Loss-of-function mutations in LEMD3 result in osteopoikilosis, Buschke-Ollendorff syndrome and melorheostosis.&lt;/strong&gt; Nature Genet. 36: 1213-1218, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15489854/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15489854&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng1453&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15489854">Hellemans et al., 2004</a>; <a href="#9" class="mim-tip-reference" title="Mumm, S., Wenkert, D., Zhang, X., McAlister, W. H., Mier, R. J., Whyte, M. P. &lt;strong&gt;Deactivating germline mutations in LEMD3 cause osteopoikilosis and Buschke-Ollendorff syndrome, but not sporadic melorheostosis.&lt;/strong&gt; J. Bone Miner. Res. 22: 243-250, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17087626/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17087626&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1359/jbmr.061102&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17087626">Mumm et al., 2007</a>; <a href="#12" class="mim-tip-reference" title="Zhang, Y., Castori, M., Ferranti, G., Paradisi, M., Wordsworth, B. P. &lt;strong&gt;Novel and recurrent germline LEMD3 mutations causing Buschke-Ollendorff syndrome and osteopoikilosis but not isolated melorheostosis.&lt;/strong&gt; Clin. Genet. 75: 556-561, 2009. Note: Erratum: Clin. Genet. 79: 401 only, 2011.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19438932/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19438932&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1399-0004.2009.01177.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19438932">Zhang et al., 2009</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=19438932+14994228+9295073+12749062+17087626+15489854" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="clinicalFeatures" class="mim-anchor"></a>
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<p><a href="#3" class="mim-tip-reference" title="Fryns, J. P., Pedersen, J. C., Vanfleteren, L., Vandeputte, F., Van den Berghe, H. &lt;strong&gt;Melorheostosis in a 3-year-old girl.&lt;/strong&gt; Acta Paediat. Belg 33: 185-187, 1980.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7211352/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7211352&lt;/a&gt;]" pmid="7211352">Fryns et al. (1980)</a> reported a 3-year-old girl with clinical and radiologic findings of melorheostosis involving the left lower limb and associated with scleroderma of the overlying soft tissue. Subsequently, at age 17 years, she was admitted to hospital for an Ilizarov operation for lengthening and axis correction of the left tibia. Arterial hypertension (220/130 mm Hg) was noted, and biochemical studies documented high plasma renin activity and high aldosterone concentrations. Renal studies showed a small left kidney, and angiography showed several intrarenal high-grade stenoses of the left renal artery with poor opacification. Partial nephrectomy with removal of the upper and middle portions of the left kidney was performed. Pathologic examination of the small and large blood vessels showed marked intimal proliferation and splitting of the elastica. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7211352" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Roger, D., Bonnetblanc, J. M., Leroux-Robert, C. &lt;strong&gt;Melorheostosis with associated minimal change nephrotic syndrome, mesenteric fibromatosis and capillary haemangiomas.&lt;/strong&gt; Dermatology 188: 166-168, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8136548/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8136548&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1159/000247127&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8136548">Roger et al. (1994)</a> reported that vascular anomalies, such as capillary hemangiomata, lymphangiectasis, vascular nevi, glomus tumors, and arteriovenous aneurysms occur in at least 5% of reported patients. This and the fact that soft tissues overlying the skeletal changes show abnormalities suggested to <a href="#4" class="mim-tip-reference" title="Fryns, J.-P. &lt;strong&gt;Melorheostosis and somatic mosaicism. (Letter)&lt;/strong&gt; Am. J. Med. Genet. 58: 199 only, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8533816/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8533816&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320580221&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8533816">Fryns (1995)</a> that 'melorheostosis, like Proteus syndrome (<a href="/entry/176920">176920</a>), may be another example of an early postzygotic mutation of the mesenchyme resulting in asymmetric involvement of skeletal structures, with concomitant vascular and hamartomatous changes in the overlying soft tissues.' <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8136548+8533816" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Mumm, S., Wenkert, D., Zhang, X., McAlister, W. H., Mier, R. J., Whyte, M. P. &lt;strong&gt;Deactivating germline mutations in LEMD3 cause osteopoikilosis and Buschke-Ollendorff syndrome, but not sporadic melorheostosis.&lt;/strong&gt; J. Bone Miner. Res. 22: 243-250, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17087626/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17087626&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1359/jbmr.061102&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17087626">Mumm et al. (2007)</a> reported 4 unrelated patients with sporadic melorheostosis. One girl was affected in the left hand, with lesions in the radial carpal bones and overlying tight skin. Another girl developed ulnar deviation of her right wrist and middle finger and her left thumb. She had significant flexion contractures of some fingers and her right elbow. An 8-year-old boy had congenital deformity of his left leg and foot caused by progressive MEL; skin atrophy affected the foot. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17087626" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Zhang, Y., Castori, M., Ferranti, G., Paradisi, M., Wordsworth, B. P. &lt;strong&gt;Novel and recurrent germline LEMD3 mutations causing Buschke-Ollendorff syndrome and osteopoikilosis but not isolated melorheostosis.&lt;/strong&gt; Clin. Genet. 75: 556-561, 2009. Note: Erratum: Clin. Genet. 79: 401 only, 2011.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19438932/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19438932&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1399-0004.2009.01177.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19438932">Zhang et al. (2009)</a> reported a 39-year-old man from the U.K. with sporadic melorheostosis. He had a painful flexion deformity of the right elbow. Radiographs showed extensive flowing endosteal hyperostosis that affected the humeral and radial shaft as well as the distal epiphyses with ectopic calcifications in the antecubital fossa. He had no relevant family history of a similar disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19438932" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Kang, H., Jha, S., Deng, Z., Fratzl-Zelman, N., Cabral, W. A., Ivovic, A., Meylan, F., Hanson, E. P., Lange, E., Katz, J., Roschger, P., Klaushofer, K., Cowen, E. W., Siegel, R. M., Marini, J. C., Bhattacharyya, T. &lt;strong&gt;Somatic activating mutations in MAP2K1 cause melorheostosis.&lt;/strong&gt; Nature Commun. 9: 1390, 2018. Note: Electronic Article.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/29643386/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;29643386&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=29643386[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/s41467-018-03720-z&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="29643386">Kang et al. (2018)</a> studied 8 patients with MEL and mosaicism for MAP2K1 mutations in affected bone. Radiographs showed the classic 'candle wax' appearance of melorheostosis. A consistent intraoperative finding while obtaining bone biopsies in these patients was extremely dense, rigid affected bone that often dulled the osteotomes and drill bits. Histomorphometric analysis of melorheostotic bone tissue revealed distinctive parallel layers of primary lamellar bone in the outer regions, an organization that underlay the surgical hardness of the bone. This newly formed compact tissue was intensely remodeled into highly porous osteonal-like bone at greater depth from the surface. Compared to unaffected bone, affected bone showed increased active bone-resorbing osteoclasts, elevated eroded surfaces, and a higher number of bone-forming osteoblasts. There was an approximately 6-fold increase in the thickness of unmineralized bone matrix (osteoid) and a greater than 50-fold increase in osteoid surface/bone surface in the affected bone samples compared to their respective unaffected counterparts. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29643386" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="molecularGenetics" class="mim-anchor"></a>
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<strong>Molecular Genetics</strong>
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<p>In samples of affected bone from 8 of 15 patients with isolated melorheostosis, who were negative for somatic or germline mutations in the LEMD3 gene (<a href="/entry/607844">607844</a>), <a href="#8" class="mim-tip-reference" title="Kang, H., Jha, S., Deng, Z., Fratzl-Zelman, N., Cabral, W. A., Ivovic, A., Meylan, F., Hanson, E. P., Lange, E., Katz, J., Roschger, P., Klaushofer, K., Cowen, E. W., Siegel, R. M., Marini, J. C., Bhattacharyya, T. &lt;strong&gt;Somatic activating mutations in MAP2K1 cause melorheostosis.&lt;/strong&gt; Nature Commun. 9: 1390, 2018. Note: Electronic Article.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/29643386/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;29643386&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=29643386[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/s41467-018-03720-z&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="29643386">Kang et al. (2018)</a> identified somatic mosaicism for missense mutations in the MAP2K1 gene (Q56P, <a href="/entry/176872#0006">176872.0006</a>; K57N, <a href="/entry/176872#0007">176872.0007</a>; and K57E, <a href="/entry/176872#0008">176872.0008</a>) that were not present in unaffected bone or peripheral blood leukocytes, or in the ExAC database. Mutant allele frequency ranged from 3 to 34% in affected bone. The authors noted that all 3 MAP2K1 variants are located in a MEK1 alpha-helix that negatively regulates kinase function, and that the 3 variants previously had been detected in malignancies, including lung cancer, melanoma, and hairy cell leukemia, and shown to cause gain-of-function effects. Mosaicism for the respective MAP2K1 mutations was confirmed in skin tissue overlying affected bone in 4 patients but was not detected in 1 patient with a lower disease burden. Functional analysis confirmed enhanced activation, resulting in increased osteoblast proliferation; however, the variants also resulted in reduced mineralization and differentiation, consistent with histologic findings of massive accumulation of unmineralized osteoid bone in affected bone tissue, as well as increased osteoclast activity, as shown by the intense remodeling that occurs in melorheostotic bone. The authors suggested that the marked variability in pattern of bone lesions observed between patients is likely due to mutations arising during different points during development, with earlier mutations resulting in an increased burden of disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29643386" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
In a 14-year-old boy with osteopoikilosis (see <a href="/entry/166700">166700</a>) and melorheostosis, who was heterozygous for a 24-bp deletion in the LEMD3 gene (<a href="/entry/607844#0010">607844.0010</a>), <a href="#11" class="mim-tip-reference" title="Whyte, M. P., Griffith, M., Trani, L., Mumm, S., Gottesman, G. S., McAlister, W. H., Krysiak, K., Lesurf, R., Skidmore, Z. L., Campbell, K. M., Rosman, I. S., Bayliss, S., Bijanki, V. N., Nenninger, A., Van Tine, B. A., Griffith, O. L., Mardis, E. R. &lt;strong&gt;Melorheostosis: exome sequencing of an associated dermatosis implicates postzygotic mosaicism of mutated KRAS.&lt;/strong&gt; Bone 101: 145-155, 2017.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/28434888/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;28434888&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.bone.2017.04.010&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="28434888">Whyte et al. (2017)</a> performed somatic event analysis of DNA from 5 patient tissue samples and detected a Q61H missense mutation in the KRAS gene (<a href="/entry/190070">190070</a>) that was present in a large linear epidermal nevus and in scleroderma-like dermatosis over the area of melorheostosis, but was not present in 2 samples of normal skin or in blood leukocytes. The variant showed a 30 to 60% allele frequency, indicating that the variant was present within most cells of the tissue samples. Bone biopsy was not performed. The authors suggested a role for postzygotic mosaicism of the KRAS mutation, perhaps facilitated by LEMD3 haploinsufficiency, in the etiology of the proband's melorheostosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28434888" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a patient with isolated melorheostosis, who was negative for somatic mutation in the MAP2K1 gene and negative for somatic or germline mutation in the LEMD3 gene, <a href="#8" class="mim-tip-reference" title="Kang, H., Jha, S., Deng, Z., Fratzl-Zelman, N., Cabral, W. A., Ivovic, A., Meylan, F., Hanson, E. P., Lange, E., Katz, J., Roschger, P., Klaushofer, K., Cowen, E. W., Siegel, R. M., Marini, J. C., Bhattacharyya, T. &lt;strong&gt;Somatic activating mutations in MAP2K1 cause melorheostosis.&lt;/strong&gt; Nature Commun. 9: 1390, 2018. Note: Electronic Article.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/29643386/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;29643386&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=29643386[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/s41467-018-03720-z&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="29643386">Kang et al. (2018)</a> detected a KRAS missense mutation (Q61R) in both affected and unaffected bone. The patient exhibited skin lesions consistent with RASopathy, and the authors suggested that the melorheostosis represented part of a more complex early embryonic mosaic RASopathy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29643386" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Exclusion Studies</em></strong></p><p>
<a href="#9" class="mim-tip-reference" title="Mumm, S., Wenkert, D., Zhang, X., McAlister, W. H., Mier, R. J., Whyte, M. P. &lt;strong&gt;Deactivating germline mutations in LEMD3 cause osteopoikilosis and Buschke-Ollendorff syndrome, but not sporadic melorheostosis.&lt;/strong&gt; J. Bone Miner. Res. 22: 243-250, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17087626/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17087626&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1359/jbmr.061102&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17087626">Mumm et al. (2007)</a> did not identify germline mutations in the LEMD3 gene (<a href="/entry/607844">607844</a>) in any of 4 unrelated patients with sporadic isolated melorheostosis. <a href="#12" class="mim-tip-reference" title="Zhang, Y., Castori, M., Ferranti, G., Paradisi, M., Wordsworth, B. P. &lt;strong&gt;Novel and recurrent germline LEMD3 mutations causing Buschke-Ollendorff syndrome and osteopoikilosis but not isolated melorheostosis.&lt;/strong&gt; Clin. Genet. 75: 556-561, 2009. Note: Erratum: Clin. Genet. 79: 401 only, 2011.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19438932/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19438932&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1399-0004.2009.01177.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19438932">Zhang et al. (2009)</a> did not identify germline or somatic mutations in the LEMD3 gene in a U.K. man with sporadic melorheostosis. Both <a href="#9" class="mim-tip-reference" title="Mumm, S., Wenkert, D., Zhang, X., McAlister, W. H., Mier, R. J., Whyte, M. P. &lt;strong&gt;Deactivating germline mutations in LEMD3 cause osteopoikilosis and Buschke-Ollendorff syndrome, but not sporadic melorheostosis.&lt;/strong&gt; J. Bone Miner. Res. 22: 243-250, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17087626/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17087626&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1359/jbmr.061102&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17087626">Mumm et al. (2007)</a> and <a href="#12" class="mim-tip-reference" title="Zhang, Y., Castori, M., Ferranti, G., Paradisi, M., Wordsworth, B. P. &lt;strong&gt;Novel and recurrent germline LEMD3 mutations causing Buschke-Ollendorff syndrome and osteopoikilosis but not isolated melorheostosis.&lt;/strong&gt; Clin. Genet. 75: 556-561, 2009. Note: Erratum: Clin. Genet. 79: 401 only, 2011.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19438932/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19438932&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1399-0004.2009.01177.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19438932">Zhang et al. (2009)</a> concluded that mutation in the LEMD3 gene does not cause isolated melorheostosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=19438932+17087626" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#5" class="mim-tip-reference" title="Happle, R. &lt;strong&gt;Segmental forms of autosomal dominant skin disorders: different types of severity reflect different states of zygosity. (Letter)&lt;/strong&gt; Am. J. Med. Genet. 66: 241-242, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8958340/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8958340&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/(SICI)1096-8628(19961211)66:2&lt;241::AID-AJMG24&gt;3.0.CO;2-S&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8958340">Happle (1996)</a> presented a concept of type 2 segmental disorders in conditions such as melorheostosis, which is nonhereditary and always shows a segmental arrangement. Type 1 segmental involvement reflects, it was suggested, heterozygosity resulting from a de novo mutation in an otherwise healthy embryo; a type 2 segmental manifestation may be best explained by loss of heterozygosity occurring in a heterozygous embryo at an early developmental stage. <a href="#6" class="mim-tip-reference" title="Happle, R. &lt;strong&gt;Melorheostosis may originate as a type 2 segmental manifestation of osteopoikilosis.&lt;/strong&gt; Am. J. Med. Genet. 125A: 221-223, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14994228/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14994228&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.20454&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="14994228">Happle (2004)</a> suggested that melorheostosis originates from an early mutation event with loss of the corresponding wildtype allele at the gene locus of osteopoikilosis (<a href="/entry/166700">166700</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8958340+14994228" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="Butkus1997" class="mim-anchor"></a>
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Butkus, C. E., Michels, V. V., Lindor, N. M., Cooney, W. P., III.
<strong>Melorheostosis in a patient with familial osteopoikilosis.</strong>
Am. J. Med. Genet. 72: 43-46, 1997.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9295073/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9295073</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9295073" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/(sici)1096-8628(19971003)72:1&lt;43::aid-ajmg9&gt;3.0.co;2-w" target="_blank">Full Text</a>]
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<a id="Debeer2003" class="mim-anchor"></a>
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Debeer, P., Pykels, E., Lammens, J., Devriendt, K., Fryns, J.-P.
<strong>Melorheostosis in a family with autosomal dominant osteopoikilosis: report of a third family.</strong>
Am. J. Med. Genet. 119A: 188-193, 2003.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12749062/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12749062</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12749062" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/ajmg.a.20072" target="_blank">Full Text</a>]
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Fryns, J. P., Pedersen, J. C., Vanfleteren, L., Vandeputte, F., Van den Berghe, H.
<strong>Melorheostosis in a 3-year-old girl.</strong>
Acta Paediat. Belg 33: 185-187, 1980.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7211352/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7211352</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7211352" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<a id="Fryns1995" class="mim-anchor"></a>
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Fryns, J.-P.
<strong>Melorheostosis and somatic mosaicism. (Letter)</strong>
Am. J. Med. Genet. 58: 199 only, 1995.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8533816/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8533816</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8533816" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/ajmg.1320580221" target="_blank">Full Text</a>]
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<a id="Happle1996" class="mim-anchor"></a>
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Happle, R.
<strong>Segmental forms of autosomal dominant skin disorders: different types of severity reflect different states of zygosity. (Letter)</strong>
Am. J. Med. Genet. 66: 241-242, 1996.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8958340/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8958340</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8958340" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/(SICI)1096-8628(19961211)66:2&lt;241::AID-AJMG24&gt;3.0.CO;2-S" target="_blank">Full Text</a>]
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<a id="Happle2004" class="mim-anchor"></a>
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Happle, R.
<strong>Melorheostosis may originate as a type 2 segmental manifestation of osteopoikilosis.</strong>
Am. J. Med. Genet. 125A: 221-223, 2004.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14994228/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14994228</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14994228" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/ajmg.a.20454" target="_blank">Full Text</a>]
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<a id="Hellemans2004" class="mim-anchor"></a>
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Hellemans, J., Preobrazhenska, O., Willaert, A., Debeer, P., Verdonk, P. C. M., Costa, T., Janssens, K., Menten, B., Van Roy, N., Vermeulen, S. J. T., Savarirayan, R., Van Hul, W., and 9 others.
<strong>Loss-of-function mutations in LEMD3 result in osteopoikilosis, Buschke-Ollendorff syndrome and melorheostosis.</strong>
Nature Genet. 36: 1213-1218, 2004.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15489854/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15489854</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15489854" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1038/ng1453" target="_blank">Full Text</a>]
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<a id="8" class="mim-anchor"></a>
<a id="Kang2018" class="mim-anchor"></a>
<div class="">
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Kang, H., Jha, S., Deng, Z., Fratzl-Zelman, N., Cabral, W. A., Ivovic, A., Meylan, F., Hanson, E. P., Lange, E., Katz, J., Roschger, P., Klaushofer, K., Cowen, E. W., Siegel, R. M., Marini, J. C., Bhattacharyya, T.
<strong>Somatic activating mutations in MAP2K1 cause melorheostosis.</strong>
Nature Commun. 9: 1390, 2018. Note: Electronic Article.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29643386/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29643386</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29643386[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29643386" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1038/s41467-018-03720-z" target="_blank">Full Text</a>]
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<a id="9" class="mim-anchor"></a>
<a id="Mumm2007" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Mumm, S., Wenkert, D., Zhang, X., McAlister, W. H., Mier, R. J., Whyte, M. P.
<strong>Deactivating germline mutations in LEMD3 cause osteopoikilosis and Buschke-Ollendorff syndrome, but not sporadic melorheostosis.</strong>
J. Bone Miner. Res. 22: 243-250, 2007.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17087626/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17087626</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17087626" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1359/jbmr.061102" target="_blank">Full Text</a>]
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<a id="Roger1994" class="mim-anchor"></a>
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Roger, D., Bonnetblanc, J. M., Leroux-Robert, C.
<strong>Melorheostosis with associated minimal change nephrotic syndrome, mesenteric fibromatosis and capillary haemangiomas.</strong>
Dermatology 188: 166-168, 1994.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8136548/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8136548</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8136548" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1159/000247127" target="_blank">Full Text</a>]
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<a id="Whyte2017" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Whyte, M. P., Griffith, M., Trani, L., Mumm, S., Gottesman, G. S., McAlister, W. H., Krysiak, K., Lesurf, R., Skidmore, Z. L., Campbell, K. M., Rosman, I. S., Bayliss, S., Bijanki, V. N., Nenninger, A., Van Tine, B. A., Griffith, O. L., Mardis, E. R.
<strong>Melorheostosis: exome sequencing of an associated dermatosis implicates postzygotic mosaicism of mutated KRAS.</strong>
Bone 101: 145-155, 2017.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28434888/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28434888</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28434888" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/j.bone.2017.04.010" target="_blank">Full Text</a>]
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<a id="12" class="mim-anchor"></a>
<a id="Zhang2009" class="mim-anchor"></a>
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Zhang, Y., Castori, M., Ferranti, G., Paradisi, M., Wordsworth, B. P.
<strong>Novel and recurrent germline LEMD3 mutations causing Buschke-Ollendorff syndrome and osteopoikilosis but not isolated melorheostosis.</strong>
Clin. Genet. 75: 556-561, 2009. Note: Erratum: Clin. Genet. 79: 401 only, 2011.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19438932/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19438932</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19438932" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1111/j.1399-0004.2009.01177.x" target="_blank">Full Text</a>]
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Marla J. F. O'Neill - updated : 06/22/2020
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Cassandra L. Kniffin - updated : 6/2/2010<br>Marla J. F. O'Neill - updated : 10/7/2005<br>Victor A. McKusick - updated : 11/19/2004<br>Victor A. McKusick - updated : 4/6/2004<br>Ada Hamosh - updated : 4/9/1999<br>Victor A. McKusick - updated : 11/4/1997
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Victor A. McKusick : 6/2/1986
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carol : 06/23/2023
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alopez : 06/22/2020<br>carol : 04/15/2015<br>terry : 4/4/2013<br>wwang : 6/7/2010<br>ckniffin : 6/2/2010<br>carol : 10/7/2005<br>alopez : 12/2/2004<br>terry : 11/19/2004<br>terry : 6/18/2004<br>tkritzer : 4/14/2004<br>terry : 4/9/2004<br>terry : 4/6/2004<br>alopez : 4/9/1999<br>carol : 12/15/1998<br>dholmes : 11/18/1997<br>mark : 11/4/1997<br>terry : 11/4/1997<br>mark : 9/13/1995<br>mimadm : 11/6/1994<br>supermim : 3/16/1992<br>supermim : 3/20/1990<br>ddp : 10/27/1989<br>marie : 3/25/1988
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<strong>#</strong> 155950
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MELORHEOSTOSIS, ISOLATED; MEL
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<strong>ORPHA:</strong> 2485; &nbsp;
<strong>DO:</strong> 4253; &nbsp;
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<strong>Phenotype-Gene Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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Gene/Locus
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Gene/Locus <br /> MIM number
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15q22.31
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Melorheostosis, isolated, somatic mosaic
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155950
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3
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MAP2K1
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176872
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because of evidence that isolated melorheostosis (MEL) is caused by somatic mutation in the MAP2K1 gene (176872) on chromosome 15q22.</p>
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<strong>Description</strong>
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<p>Melorheostosis (MEL) is characterized by 'flowing' hyperostosis of the cortex of tubular bones. The lesions are usually asymmetric and involve only 1 limb or correspond to a particular sclerotome. They may be accompanied by abnormalities of adjacent soft tissue, including joint contractures, sclerodermatous skin lesions, muscle atrophy, or hemangiomas (review by Hellemans et al., 2004). The designation combines root words meaning 'limb,' 'flow,' and 'bone.' </p><p>Melorheostosis may sometimes be a feature of Buschke-Ollendorff syndrome (BOS; 166700), a benign disorder which is caused by mutation in the LEMD3 gene (607844). Although germline or somatic LEMD3 mutations had been postulated to cause isolated melorheostosis (Butkus et al., 1997; Debeer et al., 2003; Happle, 2004; Hellemans et al., 2004), several studies have not been able to prove this (Hellemans et al., 2004; Mumm et al., 2007; Zhang et al., 2009). </p>
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<strong>Clinical Features</strong>
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<p>Fryns et al. (1980) reported a 3-year-old girl with clinical and radiologic findings of melorheostosis involving the left lower limb and associated with scleroderma of the overlying soft tissue. Subsequently, at age 17 years, she was admitted to hospital for an Ilizarov operation for lengthening and axis correction of the left tibia. Arterial hypertension (220/130 mm Hg) was noted, and biochemical studies documented high plasma renin activity and high aldosterone concentrations. Renal studies showed a small left kidney, and angiography showed several intrarenal high-grade stenoses of the left renal artery with poor opacification. Partial nephrectomy with removal of the upper and middle portions of the left kidney was performed. Pathologic examination of the small and large blood vessels showed marked intimal proliferation and splitting of the elastica. </p><p>Roger et al. (1994) reported that vascular anomalies, such as capillary hemangiomata, lymphangiectasis, vascular nevi, glomus tumors, and arteriovenous aneurysms occur in at least 5% of reported patients. This and the fact that soft tissues overlying the skeletal changes show abnormalities suggested to Fryns (1995) that 'melorheostosis, like Proteus syndrome (176920), may be another example of an early postzygotic mutation of the mesenchyme resulting in asymmetric involvement of skeletal structures, with concomitant vascular and hamartomatous changes in the overlying soft tissues.' </p><p>Mumm et al. (2007) reported 4 unrelated patients with sporadic melorheostosis. One girl was affected in the left hand, with lesions in the radial carpal bones and overlying tight skin. Another girl developed ulnar deviation of her right wrist and middle finger and her left thumb. She had significant flexion contractures of some fingers and her right elbow. An 8-year-old boy had congenital deformity of his left leg and foot caused by progressive MEL; skin atrophy affected the foot. </p><p>Zhang et al. (2009) reported a 39-year-old man from the U.K. with sporadic melorheostosis. He had a painful flexion deformity of the right elbow. Radiographs showed extensive flowing endosteal hyperostosis that affected the humeral and radial shaft as well as the distal epiphyses with ectopic calcifications in the antecubital fossa. He had no relevant family history of a similar disorder. </p><p>Kang et al. (2018) studied 8 patients with MEL and mosaicism for MAP2K1 mutations in affected bone. Radiographs showed the classic 'candle wax' appearance of melorheostosis. A consistent intraoperative finding while obtaining bone biopsies in these patients was extremely dense, rigid affected bone that often dulled the osteotomes and drill bits. Histomorphometric analysis of melorheostotic bone tissue revealed distinctive parallel layers of primary lamellar bone in the outer regions, an organization that underlay the surgical hardness of the bone. This newly formed compact tissue was intensely remodeled into highly porous osteonal-like bone at greater depth from the surface. Compared to unaffected bone, affected bone showed increased active bone-resorbing osteoclasts, elevated eroded surfaces, and a higher number of bone-forming osteoblasts. There was an approximately 6-fold increase in the thickness of unmineralized bone matrix (osteoid) and a greater than 50-fold increase in osteoid surface/bone surface in the affected bone samples compared to their respective unaffected counterparts. </p>
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<strong>Molecular Genetics</strong>
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<p>In samples of affected bone from 8 of 15 patients with isolated melorheostosis, who were negative for somatic or germline mutations in the LEMD3 gene (607844), Kang et al. (2018) identified somatic mosaicism for missense mutations in the MAP2K1 gene (Q56P, 176872.0006; K57N, 176872.0007; and K57E, 176872.0008) that were not present in unaffected bone or peripheral blood leukocytes, or in the ExAC database. Mutant allele frequency ranged from 3 to 34% in affected bone. The authors noted that all 3 MAP2K1 variants are located in a MEK1 alpha-helix that negatively regulates kinase function, and that the 3 variants previously had been detected in malignancies, including lung cancer, melanoma, and hairy cell leukemia, and shown to cause gain-of-function effects. Mosaicism for the respective MAP2K1 mutations was confirmed in skin tissue overlying affected bone in 4 patients but was not detected in 1 patient with a lower disease burden. Functional analysis confirmed enhanced activation, resulting in increased osteoblast proliferation; however, the variants also resulted in reduced mineralization and differentiation, consistent with histologic findings of massive accumulation of unmineralized osteoid bone in affected bone tissue, as well as increased osteoclast activity, as shown by the intense remodeling that occurs in melorheostotic bone. The authors suggested that the marked variability in pattern of bone lesions observed between patients is likely due to mutations arising during different points during development, with earlier mutations resulting in an increased burden of disease. </p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
In a 14-year-old boy with osteopoikilosis (see 166700) and melorheostosis, who was heterozygous for a 24-bp deletion in the LEMD3 gene (607844.0010), Whyte et al. (2017) performed somatic event analysis of DNA from 5 patient tissue samples and detected a Q61H missense mutation in the KRAS gene (190070) that was present in a large linear epidermal nevus and in scleroderma-like dermatosis over the area of melorheostosis, but was not present in 2 samples of normal skin or in blood leukocytes. The variant showed a 30 to 60% allele frequency, indicating that the variant was present within most cells of the tissue samples. Bone biopsy was not performed. The authors suggested a role for postzygotic mosaicism of the KRAS mutation, perhaps facilitated by LEMD3 haploinsufficiency, in the etiology of the proband's melorheostosis. </p><p>In a patient with isolated melorheostosis, who was negative for somatic mutation in the MAP2K1 gene and negative for somatic or germline mutation in the LEMD3 gene, Kang et al. (2018) detected a KRAS missense mutation (Q61R) in both affected and unaffected bone. The patient exhibited skin lesions consistent with RASopathy, and the authors suggested that the melorheostosis represented part of a more complex early embryonic mosaic RASopathy. </p><p><strong><em>Exclusion Studies</em></strong></p><p>
Mumm et al. (2007) did not identify germline mutations in the LEMD3 gene (607844) in any of 4 unrelated patients with sporadic isolated melorheostosis. Zhang et al. (2009) did not identify germline or somatic mutations in the LEMD3 gene in a U.K. man with sporadic melorheostosis. Both Mumm et al. (2007) and Zhang et al. (2009) concluded that mutation in the LEMD3 gene does not cause isolated melorheostosis. </p>
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<strong>History</strong>
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<p>Happle (1996) presented a concept of type 2 segmental disorders in conditions such as melorheostosis, which is nonhereditary and always shows a segmental arrangement. Type 1 segmental involvement reflects, it was suggested, heterozygosity resulting from a de novo mutation in an otherwise healthy embryo; a type 2 segmental manifestation may be best explained by loss of heterozygosity occurring in a heterozygous embryo at an early developmental stage. Happle (2004) suggested that melorheostosis originates from an early mutation event with loss of the corresponding wildtype allele at the gene locus of osteopoikilosis (166700). </p>
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<h4>
<span class="mim-font">
<strong>REFERENCES</strong>
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<ol>
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<p class="mim-text-font">
Butkus, C. E., Michels, V. V., Lindor, N. M., Cooney, W. P., III.
<strong>Melorheostosis in a patient with familial osteopoikilosis.</strong>
Am. J. Med. Genet. 72: 43-46, 1997.
[PubMed: 9295073]
[Full Text: https://doi.org/10.1002/(sici)1096-8628(19971003)72:1&lt;43::aid-ajmg9&gt;3.0.co;2-w]
</p>
</li>
<li>
<p class="mim-text-font">
Debeer, P., Pykels, E., Lammens, J., Devriendt, K., Fryns, J.-P.
<strong>Melorheostosis in a family with autosomal dominant osteopoikilosis: report of a third family.</strong>
Am. J. Med. Genet. 119A: 188-193, 2003.
[PubMed: 12749062]
[Full Text: https://doi.org/10.1002/ajmg.a.20072]
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<li>
<p class="mim-text-font">
Fryns, J. P., Pedersen, J. C., Vanfleteren, L., Vandeputte, F., Van den Berghe, H.
<strong>Melorheostosis in a 3-year-old girl.</strong>
Acta Paediat. Belg 33: 185-187, 1980.
[PubMed: 7211352]
</p>
</li>
<li>
<p class="mim-text-font">
Fryns, J.-P.
<strong>Melorheostosis and somatic mosaicism. (Letter)</strong>
Am. J. Med. Genet. 58: 199 only, 1995.
[PubMed: 8533816]
[Full Text: https://doi.org/10.1002/ajmg.1320580221]
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<p class="mim-text-font">
Happle, R.
<strong>Segmental forms of autosomal dominant skin disorders: different types of severity reflect different states of zygosity. (Letter)</strong>
Am. J. Med. Genet. 66: 241-242, 1996.
[PubMed: 8958340]
[Full Text: https://doi.org/10.1002/(SICI)1096-8628(19961211)66:2&lt;241::AID-AJMG24&gt;3.0.CO;2-S]
</p>
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<li>
<p class="mim-text-font">
Happle, R.
<strong>Melorheostosis may originate as a type 2 segmental manifestation of osteopoikilosis.</strong>
Am. J. Med. Genet. 125A: 221-223, 2004.
[PubMed: 14994228]
[Full Text: https://doi.org/10.1002/ajmg.a.20454]
</p>
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<li>
<p class="mim-text-font">
Hellemans, J., Preobrazhenska, O., Willaert, A., Debeer, P., Verdonk, P. C. M., Costa, T., Janssens, K., Menten, B., Van Roy, N., Vermeulen, S. J. T., Savarirayan, R., Van Hul, W., and 9 others.
<strong>Loss-of-function mutations in LEMD3 result in osteopoikilosis, Buschke-Ollendorff syndrome and melorheostosis.</strong>
Nature Genet. 36: 1213-1218, 2004.
[PubMed: 15489854]
[Full Text: https://doi.org/10.1038/ng1453]
</p>
</li>
<li>
<p class="mim-text-font">
Kang, H., Jha, S., Deng, Z., Fratzl-Zelman, N., Cabral, W. A., Ivovic, A., Meylan, F., Hanson, E. P., Lange, E., Katz, J., Roschger, P., Klaushofer, K., Cowen, E. W., Siegel, R. M., Marini, J. C., Bhattacharyya, T.
<strong>Somatic activating mutations in MAP2K1 cause melorheostosis.</strong>
Nature Commun. 9: 1390, 2018. Note: Electronic Article.
[PubMed: 29643386]
[Full Text: https://doi.org/10.1038/s41467-018-03720-z]
</p>
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<li>
<p class="mim-text-font">
Mumm, S., Wenkert, D., Zhang, X., McAlister, W. H., Mier, R. J., Whyte, M. P.
<strong>Deactivating germline mutations in LEMD3 cause osteopoikilosis and Buschke-Ollendorff syndrome, but not sporadic melorheostosis.</strong>
J. Bone Miner. Res. 22: 243-250, 2007.
[PubMed: 17087626]
[Full Text: https://doi.org/10.1359/jbmr.061102]
</p>
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<li>
<p class="mim-text-font">
Roger, D., Bonnetblanc, J. M., Leroux-Robert, C.
<strong>Melorheostosis with associated minimal change nephrotic syndrome, mesenteric fibromatosis and capillary haemangiomas.</strong>
Dermatology 188: 166-168, 1994.
[PubMed: 8136548]
[Full Text: https://doi.org/10.1159/000247127]
</p>
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<li>
<p class="mim-text-font">
Whyte, M. P., Griffith, M., Trani, L., Mumm, S., Gottesman, G. S., McAlister, W. H., Krysiak, K., Lesurf, R., Skidmore, Z. L., Campbell, K. M., Rosman, I. S., Bayliss, S., Bijanki, V. N., Nenninger, A., Van Tine, B. A., Griffith, O. L., Mardis, E. R.
<strong>Melorheostosis: exome sequencing of an associated dermatosis implicates postzygotic mosaicism of mutated KRAS.</strong>
Bone 101: 145-155, 2017.
[PubMed: 28434888]
[Full Text: https://doi.org/10.1016/j.bone.2017.04.010]
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Zhang, Y., Castori, M., Ferranti, G., Paradisi, M., Wordsworth, B. P.
<strong>Novel and recurrent germline LEMD3 mutations causing Buschke-Ollendorff syndrome and osteopoikilosis but not isolated melorheostosis.</strong>
Clin. Genet. 75: 556-561, 2009. Note: Erratum: Clin. Genet. 79: 401 only, 2011.
[PubMed: 19438932]
[Full Text: https://doi.org/10.1111/j.1399-0004.2009.01177.x]
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Marla J. F. O&#x27;Neill - updated : 06/22/2020<br>Cassandra L. Kniffin - updated : 6/2/2010<br>Marla J. F. O&#x27;Neill - updated : 10/7/2005<br>Victor A. McKusick - updated : 11/19/2004<br>Victor A. McKusick - updated : 4/6/2004<br>Ada Hamosh - updated : 4/9/1999<br>Victor A. McKusick - updated : 11/4/1997
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