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��ࡱ�>��	�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������y�	����bjbj��	4��{�{iZ��������	�	������������'z�6�������/'1'1'1'1'1'1'$N)�,NU'9������U'������'�f�����@�/'U��������&�\�������m��'0�'u,N,�(N,���N,��<�������U'U'�"����'������������������������������������������������������������������������N,����������	 �:	@A case report of hereditary leiomyomatosis to increase awareness of the correlation
between cutaneous lesions and RCC

Introduction
Cutaneous leiomyomas are a rare, benign smooth muscle tumors of the skin, subcategorized based on the origin of the smooth muscle within the tumor. They are classified as follows: piloleiomyomas, which originate from the erector pili; genital leiomyomas, which originate from the dartos muscle of the skin in the genital area; and angioleiomyomas, which originate from the smooth muscle of the vasculature. Most pilar leiomyomas occur singly, but can occur as multiple lesions. Reed's syndrome, also known as multiple cutaneous and uterine leiomyomatosis (MCUL: OMIM 150800) and hereditary leiomyomatosis and renal cell cancer (HLRCC: OMIM 605839), is a condition inherited as an autosomal dominant trait with incomplete penetrance, consisting of multiple pilar leiomyomas, uterine leiomyomas and, rarely, leiomyosarcomas, in the multiple cutaneous and uterine leiomyomatosis (MCUL) syndrome and in association with renal cell carcinoma in the hereditary leiomyomatosis renal cell cancer (HLRCC) syndrome. The diagnosis is made by the presence of multiple cutaneous leiomyomas with at least one histologically con�rmed leiomyoma or by a single leiomyoma in the presence of a positive family history of HLRCC. ADDIN EN.CITE  ADDIN EN.CITE.DATA [1,6] Here, we present a healthy man who presented for esthetic consultation for multiple asymptomatic lesions. Upon further investigation, he was diagnosed with leiomyomas and renal cell cancer. Therefore, it is of a great importance to recognize these skin lesions for early detection of devastating associated tumors.

Case Presentation:
26-year-old male patient, previously healthy, presented to our clinic for asymptomatic upper and lower limbs lesions of two months� duration. The patient reported being bothered esthetically from the abundance and the appearance of the lesions especially that they were affecting his work socially and professionally. 
On physical examination, he had more than 100 firm, papulonodules fixed to the skin, ranging in size from 4-8 millimeters to 1 cm, reddish-brown in color, affecting only his upper and lower limbs (Fig. 1-2). No other sites were affected and he had no mucosal lesions. There was no increase in erythema or edema when rubbed.
His past medical history was negative for skin cancers and his past surgical history was negative. There was no family history of skin problems and the generalized physical examination was normal. Our differential diagnosis included leiomyoma, dermatofibroma, and schwannoma.

Histopathological examination from an excisional biopsy revealed a dermal nodule made up of multiple intersecting fascicles of fusiform shaped cells with ample eosinophilic cytoplasm. Multiple Cigar shaped nuclei with perinuclear vacuoles and interlacing bundles of smooth-muscle fibers were also seen (Fig. 3a,b,c). All the features were suggestive of cutaneous piloleiomyomas. 
And by knowing that cutaneous piloleiomyomas can be associated with some syndromes,
a blood workup was ordered for evaluation of complete blood count (CBC), and biochemistry (BUN, creatinine and electrolytes) as well as urine analysis and urine cytology. All the laboratory workup came up as normal. Also, an ultrasound of the kidneys was done which showed two complicated cysts in the left kidney, one in the upper pole with the cysts showing echogenic content and calcifications and one in the lower pole (Fig. 4). Therefore, a CT scan was done to assess the complicated cysts in the left kidney and it showed two large malignant multi-cystic masses in the left kidney with thick septations, calcifications and soft tissue components (Bosniak IV). The right kidney showed also an exophytic heterogeneous solid lesion of its anterior lip (Fig. 5). All these findings were highly suggestive of renal carcinoma.
Patient was scheduled for total left nephrectomy and the pathology showed Clear cell carcinoma of the kidney with no evidence of capsular invasion.
Then, a right partial nephrectomy was done after complete recovery of the first surgery and the biopsy also showed Clear cell carcinoma; which led us to the diagnosis of Hereditary leiomyomatosis renal cell cancer (HLRCC) or what is known as REED syndrome. Two months after recovery, the patient came for follow-up with a quasi-disappearance of the lesions with only post inflammatory hyperpigmentation remaining. 

Discussion:
In 1854, Virchow was the first one to describe cutaneous leiomyomas as a rare, benign smooth muscle tumors of the skin. ADDIN EN.CITE  ADDIN EN.CITE.DATA [1] This is the same scientist that his work led to the discovery of virchow�s node and virchow triad. Cutaneous leiomyomas originating from the arrector pili muscles became known as piloleiomyomas. ADDIN EN.CITE <EndNote><Cite><Author>Fisher</Author><Year>1963</Year><RecNum>46</RecNum><DisplayText>[2]</DisplayText><record><rec-number>46</rec-number><foreign-keys><key app="EN" db-id="29rf0ps9wt5vvjev5vnvex00xrw0vsrprwsz" timestamp="1469569925">46</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Fisher, W. C.</author><author>Helwig, E. B.</author></authors></contributors><titles><title>LEIOMYOMAS OF THE SKIN</title><secondary-title>Arch Dermatol</secondary-title><alt-title>Archives of dermatology</alt-title></titles><periodical><full-title>Arch Dermatol</full-title><abbr-1>Archives of dermatology</abbr-1></periodical><alt-periodical><full-title>Arch Dermatol</full-title><abbr-1>Archives of dermatology</abbr-1></alt-periodical><pages>510-20</pages><volume>88</volume><edition>1963/11/01</edition><keywords><keyword>Humans</keyword><keyword>*Leiomyoma</keyword><keyword>*Pathology</keyword><keyword>*Skin Neoplasms</keyword></keywords><dates><year>1963</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>0003-987X (Print)&#xD;0003-987x</isbn><accession-num>14060062</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[2] These lesions are sensitive to touch and cold temperatures and, in rare cases, may be painful.
A century after Virchow�s first explanation, it was suggested that those leiomyomas can be present in families.  ADDIN EN.CITE <EndNote><Cite><Author>Kloepfer</Author><Year>1958</Year><RecNum>40</RecNum><DisplayText>[3]</DisplayText><record><rec-number>40</rec-number><foreign-keys><key app="EN" db-id="29rf0ps9wt5vvjev5vnvex00xrw0vsrprwsz" timestamp="1469549098">40</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kloepfer, H. W.</author><author>Krafchuk, J.</author><author>Derbes, V.</author><author>Burks, J.</author></authors></contributors><titles><title>Hereditary multiple leiomyoma of the skin</title><secondary-title>Am J Hum Genet</secondary-title><alt-title>American journal of human genetics</alt-title></titles><periodical><full-title>Am J Hum Genet</full-title><abbr-1>American journal of human genetics</abbr-1></periodical><alt-periodical><full-title>Am J Hum Genet</full-title><abbr-1>American journal of human genetics</abbr-1></alt-periodical><pages>48-52</pages><volume>10</volume><number>1</number><edition>1958/03/01</edition><keywords><keyword>*Heredity</keyword><keyword>Humans</keyword><keyword>Leiomyoma/*genetics</keyword><keyword>*Skin</keyword><keyword>Skin Neoplasms/*genetics</keyword><keyword>*LEIOMYOMA/heredity</keyword><keyword>*SKIN NEOPLASMS/heredity</keyword></keywords><dates><year>1958</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>0002-9297 (Print)&#xD;0002-9297</isbn><accession-num>13520698</accession-num><urls></urls><custom2>PMC1931875</custom2><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[3]
However, acquired cutaneous leiomyomas are the most commonly seen in literature.  ADDIN EN.CITE <EndNote><Cite><Year>2012</Year><RecNum>37</RecNum><DisplayText>[4]</DisplayText><record><rec-number>37</rec-number><foreign-keys><key app="EN" db-id="29rf0ps9wt5vvjev5vnvex00xrw0vsrprwsz" timestamp="1469545207">37</key></foreign-keys><ref-type name="Book">6</ref-type><contributors></contributors><titles><title>Fitzpatrick�s Dermatology in General Medicine</title></titles><volume>2</volume><edition>Eighth Edition</edition><dates><year>2012</year></dates><publisher>McGraw Hill</publisher><isbn>978-0-07-171755-7</isbn><urls></urls></record></Cite></EndNote>[4] Transmission of this disease is autosomal dominant with incomplete penetrance  ADDIN EN.CITE <EndNote><Cite><Author>Fernandez-Pugnaire</Author><Year>1995</Year><RecNum>38</RecNum><DisplayText>[5]</DisplayText><record><rec-number>38</rec-number><foreign-keys><key app="EN" db-id="29rf0ps9wt5vvjev5vnvex00xrw0vsrprwsz" timestamp="1469548278">38</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Fernandez-Pugnaire, M. A.</author><author>Delgado-Florencio, V.</author></authors></contributors><auth-address>Department of Medicine, School of Medicine, University of Granada, Spain.</auth-address><titles><title>Familial multiple cutaneous leiomyomas</title><secondary-title>Dermatology</secondary-title><alt-title>Dermatology (Basel, Switzerland)</alt-title></titles><periodical><full-title>Dermatology</full-title><abbr-1>Dermatology (Basel, Switzerland)</abbr-1></periodical><alt-periodical><full-title>Dermatology</full-title><abbr-1>Dermatology (Basel, Switzerland)</abbr-1></alt-periodical><pages>295-8</pages><volume>191</volume><number>4</number><edition>1995/01/01</edition><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Extremities</keyword><keyword>Facial Neoplasms/genetics/pathology</keyword><keyword>Female</keyword><keyword>Hair Follicle/pathology</keyword><keyword>Humans</keyword><keyword>Leiomyomatosis/*genetics/pathology</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Skin Neoplasms/*genetics/pathology</keyword><keyword>Thoracic Neoplasms/genetics/pathology</keyword><keyword>Uterine Neoplasms/genetics/pathology</keyword></keywords><dates><year>1995</year></dates><isbn>1018-8665 (Print)&#xD;1018-8665</isbn><accession-num>8573925</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[5], appearing mostly in early adulthood. It is a disease of both genders, where affected women can develop uterine leiomyomas, a syndrome called �multiple cutaneous and uterine leiomyomatosis� also known as familial leiomyomatosis cutis et uteri or REED syndrome. Affected males can develop renal cell cancer and this has been named hereditary leiomyomatosis and renal cell cancer.  ADDIN EN.CITE <EndNote><Cite><Year>2012</Year><RecNum>37</RecNum><DisplayText>[4]</DisplayText><record><rec-number>37</rec-number><foreign-keys><key app="EN" db-id="29rf0ps9wt5vvjev5vnvex00xrw0vsrprwsz" timestamp="1469545207">37</key></foreign-keys><ref-type name="Book">6</ref-type><contributors></contributors><titles><title>Fitzpatrick�s Dermatology in General Medicine</title></titles><volume>2</volume><edition>Eighth Edition</edition><dates><year>2012</year></dates><publisher>McGraw Hill</publisher><isbn>978-0-07-171755-7</isbn><urls></urls></record></Cite></EndNote>[4]The age-of-onset of cutaneous leiomyoma ranged from 10 to 47 years of age, with a mean age of 25 years. ADDIN EN.CITE  ADDIN EN.CITE.DATA [6] Genetic testing revealed that a loss of function mutation in the gene encoding fumarate hydratase (FH) on chromosome 1q42.3�43 was responsible of this syndrome. ADDIN EN.CITE <EndNote><Cite><Author>Alam</Author><Year>2005</Year><RecNum>42</RecNum><DisplayText>[7]</DisplayText><record><rec-number>42</rec-number><foreign-keys><key app="EN" db-id="29rf0ps9wt5vvjev5vnvex00xrw0vsrprwsz" timestamp="1469549868">42</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Alam, N. A.</author><author>Olpin, S.</author><author>Leigh, I. M.</author></authors></contributors><auth-address>Molecular and Population Genetics Laboratory, Cancer Research UK, Lincoln&apos;s Inn Fields, London WC2A 3PX, UK. ufrina.alam@gmail.com</auth-address><titles><title>Fumarate hydratase mutations and predisposition to cutaneous leiomyomas, uterine leiomyomas and renal cancer</title><secondary-title>Br J Dermatol</secondary-title><alt-title>The British journal of dermatology</alt-title></titles><periodical><full-title>Br J Dermatol</full-title><abbr-1>The British journal of dermatology</abbr-1></periodical><alt-periodical><full-title>Br J Dermatol</full-title><abbr-1>The British journal of dermatology</abbr-1></alt-periodical><pages>11-7</pages><volume>153</volume><number>1</number><edition>2005/07/21</edition><keywords><keyword>Female</keyword><keyword>Fumarate Hydratase/*genetics</keyword><keyword>Genetic Predisposition to Disease</keyword><keyword>Humans</keyword><keyword>Kidney Neoplasms/genetics</keyword><keyword>Leiomyoma/*genetics</keyword><keyword>*Mutation</keyword><keyword>Neoplastic Syndromes, Hereditary/*genetics</keyword><keyword>Skin Neoplasms/*genetics</keyword><keyword>Uterine Neoplasms/genetics</keyword></keywords><dates><year>2005</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>0007-0963 (Print)&#xD;0007-0963</isbn><accession-num>16029320</accession-num><urls></urls><electronic-resource-num>10.1111/j.1365-2133.2005.06678.x</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[7] FH is an essential enzyme for the conversion of fumarate to malate in the Krebs cycle. Fumarate accumulates due to loss of FH activity and the loss of FH function, impairs the Krebs cycle. Thereby, high fumarate levels inhibit HPH (hypoxia inducible factors prolyl hydroxylase) enzyme, therefore, leading to upregulation of HIF (hypoxia inducible factors) with concomitant increase of hypoxia response genes like vascular endothelial growth factors (VEGF) and glucose transporter-1 (GLUT-1), which will lead to more angiogenesis with a resultant higher risk of malignancy. ADDIN EN.CITE <EndNote><Cite><Author>Sudarshan</Author><Year>2007</Year><RecNum>43</RecNum><DisplayText>[8]</DisplayText><record><rec-number>43</rec-number><foreign-keys><key app="EN" db-id="29rf0ps9wt5vvjev5vnvex00xrw0vsrprwsz" timestamp="1469550396">43</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Sudarshan, S.</author><author>Linehan, W. M.</author><author>Neckers, L.</author></authors></contributors><auth-address>Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, 10 Center Drive, Bldg 10 CRC Room 1-5940, Bethesda, MD 20892-1107, USA.</auth-address><titles><title>HIF and fumarate hydratase in renal cancer</title><secondary-title>Br J Cancer</secondary-title><alt-title>British journal of cancer</alt-title></titles><periodical><full-title>Br J Cancer</full-title><abbr-1>British journal of cancer</abbr-1></periodical><alt-periodical><full-title>Br J Cancer</full-title><abbr-1>British journal of cancer</abbr-1></alt-periodical><pages>403-7</pages><volume>96</volume><number>3</number><edition>2007/01/11</edition><keywords><keyword>Carcinoma, Renal Cell/etiology/genetics</keyword><keyword>Citric Acid Cycle</keyword><keyword>Fumarate Hydratase/*physiology</keyword><keyword>Humans</keyword><keyword>Hypoxia-Inducible Factor 1, alpha Subunit/*physiology</keyword><keyword>Kidney Neoplasms/*etiology/genetics/metabolism</keyword><keyword>Leiomyomatosis/etiology/genetics</keyword><keyword>Neoplastic Syndromes, Hereditary/etiology/genetics</keyword><keyword>Von Hippel-Lindau Tumor Suppressor Protein/physiology</keyword></keywords><dates><year>2007</year><pub-dates><date>Feb 12</date></pub-dates></dates><isbn>0007-0920 (Print)&#xD;0007-0920</isbn><accession-num>17211469</accession-num><urls></urls><custom2>PMC2360036</custom2><electronic-resource-num>10.1038/sj.bjc.6603547</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[8]
The differential diagnosis of cutaneous leiomyomas can be broad with non-specific appearance of  classically painful solitary lesions. This includes the list of painful papulonodules tumours such as eccrine spiradenoma, neuroma, dermatofibroma, angiolipoma, neurilemmoma, endometrioma, glomus tumor, and granular cell tumor. However, multiple cutaneous leiomyomas, specifically piloleiomyomas, tend to have a distinct clinical appearance.  
Histopathological findings include, tumors typically centered within the reticular dermis, with focal extension into the subcutaneous fat in some cases with constant interlacing bundles or irregular collections of elongated cells with brightly eosinophilic cytoplasm and blunt-ended or cigar shaped nuclei. Mitotic figures are only very rarely seen. Tumor cells are usually uniformly positive for SMA, calponin, desmin and h-caldesmon. Histopathological differential diagnosis include dermatofibroma and neurofibroma. Discrepancy from dermatofibroma is provided by the leiomyoma's uniform cell content and configuration in addition to desmin and SMA positivity. Cellular neurofibroma is S-100 protein positive and lacks the eosinophilic cytoplasm, myofibrils and blunt-ended nuclei of leiomyoma. Differentiation from cutaneous leiomyosarcoma is based on the presence of mitoses and the usually greater nuclear pleomorphism in the latter tumor. However, the clinical history, particularly in cases with multiple lesions, often makes the diagnosis straightforward.
Although renal cell carcinoma is a part of the triad, it will not develop in all individuals with this syndrome. Only 10�16% of individuals with cutaneous leiomyomas had a renal tumor at the time of imaging. ADDIN EN.CITE <EndNote><Cite><Author>Pithukpakorn</Author><Year>1993</Year><RecNum>44</RecNum><DisplayText>[9]</DisplayText><record><rec-number>44</rec-number><foreign-keys><key app="EN" db-id="29rf0ps9wt5vvjev5vnvex00xrw0vsrprwsz" timestamp="1469552705">44</key></foreign-keys><ref-type name="Book Section">5</ref-type><contributors><authors><author>Pithukpakorn, M.</author><author>Toro, J. R.</author></authors><secondary-authors><author>Pagon, R. A.</author><author>Adam, M. P.</author><author>Ardinger, H. H.</author><author>Wallace, S. E.</author><author>Amemiya, A.</author><author>Bean, L. J. H.</author><author>Bird, T. D.</author><author>Fong, C. T.</author><author>Mefford, H. C.</author><author>Smith, R. J. H.</author><author>Stephens, K.</author></secondary-authors></contributors><titles><title>Hereditary Leiomyomatosis and Renal Cell Cancer</title><secondary-title>GeneReviews(R)</secondary-title></titles><dates><year>1993</year></dates><pub-location>Seattle (WA)</pub-location><publisher>University of Washington, Seattle&#xD;University of Washington, Seattle. All rights reserved.</publisher><accession-num>20301430</accession-num><urls></urls><language>eng</language></record></Cite></EndNote>[9] Most are unilateral, solitary & of an aggressive type, however our patient had a more aggressive disease with bilateral and multifocal kidney involvement.
Treatments for the isolated cutaneous leiomyomas are largely dictated by the patient�s degree of skin discomfort. Options include surgical excision, cryoablation, CO2 laser ablation and medications such as calcium channel blockers or alpha blockers. In addition, botulinum toxin has also been shown to decrease the intensity & frequency of the pain caused by the leiomyomas.
As for the hereditary leiomyomas, studies have shown that early hysterectomy or nephrectomy may be the treatment of choice because of their aggressive nature  ADDIN EN.CITE <EndNote><Cite><Author>Pithukpakorn</Author><Year>1993</Year><RecNum>44</RecNum><DisplayText>[9]</DisplayText><record><rec-number>44</rec-number><foreign-keys><key app="EN" db-id="29rf0ps9wt5vvjev5vnvex00xrw0vsrprwsz" timestamp="1469552705">44</key></foreign-keys><ref-type name="Book Section">5</ref-type><contributors><authors><author>Pithukpakorn, M.</author><author>Toro, J. R.</author></authors><secondary-authors><author>Pagon, R. A.</author><author>Adam, M. P.</author><author>Ardinger, H. H.</author><author>Wallace, S. E.</author><author>Amemiya, A.</author><author>Bean, L. J. H.</author><author>Bird, T. D.</author><author>Fong, C. T.</author><author>Mefford, H. C.</author><author>Smith, R. J. H.</author><author>Stephens, K.</author></secondary-authors></contributors><titles><title>Hereditary Leiomyomatosis and Renal Cell Cancer</title><secondary-title>GeneReviews(R)</secondary-title></titles><dates><year>1993</year></dates><pub-location>Seattle (WA)</pub-location><publisher>University of Washington, Seattle&#xD;University of Washington, Seattle. All rights reserved.</publisher><accession-num>20301430</accession-num><urls></urls><language>eng</language></record></Cite></EndNote>[9], as we have seen in our patient.





{Rosner, 2009 #1}{Rosner, 2009 #1}

 ADDIN EN.REFLIST 1.	Stewart, L., G. Glenn, and J.R. Toro, Cutaneous leiomyomas: a clinical marker of risk for hereditary leiomyomatosis and renal cell cancer. Dermatol Nurs, 2006. 18(4): p. 335-41; quiz 342.
2.	Fisher, W.C. and E.B. Helwig, LEIOMYOMAS OF THE SKIN. Arch Dermatol, 1963. 88: p. 510-20.
3.	Kloepfer, H.W., et al., Hereditary multiple leiomyoma of the skin. Am J Hum Genet, 1958. 10(1): p. 48-52.
4.	Fitzpatrick�s Dermatology in General Medicine. Eighth Edition ed. Vol. 2. 2012: McGraw Hill.
5.	Fernandez-Pugnaire, M.A. and V. Delgado-Florencio, Familial multiple cutaneous leiomyomas. Dermatology, 1995. 191(4): p. 295-8.
6.	Toro, J.R., et al., Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America. Am J Hum Genet, 2003. 73(1): p. 95-106.
7.	Alam, N.A., S. Olpin, and I.M. Leigh, Fumarate hydratase mutations and predisposition to cutaneous leiomyomas, uterine leiomyomas and renal cancer. Br J Dermatol, 2005. 153(1): p. 11-7.
8.	Sudarshan, S., W.M. Linehan, and L. Neckers, HIF and fumarate hydratase in renal cancer. Br J Cancer, 2007. 96(3): p. 403-7.
9.	Pithukpakorn, M. and J.R. Toro, Hereditary Leiomyomatosis and Renal Cell Cancer, in GeneReviews(R), R.A. Pagon, et al., Editors. 1993, University of Washington, Seattle 


Legends for figures:
Figure 1 and 2: papulonodules 4-8 millimeters to 1 cm reddish-brown lesions, affecting over  upper and lower limbs.
Figure 3a: (H&E, x4) multiple intersecting fascicles of fusiform shaped cells with ample eosinophilic cytoplasm
Figure 3b: (H&E, x10) multiple intersecting fascicles of fusiform shaped cells with ample eosinophilic cytoplasm
Figure 3c: (H&E, x40) Multiple Cigar shaped nuclei with perinuclear vacuoles and interlacing bundles of smooth-muscle fibers.
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Figure 5: exophytic heterogeneous solid lesion of its anterior lip in right kidney.

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$dha$gd�:�21�h:p{��|. ��A!��"��#��$��%��������	D<EndNote><Cite><Author>Toro</Author><Year>2003</Year><RecNum>41</RecNum><DisplayText>[6]</DisplayText><record><rec-number>41</rec-number><foreign-keys><key app="EN" db-id="29rf0ps9wt5vvjev5vnvex00xrw0vsrprwsz" timestamp="1469549542">41</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Toro, J. R.</author><author>Nickerson, M. L.</author><author>Wei, M. H.</author><author>Warren, M. B.</author><author>Glenn, G. M.</author><author>Turner, M. L.</author><author>Stewart, L.</author><author>Duray, P.</author><author>Tourre, O.</author><author>Sharma, N.</author><author>Choyke, P.</author><author>Stratton, P.</author><author>Merino, M.</author><author>Walther, M. M.</author><author>Linehan, W. M.</author><author>Schmidt, L. S.</author><author>Zbar, B.</author></authors></contributors><auth-address>Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Boulevard, Executive Plaza South, Rockville, MD 20892, USA. torojo@exchange.nih.gov</auth-address><titles><title>Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America</title><secondary-title>Am J Hum Genet</secondary-title><alt-title>American journal of human genetics</alt-title></titles><periodical><full-title>Am J Hum Genet</full-title><abbr-1>American journal of human genetics</abbr-1></periodical><alt-periodical><full-title>Am J Hum Genet</full-title><abbr-1>American journal of human genetics</abbr-1></alt-periodical><pages>95-106</pages><volume>73</volume><number>1</number><edition>2003/05/29</edition><keywords><keyword>Carcinoma, Renal Cell/*genetics</keyword><keyword>Female</keyword><keyword>Fumarate Hydratase/*genetics</keyword><keyword>*Genetic Predisposition to Disease</keyword><keyword>Humans</keyword><keyword>Kidney Neoplasms/*genetics</keyword><keyword>Leiomyomatosis/*genetics</keyword><keyword>Male</keyword><keyword>*Mutation</keyword><keyword>North America</keyword><keyword>Pedigree</keyword></keywords><dates><year>2003</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>0002-9297 (Print)&#xD;0002-9297</isbn><accession-num>12772087</accession-num><urls></urls><custom2>PMC1180594</custom2><electronic-resource-num>10.1086/376435</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>�	D<EndNote><Cite><Author>Toro</Author><Year>2003</Year><RecNum>41</RecNum><DisplayText>[6]</DisplayText><record><rec-number>41</rec-number><foreign-keys><key app="EN" db-id="29rf0ps9wt5vvjev5vnvex00xrw0vsrprwsz" timestamp="1469549542">41</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Toro, J. R.</author><author>Nickerson, M. L.</author><author>Wei, M. H.</author><author>Warren, M. B.</author><author>Glenn, G. M.</author><author>Turner, M. L.</author><author>Stewart, L.</author><author>Duray, P.</author><author>Tourre, O.</author><author>Sharma, N.</author><author>Choyke, P.</author><author>Stratton, P.</author><author>Merino, M.</author><author>Walther, M. M.</author><author>Linehan, W. M.</author><author>Schmidt, L. S.</author><author>Zbar, B.</author></authors></contributors><auth-address>Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Boulevard, Executive Plaza South, Rockville, MD 20892, USA. torojo@exchange.nih.gov</auth-address><titles><title>Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America</title><secondary-title>Am J Hum Genet</secondary-title><alt-title>American journal of human genetics</alt-title></titles><periodical><full-title>Am J Hum Genet</full-title><abbr-1>American journal of human genetics</abbr-1></periodical><alt-periodical><full-title>Am J Hum Genet</full-title><abbr-1>American journal of human genetics</abbr-1></alt-periodical><pages>95-106</pages><volume>73</volume><number>1</number><edition>2003/05/29</edition><keywords><keyword>Carcinoma, Renal Cell/*genetics</keyword><keyword>Female</keyword><keyword>Fumarate Hydratase/*genetics</keyword><keyword>*Genetic Predisposition to Disease</keyword><keyword>Humans</keyword><keyword>Kidney Neoplasms/*genetics</keyword><keyword>Leiomyomatosis/*genetics</keyword><keyword>Male</keyword><keyword>*Mutation</keyword><keyword>North America</keyword><keyword>Pedigree</keyword></keywords><dates><year>2003</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>0002-9297 (Print)&#xD;0002-9297</isbn><accession-num>12772087</accession-num><urls></urls><custom2>PMC1180594</custom2><electronic-resource-num>10.1086/376435</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>
D<EndNote><Cite><Author>Stewart</Author><Year>2006</Year><RecNum>39</RecNum><DisplayText>[1]</DisplayText><record><rec-number>39</rec-number><foreign-keys><key app="EN" db-id="29rf0ps9wt5vvjev5vnvex00xrw0vsrprwsz" timestamp="1469548760">39</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Stewart, L.</author><author>Glenn, G.</author><author>Toro, J. R.</author></authors></contributors><auth-address>Genetic Epidemiology Branch, National Cancer Institute, National Institutes of Health, Rockville, MD, USA.</auth-address><titles><title>Cutaneous leiomyomas: a clinical marker of risk for hereditary leiomyomatosis and renal cell cancer</title><secondary-title>Dermatol Nurs</secondary-title><alt-title>Dermatology nursing / Dermatology Nurses&apos; Association</alt-title></titles><periodical><full-title>Dermatol Nurs</full-title><abbr-1>Dermatology nursing / Dermatology Nurses&apos; Association</abbr-1></periodical><alt-periodical><full-title>Dermatol Nurs</full-title><abbr-1>Dermatology nursing / Dermatology Nurses&apos; Association</abbr-1></alt-periodical><pages>335-41; quiz 342</pages><volume>18</volume><number>4</number><edition>2006/09/05</edition><keywords><keyword>Biopsy</keyword><keyword>Carcinoma, Renal Cell/diagnosis/epidemiology/*genetics</keyword><keyword>Early Diagnosis</keyword><keyword>Female</keyword><keyword>Genes, Dominant/genetics</keyword><keyword>Genetic Predisposition to Disease/epidemiology/genetics</keyword><keyword>Genetic Testing</keyword><keyword>Germ-Line Mutation/genetics</keyword><keyword>Humans</keyword><keyword>Kidney Neoplasms/diagnosis/epidemiology/*genetics</keyword><keyword>Leiomyomatosis/diagnosis/epidemiology/*genetics</keyword><keyword>Magnetic Resonance Imaging</keyword><keyword>Male</keyword><keyword>Medical History Taking</keyword><keyword>Molecular Epidemiology</keyword><keyword>Neoplastic Syndromes, Hereditary/diagnosis/epidemiology/*genetics</keyword><keyword>Nurse&apos;s Role</keyword><keyword>Nursing Assessment</keyword><keyword>Physical Examination</keyword><keyword>Rare Diseases</keyword><keyword>Skin Neoplasms/diagnosis/epidemiology/*genetics</keyword><keyword>Uterine Neoplasms/epidemiology/genetics</keyword></keywords><dates><year>2006</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>1060-3441 (Print)&#xD;1060-3441</isbn><accession-num>16948378</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>
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R.</author><author>Nickerson, M. L.</author><author>Wei, M. H.</author><author>Warren, M. B.</author><author>Glenn, G. M.</author><author>Turner, M. L.</author><author>Stewart, L.</author><author>Duray, P.</author><author>Tourre, O.</author><author>Sharma, N.</author><author>Choyke, P.</author><author>Stratton, P.</author><author>Merino, M.</author><author>Walther, M. M.</author><author>Linehan, W. M.</author><author>Schmidt, L. S.</author><author>Zbar, B.</author></authors></contributors><auth-address>Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Boulevard, Executive Plaza South, Rockville, MD 20892, USA. torojo@exchange.nih.gov</auth-address><titles><title>Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America</title><secondary-title>Am J Hum Genet</secondary-title><alt-title>American journal of human genetics</alt-title></titles><periodical><full-title>Am J Hum Genet</full-title><abbr-1>American journal of human genetics</abbr-1></periodical><alt-periodical><full-title>Am J Hum Genet</full-title><abbr-1>American journal of human genetics</abbr-1></alt-periodical><pages>95-106</pages><volume>73</volume><number>1</number><edition>2003/05/29</edition><keywords><keyword>Carcinoma, Renal Cell/*genetics</keyword><keyword>Female</keyword><keyword>Fumarate Hydratase/*genetics</keyword><keyword>*Genetic Predisposition to Disease</keyword><keyword>Humans</keyword><keyword>Kidney Neoplasms/*genetics</keyword><keyword>Leiomyomatosis/*genetics</keyword><keyword>Male</keyword><keyword>*Mutation</keyword><keyword>North America</keyword><keyword>Pedigree</keyword></keywords><dates><year>2003</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>0002-9297 (Print)&#xD;0002-9297</isbn><accession-num>12772087</accession-num><urls></urls><custom2>PMC1180594</custom2><electronic-resource-num>10.1086/376435</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>�	D<EndNote><Cite><Author>Toro</Author><Year>2003</Year><RecNum>41</RecNum><DisplayText>[6]</DisplayText><record><rec-number>41</rec-number><foreign-keys><key app="EN" db-id="29rf0ps9wt5vvjev5vnvex00xrw0vsrprwsz" timestamp="1469549542">41</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Toro, J. R.</author><author>Nickerson, M. L.</author><author>Wei, M. H.</author><author>Warren, M. B.</author><author>Glenn, G. M.</author><author>Turner, M. L.</author><author>Stewart, L.</author><author>Duray, P.</author><author>Tourre, O.</author><author>Sharma, N.</author><author>Choyke, P.</author><author>Stratton, P.</author><author>Merino, M.</author><author>Walther, M. M.</author><author>Linehan, W. M.</author><author>Schmidt, L. S.</author><author>Zbar, B.</author></authors></contributors><auth-address>Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Boulevard, Executive Plaza South, Rockville, MD 20892, USA. torojo@exchange.nih.gov</auth-address><titles><title>Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America</title><secondary-title>Am J Hum Genet</secondary-title><alt-title>American journal of human genetics</alt-title></titles><periodical><full-title>Am J Hum Genet</full-title><abbr-1>American journal of human genetics</abbr-1></periodical><alt-periodical><full-title>Am J Hum Genet</full-title><abbr-1>American journal of human genetics</abbr-1></alt-periodical><pages>95-106</pages><volume>73</volume><number>1</number><edition>2003/05/29</edition><keywords><keyword>Carcinoma, Renal Cell/*genetics</keyword><keyword>Female</keyword><keyword>Fumarate Hydratase/*genetics</keyword><keyword>*Genetic Predisposition to Disease</keyword><keyword>Humans</keyword><keyword>Kidney Neoplasms/*genetics</keyword><keyword>Leiomyomatosis/*genetics</keyword><keyword>Male</keyword><keyword>*Mutation</keyword><keyword>North America</keyword><keyword>Pedigree</keyword></keywords><dates><year>2003</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>0002-9297 (Print)&#xD;0002-9297</isbn><accession-num>12772087</accession-num><urls></urls><custom2>PMC1180594</custom2><electronic-resource-num>10.1086/376435</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>n���������666666666vvvvvvvvv666666>666666666666666666666666666�6666666666�66666666666hH66666666666666666666666666666666666666666666666666666666666666666p66866666662����&6FVfv������2(��&6FVfv������&6FVfv������&6FVfv������&6FVfv������&6FVfv������(8HXf~$OJPJQJ^J_HmH	@nH	@sH	@tH	@@`�@NormalCJ_HaJmH	sH	tH	DA`�DDefault Paragraph FontRi�R
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