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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">LEOPARD syndrome&#44; which is currently also called Noonan syndrome with multiple lentigines &#40;NSML&#41; &#40;Online Mendelian Inheritance in Man 151100&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">1</span></a> is an autosomal dominant disease of the <span class="elsevierStyleItalic">RAS</span> &#40;rat sarcoma&#41; gene signaling pathway&#46; The acronym refers to the main manifestations of the syndrome&#44; namely&#44; lentigines&#44; electrocardiographic conduction abnormalities&#44; ocular hypertelorism&#44; pulmonary stenosis&#44; abnormal genitalia&#44; retarded growth&#44; and sensorineural deafness&#46;<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">2&#44;3</span></a> These signs are not constant&#44; however&#44; and none of them are pathognomonic&#46; We report 2 genetically confirmed cases of NSML without hypertrophic cardiopathy&#44; pulmonary stenosis&#44; or deafness&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Patient 1</span><p id="par0010" class="elsevierStylePara elsevierViewall">A 6-year-old boy&#44; the firstborn of healthy nonconsanguineous parents&#44; had been followed by the neurologist since the age of 4&#46;5 years because of developmental delays&#44; including slight speech-language impairment&#46; Physical examination revealed facial dysmorphism with large&#44; prominent&#44; low-set&#44; posteriorly rotated ears&#59; widely spaced eyes&#59; and a flat nasal bridge&#46; On the back of his neck &#40;area of the cervical spine&#41;&#44; right buttock&#44; left axilla&#44; and right knee&#44; the boy also had 4 hyperpigmented macules with irregular borders measuring 5<span class="elsevierStyleHsp" style=""></span>to 15<span class="elsevierStyleHsp" style=""></span>mm in diameter&#46; Multiple lentigines 5<span class="elsevierStyleHsp" style=""></span>mm in diameter were observed on the face&#44; trunk&#44; and extremities &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; Cardiac evaluation revealed a right bundle-branch block&#46; A hearing test was normal&#46; Testing for mutations in the <span class="elsevierStyleItalic">PTPN11</span> &#40;protein tyrosine phosphatase nonreceptor 11&#41; gene demonstrated a T468M mutation &#40;p&#46;Thr468Met&#41; in exon 12&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Patient 2</span><p id="par0015" class="elsevierStylePara elsevierViewall">A 6-year-old boy born to healthy nonconsanguineous parents was being treated by a speech therapist for delayed language acquisition and difficulty with auditory discrimination of some phonemes&#46; Physical examination revealed facial dysmorphism&#44; including an inverted triangular-shaped face&#44; short neck&#44; large low-set ears&#44; orbital hypertelorism&#44; megalocornea&#44; and pectus excavatum&#46; Numerous caf&#233; au lait macules and lentigines were present on the face&#44; neck&#44; and upper trunk &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46; Hearing and cardiac evaluations were normal&#46; Genetic testing detected the R498W mutation &#40;p&#46;Arg498Trp&#41; in axon 13 of <span class="elsevierStyleItalic">PTPN11</span>&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Discussion</span><p id="par0020" class="elsevierStylePara elsevierViewall">NSML belongs to a group of neuro-cardio-fascio-cutaneous syndromes in which germline mutations in the <span class="elsevierStyleItalic">RAS-MAPK</span> &#40;mitogen-activated protein kinase&#41; pathway are present&#46; The most characteristic dermatologic findings are pigmented lesions&#44; especially lentigines&#44; which are present in 90&#37; of patients with these syndromes&#46; Manifestations may be present from birth&#44; but they usually appear when the child is around 4<span class="elsevierStyleHsp" style=""></span>or 5<span class="elsevierStyleHsp" style=""></span>years of age and may even first present in puberty&#46;<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">2&#44;4&#44;5</span></a> Caf&#233; au lait macules&#44; which are somewhat larger than lentigines&#44; can be seen in 70&#37; to 80&#37; of patients&#46; Lesions that are darker have been called black coffee macules&#46; The most common cardiac finding in NSML is hypertrophic myocardiopathy&#44; which can be fatal&#46; Cardiac valve and coronary abnormalities may also be present&#46; Pulmonary stenosis is less common than mitral valve or aortic abnormalities&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">2</span></a> Typical electrocardiographic signs are those of left or right ventricular hypertrophy&#44; right atrial enlargement&#44; and gradual development of right bundle-branch block&#46; Deafness&#44; traditionally considered highly specific to NSML&#44; only presents in 25&#37; to 30&#37; of these patients&#59; the deficit is neurosensorial&#44; may be unilateral or bilateral&#44; and is sometimes profound &#40;&#62;<span class="elsevierStyleHsp" style=""></span>95<span class="elsevierStyleHsp" style=""></span>db&#41;&#46; Although deafness is usually diagnosed in childhood&#44; it may develop later&#44; making periodic hearing tests advisable&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">4</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Other manifestations include distinctive facial features&#59; skeletal abnormalities such as pectus carinatum or excavatum&#44; which are seen in up to 75&#37; of neonates&#59; delayed puberty and late menarche&#59; and urogenital abnormalities such as horseshoe-shaped kidney and hypospadia&#44; underdeveloped ovaries or testicles&#44; and small penis&#46;<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">2&#44;4</span></a> The slow growth observed in 25&#37; of patients does not appear to be related to endocrine dysregulation or systemic disease&#46; Eighty-five percent of patients will remain in the lower 25th percentile on growth charts&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">2</span></a> Unlike other <span class="elsevierStyleItalic">RAS</span>opathies&#44; NSML seems to confer only minimal predisposition to cancer&#44; but blood tumors<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">6</span></a> and other malignancies&#44; such as melanomas<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">7&#44;8</span></a> have been reported&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">Genetic testing is necessary for a definitive diagnosis&#46; Mutations in exons 7&#44; 12&#44; and 13 in the PTP domain of the <span class="elsevierStyleItalic">PTPN11</span> oncogene that encodes the SHP-2 phosphatase have been demonstrated in 85&#37; to 90&#37; of patients with NSML&#46; Functional SHP2 deficiency &#40;not present in Noonan syndrome&#41; is compensated for by hypersensitivity to growth factor stimulus&#44; longer contact time at the C-terminal domain &#40;pTyr ligands&#41;&#44; and the weakening of interactions of the SH2 inhibitor with the catalytic zone&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">9</span></a> The result is functional gain&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">1</span></a> At least 11 different mutations have been described to date&#46; Among them are 2 frequently recurring ones&#8212;Y279C and T468M&#8212;that have been found in over half of patients with NSML&#46;<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">2&#44;9&#44;10</span></a> Of patients who have been found to be negative for <span class="elsevierStyleItalic">PTPN11</span> mutation&#44; a third have <span class="elsevierStyleItalic">RAF1</span> &#40;Raf-1 proto-oncogene&#44; serine&#47;threonine kinase&#41; mutations and fewer than 5&#37; have <span class="elsevierStyleItalic">BRAF</span> &#40;B-Raf&#41; mutations&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">7</span></a> There is a certain correlation between genotype and phenotype&#44; such that patients who are negative for <span class="elsevierStyleItalic">PTPN11</span> mutation tend to have a higher prevalence of cardiac conduction abnormalities&#44; left ventricular or atrial hypertrophy&#44; and a family history of sudden death&#44; whereas patients who are <span class="elsevierStyleItalic">PTPN11</span>-mutation positive &#40;exon 13&#41; have greater risk of hypertrophic myocardiopathy and severe cardiac complications&#59; mutation in exon 7 is more often associated with delayed growth and deafness&#44; and <span class="elsevierStyleItalic">BRAF</span> mutations confer greater risk of cognitive disorders&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">7</span></a><span class="elsevierStyleItalic">RAF</span> mutation may cause lentigines&#44; caf&#233; au lait macules&#44; abnormal facial features&#44; hypertrophic myocardiopathy&#44; arrhythmias&#44; and delayed puberty&#46;<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">2&#44;4</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">The main differential diagnoses are other diseases linked to the <span class="elsevierStyleItalic">RAS-MAPK</span> pathway&#44;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">11</span></a> and the strong genetic-phenotypic overlap of <span class="elsevierStyleItalic">RAS</span>opathies makes clinical diagnosis difficult&#46; NSML can be phenotypically very difficult to distinguish from Noonan syndrome itself &#40;without multiple lentigines&#41; and neurofibromatosis type 1&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">12</span></a> Lentigines and deafness are not present in Noonan syndrome&#44; and caf&#233; au lait macules and hypertrophic myocardiopathy are more typical of NSML than of Noonan syndrome&#46;<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">4&#44;13</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">In conclusion&#44; the 2 cases we report show that NSML cannot be ruled out when deafness and cardiopathy are absent&#46; Genetic testing of these patients is highly advisable&#44; because the findings provide a basis for guiding follow-up and establishing prognosis&#46; However&#44; regardless of which exon is mutated&#44; all patients with NSML should receive periodic evaluations to detect late development of neurologic&#44; dermatologic&#44; cardiac&#44; or hearing complications&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Conflicts of Interest</span><p id="par0045" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Ethical Disclosures</span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Protection of human and animal subjects</span><p id="par0050" class="elsevierStylePara elsevierViewall">The authors declare that no experiments were performed on humans or animals for this investigation&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Data confidentiality</span><p id="par0055" class="elsevierStylePara elsevierViewall">The authors declare that they followed their hospitals&#8217; regulations regarding the publication of patient information and that written informed consent for voluntary participation was obtained for all patients&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Right to privacy and informed consent</span><p id="par0060" class="elsevierStylePara elsevierViewall">The authors declare that no private patient data are disclosed in this article&#46;</p></span></span></span>"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">LEOPARD syndrome is an autosomal dominant disease caused by germline mutations in the <span class="elsevierStyleItalic">RAS</span>-MAPK &#40;rat sarcoma mitogen-activated protein kinase&#41; pathway&#46; LEOPARD is an acronym for the main manifestations of the syndrome&#44; namely&#44; multiple Lentigines&#44; Electrocardiographic conduction abnormalities&#44; Ocular hypertelorism&#44; Pulmonary stenosis&#44; Abnormalities of genitalia&#44; Retardation of growth&#44; and sensorineural Deafness&#46; None of these characteristic features&#44; however&#44; are pathognomonic of LEOPARD syndrome&#44; and since they are highly variable&#44; they are often not present at the time of diagnosis&#46; We describe 2 cases of LEOPARD syndrome without hearing loss or pulmonary stenosis in which diagnosis was confirmed by identification of a mutation in the <span class="elsevierStyleItalic">PTPN11</span> gene&#46; Regular monitoring is important for the early detection of complications&#44; as these can occur at any time during the course of disease&#46;</p></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">El s&#237;ndrome LEOPARD es una enfermedad autos&#243;mica dominante producida por mutaciones germinales en la v&#237;a RAS-MAPK&#46; El acr&#243;nimo agrupa las manifestaciones m&#225;s importantes de la enfermedad &#40;L<span class="elsevierStyleItalic">entiginosis</span>&#44; E<span class="elsevierStyleItalic">CG conduction anomalies</span>&#44; O<span class="elsevierStyleItalic">cular hypertelorism&#47;hypertrophic</span> O<span class="elsevierStyleItalic">bstructive cardiomyopathy</span>&#44; P<span class="elsevierStyleItalic">ulmonary stenosis</span>&#44; A<span class="elsevierStyleItalic">bnormalities of genitalia&#44; growth</span> R<span class="elsevierStyleItalic">etardation and</span> D<span class="elsevierStyleItalic">eafness</span>&#41;&#44; pero ninguna de ellas es patognom&#243;nica ni constante&#44; por lo que muchos pacientes no las presentan en el momento del diagn&#243;stico&#46; Presentamos 2 casos de s&#237;ndrome LEOPARD sin sordera ni estenosis pulmonar en los que la detecci&#243;n de la mutaci&#243;n en el gen PTPN11 permiti&#243; confirmar la enfermedad&#44; y se&#241;alamos la importancia del seguimiento continuado para la detecci&#243;n precoz de las complicaciones&#44; ya que las mismas pueden aparecer en el transcurso de la enfermedad&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Ramos-Geldres T&#44; D&#225;vila-Seijo P&#44; Duat-Rodr&#237;guez A&#44; Noguera-Morel L&#44; Ezquieta-Zubicaray B&#44; Ros&#243;n-L&#243;pez E&#44; et al&#46; S&#237;ndrome LEOPARD sin sordera ni estenosis pulmonar&#58; a prop&#243;sito de 2 casos&#46; Actas Dermosifiliogr&#46; 2015&#59;106&#58;e19&#8211;e22&#46;</p>"
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Patient 1&#46; A&#44; Facial lentigines&#46; B&#44; Hyperpigmented lesions of various sizes on the lower limbs&#59; the largest was located on the right buttock&#46;</p>"
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          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Patient 2&#46; A&#44; Pectus excavatum&#44; a skeletal abnormality that is common in patients with mutations in the <span class="elsevierStyleItalic">RAS-MAPK</span> &#40;rat sarcoma mitogen-activated protein kinase&#41; pathway&#59; hyperpigmented lenticular lesions on the trunk&#46; B&#44; Hyperpigmented macule with irregular borders along with multiple lentigines on the left side of the neck&#46;</p>"
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      "titulo" => "References"
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                  "referenciaCompleta" => "Qiu W&#44; Wang X&#44; Romanov V&#44; Hutchinson A&#44; Lin A&#44; Ruzanov M&#44; et al&#46; Structural insights into Noonan&#47;LEOPARD syndrome-related mutants of protein-tyrosine phosphatase SHP2 &#40;PTPN11&#41;&#46; BMC Struct Biol&#46; 2014&#59;14&#58;10&#46;"
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                          "etal" => false
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e- Case Report
LEOPARD Syndrome Without Hearing Loss or Pulmonary Stenosis: A Report of 2 Cases
Síndrome LEOPARD sin sordera ni estenosis pulmonar: a propósito de 2 casos
T.T. Ramos-Geldresa, P. Dávila-Seijob, A. Duat-Rodríguezc, L. Noguera-Morela, B. Ezquieta-Zubicarayd, E. Rosón-Lópeze, A. Hernández-Martína,
Corresponding author
ahernandez_hnj@yahoo.es

Corresponding author.
, A. Torrelo-Fernándeza
a Servicio de Dermatología, Hospital Infantil del Niño Jesús, Madrid, Spain
b Dermatology and Venereology Department, Umeå University Hospital, Umeå (Suecia)
c Servicio de Neurología, Hospital Infantil del Niño Jesús, Madrid, Spain
d Laboratorio de Diagnóstico Molecular, Hospital Materno Infantil, Hospital Universitario Gregorio Marañón, Madrid, Spain
e Servicio de Dermatología, Complexo Hospitalario Universitario de Santiago de Compostela, Santiago de Compostela, Spain
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Patient 1&#46; A&#44; Facial lentigines&#46; B&#44; Hyperpigmented lesions of various sizes on the lower limbs&#59; the largest was located on the right buttock&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">LEOPARD syndrome&#44; which is currently also called Noonan syndrome with multiple lentigines &#40;NSML&#41; &#40;Online Mendelian Inheritance in Man 151100&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">1</span></a> is an autosomal dominant disease of the <span class="elsevierStyleItalic">RAS</span> &#40;rat sarcoma&#41; gene signaling pathway&#46; The acronym refers to the main manifestations of the syndrome&#44; namely&#44; lentigines&#44; electrocardiographic conduction abnormalities&#44; ocular hypertelorism&#44; pulmonary stenosis&#44; abnormal genitalia&#44; retarded growth&#44; and sensorineural deafness&#46;<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">2&#44;3</span></a> These signs are not constant&#44; however&#44; and none of them are pathognomonic&#46; We report 2 genetically confirmed cases of NSML without hypertrophic cardiopathy&#44; pulmonary stenosis&#44; or deafness&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Patient 1</span><p id="par0010" class="elsevierStylePara elsevierViewall">A 6-year-old boy&#44; the firstborn of healthy nonconsanguineous parents&#44; had been followed by the neurologist since the age of 4&#46;5 years because of developmental delays&#44; including slight speech-language impairment&#46; Physical examination revealed facial dysmorphism with large&#44; prominent&#44; low-set&#44; posteriorly rotated ears&#59; widely spaced eyes&#59; and a flat nasal bridge&#46; On the back of his neck &#40;area of the cervical spine&#41;&#44; right buttock&#44; left axilla&#44; and right knee&#44; the boy also had 4 hyperpigmented macules with irregular borders measuring 5<span class="elsevierStyleHsp" style=""></span>to 15<span class="elsevierStyleHsp" style=""></span>mm in diameter&#46; Multiple lentigines 5<span class="elsevierStyleHsp" style=""></span>mm in diameter were observed on the face&#44; trunk&#44; and extremities &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; Cardiac evaluation revealed a right bundle-branch block&#46; A hearing test was normal&#46; Testing for mutations in the <span class="elsevierStyleItalic">PTPN11</span> &#40;protein tyrosine phosphatase nonreceptor 11&#41; gene demonstrated a T468M mutation &#40;p&#46;Thr468Met&#41; in exon 12&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Patient 2</span><p id="par0015" class="elsevierStylePara elsevierViewall">A 6-year-old boy born to healthy nonconsanguineous parents was being treated by a speech therapist for delayed language acquisition and difficulty with auditory discrimination of some phonemes&#46; Physical examination revealed facial dysmorphism&#44; including an inverted triangular-shaped face&#44; short neck&#44; large low-set ears&#44; orbital hypertelorism&#44; megalocornea&#44; and pectus excavatum&#46; Numerous caf&#233; au lait macules and lentigines were present on the face&#44; neck&#44; and upper trunk &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46; Hearing and cardiac evaluations were normal&#46; Genetic testing detected the R498W mutation &#40;p&#46;Arg498Trp&#41; in axon 13 of <span class="elsevierStyleItalic">PTPN11</span>&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Discussion</span><p id="par0020" class="elsevierStylePara elsevierViewall">NSML belongs to a group of neuro-cardio-fascio-cutaneous syndromes in which germline mutations in the <span class="elsevierStyleItalic">RAS-MAPK</span> &#40;mitogen-activated protein kinase&#41; pathway are present&#46; The most characteristic dermatologic findings are pigmented lesions&#44; especially lentigines&#44; which are present in 90&#37; of patients with these syndromes&#46; Manifestations may be present from birth&#44; but they usually appear when the child is around 4<span class="elsevierStyleHsp" style=""></span>or 5<span class="elsevierStyleHsp" style=""></span>years of age and may even first present in puberty&#46;<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">2&#44;4&#44;5</span></a> Caf&#233; au lait macules&#44; which are somewhat larger than lentigines&#44; can be seen in 70&#37; to 80&#37; of patients&#46; Lesions that are darker have been called black coffee macules&#46; The most common cardiac finding in NSML is hypertrophic myocardiopathy&#44; which can be fatal&#46; Cardiac valve and coronary abnormalities may also be present&#46; Pulmonary stenosis is less common than mitral valve or aortic abnormalities&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">2</span></a> Typical electrocardiographic signs are those of left or right ventricular hypertrophy&#44; right atrial enlargement&#44; and gradual development of right bundle-branch block&#46; Deafness&#44; traditionally considered highly specific to NSML&#44; only presents in 25&#37; to 30&#37; of these patients&#59; the deficit is neurosensorial&#44; may be unilateral or bilateral&#44; and is sometimes profound &#40;&#62;<span class="elsevierStyleHsp" style=""></span>95<span class="elsevierStyleHsp" style=""></span>db&#41;&#46; Although deafness is usually diagnosed in childhood&#44; it may develop later&#44; making periodic hearing tests advisable&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">4</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Other manifestations include distinctive facial features&#59; skeletal abnormalities such as pectus carinatum or excavatum&#44; which are seen in up to 75&#37; of neonates&#59; delayed puberty and late menarche&#59; and urogenital abnormalities such as horseshoe-shaped kidney and hypospadia&#44; underdeveloped ovaries or testicles&#44; and small penis&#46;<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">2&#44;4</span></a> The slow growth observed in 25&#37; of patients does not appear to be related to endocrine dysregulation or systemic disease&#46; Eighty-five percent of patients will remain in the lower 25th percentile on growth charts&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">2</span></a> Unlike other <span class="elsevierStyleItalic">RAS</span>opathies&#44; NSML seems to confer only minimal predisposition to cancer&#44; but blood tumors<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">6</span></a> and other malignancies&#44; such as melanomas<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">7&#44;8</span></a> have been reported&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">Genetic testing is necessary for a definitive diagnosis&#46; Mutations in exons 7&#44; 12&#44; and 13 in the PTP domain of the <span class="elsevierStyleItalic">PTPN11</span> oncogene that encodes the SHP-2 phosphatase have been demonstrated in 85&#37; to 90&#37; of patients with NSML&#46; Functional SHP2 deficiency &#40;not present in Noonan syndrome&#41; is compensated for by hypersensitivity to growth factor stimulus&#44; longer contact time at the C-terminal domain &#40;pTyr ligands&#41;&#44; and the weakening of interactions of the SH2 inhibitor with the catalytic zone&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">9</span></a> The result is functional gain&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">1</span></a> At least 11 different mutations have been described to date&#46; Among them are 2 frequently recurring ones&#8212;Y279C and T468M&#8212;that have been found in over half of patients with NSML&#46;<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">2&#44;9&#44;10</span></a> Of patients who have been found to be negative for <span class="elsevierStyleItalic">PTPN11</span> mutation&#44; a third have <span class="elsevierStyleItalic">RAF1</span> &#40;Raf-1 proto-oncogene&#44; serine&#47;threonine kinase&#41; mutations and fewer than 5&#37; have <span class="elsevierStyleItalic">BRAF</span> &#40;B-Raf&#41; mutations&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">7</span></a> There is a certain correlation between genotype and phenotype&#44; such that patients who are negative for <span class="elsevierStyleItalic">PTPN11</span> mutation tend to have a higher prevalence of cardiac conduction abnormalities&#44; left ventricular or atrial hypertrophy&#44; and a family history of sudden death&#44; whereas patients who are <span class="elsevierStyleItalic">PTPN11</span>-mutation positive &#40;exon 13&#41; have greater risk of hypertrophic myocardiopathy and severe cardiac complications&#59; mutation in exon 7 is more often associated with delayed growth and deafness&#44; and <span class="elsevierStyleItalic">BRAF</span> mutations confer greater risk of cognitive disorders&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">7</span></a><span class="elsevierStyleItalic">RAF</span> mutation may cause lentigines&#44; caf&#233; au lait macules&#44; abnormal facial features&#44; hypertrophic myocardiopathy&#44; arrhythmias&#44; and delayed puberty&#46;<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">2&#44;4</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">The main differential diagnoses are other diseases linked to the <span class="elsevierStyleItalic">RAS-MAPK</span> pathway&#44;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">11</span></a> and the strong genetic-phenotypic overlap of <span class="elsevierStyleItalic">RAS</span>opathies makes clinical diagnosis difficult&#46; NSML can be phenotypically very difficult to distinguish from Noonan syndrome itself &#40;without multiple lentigines&#41; and neurofibromatosis type 1&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">12</span></a> Lentigines and deafness are not present in Noonan syndrome&#44; and caf&#233; au lait macules and hypertrophic myocardiopathy are more typical of NSML than of Noonan syndrome&#46;<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">4&#44;13</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">In conclusion&#44; the 2 cases we report show that NSML cannot be ruled out when deafness and cardiopathy are absent&#46; Genetic testing of these patients is highly advisable&#44; because the findings provide a basis for guiding follow-up and establishing prognosis&#46; However&#44; regardless of which exon is mutated&#44; all patients with NSML should receive periodic evaluations to detect late development of neurologic&#44; dermatologic&#44; cardiac&#44; or hearing complications&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Conflicts of Interest</span><p id="par0045" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Ethical Disclosures</span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Protection of human and animal subjects</span><p id="par0050" class="elsevierStylePara elsevierViewall">The authors declare that no experiments were performed on humans or animals for this investigation&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Data confidentiality</span><p id="par0055" class="elsevierStylePara elsevierViewall">The authors declare that they followed their hospitals&#8217; regulations regarding the publication of patient information and that written informed consent for voluntary participation was obtained for all patients&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Right to privacy and informed consent</span><p id="par0060" class="elsevierStylePara elsevierViewall">The authors declare that no private patient data are disclosed in this article&#46;</p></span></span></span>"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">LEOPARD syndrome is an autosomal dominant disease caused by germline mutations in the <span class="elsevierStyleItalic">RAS</span>-MAPK &#40;rat sarcoma mitogen-activated protein kinase&#41; pathway&#46; LEOPARD is an acronym for the main manifestations of the syndrome&#44; namely&#44; multiple Lentigines&#44; Electrocardiographic conduction abnormalities&#44; Ocular hypertelorism&#44; Pulmonary stenosis&#44; Abnormalities of genitalia&#44; Retardation of growth&#44; and sensorineural Deafness&#46; None of these characteristic features&#44; however&#44; are pathognomonic of LEOPARD syndrome&#44; and since they are highly variable&#44; they are often not present at the time of diagnosis&#46; We describe 2 cases of LEOPARD syndrome without hearing loss or pulmonary stenosis in which diagnosis was confirmed by identification of a mutation in the <span class="elsevierStyleItalic">PTPN11</span> gene&#46; Regular monitoring is important for the early detection of complications&#44; as these can occur at any time during the course of disease&#46;</p></span>"
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        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">El s&#237;ndrome LEOPARD es una enfermedad autos&#243;mica dominante producida por mutaciones germinales en la v&#237;a RAS-MAPK&#46; El acr&#243;nimo agrupa las manifestaciones m&#225;s importantes de la enfermedad &#40;L<span class="elsevierStyleItalic">entiginosis</span>&#44; E<span class="elsevierStyleItalic">CG conduction anomalies</span>&#44; O<span class="elsevierStyleItalic">cular hypertelorism&#47;hypertrophic</span> O<span class="elsevierStyleItalic">bstructive cardiomyopathy</span>&#44; P<span class="elsevierStyleItalic">ulmonary stenosis</span>&#44; A<span class="elsevierStyleItalic">bnormalities of genitalia&#44; growth</span> R<span class="elsevierStyleItalic">etardation and</span> D<span class="elsevierStyleItalic">eafness</span>&#41;&#44; pero ninguna de ellas es patognom&#243;nica ni constante&#44; por lo que muchos pacientes no las presentan en el momento del diagn&#243;stico&#46; Presentamos 2 casos de s&#237;ndrome LEOPARD sin sordera ni estenosis pulmonar en los que la detecci&#243;n de la mutaci&#243;n en el gen PTPN11 permiti&#243; confirmar la enfermedad&#44; y se&#241;alamos la importancia del seguimiento continuado para la detecci&#243;n precoz de las complicaciones&#44; ya que las mismas pueden aparecer en el transcurso de la enfermedad&#46;</p></span>"
      ]
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      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Ramos-Geldres T&#44; D&#225;vila-Seijo P&#44; Duat-Rodr&#237;guez A&#44; Noguera-Morel L&#44; Ezquieta-Zubicaray B&#44; Ros&#243;n-L&#243;pez E&#44; et al&#46; S&#237;ndrome LEOPARD sin sordera ni estenosis pulmonar&#58; a prop&#243;sito de 2 casos&#46; Actas Dermosifiliogr&#46; 2015&#59;106&#58;e19&#8211;e22&#46;</p>"
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Patient 1&#46; A&#44; Facial lentigines&#46; B&#44; Hyperpigmented lesions of various sizes on the lower limbs&#59; the largest was located on the right buttock&#46;</p>"
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        "etiqueta" => "Figure 2"
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          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Patient 2&#46; A&#44; Pectus excavatum&#44; a skeletal abnormality that is common in patients with mutations in the <span class="elsevierStyleItalic">RAS-MAPK</span> &#40;rat sarcoma mitogen-activated protein kinase&#41; pathway&#59; hyperpigmented lenticular lesions on the trunk&#46; B&#44; Hyperpigmented macule with irregular borders along with multiple lentigines on the left side of the neck&#46;</p>"
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                          "etal" => false
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                        0 => array:2 [
                          "etal" => true
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Article information
ISSN: 15782190
Original language: English
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2015 October 1 0 1
2015 September 0 1 1
2015 August 0 2 2
2015 July 3 5 8
2015 June 2 6 8
2015 May 7 4 11
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Idiomas
Actas Dermo-Sifiliográficas
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¿Es usted profesional sanitario apto para prescribir o dispensar medicamentos?

Are you a health professional able to prescribe or dispense drugs?