Case and Research Letter
Cerebral Cavernous Malformation: When the Key to Diagnosis Is on the Skin
Cavernomatosis cerebral múltiple: cuando la clave del diagnóstico está en la piel
M.M. Escudero-Góngora
, A. Bauzá, A. Giacaman, A. Martín-Santiago
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Servicio de Dermatología, Hospital Universitario Son Espases, Palma de Mallorca, Spain
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Angioqueratoma localizado en la rodilla. 2b. Imagen dermatoscópica donde se observan lagunas vasculares y costra superficial. 2c. Imagen histológica donde se observan vasos a nivel de la dermis con trombos de fibrina acompañados de hiperplasia epidérmica (H/E, ×4). 2d. RM cerebral, corte axial T2: cavernoma cerebral.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "M.M. Escudero-Góngora, A. Bauzá, A. Giacaman, A. Martín-Santiago" "autores" => array:4 [ 0 => array:2 [ "nombre" => "M.M." "apellidos" => "Escudero-Góngora" ] 1 => array:2 [ "nombre" => "A." "apellidos" => "Bauzá" ] 2 => array:2 [ "nombre" => "A." "apellidos" => "Giacaman" ] 3 => array:2 [ "nombre" => "A." 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Escudero-Góngora, A. Bauzá, A. Giacaman, A. Martín-Santiago" "autores" => array:4 [ 0 => array:4 [ "nombre" => "M.M." "apellidos" => "Escudero-Góngora" "email" => array:1 [ 0 => "mmarescudero88@gmail.com" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:2 [ "nombre" => "A." "apellidos" => "Bauzá" ] 2 => array:2 [ "nombre" => "A." "apellidos" => "Giacaman" ] 3 => array:2 [ "nombre" => "A." "apellidos" => "Martín-Santiago" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Servicio de Dermatología, Hospital Universitario Son Espases, Palma de Mallorca, Spain" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Cavernomatosis cerebral múltiple: cuando la clave del diagnóstico está en la piel" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1535 "Ancho" => 1521 "Tamanyo" => 414530 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">A, Angiokeratoma on the knee. B, Dermoscopic image with vascular lacunae and a superficial scab. C, Histology showing vessels with fibrin thrombi in the dermis and epidermal hyperplasia. Hematoxylin and eosin, original magnification<span class="elsevierStyleHsp" style=""></span>×4. D, Axial T2-weighted cerebral magnetic resonance image: cerebral cavernous malformation.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Multiple cerebral cavernous malformations (MCCMs) is characterized by the presence of multiple vascular malformations in the central nervous system. It can also affect the retina and the skin. The disease usually presents sporadically; of the patients that present the familial form, the majority show autosomal dominant inheritance.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">1</span></a> We describe 2 families with familial MCCMs diagnosed because of skin lesions detected in 2 children of 12 and 13 years of age.</p><p id="par0010" class="elsevierStylePara elsevierViewall">Our first patient was a 12-year-old boy with no past history of interest. He was seen for asymptomatic skin lesions of vascular appearance that had been present for a year. Physical examination revealed 2 reddish papules similar to cherry angiomas on the neck and right leg (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>A), 3 reddish-pink macules with a dotted dermoscopic pattern on the trunk and left leg (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>B), an erythematous macule on the trunk, with a reticulated vascular dermoscopic pattern (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a><span class="elsevierStyleHsp" style=""></span>C), and 2 small, violaceous angiokeratoma-like papules on the trunk and left leg (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>D). The initial family history was negative, but a targeted medical history revealed the presence of cerebrovascular lesions in the maternal grandmother, diagnosed on magnetic resonance imaging (MRI) performed 5 years earlier for sudden onset hearing loss. Skin examination of the grandmother revealed multiple reddish, cherry angioma-type papules on the trunk. The medical history and physical examination of the other family members only detected 2 bluish nodular lesions suggestive of venous malformations on the right arm of the patient's mother. Given the family history, MRIs of the patient and his mother were requested, observing the presence of cerebral cavernous malformations in both of them. Genetic analysis was performed on the 3 affected family members, revealing the c.268C<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>T mutation, a substitution of arginine that gives rise to a stop codon at position 90 of exon 6 of gene <span class="elsevierStyleItalic">KRIT1 (CCM1)</span> (Molecular Genetics Laboratory, Hôpital Lariboisière, Paris, France), which confirmed the diagnosis of MCCMs.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0015" class="elsevierStylePara elsevierViewall">The second patient was a 13 year-old boy with no past history of interest. He presented a lesion that had arisen on his knee some months earlier. The clinical manifestations, dermoscopy, and histology were suggestive of angiokeratoma (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>, A-C). The medical history revealed that the father had been diagnosed with MCCMs. The patient's MRI revealed MCCMs (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>D). The genetic analysis showed a pattern of deletion of exons 1, 2, and 3 of gene <span class="elsevierStyleItalic">KRIT1 (CCM1)</span> (Genetics Department, Fundación Jiménez Díaz, Madrid, Spain).</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0020" class="elsevierStylePara elsevierViewall">MCCMs can arise sporadically (80%) or be familial (20%).<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">2</span></a> The familial form has an autosomal dominant pattern of inheritance with variable clinical penetrance. To date, 3 responsible genes have been identified—<span class="elsevierStyleItalic">CCM1 (KRIT1), CCM2 (MGC4607)</span>, and <span class="elsevierStyleItalic">CCM3 (PDCD10)</span>—with more than 100 different mutations.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">3</span></a> The <span class="elsevierStyleItalic">KRIT1</span> gene, detected in both our families, is the most common mutation in patients with skin lesions.<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">4,5</span></a> The etiology and pathogenic mechanism are unknown, although it has been observed that the 3 proteins coded by the responsible genes (<span class="elsevierStyleItalic">KRIT1</span>, <span class="elsevierStyleItalic">MGC4607</span>, and <span class="elsevierStyleItalic">PDCD10</span>) are implicated in angiogenesis and in vascular remodeling.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">6</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">In MCCMs, the cerebral lesions remain asymptomatic in up to 40% of patients.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">7</span></a> Clinical manifestations include epileptic crises, headaches, and focal neurological deficits, due either to hemorrhage or to the compression of adjacent structures. The diagnosis is based on imaging studies, preferentially MRI.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">7</span></a> No action protocols or guidelines have been drawn up to specify the monitoring and follow-up of these patients.</p><p id="par0030" class="elsevierStylePara elsevierViewall">In 2009, Sirvente et al.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">4</span></a> presented the longest series of patients with MCCMs, with 417 cases, and reported skin involvement in 9%. Those authors described 3 types of vascular skin involvement: hyperkeratotic capillary-venous malformation, which is the most common (39%) and specific; capillary malformation (34%); and venous malformation (21%). Furthermore, they described 2 types of capillary malformations: punctate capillary malformation (most common) and port wine stain capillary malformation. The majority of patients in that series presented solitary vascular skin lesions, which can make the diagnosis difficult to suspect clinically if there is no family history of the disease.</p><p id="par0035" class="elsevierStylePara elsevierViewall">In conclusion, we have presented 2 families with MCCMs and skin involvement. Our first patient had multiple and varied vascular lesions, whereas the second had a single lesion, an angiokeratoma.</p><p id="par0040" class="elsevierStylePara elsevierViewall">When these cutaneous vascular lesions are detected, especially if they are multiple or in pediatric patients, it is important to take a detailed targeted medical history to detect any history of skin or cerebral lesions in relatives and to consider to performing cerebral MRI or molecular studies. Additional studies allow central nervous system lesions to be detected early to be able to plan the therapeutic strategy and rapid intervention in patients who develop neurological symptoms.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Conflicts of Interest</span><p id="par0045" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Conflicts of Interest" ] 1 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Escudero-Góngora MM, Bauzá A, Giacaman A, Martín-Santiago A. Cavernomatosis cerebral múltiple: cuando la clave del diagnóstico está en la piel. Actas Dermosifiliogr. 2017;108:680–683.</p>" ] ] "multimedia" => array:2 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2425 "Ancho" => 2333 "Tamanyo" => 581047 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Distinct vascular lesions in our first patient. A, Cherry angioma on the right leg, with vascular lacunae and desquamating collarettes in the dermoscopic image. B, Capillary malformation on the left leg with a dotted vascular dermoscopic pattern. C, Capillary malformation with a reticulated vascular dermoscopic pattern. D, Angiokeratoma-like lesion with a dark lacuna in the dermoscopic image.</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1535 "Ancho" => 1521 "Tamanyo" => 414530 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">A, Angiokeratoma on the knee. B, Dermoscopic image with vascular lacunae and a superficial scab. C, Histology showing vessels with fibrin thrombi in the dermis and epidermal hyperplasia. Hematoxylin and eosin, original magnification<span class="elsevierStyleHsp" style=""></span>×4. D, Axial T2-weighted cerebral magnetic resonance image: cerebral cavernous malformation.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:7 [ 0 => array:3 [ "identificador" => "bib0040" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Cerebral cavernous malformations. Incidence and familial occurrence" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "D. Rigamonti" 1 => "M.N. Hadley" 2 => "B.P. Drayer" 3 => "P.C. Johnson" 4 => "K. Hoenig-Rigamonti" 5 => "J.T. Knight" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJM198808113190605" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med." 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| año/Mes | Html | Total | |
|---|---|---|---|
| 2024 Noviembre | 10 | 11 | 21 |
| 2024 Octubre | 96 | 43 | 139 |
| 2024 Septiembre | 122 | 29 | 151 |
| 2024 Agosto | 159 | 65 | 224 |
| 2024 Julio | 102 | 37 | 139 |
| 2024 Junio | 102 | 28 | 130 |
| 2024 Mayo | 95 | 38 | 133 |
| 2024 Abril | 101 | 21 | 122 |
| 2024 Marzo | 106 | 19 | 125 |
| 2024 Febrero | 124 | 37 | 161 |
| 2024 Enero | 81 | 32 | 113 |
| 2023 Diciembre | 124 | 25 | 149 |
| 2023 Noviembre | 122 | 27 | 149 |
| 2023 Octubre | 100 | 35 | 135 |
| 2023 Septiembre | 111 | 32 | 143 |
| 2023 Agosto | 91 | 17 | 108 |
| 2023 Julio | 93 | 43 | 136 |
| 2023 Junio | 100 | 37 | 137 |
| 2023 Mayo | 130 | 30 | 160 |
| 2023 Abril | 96 | 24 | 120 |
| 2023 Marzo | 100 | 30 | 130 |
| 2023 Febrero | 100 | 19 | 119 |
| 2023 Enero | 92 | 22 | 114 |
| 2022 Diciembre | 102 | 41 | 143 |
| 2022 Noviembre | 68 | 25 | 93 |
| 2022 Octubre | 54 | 23 | 77 |
| 2022 Septiembre | 60 | 38 | 98 |
| 2022 Agosto | 86 | 28 | 114 |
| 2022 Julio | 58 | 47 | 105 |
| 2022 Junio | 53 | 32 | 85 |
| 2022 Mayo | 136 | 44 | 180 |
| 2022 Abril | 110 | 50 | 160 |
| 2022 Marzo | 106 | 57 | 163 |
| 2022 Febrero | 104 | 46 | 150 |
| 2022 Enero | 112 | 52 | 164 |
| 2021 Diciembre | 75 | 61 | 136 |
| 2021 Noviembre | 94 | 44 | 138 |
| 2021 Octubre | 228 | 62 | 290 |
| 2021 Septiembre | 94 | 39 | 133 |
| 2021 Agosto | 93 | 70 | 163 |
| 2021 Julio | 105 | 28 | 133 |
| 2021 Junio | 84 | 34 | 118 |
| 2021 Mayo | 101 | 58 | 159 |
| 2021 Abril | 113 | 92 | 205 |
| 2021 Marzo | 87 | 54 | 141 |
| 2021 Febrero | 94 | 38 | 132 |
| 2021 Enero | 65 | 25 | 90 |
| 2020 Diciembre | 56 | 23 | 79 |
| 2020 Noviembre | 72 | 20 | 92 |
| 2020 Octubre | 46 | 13 | 59 |
| 2020 Septiembre | 51 | 26 | 77 |
| 2020 Agosto | 38 | 27 | 65 |
| 2020 Julio | 31 | 25 | 56 |
| 2020 Junio | 46 | 39 | 85 |
| 2020 Mayo | 41 | 28 | 69 |
| 2020 Abril | 28 | 17 | 45 |
| 2020 Marzo | 26 | 13 | 39 |
| 2020 Febrero | 2 | 0 | 2 |
| 2019 Diciembre | 4 | 0 | 4 |
| 2019 Septiembre | 10 | 2 | 12 |
| 2019 Julio | 3 | 2 | 5 |
| 2019 Mayo | 2 | 0 | 2 |
| 2019 Marzo | 2 | 0 | 2 |
| 2019 Febrero | 4 | 0 | 4 |
| 2018 Diciembre | 6 | 0 | 6 |
| 2018 Noviembre | 2 | 0 | 2 |
| 2018 Octubre | 3 | 0 | 3 |
| 2018 Septiembre | 3 | 0 | 3 |
| 2018 Mayo | 2 | 0 | 2 |
| 2018 Febrero | 35 | 7 | 42 |
| 2018 Enero | 53 | 13 | 66 |
| 2017 Diciembre | 68 | 10 | 78 |
| 2017 Noviembre | 48 | 10 | 58 |
| 2017 Octubre | 44 | 16 | 60 |
| 2017 Septiembre | 122 | 37 | 159 |
| 2017 Agosto | 15 | 13 | 28 |
| 2017 Julio | 2 | 13 | 15 |
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