Case and Research Letters
Fabry Disease and the Clinical Spectrum of Angiokeratomas
Enfermedad de Fabry: espectro clínico de los angioqueratomas
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Guinovart, I. Bielsa, G. Pintos-Morell, C. Ferrándiz" "autores" => array:4 [ 0 => array:4 [ "nombre" => "R.M." "apellidos" => "Guinovart" "email" => array:1 [ 0 => "rosa_guinovart@hotmail.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">¿</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "I." "apellidos" => "Bielsa" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 2 => array:3 [ "nombre" => "G." "apellidos" => "Pintos-Morell" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 3 => array:3 [ "nombre" => "C." "apellidos" => "Ferrándiz" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Servicio de Dermatología, Hospital Universitari Germans Trias i Pujol, Badalona, Universitat Autònoma de Barcelona, Badalona, Barcelona, Spain" "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Servicio de Pediatría, Hospital Universitari Germans Trias i Pujol, Badalona, Universitat Autònoma de Barcelona, Badalona, Barcelona, Spain" "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Enfermedad de Fabry: espectro clínico de los angioqueratomas" ] ] "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" => 1747 "Ancho" => 1335 "Tamanyo" => 399512 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Angiokeratomas on the left side of the vulva (patient #2).</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">After Gaucher disease, Fabry disease is the most common storage disease caused by the progressive accumulation of glycosphingolipids in multiple organs. Clinical presentation is very varied, and furthermore, the manifestations in many of the organs affected are nonspecific.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Diagnosis is thus challenging and often delayed. The average time from onset of symptoms to a diagnosis of Fabry disease is around 10 years.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Cutaneous involvement is common and is one of the key signs that can lead a physician to suspect the disease. Skin manifestations include angiokeratomas, telangiectasias, abnormal sweating, and lymphedema. Recent studies of cutaneous involvement in Fabry disease have shown that the clinical spectrum of angiokeratomas is also varied.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> We performed a retrospective review of skin lesions in 5 patients (4 males and 1 female) with Fabry disease, with a particular focus on the clinical variants of angiokeratomas. The main clinical features are shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>. The majority of patients, including the only woman, had classic extracutaneous manifestations. The mean age at onset of angiokeratomas was 17.2 years. Patients #4 and #5 had a classic bathing trunk appearance, and patient #5 also had less hyperkeratotic vascular lesions on the palms of both hands. The other 3 patients had less characteristic angiokeratomas. Patient #1 had small, isolated lesions around the mouth and the umbilicus (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>), while patient #3 had extensive angiokeratomas distributed almost exclusively on the left side of the body. Finally, patient #2, who was heterozygous, had lesions in the form of angiokeratomas on the left side of the vulva (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>) and small isolated lesions on the anterior surface of the trunk. Just 2 of the patients had hypohidrosis. With the exception of patient #1, all the patients were receiving enzyme replacement treatment, with a mean uninterrupted treatment period of 9 years; there had been no signs of the angiokeratomas disappearing or becoming smaller or any improvements in the other skin manifestations.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0010" class="elsevierStylePara elsevierViewall">Angiokeratoma corporis diffusum is one of the 5 known types of angiokeratoma.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> It is highly characteristic of Fabry disease, but can also be seen in other lysosomal storage diseases.<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5,6</span></a> Angiokeratomas, which can appear in childhood or adulthood, develop in 66% of male patients with Fabry disease and in 36% of female patients.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> While the term <span class="elsevierStyleItalic">angiokeratoma corporis diffusum</span> suggests the presence of multiple angiokeratomas, this is not always the case. Furthermore, as seen in 3 of the 5 cases we describe, the lesions can appear in isolation or in clusters and can affect any part of the skin, mucous membranes, or genitals. Angiokeratomas classically occur in a bathing trunk distribution, referred to as such because the lesions typically affect the buttocks, the thighs, and the genitals. Of particular interest in our series was the unilateral, left-sided, distribution observed in 1 patient and the presence of small lesions in 2 patients (around the mouth and the umbilicus in one case and on the genital mucosa in the other). The detection of angiokeratomas on the genital mucosa can erroneously lead to a diagnosis of angiokeratoma of Fordyce.</p><p id="par0015" class="elsevierStylePara elsevierViewall">The diagnosis of Fabry disease in a patient with lesions in less common sites is more difficult, but physicians should maintain a high level of clinical suspicion. While manifestations of the disease generally appear after the first decade of life, with acroparesthesia, angiokeratomas, exercise intolerance, and eye and gastrointestinal disorders, the main complications appear in young adults, who develop renal, cardiac, and cerebrovascular signs and symptoms. Considering that specific treatment is available for Fabry disease, early diagnosis (often based on the detection of angiokeratomas) is important, as timely treatment can prevent the development of serious, irreversible complications. Dermatologists can play a key role in this respect.</p><p id="par0020" class="elsevierStylePara elsevierViewall">Enzyme replacement therapy (with agalsidase alpha) is the only specific treatment available for Fabry disease, and has been shown to stabilize renal function and reduce left ventricular hypertrophy.<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8–10</span></a> In our series, treatment did not improve any of the skin manifestations present before treatment initiation.</p><p id="par0025" class="elsevierStylePara elsevierViewall">In conclusion, the detection of angiokeratomas, regardless of their location or distribution, should alert the dermatologist to a possible diagnosis of Fabry disease and prompt the performance of relevant tests to confirm or rule out this serious, treatable disease. Young relatives of newly diagnosed patients should also be studied, with a particular focus on symptoms that may have been missed or interpreted incorrectly.</p></span>" "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara">Please cite this article as: Guinovart RM, et al. Enfermedad de Fabry: espectro clínico de los angioqueratomas. Actas Dermosifiliogr. 2013;104:261–3.</p>" ] ] "multimedia" => array:3 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1247 "Ancho" => 1667 "Tamanyo" => 204153 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Small lesions in the form of angiokeratomas around the umbilicus (patient #1).</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" => 1747 "Ancho" => 1335 "Tamanyo" => 399512 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Angiokeratomas on the left side of the vulva (patient #2).</p>" ] ] 2 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Abbreviations: ERT, enzyme replacement therapy; F, female; M, male.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Patient \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Sex (M/F)/Age, y \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Extracutaneous Manifestations \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Location of Angiokeratomas \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Age at Onset of Angiokeratomas, y \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Duration of ERT, y \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Other Skin Manifestations \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleBold">1</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">M/11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Exercise intoleranceCornea verticillata \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Around mouth and umbilicus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No treatment \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">None \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleBold">2</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">F/36 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">AcroparesthesiaExercise intoleranceTinnitusDiarrheaCornea verticillata \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Left lumbar region, vulva \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">25 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hypohidrosis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleBold">3</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">M/24 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">AcroparesthesiaExercise intoleranceTinnitusAbdominal painCornea verticillata \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Left body \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">None \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleBold">4</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">M/50 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Left ventricular hypertrophyProteinuriaExercise intoleranceDiarrhea \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Flank, waist, and medial aspect of thighs \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">34 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hypohidrosis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleBold">5</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">M/32 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">AcroparesthesiaVascular tortuosity in both eyes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Thighs, buttocks, genitals, and palms \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">14 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">None \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab183298.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Clinical Findings.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 14 | 15 | 29 |
| 2024 October | 157 | 57 | 214 |
| 2024 September | 194 | 57 | 251 |
| 2024 August | 238 | 70 | 308 |
| 2024 July | 218 | 72 | 290 |
| 2024 June | 178 | 54 | 232 |
| 2024 May | 152 | 58 | 210 |
| 2024 April | 128 | 26 | 154 |
| 2024 March | 134 | 60 | 194 |
| 2024 February | 116 | 48 | 164 |
| 2024 January | 102 | 54 | 156 |
| 2023 December | 103 | 35 | 138 |
| 2023 November | 110 | 40 | 150 |
| 2023 October | 123 | 41 | 164 |
| 2023 September | 105 | 35 | 140 |
| 2023 August | 62 | 23 | 85 |
| 2023 July | 84 | 54 | 138 |
| 2023 June | 90 | 41 | 131 |
| 2023 May | 90 | 40 | 130 |
| 2023 April | 78 | 33 | 111 |
| 2023 March | 45 | 51 | 96 |
| 2023 February | 46 | 30 | 76 |
| 2023 January | 49 | 47 | 96 |
| 2022 December | 63 | 52 | 115 |
| 2022 November | 31 | 42 | 73 |
| 2022 October | 56 | 30 | 86 |
| 2022 September | 39 | 50 | 89 |
| 2022 August | 40 | 41 | 81 |
| 2022 July | 44 | 43 | 87 |
| 2022 June | 41 | 33 | 74 |
| 2022 May | 55 | 46 | 101 |
| 2022 April | 104 | 46 | 150 |
| 2022 March | 84 | 65 | 149 |
| 2022 February | 54 | 29 | 83 |
| 2022 January | 59 | 36 | 95 |
| 2021 December | 49 | 54 | 103 |
| 2021 November | 61 | 46 | 107 |
| 2021 October | 66 | 66 | 132 |
| 2021 September | 57 | 50 | 107 |
| 2021 August | 33 | 29 | 62 |
| 2021 July | 43 | 54 | 97 |
| 2021 June | 45 | 46 | 91 |
| 2021 May | 37 | 35 | 72 |
| 2021 April | 79 | 65 | 144 |
| 2021 March | 68 | 27 | 95 |
| 2021 February | 67 | 22 | 89 |
| 2021 January | 39 | 23 | 62 |
| 2020 December | 38 | 16 | 54 |
| 2020 November | 35 | 11 | 46 |
| 2020 October | 44 | 14 | 58 |
| 2020 September | 54 | 9 | 63 |
| 2020 August | 32 | 23 | 55 |
| 2020 July | 28 | 20 | 48 |
| 2020 June | 48 | 26 | 74 |
| 2020 May | 29 | 22 | 51 |
| 2020 April | 30 | 30 | 60 |
| 2020 March | 28 | 18 | 46 |
| 2020 February | 6 | 11 | 17 |
| 2020 January | 0 | 14 | 14 |
| 2019 December | 0 | 7 | 7 |
| 2019 October | 0 | 1 | 1 |
| 2019 September | 1 | 3 | 4 |
| 2019 July | 0 | 2 | 2 |
| 2019 June | 0 | 21 | 21 |
| 2019 May | 4 | 37 | 41 |
| 2019 April | 0 | 18 | 18 |
| 2019 March | 0 | 14 | 14 |
| 2019 January | 1 | 1 | 2 |
| 2018 December | 0 | 2 | 2 |
| 2018 November | 1 | 1 | 2 |
| 2018 October | 1 | 2 | 3 |
| 2018 September | 4 | 4 | 8 |
| 2018 August | 0 | 13 | 13 |
| 2018 July | 0 | 8 | 8 |
| 2018 June | 0 | 11 | 11 |
| 2018 May | 0 | 13 | 13 |
| 2018 April | 0 | 8 | 8 |
| 2018 March | 1 | 10 | 11 |
| 2018 February | 40 | 11 | 51 |
| 2018 January | 67 | 13 | 80 |
| 2017 December | 89 | 12 | 101 |
| 2017 November | 57 | 10 | 67 |
| 2017 October | 70 | 20 | 90 |
| 2017 September | 50 | 64 | 114 |
| 2017 August | 48 | 17 | 65 |
| 2017 July | 28 | 41 | 69 |
| 2017 June | 53 | 25 | 78 |
| 2017 May | 42 | 26 | 68 |
| 2017 April | 41 | 29 | 70 |
| 2017 March | 32 | 24 | 56 |
| 2017 February | 40 | 17 | 57 |
| 2017 January | 40 | 24 | 64 |
| 2016 December | 65 | 8 | 73 |
| 2016 November | 81 | 7 | 88 |
| 2016 October | 117 | 22 | 139 |
| 2016 September | 101 | 18 | 119 |
| 2016 August | 90 | 4 | 94 |
| 2016 July | 58 | 8 | 66 |
| 2016 June | 8 | 13 | 21 |
| 2016 May | 4 | 6 | 10 |
| 2016 April | 6 | 8 | 14 |
| 2016 March | 3 | 1 | 4 |
| 2016 February | 4 | 8 | 12 |
| 2016 January | 9 | 1 | 10 |
| 2015 December | 7 | 0 | 7 |
| 2015 November | 8 | 2 | 10 |
| 2015 October | 4 | 2 | 6 |
| 2015 September | 5 | 1 | 6 |
| 2015 August | 8 | 0 | 8 |
| 2015 July | 69 | 110 | 179 |
| 2015 June | 61 | 12 | 73 |
| 2015 May | 88 | 11 | 99 |
| 2015 April | 102 | 28 | 130 |
| 2015 March | 38 | 2 | 40 |
| 2015 February | 33 | 12 | 45 |
| 2015 January | 41 | 11 | 52 |
| 2014 December | 51 | 4 | 55 |
| 2014 November | 25 | 3 | 28 |
| 2014 October | 42 | 6 | 48 |
| 2014 September | 46 | 4 | 50 |
| 2014 August | 46 | 5 | 51 |
| 2014 July | 38 | 7 | 45 |
| 2014 June | 67 | 5 | 72 |
| 2014 May | 54 | 11 | 65 |
| 2014 April | 51 | 5 | 56 |
| 2014 March | 51 | 12 | 63 |
| 2014 February | 46 | 12 | 58 |
| 2014 January | 61 | 6 | 67 |
| 2013 December | 59 | 12 | 71 |
| 2013 November | 60 | 9 | 69 |
| 2013 October | 448 | 7 | 455 |
| 2013 September | 951 | 5 | 956 |
| 2013 August | 781 | 4 | 785 |
| 2013 July | 140 | 6 | 146 |
| 2013 June | 2 | 8 | 10 |
| 2013 May | 4 | 5 | 9 |
| 2013 April | 5 | 6 | 11 |
Show all
