Scientific Letter
Mutation in RET gene: Prophylactic thyroidectomy and postoperative follow-up
Mutación en gen RET: tiroidectomía profiláctica y valoración postoperatoria
Raquel Villamayor Martína, Andrea Bartuccia, María Teresa Muñoz Calvoa,b,c,
, Jesús Pozo Romána,b,c, Jesús Argentea,b,c
Corresponding author
a Servicio de Endocrinología, Hospital Infantil Universitario Niño Jesús, Madrid, Spain
b Departamento de Pediatría, Universidad Autónoma de Madrid, Madrid, Spain
c Centro de Investigación Biomédica en Red sobre Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
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"paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "266" "paginaFinal" => "267" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Raquel Villamayor Martín, Andrea Bartucci, María Teresa Muñoz Calvo, Jesús Pozo Román, Jesús Argente" "autores" => array:5 [ 0 => array:3 [ "nombre" => "Raquel" "apellidos" => "Villamayor Martín" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 1 => array:3 [ "nombre" => "Andrea" "apellidos" => "Bartucci" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 2 => array:4 [ "nombre" => "María Teresa" "apellidos" => "Muñoz Calvo" "email" => array:1 [ 0 => "munozmaite@yahoo.es" ] "referencia" => array:4 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] 2 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] 3 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 3 => array:3 [ "nombre" => "Jesús" "apellidos" => "Pozo Román" "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] 2 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] 4 => array:3 [ "nombre" => "Jesús" "apellidos" => "Argente" "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] 2 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Servicio de Endocrinología, Hospital Infantil Universitario Niño Jesús, Madrid, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Departamento de Pediatría, Universidad Autónoma de Madrid, Madrid, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Centro de Investigación Biomédica en Red sobre Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Mutación en gen <span class="elsevierStyleItalic">RET:</span> tiroidectomía profiláctica y valoración postoperatoria" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 942 "Ancho" => 2500 "Tamanyo" => 205378 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Chest CT images (axial and coronal views) showing a 4<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>2<span class="elsevierStyleHsp" style=""></span>mm nodule in the upper left lobe.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Medullary thyroid carcinoma (MTC) is a feature of type 2 multiple endocrine neoplasias (MEN2). Subtype A (MEN2A) is characterised by MTC, pheochromocytoma (50% of patients, usually bilateral) and occasionally parathyroid hyperplasia or adenoma (20%–30% of patients). It is a dominant autosomal hereditary disease that results from germline mutations in the <span class="elsevierStyleItalic">RET</span> proto-oncogene (10q11.2) in 98% of cases.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">1</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">We present the case of a girl aged 4 years and 10 months referred after detection of a Cys634Arg mutation in exon 11 of the <span class="elsevierStyleItalic">RET</span> proto-oncogene. The mother had received a diagnosis of MEN2A (with MTC, bilateral suprarenal pheochromocytoma and hyperparathyroidism) five years before; genetic testing was performed in family members, and was positive in our patient. The maternal uncle had died at age 27 years of thyroid carcinoma, and the maternal grandmother had died during childbirth (at age 38 years) from an unknown cause. The relevant medical history of the patient consisted in her use of hearing aids to manage sensorineural hearing loss secondary to a perinatal hypoxic–ischaemic episode.</p><p id="par0015" class="elsevierStylePara elsevierViewall">The patient underwent prophylactic total thyroidectomy at age 4 years and 11 months. During the preoperative period, thyroid function was normal, tests for antithyroglobulin and antimicrosomal antibodies were negative, levels of calcium, phosphorus, alkaline phosphatase and parathyroid hormone (PTH) were normal, and the baseline measurement of calcitonin level was high (16.4<span class="elsevierStyleHsp" style=""></span>pg/ml; normal range, 1–4.8). Urine levels of catecholamines and metanephrines and serum levels of thyroglobulin and carcinoembryonic antigen (CEA) were normal. The findings of the abdominal and thyroid ultrasound examinations were normal. Histopathological examination of thyroid tissue revealed multiple sites of medullary microcarcinoma. Immunochemical assays of neoplastic samples were positive for calcitonin, chromogranin and CEA. The Ki-67 proliferation index was less than 1%, and indicated a benign course.</p><p id="par0020" class="elsevierStylePara elsevierViewall">During the postoperative period, the patient had no disturbances of calcium-phosphate metabolism and her calcitonin levels normalised (1.4<span class="elsevierStyleHsp" style=""></span>pg/ml; normal range, 1–4.8), and hormone replacement therapy was initiated with L-thyroxin. The CT scan of the chest and abdomen performed after surgery as part of the staging workup detected a 4<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>2<span class="elsevierStyleHsp" style=""></span>mm nodule in the upper lobe of the left lung (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). Such a finding in the context of MTC associated with a <span class="elsevierStyleItalic">RET</span> mutation, considered to carry high risk, led to suspecting a metastatic lesion as a the most likely possibility, and the patient underwent resection of the lesion guided by CT. The histopathological examination of the lesion revealed that it was a necrotising epithelioid granuloma. This led to the diagnosis of pulmonary tuberculosis, confirmed by a positive Mantoux test (20<span class="elsevierStyleHsp" style=""></span>mm) and testing of gastric lavage and coughed-up sputum specimens. Treatment with isoniazid, pyrazinamide and rifampicin was initiated. In addition, the father was identified as the index case with active pulmonary tuberculosis, and was also prescribed an antituberculosis regimen.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0025" class="elsevierStylePara elsevierViewall">At the time of this writing, the patient remains asymptomatic and receives hormone replacement therapy with levothyroxine at a dose of 150<span class="elsevierStyleHsp" style=""></span>μg/day. Serum levels of calcitonin, metanephrines and CEA are normal.</p><p id="par0030" class="elsevierStylePara elsevierViewall">The presence of an index case of MTC calls for genetic testing of family members. Prophylactic thyroidectomy is the only curative treatment, and the decision to operate is based on the type of mutation (<span class="elsevierStyleItalic">RET</span> genotype),<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">1,2</span></a> as there is a 100% correlation between the presence of disease and mutation carrier status.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">3</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">The Cys634Arg mutation in exon 11 of the <span class="elsevierStyleItalic">RET</span> proto-oncogene found in our patient and her mother is considered high-risk, and is an indication for total thyroidectomy as soon as possible after diagnosis, preferably before age 4 years.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">2</span></a> Prior to surgery, patients must undergo an evaluation to rule out the presence of pheochromocytoma (yearly measurement of metanephrines in serum and urine) and hyperparathyroidism (calcium PTH levels), starting at age 10 years and, in carriers of the 634 mutation, from the time of diagnosis.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">4</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">The postoperative follow-up involves the periodic measurement of serum calcitonin levels accompanied by high-resolution thyroid ultrasound examination.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">4</span></a> Detectable calcitonin levels indicate the presence of distant metastases, and require performance of CT of the neck, mediastinum, lung and liver, and in case a suspicious nodule is detected, an ultrasound-guided fine needle aspiration biopsy.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">5</span></a> In our patient, a lung nodule was detected and resected under CT guidance, which examination identified as a tuberculous necrotising epithelioid cell granuloma.</p><p id="par0045" class="elsevierStylePara elsevierViewall">When patients develop isolated metastases, these should be resected, as radiotherapy and chemotherapy are used as palliative measures. Tyrosine-kinase inhibitors<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">6</span></a> have been approved by the FDA for the treatment of metastatic MTC in adults, but have not been authorised for use in the paediatric population.</p></span>" "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Villamayor Martín R, Bartucci A, Muñoz Calvo MT, Pozo Román J, Argente J. Mutación en gen <span class="elsevierStyleItalic">RET:</span> tiroidectomía profiláctica y valoración postoperatoria. An Pediatr (Barc). 2016;85:266–267.</p>" ] ] "multimedia" => array:1 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 942 "Ancho" => 2500 "Tamanyo" => 205378 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Chest CT images (axial and coronal views) showing a 4<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>2<span class="elsevierStyleHsp" style=""></span>mm nodule in the upper left lobe.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:6 [ 0 => array:3 [ "identificador" => "bib0035" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "RET gene mutations (genotype and phenotype) of multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "G.W. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 5 | 8 | 13 |
| 2024 October | 45 | 39 | 84 |
| 2024 September | 59 | 36 | 95 |
| 2024 August | 68 | 61 | 129 |
| 2024 July | 57 | 44 | 101 |
| 2024 June | 61 | 24 | 85 |
| 2024 May | 54 | 34 | 88 |
| 2024 April | 50 | 37 | 87 |
| 2024 March | 41 | 23 | 64 |
| 2024 February | 39 | 30 | 69 |
| 2024 January | 44 | 26 | 70 |
| 2023 December | 24 | 16 | 40 |
| 2023 November | 36 | 28 | 64 |
| 2023 October | 36 | 35 | 71 |
| 2023 September | 30 | 20 | 50 |
| 2023 August | 35 | 19 | 54 |
| 2023 July | 36 | 35 | 71 |
| 2023 June | 34 | 28 | 62 |
| 2023 May | 56 | 26 | 82 |
| 2023 April | 33 | 24 | 57 |
| 2023 March | 54 | 26 | 80 |
| 2023 February | 35 | 23 | 58 |
| 2023 January | 35 | 31 | 66 |
| 2022 December | 53 | 34 | 87 |
| 2022 November | 50 | 42 | 92 |
| 2022 October | 65 | 60 | 125 |
| 2022 September | 53 | 77 | 130 |
| 2022 August | 61 | 65 | 126 |
| 2022 July | 37 | 51 | 88 |
| 2022 June | 48 | 36 | 84 |
| 2022 May | 46 | 38 | 84 |
| 2022 April | 45 | 44 | 89 |
| 2022 March | 61 | 58 | 119 |
| 2022 February | 57 | 42 | 99 |
| 2022 January | 75 | 57 | 132 |
| 2021 December | 68 | 59 | 127 |
| 2021 November | 68 | 50 | 118 |
| 2021 October | 86 | 73 | 159 |
| 2021 September | 68 | 53 | 121 |
| 2021 August | 39 | 52 | 91 |
| 2021 July | 53 | 37 | 90 |
| 2021 June | 66 | 54 | 120 |
| 2021 May | 72 | 45 | 117 |
| 2021 April | 114 | 82 | 196 |
| 2021 March | 91 | 52 | 143 |
| 2021 February | 52 | 38 | 90 |
| 2021 January | 79 | 30 | 109 |
| 2020 December | 81 | 46 | 127 |
| 2020 November | 54 | 22 | 76 |
| 2020 October | 50 | 20 | 70 |
| 2020 September | 40 | 22 | 62 |
| 2020 August | 38 | 21 | 59 |
| 2020 July | 32 | 18 | 50 |
| 2020 June | 53 | 15 | 68 |
| 2020 May | 62 | 26 | 88 |
| 2020 April | 38 | 20 | 58 |
| 2020 March | 62 | 27 | 89 |
| 2020 February | 37 | 14 | 51 |
| 2020 January | 45 | 23 | 68 |
| 2019 December | 77 | 16 | 93 |
| 2019 November | 66 | 24 | 90 |
| 2019 October | 762 | 15 | 777 |
| 2019 September | 37 | 18 | 55 |
| 2019 August | 52 | 23 | 75 |
| 2019 July | 50 | 28 | 78 |
| 2019 June | 46 | 23 | 69 |
| 2019 May | 40 | 37 | 77 |
| 2019 April | 77 | 31 | 108 |
| 2019 March | 43 | 23 | 66 |
| 2019 February | 57 | 21 | 78 |
| 2019 January | 49 | 26 | 75 |
| 2018 December | 54 | 42 | 96 |
| 2018 November | 72 | 36 | 108 |
| 2018 October | 97 | 27 | 124 |
| 2018 September | 46 | 25 | 71 |
| 2018 August | 3 | 0 | 3 |
| 2018 July | 5 | 0 | 5 |
| 2018 June | 2 | 0 | 2 |
| 2018 May | 4 | 0 | 4 |
| 2018 April | 19 | 0 | 19 |
| 2018 March | 24 | 0 | 24 |
| 2018 February | 13 | 0 | 13 |
| 2018 January | 22 | 0 | 22 |
| 2017 December | 25 | 0 | 25 |
| 2017 November | 19 | 0 | 19 |
| 2017 October | 11 | 0 | 11 |
| 2017 September | 15 | 0 | 15 |
| 2017 August | 15 | 0 | 15 |
| 2017 July | 25 | 1 | 26 |
| 2017 June | 25 | 10 | 35 |
| 2017 May | 24 | 12 | 36 |
| 2017 April | 28 | 23 | 51 |
| 2017 March | 16 | 11 | 27 |
| 2017 February | 12 | 9 | 21 |
| 2017 January | 8 | 8 | 16 |
| 2016 December | 27 | 11 | 38 |
| 2016 November | 37 | 21 | 58 |
| 2016 October | 11 | 18 | 29 |
| 2016 September | 0 | 1 | 1 |
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