SCIENTIFIC LETTER 417 Francisco José Sebastián Cuevas * , María Isabel Lázaro Carre˜ no, Ana Barrés Fernández, Sandra Noguera Carrasco, Carlos Miguel Angelats Hospital Clínico Universitario de Valencia, Departamento de Pediatría, Universidad de Valencia, Valencia, Spain * Corresponding author. E-mail address: fran.sebastian.21@hotmail.com (F.J. Sebastián Cuevas). 14 October 2019 18 January 2020 https://doi.org/10.1016/j.anpede.2020.10.003 2341-2879/ © 2020 Published by Elsevier Espa˜ na, S.L.U. on behalf of Asociaci´ on Espa˜ nola de Pediatr´ ıa. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/). Graves disease with negative TSH receptor antibodies: a presentation of 5 cases  Enfermedad de Graves con autoanticuerpos contra el receptor de la TSH negativos: a propósito de 5 casos To the Editor: Graves disease (GD) is the leading cause of hyperthyroidism in the paediatric population. It is an autoimmune disease characterised by the production of antibodies against the thyroid stimulating hormone receptor (TSHR) and progres- sive infiltration of the thyroid by T and B lymphocytes. 1 There are 3 types of antibodies that bind TSHR, or thyroid receptor antibodies (TRAb): thyroid-stimulating antibodies (TSAb); TSH-stimulation blocking antibodies (TBAb) and so- called ‘‘neutral’’ TRAb. 1 These antibodies can be detected by immunoassays with a sensitivity of up to 98% in third- generation binding assays, 1,2 or by means of cell-based bioassays, which measure functional activity and may even be more sensitive. 1---3 The diagnosis of GD is based on the detection of lower- than-normal levels of TSH and presence of TRAb. 4 However, TRAb are not found in some patients that have clinical man- ifestations, a hormone profile and imaging features highly indicative of GD. 3 Table 1 summarises 5 paediatric cases of this clinical presentation that has yet to be thoroughly investigated and not well understood. Case 1: pubertal patient with a personal and fam- ily history of autoimmune disease presenting with clinical hyperthyroidism with low levels of TSH and levels of free thyroxine (T 4 ) in the upper limit of normal in succes- sive laboratory tests in the 2 months that followed. The  Please cite this article as: Scatti Regàs A, Pujol Borrell R, Fer- rer Costa R, Puerto Carranza E, Clemente León M. Enfermedad de Graves con autoanticuerpos contra el receptor de la TSH negativos: a propósito de 5 casos. An Pediatr (Barc). 2020;93:417---419. levels of anti-thyroid peroxidase (TPO) antibodies and anti- thyroglobulin (TG) antibodies were high, and the findings of the ultrasound examination were compatible with thy- roiditis. The disease is currently controlled with antithyroid drugs. Case 2: adolescent aged 14 years presenting with manifestations characteristic of hypothyroidism at onset: asthenia, malaise, somnolence, abdominal pain, constipa- tion and decreased appetite. The relevant findings of blood tests were a low level of TSH with an initially normal level of free T 4 , with progression within a month to a presentation more characteristic of hyperthyroidism: palpitations, agita- tion, insomnia, palpebral retraction, goitre and elevation of free T 4 . Case 3: girl aged 10 years with clinical and biochemical features compatible with hyperthyroidism. During the fol- low-up, the patient exhibited hypothyroidism at low doses of methimazole, leading to discontinuation of treatment after 1.5 years, upon which the patient relapsed and was finally treated with radioiodine. The TRAb detection tests were mildly positive using first-generation assays at 3 years from onset, and later became clearly positive with second- generation binding assays. Case 4: newborn infant that developed transient neonatal hyperthyroidism with a family history of GD in the mother, who had undergone thyroidectomy for treatment of papil- lary thyroid cancer. The results of second-generation binding assays for detection of TRAb were negative in both mother and child. Case 5: patient presenting with early-onset persistent hyperthyroidism with a family history of hyperthyroidism and negative TRAb results. The results of gene testing for TSHR-activating mutations were negative. The patient is scheduled to receive radioiodine for curative treatment. Although there are few studies in the paediatric pop- ulation, it appears that patients with hyperthyroidism compatible with GD and undetectable levels of TRAb exhibit thyrotoxicosis with milder clinical manifestations and bio- chemical abnormalities. 3 In this regard, our findings were consistent with the existing literature: none of the 5 patients had thyroid eye disease or pretibial myxoedema, and the levels of free T 4 at diagnosis were not very high.