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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Central diabetes insipidus &#40;CDI&#41; is a rare entity in the paediatric age group&#44; with an annual incidence of 4 patients per 100<span class="elsevierStyleHsp" style=""></span>000 individuals&#46;<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">1&#44;2</span></a> It is due to the deficient secretion or release of antidiuretic hormone &#40;ADH&#41;&#44; also known as vasopressin&#44; and polyuria and polydipsia are the most frequent presenting symptoms at the time of diagnosis&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">3</span></a> It needs to be differentiated from nephrogenic diabetes insipidus&#44; due to resistance of the kidneys to ADH&#44; and from primary polyuria due to excessive fluid intake&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">The aetiology of CDI in the paediatric population is heterogeneous and includes forms secondary to central nervous system tumours &#40;germinoma or craniopharyngioma&#44; among others&#41;&#44; cranial malformations&#44; neurosurgery&#44; head trauma&#44; autoimmune hypophysitis or diseases that cause infiltration in the hypothalamic-pituitary region &#40;neoplasia&#44; sarcoidosis or histiocytosis&#41;&#46; Genetic aetiologies are infrequent &#40;genetic defects in ADH synthesis&#8212;mutation in the <span class="elsevierStyleItalic">AVP</span> gene&#8212;that may have an autosomal recessive&#44; autosomal dominant or X-linked pattern of inheritance&#41;&#46; Nephrogenic diabetes insipidus is a disorder with X-linked inheritance caused by mutations in the arginine vasopressin receptor 2 gene &#40;<span class="elsevierStyleItalic">AVPR2</span>&#41; or with autosomal or recessive inheritance cause by mutations in the aquaporin 2 gene &#40;AQP2&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">1</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">All patients given a diagnosis of CDI should undergo a magnetic resonance imaging &#40;MRI&#41; examination to confirm the diagnosis &#40;absence of the bright spot corresponding to the posterior pituitary in T1-weighted images&#41; and perhaps even determine its aetiology&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">4</span></a> The presence of a thickened pituitary stalk at diagnosis of diabetes insipidus or during the follow-up is suggestive&#44; although no pathognomonic&#44; of pituitary infiltration associated with a tumour&#46; At any rate&#44; a variable percentage of CDI cases&#44; which depending on the case series varies between 20&#37; and 50&#37;&#44; with or without pituitary stalk thickening&#44; are considered idiopathic &#40;ICDI&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0150"><span class="elsevierStyleSup">5&#44;6</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">The aim of our study was to analyse the clinical characteristics and outcomes of a group of patients given a diagnosis of CDI during childhood or adolescence&#44; and to evaluate the association between pituitary stalk thickening and a neoplastic aetiology and the presence of other hormone deficiencies&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070"><span class="elsevierStyleItalic">Sample &#44; Clinical and auxological evalutation etc&#46;</span></span><p id="par0025" class="elsevierStylePara elsevierViewall">&#8226; <span class="elsevierStyleItalic">Sample&#46;</span> We performed a retrospective review of the cases of 15 patients given a diagnosis of CDI between 2003 and 2016 managed at a children&#39;s hospital&#46; The diagnosis of CDI was based on a positive personal history of polyuria and polydipsia and the results of the water deprivation test&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">7</span></a> To determine the central aetiology of the diabetes&#44; patients underwent a desmopressin test &#40;DDAVP&#59; 0&#46;1<span class="elsevierStyleHsp" style=""></span>IU&#47;kg delivered intravenously&#41;&#44; and CDI was considered confirmed in case of a 50&#37; increase in urine osmolality relative to baseline&#46; In patients what presented with a plasma osmolality greater than 295<span class="elsevierStyleHsp" style=""></span>mOsm&#47;kg and a plasma sodium level greater than 145<span class="elsevierStyleHsp" style=""></span>mEq&#47;L&#44; the water deprivation test was not performed and was replaced by direct administration of vasopressin&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">&#8226; <span class="elsevierStyleItalic">Clinical and auxological evaluation</span>&#46; We retrieved data on the symptoms&#44; anthropometric measurements and Tanner stage of pubertal development recorded at diagnosis and every 6 months during the follow-up&#46;<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">8&#44;9</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">&#8226; <span class="elsevierStyleItalic">Pituitary function&#46;</span> Every year&#44; serum levels of insulin-like growth factor-1 &#40;IGF-1&#41; and insulin-like growth factor binding protein-3 &#40;IGFBP-3&#41; were measured as indirect markers of growth hormone &#40;GH&#41; deficiency&#46; Also&#44; serum levels of thyroid-stimulating hormone &#40;TSH&#41;&#44; free T4 and cortisol and the serum testosterone&#47;estradiol ratio were measured every 6 months&#46; When considered necessary to diagnose a potential deficiency&#44; patients underwent a growth hormone stimulation test &#40;clonidine stimulation test and insulin-induced hypoglycaemia test&#41;&#44; gonadotropin stimulation test &#40;luteinising hormone-releasing hormone &#91;LHRH&#93; test&#41; and adrenocorticotropin &#40;ACTH&#41; stimulation test&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">- Thyroid-stimulating hormone deficiency was defined as a decreased free T4 level &#40;&#60;0&#46;65<span class="elsevierStyleHsp" style=""></span>ng&#47;dL&#41; accompanied by decreased levels of TSH or a normal TSH value inconsistent with the level of free T4&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">- Adrenocorticotropin deficiency was diagnosed in patients with basal serum cortisol levels &#40;8 <span class="elsevierStyleSmallCaps">am</span>&#41; of less than 8<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;dL and a peak cortisol level of less than 18<span class="elsevierStyleHsp" style=""></span>pg&#47;mL in the ACTH stimulation test&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">- Gonadotropin deficiency was suspected in male patients with a testicular volume of less than 4<span class="elsevierStyleHsp" style=""></span>mL at age 14 years and female patients that had not exhibited thelarche by age 13 years&#46; When serum levels of sex steroids were in the prepubertal range in these patients&#44; a LHRH stimulation test was performed to confirm the diagnosis of gonadotropin deficiency due to an absent or insufficient response of luteinising hormone &#40;LH&#41; and follicle-stimulating hormone &#40;FSH&#41;&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">&#8226; <span class="elsevierStyleItalic">Neuroimaging&#46;</span> The neuroimaging evaluation consisted of a cranial MRI scan following the routine protocol &#40;T1-weighted sagittal view&#44; FLAIR axial view&#44; T2-weighted coronal view and diffusion-weighted imaging&#41; and a specific study of the pituitary region &#40;T1- and T2-weighted sagittal views&#44; T1-weighted coronal view and&#44; following administration of intravenous paramagnetic contrast&#44; post-contrast T1-weighted sagittal and coronal views&#41;&#46; The same protocol was applied when MRI was required during the follow-up&#46; Two neuroradiologists measured the thickness of the proximal pituitary stalk independently&#44; with diameters of less than 3<span class="elsevierStyleHsp" style=""></span>mm considered normal&#46; Pituitary stalk thickening was classified as mild &#40;3&#8211;3&#46;9<span class="elsevierStyleHsp" style=""></span>mm&#41;&#44; moderate &#40;4&#8211;6&#46;5<span class="elsevierStyleHsp" style=""></span>mm&#41; or severe &#40;&#62;6&#46;5<span class="elsevierStyleHsp" style=""></span>mm&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">2</span></a> In patients in whom it had not been possible to establish the aetiology of the diabetes in the initial evaluation&#44; the follow-up included performance of a cranial MRI scan every 6&#8211;12 months&#46; Patients that received a diagnosis of neoplasm or histiocytosis underwent follow-up MRI examinations in adherence to the oncology protocol applicable to each case&#46;</p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075"><span class="elsevierStyleBold">Other tests</span></span><p id="par0060" class="elsevierStylePara elsevierViewall">- In patients with suspected germinoma&#44; measurement of levels of &#945;-fetoprotein &#40;AFP&#41; and the &#223; fraction of human chorionic gonadotropin &#40;&#946;-HCG&#41; in plasma and cerebrospinal fluid &#40;CSF&#41;&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">- Histopathological examination of skin lesions and transsphenoidal biopsies of pituitary masses&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Statistical analysis&#46;</span> We performed the analyses with the software SPSS version 20&#46; We compared categorical variables by means of the Fisher exact test and evaluated the linear association between pairs of ordinal quantitative variables by means of the Spearman correlation coefficient&#46; We defined statistical significance as a <span class="elsevierStyleItalic">P</span>-value of less than &#46;05&#46;</p></span></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Results</span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Patients</span><p id="par0075" class="elsevierStylePara elsevierViewall">The study included 15 patients with a mean age at diagnosis of 9&#46;6 years &#40;range&#44; 1&#46;3&#8211;15&#46;9 years&#41;&#46; The sex distribution was 66&#46;7&#37; female and 33&#46;3&#37; male&#46; All patients presented with polyuria and polydipsia&#44; and the mean time elapsed from onset of symptoms to the diagnosis of CDI was 3 months &#40;range&#44; 7&#8211;32 months&#41;&#46; Furthermore&#44; 53&#37; presented associated symptoms&#58; headache with amblyopia in 26&#46;6&#37; &#40;cases 10&#44; 12&#44; 14 and 15&#59; <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41; and a decreased growth velocity in 26&#46;6&#37; &#40;cases 7&#44; 9&#44; 11 and 13&#41;&#46; All of them received a diagnosis of germinoma&#44; and the ophthalmologic manifestations were due to refractive errors&#44; with normal findings in the visual field test in all cases&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0080" class="elsevierStylePara elsevierViewall">The median duration of follow-up of the patients was 5&#46;5 years &#40;range&#44; 1&#46;6&#8211;11&#46;8 years&#41;&#46; As of this writing&#44; 6 patients &#40;40&#37;&#41; remain in follow-up&#44; with a mean age of 17&#46;6<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;78 years&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Neuroimaging</span><p id="par0085" class="elsevierStylePara elsevierViewall">In the initial MRI evaluation&#44; 9 of the 15 patients presented with a thickened pituitary stalk with diameters ranging from 3 to 30<span class="elsevierStyleHsp" style=""></span>mm &#40;mild in 2&#44; moderate in 2 and severe in 5&#41;&#46; The final diagnosis in these 9 patients was germinoma in 7 and histiocytosis in 2 &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; The bright spot corresponding to the posterior pituitary gland was missing in all patients in the initial MRI evaluation&#46; Patients 1 and 2 had received a Langerhans cell histiocytosis &#40;LCH&#41; diagnosis based on the histopathological examination of samples of skin lesions that were the initial presenting symptom in both cases at ages 2&#46;2 and 1&#46;6 years&#46; After 4 and 9 years of follow-up&#44; respectively&#44; they developed symptoms compatible with CDI&#46; The MRI evaluation of 4 and the 7 patients with a diagnosis of germinoma revealed a pineal gland cyst&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0090" class="elsevierStylePara elsevierViewall">In 5 of the 6 patients that did not have a thickened pituitary stalk at diagnosis&#44; follow-up MRI examinations revealed thickening&#46; The final diagnoses in these patients were germinoma &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#41;&#44; histiocytosis &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#41; and ICDI &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#41;&#44; with a mean delay of 1&#46;6<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;5 years from the initial MRI examination&#46; Patient 6 received a diagnosis of ICDI at age 1&#46;3 years&#44; with normal MRI findings at diagnosis&#46; After 1&#46;2 years of follow-up&#44; imaging revealed thickening of the pituitary stalk coinciding the development of skin lesions&#59; the histopathological examination of biopsy specimens of these lesions led to the diagnosis of histiocytosis&#46; <a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a> shows the progressive thickening of the pituitary stalk in one of the patients that had received an initial diagnosis of ICDI&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0095" class="elsevierStylePara elsevierViewall">The thickening developed by patients 3 and 4 &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#44; who received a diagnosis of ICDI&#44; was mild and resolved spontaneously in approximately 1 year&#46; Patient 5 &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#44; with a diagnosis of ICDI&#44; remained in follow-up for 6&#46;8 years until age 17 years&#44; with no evidence of pituitary stalk thickening at any point&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">At the end of follow-up&#44; the aetiological diagnoses were the following&#58; germinoma in 9 patients &#40;60&#37;&#41;&#44; LCH in 3 &#40;20&#37;&#41; and ICDI in 3 &#40;20&#37;&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; We found a statistically significant association between pituitary stalk thickening and confirmation of a neoplastic aetiology by the end of follow-up &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;02&#41;&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Histopathological examination</span><p id="par0105" class="elsevierStylePara elsevierViewall">A biopsy specimen was obtained from the 8 patients in whom the MRI examination revealed the presence of a suprasellar mass&#44; and the histological features were compatible with germinoma in all&#46; The remaining patient with a diagnosis of germinoma had been referred from their local hospital with a suspected diagnosis of craniopharyngioma with compatible MRI findings&#46; In our hospital&#44; they underwent a lumbar puncture&#44; and the examination of the specimen revealed atypical cells compatible with a germline tumour&#44; so&#44; foregoing a biopsy&#44; treatment was initiated following the established protocol&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">Patients 1&#44; 2 and 6 received a diagnosis of histiocytosis based on the findings of the biopsy of their skin lesions&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">A histopathological evaluation was not performed in the rest of the patients&#44; as they did not present with significant thickening of the pituitary stalk&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Abnormalities in the hypothalamic-pituitary axis</span><p id="par0120" class="elsevierStylePara elsevierViewall">All patients in the sample had an initial diagnosis of CDI and 67&#37; developed at least one pituitary hormone deficiency&#44; in most cases in the first 2 years of follow-up&#46; The most frequent deficiency was GH deficiency &#40;60&#37;&#41; followed by TSH deficiency &#40;53&#37;&#41;&#44; ACTH deficiency &#40;40&#37;&#41; and LH&#47;FSH deficiency &#40;33&#37;&#41;&#46; Only 5 patients &#40;patients 1&#44; 2&#44; 4&#44; 5 and 10&#41; had isolated ADH deficiency &#40;<a class="elsevierStyleCrossRefs" href="#tbl0005">Tables 1 and 2</a>&#41;&#46; All patients that had more than 2 pituitary hormone deficiencies developed them before receiving cancer treatment&#44; except 2&#58; patient 6 developed ACTH and GH deficiency after treatment with vinblastine&#44; and patient 11 developed TSH&#44; ACTH and GH deficiency after undergoing surgery&#44; chemotherapy per protocol and cranial irradiation &#40;54<span class="elsevierStyleHsp" style=""></span>Gy&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0125" class="elsevierStylePara elsevierViewall">The mean time elapsed from diagnosis of CDI to the development of additional hormone deficiencies was 0&#46;43 years &#40;range&#44; 0&#8211;2&#46;3&#41; for TSH &#40;8 patients&#41;&#59; 0&#46;46 years &#40;range&#44; 0&#8211;7&#46;6&#41; for GH &#40;9 patients&#41; and 0&#46;92 years &#40;range&#44; 0&#8211;2&#46;3&#41; for ACTH &#40;6 patients&#41;&#46; Four out of 14 patients &#40;28&#46;5&#37;&#44; 2 female and 2 male&#41; developed gonadotropin deficiency &#40;LH&#47;FSH&#41;&#46; In patient 7&#44; it was not possible to assess a probable LH&#47;FSH deficiency because the patient was in the prepubertal stage at the time of the study&#46; <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> presents the order in which hormone deficiencies developed in each patient&#44; and <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> the association between the type of thickening and the type and number of deficiencies&#46; We found a positive linear correlation &#40;<span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;64&#41; between the number of hormone deficiencies and pituitary stalk thickening at the end of follow-up&#44; which was statistically significant &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;009&#41;&#46; However&#44; we did not find a statistically significant association between the presence of multiple hormone deficiencies &#40;CDI plus two or more pituitary hormone deficiencies&#41; and a neoplastic aetiology&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Other tests</span><p id="par0130" class="elsevierStylePara elsevierViewall">All patients given a diagnosis of germinoma &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>9&#41; exhibited elevation of AFP &#40;&#62;0&#46;4<span class="elsevierStyleHsp" style=""></span>ng&#47;mL&#41; and &#223;-HCG &#40;&#62;5<span class="elsevierStyleHsp" style=""></span>mIU&#47;mL&#41; in CSF&#46; On the other hand&#44; increased serum levels of AFP &#40;&#62;15<span class="elsevierStyleHsp" style=""></span>ng&#47;mL&#41; were only found in 1&#47;8 patients &#40;12&#46;5&#37;&#41;&#44; and elevation of serum &#946;-HCG &#40;&#62;5<span class="elsevierStyleHsp" style=""></span>mIU&#47;mL&#41; in only 2&#47;7 patients &#40;28&#46;6&#37;&#41;&#46;</p></span></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Discussion</span><p id="par0135" class="elsevierStylePara elsevierViewall">We made a retrospective review of the characteristics and clinical outcomes of the 15 patients given a diagnosis of CDI in the past 13 years in our hospital&#46; The study was particularly focused on the presence at diagnosis or subsequent development of a thickened pituitary stalk and its association with the presence or development of other pituitary hormone deficiencies&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">In our sample&#44; the time elapsed from onset of symptoms and the aetiological diagnosis of CDI was typically long&#44; of more than 2 years&#44; especially in patients with mild or no abnormal imaging findings at the time of diagnosis of CDI&#44; which can be explained by the challenges in diagnosis a disease with a slow course and localised in a hard-to-access region that has multiple functions&#44; such as the hypothalamic-pituitary region&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">Forty percent of the patients in the sample &#40;6&#8211;15&#41; received an initial diagnosis of idiopathic CDI&#59; a percentage that dropped in a relatively short period of time &#40;between 1 and 2&#46;2 years&#41; by 50&#37; to only 20&#37; of the patients&#46; This reduction over time in the proportion of cases of CDI considered idiopathic was greater compared to similar studies&#44; which have reported decreases of approximately 20&#37; &#40;18&#37;&#8211;22&#37;&#41;&#44; with a median duration of follow-up of 2&#46;3&#8211;10 years&#46;<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">6&#44;10&#44;11</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">The final proportion of ICDI &#40;20&#37; in our sample&#41; varies widely among recently published case series&#44;<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">11&#44;12</span></a> ranging between the 5&#46;7&#37; reported by Hunter et al&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">13</span></a> and the 52&#37; reported by Maghnie et al&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">14</span></a> This variability is mostly due to the heterogeneity of the follow-up protocols applied to these patients&#44; especially in relation to the interval at which follow-up MRI examinations are performed&#44; as shorter time intervals&#44; especially in the first few years after diagnosis &#40;in our hospital&#44; ever 6&#8211;12 months for at least the first 2&#8211;3 years&#41; allow the early detection of pituitary stalk thickening&#44; thus manifesting the presence of an underlying disease&#44; frequently of a neoplastic nature and potentially severe&#46;<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">15&#44;16</span></a> However&#44; the detection of pituitary stalk thickening&#44; especially if mild&#44; does not necessarily correspond to the presence of a tumour&#46; Two of our patients with suspected ICDI developed mild thickening of the stalk during the follow-up that eventually resolved spontaneously&#46; These transient thickening suggests the possibility of hypophysitis of an inflammatory and&#47;or autoimmune aetiology&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">17</span></a> There have been occasional reports of the detection of antibodies against vasopressin and other antibodies in this context whose measurement could be useful in the diagnosis of some patients&#44; but which was not performed in our sample&#46; This clinical picture is associated with a low risk of developing histiocytosis or germinoma in the future&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">18</span></a></p><p id="par0155" class="elsevierStylePara elsevierViewall">In our sample&#44; the most frequent aetiology was neoplastic&#44; identified in 60&#37; at the time of diagnosis and in 80&#37; by the end of follow-up&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">19</span></a> Early detection of thickening is essential&#44; as our case series demonstrates that the presence of a thickened pituitary stalk is associated with an increased risk of underlying tumours&#46; In the case series presented by Werny et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">6</span></a> the presence of a thickened pituitary stalk at diagnosis was significantly associated with a neoplastic aetiology&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">Germinomas amount to approximately 5&#37; of all central nervous system tumours&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">20</span></a> In our study&#44; it was the most frequent cause of CDI&#44; accounting for 60&#37; of cases&#44; although other studies with larger samples have reported lower percentages &#40;10&#37;-38&#37;&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0230"><span class="elsevierStyleSup">21&#44;22</span></a> Thickening of part or all of the pituitary stalk may be the sole presenting feature of small germinomas&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">10</span></a></p><p id="par0165" class="elsevierStylePara elsevierViewall">When it came to the patients with LCH&#44; two ouf of three had a thickened pituitary stalk at the time of diagnosis of CDI&#59; Grois et al&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">23</span></a> found this feature in the initial evaluation in 71&#37; of cases of CDI secondary to LCH&#46; This difference could be due to the small number of patients given an initial diagnosis of histiocytosis&#46; We did not find any cases of familial neurogenic diabetes insipidus or CDI of a genetic aetiology&#44; which was consistent with previous studies<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">11&#44;13</span></a>&#59; in larger studies&#44; monogenic forms account for less than 10&#37; of the total cases of CDI&#46;<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">6&#44;10&#44;14</span></a></p><p id="par0170" class="elsevierStylePara elsevierViewall">In our study&#44; the hyperintense signal characteristic of the posterior pituitary was absent in the initial MRI scan of 100&#37; patients with CDI&#44; but this was a higher percentage compared to studies with larger samples &#40;81&#37;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">6</span></a>&#8211;94&#37;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">14</span></a>&#41;&#46; Thus&#44; the presence of this bright spot does not rule out CDI&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">23</span></a></p><p id="par0175" class="elsevierStylePara elsevierViewall">The hormone evaluation revealed more than 1 deficiency in 67&#37; of our patients&#44; which was consistent with previous studies that have reported percentages of patients with more than 1 hormone deficiency ranging from 53&#46;8&#37; &#40;Liu et al&#46;&#41;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">12</span></a> to 81&#46;4&#37; &#40;Di Iorgi et al&#46;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">10</span></a> The most frequent deficiency concerned GH&#44; which was also consistent with the literature&#46;</p><p id="par0180" class="elsevierStylePara elsevierViewall">Another test that should be performed in patients with CDI of suspected neoplastic aetiology is the measurement of AFP and &#946;-HCG levels in plasma and CSF&#44; which are tumour markers&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">24</span></a> As observed in other studies&#44; most patients with germinoma had normal serum levels of AFP and &#946;-HCG with elevation in CSF&#46; The measurement of these markers in plasma show low sensivity sensitive as in CSH&#46; Thus&#44; they should be measured routinely in CSF&#44; especially considering that their elevation is highly suggestive of a germ cell tumour&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">25</span></a></p><p id="par0185" class="elsevierStylePara elsevierViewall">Based on a detailed analysis of the data in our study and a review of the literature&#44; we may conclude the following&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">&#8226;</span><p id="par0190" class="elsevierStylePara elsevierViewall">All patients with CDI require monitoring of auxologic parameters and hormone levels at least every 6 months to identify pituitary deficiencies that can develop gradually over time&#44; especially in the first 2 years following diagnosis of CDI&#44; with particular emphasis on GH deficiency on account of its high frequency&#46;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">&#8226;</span><p id="par0195" class="elsevierStylePara elsevierViewall">The follow-up of patients with ICDI should include a MRI scan every 6&#8211;12 months based on the detected hormonal abnormalities&#44; at least for the first 2&#8211;3 years after diagnosis&#44; as 50&#37; of the patients in our sample received a diagnosis of germinoma and histiocytosis in this time interval&#46;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">&#8226;</span><p id="par0200" class="elsevierStylePara elsevierViewall">The presence and degree of pituitary stalk thickening in patients with CDI could be directly correlated to the presence or future development of other hormone deficiencies&#46;</p></li></ul></p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Conflicts of interest</span><p id="par0205" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare&#46;</p></span></span>"
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              "titulo" => "Introducci&#243;n"
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          "titulo" => "Introduction"
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          "titulo" => "Sample &#44; Clinical and auxological evalutation etc&#46;"
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              "titulo" => "Patients"
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              "titulo" => "Neuroimaging"
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              "titulo" => "Histopathological examination"
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              "titulo" => "Abnormalities in the hypothalamic-pituitary axis"
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    "pdfFichero" => "main.pdf"
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    "fechaRecibido" => "2017-11-20"
    "fechaAceptado" => "2018-05-02"
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        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec1105639"
          "palabras" => array:4 [
            0 => "Central diabetes insipidus"
            1 => "Pituitary stalk"
            2 => "Germinoma"
            3 => "Histiocytosis Langerhans-cell"
          ]
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      ]
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        0 => array:4 [
          "clase" => "keyword"
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          "palabras" => array:4 [
            0 => "Diabetes ins&#237;pida central"
            1 => "Tallo hipofisario"
            2 => "Germinoma"
            3 => "Histiocitosis de c&#233;lulas de Langerhans"
          ]
        ]
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      "en" => array:3 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Background</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Central diabetes insipidus &#40;CDI&#41; is a rare disorder in children&#46; The aetiology of CDI in childhood is heterogeneous&#46; The aim of this study is to illustrate the importance of a careful clinical and neuro-radiological follow-up of the pituitary and hypothalamus region in order to identify the aetiology and the development of associated hormonal deficiencies&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Clinical and auxological variables of 15 children diagnosed with CDI were retrospectively analysed in a paediatric hospital&#46; Evaluations of adenohypophyseal function and cranial MRI were performed periodically&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">The mean age at diagnosis of CDI was 9&#46;6 years &#40;range&#58; 1&#46;32&#8211;15&#46;9&#41;&#46; The aetiological diagnosis could be established initially in 9 of the 15 patients&#44; as 7 with a germinoma and 2 with a histiocytosis&#46; After a mean follow-up of 5&#46;5 years &#40;range&#58; 1&#46;6&#8211;11&#46;8&#41;&#44; the number of idiopathic cases was reduced by half&#46; At the end of the follow-up&#44; the aetiological diagnoses were&#58; 9 germinoma &#40;60&#37;&#41;&#44; 3 histiocytosis &#40;20&#37;&#41;&#44; and 3 idiopathic CDI &#40;20&#37;&#41;&#46; There is a statistically significant association between stalk thickening and tumour aetiology&#46; At least one adenohypophyseal hormonal deficiency was found in 67&#37; of cases&#44; with the majority developing in the first two years of follow-up&#46; Growth hormone deficiency &#40;60&#37;&#41; was the most prevalent&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusion</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">The follow-up of CDI should include hormone evaluation with special attention&#44; due to its frequency&#44; to GH deficiency&#46; In addition&#44; a biannual MRI in an idiopathic CDI should be performed&#44; at least during the first 2&#8211;3 years after diagnosis&#44; as 50&#37; of them were diagnosed with a germinoma or histiocytosis during this period&#46;</p></span>"
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            "titulo" => "Background"
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            "titulo" => "Methods"
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        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Introducci&#243;n</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">La diabetes ins&#237;pida central &#40;DIC&#41; es una entidad poco frecuente en la edad pedi&#225;trica&#44; siendo su etiolog&#237;a heterog&#233;nea&#46; El objetivo de nuestro trabajo es demostrar que el seguimiento cl&#237;nico y neurorradiol&#243;gico de la regi&#243;n hipot&#225;lamo-hipofisaria&#44; puede ayudar a establecer el diagn&#243;stico etiol&#243;gico de DIC y la presencia de otros d&#233;ficits hormonales&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">M&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Se revisaron de forma retrospectiva 15 pacientes diagnosticados de DIC en un hospital pedi&#225;trico&#46; Se analizaron las caracter&#237;sticas cl&#237;nicas y auxol&#243;gicas&#59; as&#237; como la valoraci&#243;n de la funci&#243;n adenohipofisaria junto con RM craneal de manera peri&#243;dica&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">La mediana de edad al diagn&#243;stico fue de 9&#44;6 a&#241;os &#40;rango&#58; 1&#44;3-15&#44;9&#41;&#46; El diagn&#243;stico etiol&#243;gico pudo establecerse en 9 de los 15 pacientes &#40;germinomas&#58; 7 e histiocitosis&#58; 2&#41;&#46; Tras una mediana de seguimiento de 5&#44;5 a&#241;os &#40;rango&#58; 1&#44;6-11&#44;8&#41;&#44; los casos idiop&#225;ticos se redujeron a la mitad&#46; Finalmente&#44; los diagn&#243;sticos etiol&#243;gicos fueron&#58; germinoma 9 &#40;60&#37;&#41;&#44; histiocitosis 3 &#40;20&#37;&#41; y DIC idiop&#225;tica 3 &#40;20&#37;&#41;&#46; Existe una asociaci&#243;n estad&#237;sticamente significativa entre el engrosamiento del tallo y la etiolog&#237;a tumoral&#46; El 67&#37; desarroll&#243;&#44; al menos&#44; una deficiencia hormonal adenohipofisaria&#44; la mayor&#237;a en los dos primeros a&#241;os de seguimiento&#46; El d&#233;ficit m&#225;s prevalente fue el de hormona de crecimiento &#40;60&#37;&#41;&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">En todos los pacientes con DIC se deber&#225; realizar un control auxol&#243;gico y hormonal&#44; con especial atenci&#243;n&#44; por su frecuencia&#44; a la deficiencia de GH&#44; y en aquellos con DIC idiop&#225;tica se deber&#237;a incluir una RM semestral&#44; al menos durante los 2-3 primeros a&#241;os despu&#233;s del diagn&#243;stico&#44; pues en nuestro estudio el 50&#37; fueron diagnosticados de germinomas o histiocitosis en este periodo&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0030">Please cite this article as&#58; Corredor Andr&#233;s B&#44; Mu&#241;oz Calvo MT&#44; L&#243;pez Pino MA&#44; M&#225;rquez Rivera M&#44; Travieso Su&#225;rez L&#44; Pozo Rom&#225;n J&#44; et al&#46; Engrosamiento del tallo hipofisario en ni&#241;os y adolescentes con diabetes ins&#237;pida central&#58; causas y consecuencias&#46; An Pediatr &#40;Barc&#41;&#46; 2019&#59;90&#58;293&#8211;300&#46;</p>"
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          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Flow chart of patients with a diagnosis of central diabetes insipidus&#44; showing the presence of pituitary stalk thickening and its association with the aetiology of diabetes&#46; CDI&#44; central diabetes insipidus&#59; ICDI&#44; idiopathic central diabetes insipidus&#46;</p>"
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          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">&#40;A and B&#41; MRI imaging in patient with central diabetes insipidus &#40;Patient 8&#44; Table 1&#41;&#46; Post-contrast T1-weighted sagittal view&#44; with 24 months elapsed between scans&#46; &#40;A&#41; Initial MRI scan at diagnosis&#58; no abnormal findings&#44; with normal pituitary stalk&#46; &#40;B&#41; Marked thickening of pituitary stalk with nodular enhancement suggestive of neoplastic disease &#40;germinoma eventually confirmed by biopsy&#41;&#46; Absence of hyperintense spot corresponding to posterior pituitary in T1-weighted images&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Patient&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Age at diagnosis &#40;years&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Stalk in MRI &#40;thickening&#41;<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Initial diagnosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Time &#40;years&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Maximum stalk thickening&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Diagnosis at the end of follow-up&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Order of development of hormone deficiencies&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">6&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Mild &#40;3<span class="elsevierStyleHsp" style=""></span>mm&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Histiocytosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Mild &#40;3<span class="elsevierStyleHsp" style=""></span>mm&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Histiocytosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ADH&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">10&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Mild &#40;3<span class="elsevierStyleHsp" style=""></span>mm&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Histiocytosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&#46;7&#42;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Moderate &#40;5<span class="elsevierStyleHsp" style=""></span>mm&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Histiocytosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ADH&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">6&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No thickening&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Idiopathic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Mild &#40;3<span class="elsevierStyleHsp" style=""></span>mm&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Idiopathic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ADH&#44; GH&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No thickening&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Idiopathic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;9<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Mild &#40;3<span class="elsevierStyleHsp" style=""></span>mm&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Idiopathic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ADH&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No thickening&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Idiopathic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No thickening&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Idiopathic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ADH&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No thickening&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Idiopathic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;2<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Moderate &#40;6<span class="elsevierStyleHsp" style=""></span>mm&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Histiocytosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ADH&#44; TSH&#44; <span class="elsevierStyleBold">ACTH</span>&#44; <span class="elsevierStyleBold">GH</span><span class="elsevierStyleSup">c</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No thickening&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Idiopathic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&#46;2<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Moderate &#40;5<span class="elsevierStyleHsp" style=""></span>mm&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Germinoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ADH&#44; GH&#44; TSH&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">9&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No thickening&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Idiopathic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Severe &#40;10<span class="elsevierStyleHsp" style=""></span>mm&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Germinoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ADH&#44; ACTH&#44; TSH&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">15&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Moderate &#40;5<span class="elsevierStyleHsp" style=""></span>mm&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Germinoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Moderate &#40;5<span class="elsevierStyleHsp" style=""></span>mm&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Germinoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ADH&#44; GH&#44; TSH&#44; FSH-LH&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">11&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Severe &#40;12<span class="elsevierStyleHsp" style=""></span>mm&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Germinoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Severe &#40;12<span class="elsevierStyleHsp" style=""></span>mm&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Germinoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ADH&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">8&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Severe &#40;30<span class="elsevierStyleHsp" style=""></span>mm&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Germinoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Severe &#40;30<span class="elsevierStyleHsp" style=""></span>mm&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Germinoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ADH&#44; <span class="elsevierStyleBold">TSH</span>&#44; <span class="elsevierStyleBold">ACTH</span>&#44; <span class="elsevierStyleBold">GH</span><span class="elsevierStyleSup">d</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">15&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Severe &#40;26<span class="elsevierStyleHsp" style=""></span>mm&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Germinoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Severe &#40;26<span class="elsevierStyleHsp" style=""></span>mm&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Germinoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ADH&#44; TSH&#44; ACTH&#44; GH&#44; LH-FSH&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">9&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Moderate &#40;4<span class="elsevierStyleHsp" style=""></span>mm&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Germinoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&#46;6&#42;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Severe &#40;8<span class="elsevierStyleHsp" style=""></span>mm&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Germinoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ADH&#44; GH&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">15&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Severe &#40;9<span class="elsevierStyleHsp" style=""></span>mm&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Germinoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Severe &#40;9<span class="elsevierStyleHsp" style=""></span>mm&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Germinoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ADH&#44; TSH&#44; GH&#44; LH-FSH&#44; ACTH&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">15&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">11&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Severe &#40;26<span class="elsevierStyleHsp" style=""></span>mm&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Germinoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Severe &#40;26<span class="elsevierStyleHsp" style=""></span>mm&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Germinoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ADH&#44; TSH&#44; ACTH&#44; LH-FSH&#44; GH&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "notaPie" => array:2 [
            0 => array:3 [
              "identificador" => "tblfn0005"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">MRI scan performed at diagnosis&#46; When present&#44; pituitary stalk thickening was classified as mild &#40;3&#8211;3&#46;9<span class="elsevierStyleHsp" style=""></span>mm&#41;&#44; moderate &#40;4&#8211;6&#46;5<span class="elsevierStyleHsp" style=""></span>mm&#41; or severe &#40;&#62;6&#46;5<span class="elsevierStyleHsp" style=""></span>mm&#41;&#46;</p>"
            ]
            1 => array:3 [
              "identificador" => "tblfn0010"
              "etiqueta" => "b"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Time elapsed from the initial MRI to detection of stalk thickening in patients that did not have thickening at diagnosis&#46;&#42;Time elapsed from the inicial MRI to the increase of stalk thickening in patients had thickening at diagnosis&#44;</p> <p class="elsevierStyleNotepara" id="npar0015">The deficiencies that developed after chemotherapy &#40;vinblastine&#41;<span class="elsevierStyleSup">c</span>&#44; surgery&#44; chemotherapy per protocol and cranial irradiation &#40;54<span class="elsevierStyleHsp" style=""></span>Gy&#41;<span class="elsevierStyleSup">d</span> are presented in boldface&#46;</p> <p class="elsevierStyleNotepara" id="npar0020">ACTH&#44; adrenocorticotropin&#59; ADH&#44; antidiuretic hormone&#59; GH&#44; growth hormone&#59; LH-FSH&#44; luteinising hormone&#47;follicle stimulating hormone&#59; MRI&#44; magnetic resonance imaging&#59; TSH&#44; thyroid stimulating hormone&#46;</p>"
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Radiological characteristics of the pituitary stalk of the patients during the follow-up&#46;</p>"
        ]
      ]
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        "identificador" => "tbl0010"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
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            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:3 [
          "leyenda" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">ACTH&#44; adrenocorticotropin&#59; ADH&#44; antidiuretic hormone&#59; GH&#44; growth hormone&#59; LH-FSH&#44; luteinising hormone&#47;follicle stimulating hormone&#59; TSH&#44; thyroid stimulating hormone&#46;</p>"
          "tablatextoimagen" => array:2 [
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              "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"><th class="td-with-role" title="table-head ; entry_with_role_rowhead " align="left" valign="top" scope="col">Hormone deficiency<span class="elsevierStyleSup">a</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " colspan="4" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Maximum thickening of pituitary stalk</th><th class="td" title="table-head  " align="left" valign="top" scope="col">Total&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Type&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Absent&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Mild&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Moderate&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Severe&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">ADH&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">15&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">GH&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">9 &#40;60&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">TSH&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4 &#40;28&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4 &#40;26&#46;7&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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