Changes in the epidemiological profile of pituitary stalk thickening among pediatric population in Chile during COVID-19 pandemic

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Guarda, Cecilia Okuma, Maria Isabel Hernandez This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3154962/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose Pituitary stalk thickening (PST) is a rare disease affecting mainly adults. Pediatric cases are infrequent. The aim of this study is to evaluate the frequency of pediatric patients with PST during the pandemic outbreak of COVID-19 in Chile and compare it with previous data. Methods A retrospective chart review was conducted in patients with PST diagnosed during COVID-19 outbreak. Patients <18 years with pituitary stalk width of 3mm or more at pituitary insertion and/or 4mm or more at optic chiasm were included. In order to characterize and compare these cases with those already published, a review of the literature was performed. Results Nine patients were diagnosed with PST. Seven were girls. Mean age at the onset of symptoms was 10.36 years (2.4-17). Germinal cell tumors (GCT) were diagnosed in 8 patients and Langerhans cell histiocytosis in one. All patients had negative tumor markers, arginine-vasopressin deficiency (AVD) and at least one anterior pituitary hormonal deficit at diagnosis. Diagnoses were confirmed histologically in all patients, and four required a second biopsy. We found a frequency of 4 patients per year with PST due to GCT which is twice the one expected in the same population in Chile. Conclusion A surprisingly high frequency of PST presented during the COVID-19 pandemic among Chilean pediatric patients, being GCT the most frequent etiology. The reasons behind this increase in reported cases are still to be elucidated. Pituitary stalk thickening Pituitary hormones Child Pituitary stalk Germinoma Multiple anterior pituitary hormone deficiency Figures Figure 1 Introduction Pituitary stalk thickening (PST) is a rare condition in pediatric patients. There are few studies published in the pediatric population, therefore the definition is controversial and has been difficult to establish. The advances in imaging techniques and the use of magnetic resonance imaging (MRI) have provided a better understanding of the disorders affecting the pituitary stalk and are fundamental to properly characterize the stalk size and shape [ 1 ]. In adults, the size considered normal for the pituitary stalk transverse diameter are 1.91 ± 0.4 mm at pituitary insertion and 3.25 ± 0.56 mm at optic chiasm [ 2 ]. A width of more than 3 mm has been used to define PST [ 3 ]. In children there is scarce data due to lack of neuroimaging in healthy children, therefore the definition has been controversial in the past years. Recently, a consensus guideline by the UK group defined PST in children as 3 mm or more at pituitary insertion and/or 4 mm or more at the optic chiasm [ 4 ]. Patients with PST may have neuroendocrine and/or visual impairment. The most frequent clinical manifestations are anterior pituitary dysfunction, AVD, visual field deficits and signs of elevated intracranial pressure. Regarding pituitary dysfunction, the most common clinical presentation is polyuria and polydipsia [ 5 ]. AVD is very common and other anterior pituitary hormone deficits occur in half of the patients [ 2 , 6 ]. The spectrum of etiologies involved in PST is broad and can be divided in neoplastic, congenital, inflammatory/infectious or autoimmune diseases. The most common causes in pediatric patients are neoplastic, followed by congenital lesions. In regard to neoplastic etiology, the most frequent cause is GCT, followed by Langerhans cell histiocytosis (LCH) [ 7 , 8 ]. The congenital lesions most frequently described were pituitary hypoplasia and Rathke’s cleft cysts [ 7 , 8 ]. The inflammatory/infectious and autoimmune diseases in the pediatric population are extremely rare [ 2 ]. The etiological diagnosis is challenging and after a detailed history and an extensive clinical evaluation, the first line investigations include general lab workup, serum tumor markers, anterior and posterior pituitary function, optometry and imaging studies searching for lesions compatible with LCH. If the etiology remains unidentified, the second line investigations involve cerebrospinal fluid (CSF) tumor markers and whole-body imaging, especially in progressive disease. Pituitary stalk biopsy should be considered if second line investigations results are negative [ 2 ]. MRI at the moment of the diagnosis can provide additional information. Some features, such as pituitary hypoplasia, absent posterior pituitary bright spot or midline brain defects, are associated with other clinical conditions [ 9 ]. During the COVID-19 pandemic in Chile we identified an increased number of pediatric cases of PST compared to previous years. In the present study we retrospectively analyzed clinical, biochemical, radiological and histological data of pediatric patients diagnosed with PST during COVID-19 pandemic in Chile. Methods A retrospective chart review of clinical, radiological and histological data was conducted on nine patients with confirmation of PST diagnosed during COVID-19 outbreak. Data was collected from electronic records within the Instituto de Neurocirugía, Asenjo (INCA) in Santiago of Chile and from referrals from other centers. An additional active search of patients was made through consultation to neurosurgeons, oncologists and pediatric endocrinologists around the country. Due to national policies, all pediatric patients with cancer are registered in a centralized database of a national children’s antineoplastic drug program (PINDA), from which information regarding previous cases was obtained. The inclusion criteria were patients < 18 years with pituitary stalk thickening, defined by the UK consensus: 3 mm or more at pituitary insertion and/or 4 mm or more at the optic chiasm. All patients had their weight, height and BMI at presentation. The pubertal development (Tanner stage) was defined by a pediatric endocrinologist. The clinical data analyzed included symptoms of anterior and posterior pituitary deficiencies and neuro-ophthalmologic symptoms. Other symptoms described were also included. The anterior pituitary function was evaluated at the first clinical visit by measurement of serum IGF-1 levels and growth hormone (GH) stimulation test if necessary, TSH and thyroid hormone levels, ACTH and cortisol, LH/FSH, testosterone or estradiol and prolactin. The diagnosis of growth hormone deficiency (GHD) was made in patients with clinical manifestations associated with low IGF-1 levels. Two patients underwent a GH stimulation test with clonidine and GHD was defined if the peak was < 7 ug/L. The hypothalamus-pituitary-adrenal (HPA) axis insufficiency was diagnosed with the presence of low serum cortisol levels at 08 AM (< 80 nmol/L) or after low dose ACTH (1 mcg) stimulation test if the peak was < 497 nmol/L. Central hypothyroidism was diagnosed when free T4 levels were low associated with inappropriately normal or low TSH levels. The dysfunction of hypothalamus-pituitary-gonadal (HPG) axis was diagnosed in patients with failure of pubertal progression or amenorrhea with low gonadotropins levels and low estradiol or testosterone levels. Hyperprolactinemia was defined with levels above the normal reference range. The posterior pituitary function was evaluated through calculated serum osmolality (Osmp) using levels of sodium, glucose and urea. Urine osmolality (Osmu) was estimated by urine density. The diagnosis of AVD was made in patients with polydipsia and polyuria associated with Osmp > 300 mOsm/kg and OsmU < 300 mOsm/kg. Tumor markers for germ cell tumors (GCT) were measured - alpha-fetoprotein (AFP) and human chorionic gonadotropin (hCG)) in serum and cerebrospinal fluid (CSF) - in all patients. The whole cohort underwent neuro-ophthalmologic evaluation. Visual field was evaluated with Goldman campimetry. The 3T Skyra and 1.5T Philips MRI was evaluated by an expert neuroradiologist, and the anatomy of the pituitary region was described. The pituitary stalk was measured at pituitary insertion and optic chiasm level, and the maximum diameter (Dmax) was defined. The pituitary was measured, and the posterior pituitary bright spot was evaluated. Midline brain defects and optic chiasm involvement were described. The surgical protocol was analyzed, and etiological diagnosis was made by biopsy in all patients. If the patient went through more than one biopsy, all of them were included for the analysis. A review of the literature was performed in order to characterize and compare our results with those previously published. The study was approved by the Institutional Review Board and the local Ethics committee. Results Nine patients were diagnosed with PST during the pandemic period, seven girls and two boys. Mean age at diagnosis was 10.36 years (range, 2.4–17 years). Three patients presented with headache, two with poor growth, two with failure of pubertal progression, one with primary amenorrhea and one patient with visual acuity impairment. At diagnosis all patients presented with polydipsia and polyuria. Short stature or poor growth was present in 77.8% of the patients. Half of the patients had neuro-ophthalmologic symptoms (Table 1 ). One patient presented with cholestatic hepatitis as an additional feature. Table 1 Symptoms at diagnosis Number of patients (%) Short stature and/or poor growth 7 (77.8) Symptoms of hypothyroidism 3 (33.3) Asthenia 2 (22.2) Polydipsia – Polyuria 9 (100) Amenorrhea or delayed puberty 3 (33.3) Neuro-ophthalmologic symptoms 5 (55.5) The hormonal assessment proved all patients had AVD and GHD. Seven patients had central hypothyroidism, five had central adrenal insufficiency, three had hypogonadotropic hypogonadism and six had hyperprolactinemia (Table 2 ). Tumor markers were negative in all patients. Evaluation of the visual field was abnormal in five patients. Table 2 Endocrine disturbances at diagnosis Number of patients (%) AVD 9 (100) GHD 9 (100) HPT 7 (77.8) HPA 5 (55.5) HPG 3 (33.3) HPRL 6 (66.7) AVD, arginine vasopressin deficiency; GHD, growth hormone deficiency; HPT, hypothalamic pituitary thyroid axis; HPA, hypothalamic pituitary adrenal axis; HPG, hypothalamic pituitary gonadal axis; HPRL, hyperprolactinemia . At the initial MRI, the median Dmax of the pituitary stalk was 8.1 mm (range, 4.6–13 mm) and six patients had optic chiasm abnormalities due to compression. None of the patients had midline defects. Remarkably, all of them had absence of T1WI hyperintensity bright spot (Fig. 1 ). The diagnosis was made by biopsy in all patients. In one patient the biopsy was obtained from a lesion in the liver and the histological diagnosis was Langerhans cell histiocytosis (LCH). The other eight patients went through pituitary stalk biopsy. Four patients required a second biopsy to make the definitive diagnosis as the first biopsy was informed as hypophysitis. The definitive diagnosis in these eight patients was pure GCT. The clinical and radiological data were summarized in Table 3 . Table 3 Description of patients with pituitary stalk thickening N° Age at diagnosis (y) Gender D max (mm) Pituitary stalk Endocrine disturbance Neuro- opthalmologic symptoms (Y = Yes / N = No) Tumor markers in serum and CSF (hCG and AFP) Diagnosis 1 7.1 F 4.6 AVD, GHD, HPT, HPA, HPRL Y Negative Pure germinoma 2 13.9 F 7.64 AVD, GHD, HPT, HPA, HPG, HPRL Y Negative Pure germinoma 3 7.3 M 5.0 AVD, GHD, HPA, HPRL N Negative Pure germinoma 4 15.6 F 8.46 AVD, GHD, HPT, HPA, HPG, HPRL Y Negative Pure germinoma 5 8.1 F 13.0 AVD, GHD, HPT, HPRL Y Negative Pure germinoma 6 17 F 12.5 AVD, GHD, HPT, HPA, HPG Y Negative Pure germinoma 7 10.3 F 8.1 AVD, GHD, HPT N Negative Pure germinoma 8 2.4 M 10.0 AVD, GHD, HPT N Negative LCH 9 11.5 F 5.16 AVD, GHD, HPRL N Negative Pure germinoma AVD, arginine vasopressin deficiency; GHD, growth hormone deficiency; HPT, hypothalamic pituitary thyroid axis; HPA, hypothalamic pituitary adrenal axis; HPG, hypothalamic pituitary gonadal axis; HPRL, hyperprolactinemia; LCH, Langerhans cell histiocytosis . Discussion In the present study, nine pediatric patients with a thorough clinical evaluation including hormonal profile, tumor markers, neuroradiological characteristics and pathology results were diagnosed with PST during the COVID-19 pandemic period. Eight patients in our cohort were finally diagnosed with GCT. In Chile, management of neoplastic diseases in children is guaranteed by social security, which ensures access to diagnosis and treatment, and makes notification mandatory. The patients were evaluated and treated in the National children’s antineoplastic drug program (PINDA). Therefore, the national records of these patients is mandatory, leading to a precise statistical data. We observed a higher frequency in girls. Scarce data is available to compare sex-specific differences in patients with GCT and PST. Chen et al published a case series of patients with GCT with isolated pituitary stalk involvement and described eleven patients in a period of six years (2015–2021) with no significant differences in sex [ 5 ]. However, GCT are described more frequently in males than females, with a ratio of about 4 to 1 [ 10 ]. All patients were diagnosed with AVD and at least one anterior pituitary defect. In other series, up to two-thirds of the patients developed AVD and a half had one or more anterior pituitary deficiencies [ 7 , 8 , 11 ]. This higher anterior and posterior pituitary involvement can be explained due to delayed referral during the pandemic, as seen in other conditions during the outbreak of COVID-19 [ 12 ]. Regrettably, the COVID-19 pandemic has considerably changed healthcare systems and studies have shown an increase in delayed referral of brain tumors in pediatric patients during the pandemic [ 13 ]. In this study a neoplastic cause was found in all patients, being pure GCT the most frequent diagnosis. Thus, the most common causes were neoplasms, similar to previous studies [ 7 ]. Hamilton et al [ 8 ] published a case series of 65 patients with infundibular lesions, 21 were pediatric patients. They found 13 congenital lesions (all pituitary hypoplasias) and 8 tumors in children. Of the neoplastic causes, four patients had Langerhans cell histiocytosis (LCH), two patients had GCT and the other two patients had metastatic glioblastoma multiforme and primitive neuroectodermal tumor. A Mayo Clinic study published in 2013 [ 12 ], found 152 pituitary stalk lesions in a 20-year period. The causes were identified in 61% of patients and were due to neoplastic lesions in 32%, inflammatory lesions in 20% and congenital anomalies in 9% of patients. However, only 11% of the patients were younger than 21 years old. LCH was classified as an inflammatory lesion in this study, thus the neoplastic causes were even more prevalent. Zhou et al [ 7 ] described 321 patients with PST and included 91 pediatric patients (28.3%). The mean age at which PST was diagnosed in pediatric patients was 11 years. The most common causes were neoplasms, and the most frequent tumor in pediatric patients was GCT (67%), followed by LCH (19%) and craniopharyngioma (7%). They found 16 patients with congenital lesions; all were identified as Rathke's cleft cyst. Yoon et al [ 14 ] characterized 76 pediatric patients with pituitary stalk lesions. Of these patients, 68.4% had neoplasms and 21.1% had congenital lesions. Of the neoplastic lesions, intracranial GCT was the most common etiology (40.4%), followed by LCH (28.8%). Recently, Moszczyńska et al [ 15 ] reported a cohort of 23 patients with PST in Poland. The median age at diagnosis was 9.68 years. The most common cause was GCT (73.9%), followed by LCH. Polyuria and polydipsia was present in 82,6% of the patients (Table 4 ). Table 4 Review of published data on PST in pediatric patients [ 7 , 8 , 13 ] Reference Pediatric patients (number and %) Sex (% females) GCT (%) LCH (%) Others (%) Turcu et al (2013) 17 (11%) 60 6.5 7.60 85.9 Zhou et al (2019) 91 (28.3%) 55.5 29.9 20.4 49.6 Hamilton et al (2007) 21 (32.3%) Not described 6.2 6.2 87.6 Zepeda et al (2023) 9 (100%) 77.8 88.9 11.1 0 The neoplastic causes in our study are higher than published data because we included only pediatric patients . Therefore, neoplasms remain the most frequent cause of PST in pediatric patients. Hence, it is important to make a prompt diagnosis to improve the outcomes. As described by Turcu et al [ 11 ], the most frequent pattern in MRI of infundibulo-hypophyseal involvement among this cohort was uniform enhancement in V-shape and round/diamond configuration [ 11 ]. In our case series, tumor markers were negative in serum and CSF in all patients, eight of which were diagnosed with pure GCT by biopsy. Pure GCT may secrete small amounts of hCG and AFP in serum and CSF, through their syncytiotrophoblastic component [ 6 ]. Therefore, tumor markers are usually negative. The clinical diagnostic value of hCG and AFP has some pitfalls. First, the sensitivity and specificity of these markers varies depending on anatomical involvement, subtype of tumor and progression of the disease, with markedly elevated concentrations occurring in less frequent subtypes of GCT [ 16 ]. Second, not all immunoassays have been validated for use in CSF [ 17 ]. Third, the cut-off values are not well established. One study tried to determine the cut-off values that provide the best sensitivity and specificity. A combination of CSF hCG ≥ 8.2 IU/, serum hCG ≥ 2.5 UI/L, CSF AFP ≥ 3.8 ng/mL and serum AFP ≥ 25 ng/mL increased total diagnostic sensitivity to 65.4% [ 18 ]. Because of these limitations, new tumor markers are under investigation and microRNAs have shown promising results in recent publications [ 19 ]. All patients in this cohort underwent transsphenoidal biopsy because they met criteria defined by UK consensus [ 4 ]. All of them had a progressive PST with visual and/or pituitary involvement with negative first and second line investigations. However, the etiological diagnosis still remains challenging, as 44.4% of the patients in this case series required a second biopsy due to a pathological diagnosis of hypophysitis, which is an extremely rare cause in pediatric patients. In patients with GCT there is an immune response to the tumor, which generates an inflammatory peritumoral reaction that can be misdiagnosed as hypophysitis [ 20 ]. In these four cases, final diagnosis after a second biopsy was GCT. Interestingly, one patient was first diagnosed as LCH by clinical and neuroimaging findings, but developed progressive enlargement of pituitary stalk despite treatment and finally required biopsy of pituitary stalk which was consistent with GCT. The estimated frequency based on national statistics is 2 patients with GCT with pituitary stalk involvement per year. The frequency of PST due to GCT in pediatric patients observed during the COVID-19 pandemic period was 4 patients per year. Thus, during the pandemic of COVID-19 the frequency of patients with GCT has doubled. All patients went through a PCR test for COVID-19 before surgery and all tested negative. However, it was not investigated if they previously had SARS-CoV2 infection. The reason for this increase in frequency remains inconclusive. Many reasons might be associated, like delayed diagnosis, increased interest in reporting infrequent manifestations of central nervous neoplasms or lack of specific studies, but there are also potential carcinogenic characteristics of SARS-CoV2 that may lead to progression of the tumor by modifying metabolic pathways of tumor cells [ 21 ]. The main strength of the present study is that this is the first report in Chile and in Latin America of pediatric patients with PST, with a thorough clinical, endocrinological, radiological and histological description. Nevertheless, it also has limitations, as there are some cases that may have been missed due to under-report of other non-neoplastic causes in smaller centers. However, this case series raises awareness of this infrequent disease. Conclusions A surprisingly higher than expected frequency of PST was found during the COVID-19 pandemic among Chilean pediatric patients. The management of these patients is complex and requires adult and pediatric neuroendocrinologists, experienced neurosurgeons, neuroradiologists, neurooncologists, neuroophthalmologists and neuropathologists. Furthermore, these patients should undergo long-term follow-up, as diagnostic tests have some limitations. Thus, it is important to establish new markers and more precise diagnostic tools to assess patients with PST in order to make a prompt diagnosis and avoid unnecessary risk in our patients. Further research is needed to establish if there is a causative relationship between this high frequency of PST and the COVID-19 pandemic, especially among girls. The reasons behind this increased frequency are still under investigation and are yet to be elucidated. Declarations Acknowledgments We would like to acknowledge with gratitude to Dr. Fernando Cassorla for the generous help on review and comments, to our colleagues that contribute with their patients (José Pablo Fernandez Vergara, Fernanda Peña Manubens, Claudia Godoy Cortes, María Fernanda Ochoa Molina, David Rojas Salazar, Nimia Vallejos Carle, Javiera Basaure Orostica, Carolina Valdes Fuentealba, Vivian Gallardo Tampier, Cristian Naudy Martinez, Pablo Villanueva Garin) and to our patients and their families. Data Availability Some or all datasets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request. The authors have no fundings to declare. The authors have nothing to disclose. The study was approved by the Institutional Review Board and the local Ethics committee. References Godano E, Morana G, Di Iorgi N, et al. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3154962","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":217121955,"identity":"eca28a54-201e-4d6e-a03d-28c752b560ea","order_by":0,"name":"Diego Zepeda","email":"","orcid":"","institution":"Institute of Maternal and Chiled Research (IDIMI), Faculty of Medicine, Universidad de Chile","correspondingAuthor":false,"prefix":"","firstName":"Diego","middleName":"","lastName":"Zepeda","suffix":""},{"id":217121956,"identity":"637303b2-6bf3-42c8-99cc-0c04b0bd9121","order_by":1,"name":"Francisco J. Guarda","email":"","orcid":"","institution":"Endocrinology Department, School of Medicine, Pontificia Universidad Católica de Chile","correspondingAuthor":false,"prefix":"","firstName":"Francisco","middleName":"J.","lastName":"Guarda","suffix":""},{"id":217121957,"identity":"c1b4dec1-96ec-4554-bdcd-c68986f6730c","order_by":2,"name":"Cecilia Okuma","email":"","orcid":"","institution":"Instituto de Neurocirugía Asenjo","correspondingAuthor":false,"prefix":"","firstName":"Cecilia","middleName":"","lastName":"Okuma","suffix":""},{"id":217121958,"identity":"e66f4c50-4ead-484e-8bd4-558c320eac33","order_by":3,"name":"Maria Isabel Hernandez","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA4ElEQVRIiWNgGAWjYDACZh4o4wAD4wMgycMH4jwgUguzAUgLG4iTgNcahBY2CTBJSItuO+/Bx5U77PL4jrc/q+apuSPDxt7A+AGfFrPDfMmGZ88kF0ueOZB2m+fYMx42ngPMEvi18JhJNrYxJ264kXDsNm/DYR42iQQ2vA4DajH/2dhWn7jh/sO2YrAW+QcEtZgxNrYdBtrCzMYMsYWBoBZjoMOOJ848k8YsOecYUAtPYjN+v5w/Y/ixsa06se/48Ycf3tQctudnP3zwwwc8WrABxgYSNYyCUTAKRsEoQAcA9Q1N6sT1/goAAAAASUVORK5CYII=","orcid":"","institution":"Institute of Maternal and Chiled Research (IDIMI), Faculty of Medicine, Universidad de Chile","correspondingAuthor":true,"prefix":"","firstName":"Maria","middleName":"Isabel","lastName":"Hernandez","suffix":""}],"badges":[],"createdAt":"2023-07-10 03:14:12","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3154962/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3154962/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":39982026,"identity":"098ca8a2-3b06-48bc-849c-fbf7531fa28e","added_by":"auto","created_at":"2023-07-13 14:17:41","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":688279,"visible":true,"origin":"","legend":"\u003cp\u003eMRI of a patient with PST at pituitary insertion (A) and optic chiasm (B)\u003c/p\u003e","description":"","filename":"Fig1.png","url":"https://assets-eu.researchsquare.com/files/rs-3154962/v1/d3c6cda4e3134a40802e6fb3.png"},{"id":40530383,"identity":"131fe34a-0b16-42b7-ba95-821ab51fc620","added_by":"auto","created_at":"2023-07-25 11:37:26","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1215054,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3154962/v1/161c41fa-d279-4f75-9633-e01d73d8ccad.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Changes in the epidemiological profile of pituitary stalk thickening among pediatric population in Chile during COVID-19 pandemic","fulltext":[{"header":"Introduction","content":"\u003cp\u003ePituitary stalk thickening (PST) is a rare condition in pediatric patients. There are few studies published in the pediatric population, therefore the definition is controversial and has been difficult to establish. The advances in imaging techniques and the use of magnetic resonance imaging (MRI) have provided a better understanding of the disorders affecting the pituitary stalk and are fundamental to properly characterize the stalk size and shape [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn adults, the size considered normal for the pituitary stalk transverse diameter are 1.91\u0026thinsp;\u0026plusmn;\u0026thinsp;0.4 mm at pituitary insertion and 3.25\u0026thinsp;\u0026plusmn;\u0026thinsp;0.56 mm at optic chiasm [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. A width of more than 3 mm has been used to define PST [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. In children there is scarce data due to lack of neuroimaging in healthy children, therefore the definition has been controversial in the past years. Recently, a consensus guideline by the UK group defined PST in children as 3 mm or more at pituitary insertion and/or 4 mm or more at the optic chiasm [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePatients with PST may have neuroendocrine and/or visual impairment. The most frequent clinical manifestations are anterior pituitary dysfunction, AVD, visual field deficits and signs of elevated intracranial pressure. Regarding pituitary dysfunction, the most common clinical presentation is polyuria and polydipsia [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. AVD is very common and other anterior pituitary hormone deficits occur in half of the patients [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe spectrum of etiologies involved in PST is broad and can be divided in neoplastic, congenital, inflammatory/infectious or autoimmune diseases. The most common causes in pediatric patients are neoplastic, followed by congenital lesions. In regard to neoplastic etiology, the most frequent cause is GCT, followed by Langerhans cell histiocytosis (LCH) [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. The congenital lesions most frequently described were pituitary hypoplasia and Rathke\u0026rsquo;s cleft cysts [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. The inflammatory/infectious and autoimmune diseases in the pediatric population are extremely rare [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe etiological diagnosis is challenging and after a detailed history and an extensive clinical evaluation, the first line investigations include general lab workup, serum tumor markers, anterior and posterior pituitary function, optometry and imaging studies searching for lesions compatible with LCH. If the etiology remains unidentified, the second line investigations involve cerebrospinal fluid (CSF) tumor markers and whole-body imaging, especially in progressive disease. Pituitary stalk biopsy should be considered if second line investigations results are negative [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eMRI at the moment of the diagnosis can provide additional information. Some features, such as pituitary hypoplasia, absent posterior pituitary bright spot or midline brain defects, are associated with other clinical conditions [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eDuring the COVID-19 pandemic in Chile we identified an increased number of pediatric cases of PST compared to previous years.\u003c/p\u003e \u003cp\u003eIn the present study we retrospectively analyzed clinical, biochemical, radiological and histological data of pediatric patients diagnosed with PST during COVID-19 pandemic in Chile.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eA retrospective chart review of clinical, radiological and histological data was conducted on nine patients with confirmation of PST diagnosed during COVID-19 outbreak. Data was collected from electronic records within the Instituto de Neurocirug\u0026iacute;a, Asenjo (INCA) in Santiago of Chile and from referrals from other centers. An additional active search of patients was made through consultation to neurosurgeons, oncologists and pediatric endocrinologists around the country. Due to national policies, all pediatric patients with cancer are registered in a centralized database of a national children\u0026rsquo;s antineoplastic drug program (PINDA), from which information regarding previous cases was obtained.\u003c/p\u003e \u003cp\u003eThe inclusion criteria were patients\u0026thinsp;\u0026lt;\u0026thinsp;18 years with pituitary stalk thickening, defined by the UK consensus: 3 mm or more at pituitary insertion and/or 4 mm or more at the optic chiasm.\u003c/p\u003e \u003cp\u003eAll patients had their weight, height and BMI at presentation. The pubertal development (Tanner stage) was defined by a pediatric endocrinologist. The clinical data analyzed included symptoms of anterior and posterior pituitary deficiencies and neuro-ophthalmologic symptoms. Other symptoms described were also included.\u003c/p\u003e \u003cp\u003eThe anterior pituitary function was evaluated at the first clinical visit by measurement of serum IGF-1 levels and growth hormone (GH) stimulation test if necessary, TSH and thyroid hormone levels, ACTH and cortisol, LH/FSH, testosterone or estradiol and prolactin.\u003c/p\u003e \u003cp\u003eThe diagnosis of growth hormone deficiency (GHD) was made in patients with clinical manifestations associated with low IGF-1 levels. Two patients underwent a GH stimulation test with clonidine and GHD was defined if the peak was \u0026lt;\u0026thinsp;7 ug/L.\u003c/p\u003e \u003cp\u003eThe hypothalamus-pituitary-adrenal (HPA) axis insufficiency was diagnosed with the presence of low serum cortisol levels at 08 AM (\u0026lt;\u0026thinsp;80 nmol/L) or after low dose ACTH (1 mcg) stimulation test if the peak was \u0026lt;\u0026thinsp;497 nmol/L.\u003c/p\u003e \u003cp\u003eCentral hypothyroidism was diagnosed when free T4 levels were low associated with inappropriately normal or low TSH levels.\u003c/p\u003e \u003cp\u003eThe dysfunction of hypothalamus-pituitary-gonadal (HPG) axis was diagnosed in patients with failure of pubertal progression or amenorrhea with low gonadotropins levels and low estradiol or testosterone levels.\u003c/p\u003e \u003cp\u003eHyperprolactinemia was defined with levels above the normal reference range.\u003c/p\u003e \u003cp\u003eThe posterior pituitary function was evaluated through calculated serum osmolality (Osmp) using levels of sodium, glucose and urea. Urine osmolality (Osmu) was estimated by urine density. The diagnosis of AVD was made in patients with polydipsia and polyuria associated with Osmp\u0026thinsp;\u0026gt;\u0026thinsp;300 mOsm/kg and OsmU\u0026thinsp;\u0026lt;\u0026thinsp;300 mOsm/kg.\u003c/p\u003e \u003cp\u003eTumor markers for germ cell tumors (GCT) were measured - alpha-fetoprotein (AFP) and human chorionic gonadotropin (hCG)) in serum and cerebrospinal fluid (CSF) - in all patients. The whole cohort underwent neuro-ophthalmologic evaluation. Visual field was evaluated with Goldman campimetry. The 3T Skyra and 1.5T Philips MRI was evaluated by an expert neuroradiologist, and the anatomy of the pituitary region was described. The pituitary stalk was measured at pituitary insertion and optic chiasm level, and the maximum diameter (Dmax) was defined. The pituitary was measured, and the posterior pituitary bright spot was evaluated. Midline brain defects and optic chiasm involvement were described.\u003c/p\u003e \u003cp\u003eThe surgical protocol was analyzed, and etiological diagnosis was made by biopsy in all patients. If the patient went through more than one biopsy, all of them were included for the analysis.\u003c/p\u003e \u003cp\u003e A review of the literature was performed in order to characterize and compare our results with those previously published.\u003c/p\u003e \u003cp\u003eThe study was approved by the Institutional Review Board and the local Ethics committee.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eNine patients were diagnosed with PST during the pandemic period, seven girls and two boys. Mean age at diagnosis was 10.36 years (range, 2.4\u0026ndash;17 years). Three patients presented with headache, two with poor growth, two with failure of pubertal progression, one with primary amenorrhea and one patient with visual acuity impairment.\u003c/p\u003e \u003cp\u003eAt diagnosis all patients presented with polydipsia and polyuria. Short stature or poor growth was present in 77.8% of the patients. Half of the patients had neuro-ophthalmologic symptoms (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). One patient presented with cholestatic hepatitis as an additional feature.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSymptoms at diagnosis\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNumber of patients (%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eShort stature and/or poor growth\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (77.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSymptoms of hypothyroidism\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (33.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAsthenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (22.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePolydipsia \u0026ndash; Polyuria\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (100)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAmenorrhea or delayed puberty\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (33.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeuro-ophthalmologic symptoms\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (55.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe hormonal assessment proved all patients had AVD and GHD. Seven patients had central hypothyroidism, five had central adrenal insufficiency, three had hypogonadotropic hypogonadism and six had hyperprolactinemia (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Tumor markers were negative in all patients. Evaluation of the visual field was abnormal in five patients.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eEndocrine disturbances at diagnosis\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNumber of patients (%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAVD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (100)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGHD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (100)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHPT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (77.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHPA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (55.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHPG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (33.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHPRL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (66.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003e\u003csup\u003eAVD, arginine vasopressin deficiency; GHD, growth hormone deficiency; HPT, hypothalamic pituitary thyroid axis; HPA, hypothalamic pituitary adrenal axis; HPG, hypothalamic pituitary gonadal axis; HPRL, hyperprolactinemia\u003c/sup\u003e.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eAt the initial MRI, the median Dmax of the pituitary stalk was 8.1 mm (range, 4.6\u0026ndash;13 mm) and six patients had optic chiasm abnormalities due to compression. None of the patients had midline defects. Remarkably, all of them had absence of T1WI hyperintensity bright spot (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe diagnosis was made by biopsy in all patients. In one patient the biopsy was obtained from a lesion in the liver and the histological diagnosis was Langerhans cell histiocytosis (LCH). The other eight patients went through pituitary stalk biopsy. Four patients required a second biopsy to make the definitive diagnosis as the first biopsy was informed as hypophysitis. The definitive diagnosis in these eight patients was pure GCT.\u003c/p\u003e \u003cp\u003eThe clinical and radiological data were summarized in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDescription of patients with pituitary stalk thickening\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eN\u0026deg;\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAge at diagnosis (y)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGender\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eD\u003csub\u003emax\u003c/sub\u003e (mm)\u003c/p\u003e \u003cp\u003ePituitary stalk\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eEndocrine disturbance\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNeuro-\u003c/p\u003e \u003cp\u003eopthalmologic symptoms\u003c/p\u003e \u003cp\u003e(Y\u0026thinsp;=\u0026thinsp;Yes / N\u0026thinsp;=\u0026thinsp;No)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eTumor markers in serum and CSF (hCG and AFP)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eDiagnosis\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAVD, GHD, HPT, HPA, HPRL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eY\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003ePure germinoma\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e7.64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAVD, GHD, HPT, HPA, HPG, HPRL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eY\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003ePure germinoma\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAVD, GHD, HPA, HPRL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003ePure germinoma\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8.46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAVD, GHD, HPT, HPA, HPG, HPRL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eY\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003ePure germinoma\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e13.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAVD, GHD, HPT, HPRL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eY\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003ePure germinoma\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e12.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAVD, GHD, HPT, HPA, HPG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eY\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003ePure germinoma\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAVD, GHD, HPT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003ePure germinoma\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e10.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAVD, GHD, HPT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eLCH\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAVD, GHD, HPRL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003ePure germinoma\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"8\"\u003e\u003csup\u003eAVD, arginine vasopressin deficiency; GHD, growth hormone deficiency; HPT, hypothalamic pituitary thyroid axis; HPA, hypothalamic pituitary adrenal axis; HPG, hypothalamic pituitary gonadal axis; HPRL, hyperprolactinemia; LCH, Langerhans cell histiocytosis\u003c/sup\u003e.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn the present study, nine pediatric patients with a thorough clinical evaluation including hormonal profile, tumor markers, neuroradiological characteristics and pathology results were diagnosed with PST during the COVID-19 pandemic period. Eight patients in our cohort were finally diagnosed with GCT. In Chile, management of neoplastic diseases in children is guaranteed by social security, which ensures access to diagnosis and treatment, and makes notification mandatory. The patients were evaluated and treated in the National children\u0026rsquo;s antineoplastic drug program (PINDA). Therefore, the national records of these patients is mandatory, leading to a precise statistical data.\u003c/p\u003e \u003cp\u003eWe observed a higher frequency in girls. Scarce data is available to compare sex-specific differences in patients with GCT and PST. Chen et al published a case series of patients with GCT with isolated pituitary stalk involvement and described eleven patients in a period of six years (2015\u0026ndash;2021) with no significant differences in sex [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. However, GCT are described more frequently in males than females, with a ratio of about 4 to 1 [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAll patients were diagnosed with AVD and at least one anterior pituitary defect. In other series, up to two-thirds of the patients developed AVD and a half had one or more anterior pituitary deficiencies [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. This higher anterior and posterior pituitary involvement can be explained due to delayed referral during the pandemic, as seen in other conditions during the outbreak of COVID-19 [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Regrettably, the COVID-19 pandemic has considerably changed healthcare systems and studies have shown an increase in delayed referral of brain tumors in pediatric patients during the pandemic [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn this study a neoplastic cause was found in all patients, being pure GCT the most frequent diagnosis. Thus, the most common causes were neoplasms, similar to previous studies [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHamilton et al [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] published a case series of 65 patients with infundibular lesions, 21 were pediatric patients. They found 13 congenital lesions (all pituitary hypoplasias) and 8 tumors in children. Of the neoplastic causes, four patients had Langerhans cell histiocytosis (LCH), two patients had GCT and the other two patients had metastatic glioblastoma multiforme and primitive neuroectodermal tumor.\u003c/p\u003e \u003cp\u003eA Mayo Clinic study published in 2013 [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], found 152 pituitary stalk lesions in a 20-year period. The causes were identified in 61% of patients and were due to neoplastic lesions in 32%, inflammatory lesions in 20% and congenital anomalies in 9% of patients. However, only 11% of the patients were younger than 21 years old. LCH was classified as an inflammatory lesion in this study, thus the neoplastic causes were even more prevalent.\u003c/p\u003e \u003cp\u003eZhou et al [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] described 321 patients with PST and included 91 pediatric patients (28.3%). The mean age at which PST was diagnosed in pediatric patients was 11 years. The most common causes were neoplasms, and the most frequent tumor in pediatric patients was GCT (67%), followed by LCH (19%) and craniopharyngioma (7%). They found 16 patients with congenital lesions; all were identified as Rathke's cleft cyst.\u003c/p\u003e \u003cp\u003eYoon et al [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] characterized 76 pediatric patients with pituitary stalk lesions. Of these patients, 68.4% had neoplasms and 21.1% had congenital lesions. Of the neoplastic lesions, intracranial GCT was the most common etiology (40.4%), followed by LCH (28.8%).\u003c/p\u003e \u003cp\u003eRecently, Moszczyńska et al [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] reported a cohort of 23 patients with PST in Poland. The median age at diagnosis was 9.68 years. The most common cause was GCT (73.9%), followed by LCH. Polyuria and polydipsia was present in 82,6% of the patients (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eReview of published data on PST in pediatric patients [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePediatric patients (number and %)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSex (% females)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGCT (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLCH (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eOthers (%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTurcu et al (2013)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17 (11%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e6.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e7.60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e85.9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eZhou et al (2019)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e91 (28.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e55.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e29.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e20.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e49.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHamilton et al (2007)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21 (32.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNot described\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e6.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e6.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e87.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eZepeda et al (2023)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e77.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e88.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e11.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003csup\u003eThe neoplastic causes in our study are higher than published data because we included only pediatric patients\u003c/sup\u003e.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eTherefore, neoplasms remain the most frequent cause of PST in pediatric patients. Hence, it is important to make a prompt diagnosis to improve the outcomes.\u003c/p\u003e \u003cp\u003eAs described by Turcu et al [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], the most frequent pattern in MRI of infundibulo-hypophyseal involvement among this cohort was uniform enhancement in V-shape and round/diamond configuration [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn our case series, tumor markers were negative in serum and CSF in all patients, eight of which were diagnosed with pure GCT by biopsy. Pure GCT may secrete small amounts of hCG and AFP in serum and CSF, through their syncytiotrophoblastic component [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Therefore, tumor markers are usually negative.\u003c/p\u003e \u003cp\u003eThe clinical diagnostic value of hCG and AFP has some pitfalls. First, the sensitivity and specificity of these markers varies depending on anatomical involvement, subtype of tumor and progression of the disease, with markedly elevated concentrations occurring in less frequent subtypes of GCT [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Second, not all immunoassays have been validated for use in CSF [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Third, the cut-off values are not well established. One study tried to determine the cut-off values that provide the best sensitivity and specificity. A combination of CSF hCG\u0026thinsp;\u0026ge;\u0026thinsp;8.2 IU/, serum hCG\u0026thinsp;\u0026ge;\u0026thinsp;2.5 UI/L, CSF AFP\u0026thinsp;\u0026ge;\u0026thinsp;3.8 ng/mL and serum AFP\u0026thinsp;\u0026ge;\u0026thinsp;25 ng/mL increased total diagnostic sensitivity to 65.4% [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Because of these limitations, new tumor markers are under investigation and microRNAs have shown promising results in recent publications [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAll patients in this cohort underwent transsphenoidal biopsy because they met criteria defined by UK consensus [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. All of them had a progressive PST with visual and/or pituitary involvement with negative first and second line investigations. However, the etiological diagnosis still remains challenging, as 44.4% of the patients in this case series required a second biopsy due to a pathological diagnosis of hypophysitis, which is an extremely rare cause in pediatric patients. In patients with GCT there is an immune response to the tumor, which generates an inflammatory peritumoral reaction that can be misdiagnosed as hypophysitis [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. In these four cases, final diagnosis after a second biopsy was GCT. Interestingly, one patient was first diagnosed as LCH by clinical and neuroimaging findings, but developed progressive enlargement of pituitary stalk despite treatment and finally required biopsy of pituitary stalk which was consistent with GCT.\u003c/p\u003e \u003cp\u003eThe estimated frequency based on national statistics is 2 patients with GCT with pituitary stalk involvement per year. The frequency of PST due to GCT in pediatric patients observed during the COVID-19 pandemic period was 4 patients per year. Thus, during the pandemic of COVID-19 the frequency of patients with GCT has doubled. All patients went through a PCR test for COVID-19 before surgery and all tested negative. However, it was not investigated if they previously had SARS-CoV2 infection. The reason for this increase in frequency remains inconclusive. Many reasons might be associated, like delayed diagnosis, increased interest in reporting infrequent manifestations of central nervous neoplasms or lack of specific studies, but there are also potential carcinogenic characteristics of SARS-CoV2 that may lead to progression of the tumor by modifying metabolic pathways of tumor cells [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe main strength of the present study is that this is the first report in Chile and in Latin America of pediatric patients with PST, with a thorough clinical, endocrinological, radiological and histological description. Nevertheless, it also has limitations, as there are some cases that may have been missed due to under-report of other non-neoplastic causes in smaller centers. However, this case series raises awareness of this infrequent disease.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eA surprisingly higher than expected frequency of PST was found during the COVID-19 pandemic among Chilean pediatric patients. The management of these patients is complex and requires adult and pediatric neuroendocrinologists, experienced neurosurgeons, neuroradiologists, neurooncologists, neuroophthalmologists and neuropathologists. Furthermore, these patients should undergo long-term follow-up, as diagnostic tests have some limitations. Thus, it is important to establish new markers and more precise diagnostic tools to assess patients with PST in order to make a prompt diagnosis and avoid unnecessary risk in our patients.\u003c/p\u003e \u003cp\u003eFurther research is needed to establish if there is a causative relationship between this high frequency of PST and the COVID-19 pandemic, especially among girls. The reasons behind this increased frequency are still under investigation and are yet to be elucidated.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to acknowledge with gratitude to Dr. Fernando Cassorla for the generous help on review and comments, to our colleagues that contribute with their patients (Jos\u0026eacute; Pablo Fernandez Vergara, Fernanda Pe\u0026ntilde;a Manubens, Claudia Godoy Cortes, Mar\u0026iacute;a Fernanda Ochoa Molina, David Rojas Salazar, Nimia Vallejos Carle, Javiera Basaure Orostica, Carolina Valdes Fuentealba, Vivian Gallardo Tampier, Cristian Naudy Martinez, Pablo Villanueva Garin) and to our patients and their families.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eData Availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSome or all datasets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003eThe authors have no fundings to declare. The authors have nothing to disclose.\u003c/p\u003e\n\u003cp\u003eThe study was approved by the Institutional Review Board and the local Ethics committee.\u0026nbsp;\u003c/p\u003e\n"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eGodano E, Morana G, Di Iorgi N, et al. Role of MRI T2DRIVE in the assessment of pituitary stalk abnormalities without gadolinium in pituitary diseases. Eur J Endocrinol 2018;178: 613\u0026ndash;22. \u003c/li\u003e\n\u003cli\u003eCatford S, Wang YY, Wong R. Pituitary stalk lesions: systematic review and clinical guidance. Clin Endocrinol (Oxf). 2016 Oct;85(4):507-21.\u003c/li\u003e\n\u003cli\u003eLing SY, Zhao ZY, Tao B, Zhao HY, Su TW, Jiang YR, Xie J, Sun QF, Bian LG, Sun K, He NY, Yan FH, Wang WQ, Ning G, Sun LH, Liu JM. Pituitary stalk thickening in a large cohort: Toward more accurate predictors of pituitary dysfunction and etiology. Endocr Pract. 2019 Jun;25(6):534-544.\u003c/li\u003e\n\u003cli\u003eCerbone M, Visser J, Bulwer C, Ederies A, Vallabhaneni K, Ball S, Kamaly-Asl I, Grossman A, Gleeson H, Korbonits M, Nanduri V, Tziaferi V, Jacques T, Spoudeas HA. Management of children and young people with idiopathic pituitary stalk thickening, central diabetes insipidus, or both: a national clinical practice consensus guideline. Lancet Child Adolesc Health. 2021 Sep;5(9):662-676.\u003c/li\u003e\n\u003cli\u003eChen H, Ni M, Xu Y, Zhong LY. Pituitary Stalk Germ Cell Tumors: Retrospective Case Series and Literature Review. Int J Endocrinol. 2022 Mar 26;2022:9213220.\u003c/li\u003e\n\u003cli\u003eFrappaz D, Dhall G, Murray MJ, Goldman S, Faure Conter C, Allen J, Kortmann RD, Haas-Kogen D, Morana G, Finlay J, Nicholson JC, Bartels U, Souweidane M, Sch\u0026ouml;nberger S, Vasiljevic A, Robertson P, Albanese A, Alapetite C, Czech T, Lau CC, Wen P, Schiff D, Shaw D, Calaminus G, Bouffet E. EANO, SNO and Euracan consensus review on the current management and future development of intracranial germ cell tumors in adolescents and young adults. Neuro Oncol. 2022 Apr 1;24(4):516-527.\u003c/li\u003e\n\u003cli\u003eZhou X, Zhu H, Yao Y, Lian X, Feng F, Wang L, Liu S, Deng K, You H, Yang H, Lu L. Etiological Spectrum and Pattern of Change in Pituitary Stalk Thickening: Experience in 321 Patients. J Clin Endocrinol Metab. 2019 Aug 1;104(8):3419-3427. doi: 10.1210/jc.2018-02297. PMID: 30892632.\u003c/li\u003e\n\u003cli\u003eHamilton BE, Salzman KL, Osborn AG. Anatomic and pathologic spectrum of pituitary infundibulum lesions. AJR Am J Roentgenol. 2007;188:W223\u0026ndash;232. \u003c/li\u003e\n\u003cli\u003eSbardella E, Joseph RN, Jafar\u0026shy;Mohammadi B, Isidori AM, Cudlip S, Grossman AB. Pituitary stalk thickening: the role of an innovative MRI imaging analysis which may assist in determining clinical management. Eur J Endocrinol 2016; 175: 255\u0026ndash;63.\u003c/li\u003e\n\u003cli\u003eGoodwin TL, Sainani K, Fisher PG. Incidence patterns of central nervous system germ cell tumors: a SEER study. J Pediatr Hematol Oncol. 2009;31:541\u0026ndash;4.\u003c/li\u003e\n\u003cli\u003eTurcu AF, Erickson BJ, Lin E, et al. Pituitary stalk lesions: the Mayo Clinic experience. J Clin Endocrinol Metab 2013; 98: 1812\u0026ndash;18. \u003c/li\u003e\n\u003cli\u003eHelsper CW, Van Gils CH, Van Erp NF, Siepman van den Berg MFR, Rogouti O, Van Asselt KM, Maarsingh OR, Muris J, Brandenbarg D, Siesling S, De Wit NJ, Grant MP, On Behalf Of The Covid And Cancer Consortium. Impact of the COVID-19 Outbreak-Delayed Referral of Colorectal and Lung Cancer in Primary Care: A National Retrospective Cohort Study. Cancers (Basel). 2023 Feb 25;15(5):1462. \u003c/li\u003e\n\u003cli\u003eCarai A, Locatelli F, Mastronuzzi A. Delayed referral of pediatric brain tumors during COVID-19 pandemic. Neuro Oncol. 2020 Dec 18;22(12):1884-1886.\u003c/li\u003e\n\u003cli\u003eYoon SC, Shin CH, Yang SW, Lee SY. Clinical and radiological features of pituitary stalk lesions in children and adolescents. Ann Pediatr Endocrinol Metab. 2014;19(4):202\u0026ndash;207.\u003c/li\u003e\n\u003cli\u003eMoszczyńska E, Kunecka K, Baszyńska-Wilk M, Perek-Polnik M, Majak D, Grajkowska W. Pituitary Stalk Thickening: Causes and Consequences. The Children\u0026apos;s Memorial Health Institute Experience and Literature Review. Front Endocrinol (Lausanne). 2022 May 20;13:868558. \u003c/li\u003e\n\u003cli\u003eJones AR, McNeil A, Yates C, Krishnamurthy B, Hamblin PS. Difficulties in cerebrospinal fluid \u0026beta;hCG interpretation in a patient with an infundibular lesion. Endocrinol Diabetes Metab Case Rep. 2018 Feb 23;2018:17-0168.\u003c/li\u003e\n\u003cli\u003eShajani-Yi Z, Martin IW, Brunelle AA \u0026amp; Cervinski MA. Method validation of human chorionic gonadotrophin and \u0026alpha;-fetoprotein in cerebrospinal fluid: aiding the diagnosis of intracranial germ cell tumours. Journal of Applied Laboratory Medicine 2017 2 65\u0026ndash;75.\u003c/li\u003e\n\u003cli\u003eHu M, Guan H, Lau CC, Terashima K, Jin Z, Cui L, Wang Y, Li G, Yao Y, Guo Y, Li YM, Zhong D, Xiao J, Wan X, Lian X, Feng F, Ren H, Zhao Y, Cheng X, Gu F. An update on the clinical diagnostic value of \u0026beta;-hCG and \u0026alpha;FP for intracranial germ cell tumors. Eur J Med Res. 2016 Mar 12;21:10.\u003c/li\u003e\n\u003cli\u003eMurray MJ, Horan G, Lowis S, Nicholson JC. Highlights from the Third International Central Nervous System Germ Cell Tumour symposium: laying the foundations for future consensus. Ecancermedicalscience. 2013 Jul 17;7:333.\u003c/li\u003e\n\u003cli\u003eS. L. Mootha, A. J. Barkovich, M. M. Grumbach et al., \u0026ldquo;Idiopathic hypothalamic diabetes insipidus, pituitary stalk thickening, and the occult intracranial germinoma in children and adolescents,\u0026rdquo; Journal of Clinical Endocrinology \u0026amp; Metabolism, vol. 82, no. 5, pp. 1362\u0026ndash;1367, 1997.\u003c/li\u003e\n\u003cli\u003eLi YS, Ren HC, Cao JH. Correlation of SARS‑CoV‑2 to cancer: Carcinogenic or anticancer? (Review). Int J Oncol. 2022 Apr;60(4):42. \u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Pituitary stalk thickening, Pituitary hormones, Child, Pituitary stalk, Germinoma, Multiple anterior pituitary hormone deficiency","lastPublishedDoi":"10.21203/rs.3.rs-3154962/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3154962/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003ePurpose\u003c/p\u003e\n\u003cp\u003ePituitary stalk thickening (PST) is a rare disease affecting mainly adults. Pediatric cases are infrequent. The aim of this study is to evaluate the frequency of pediatric patients with PST during the pandemic outbreak of COVID-19 in Chile and compare it with previous data.\u003c/p\u003e\n\u003cp\u003eMethods\u003c/p\u003e\n\u003cp\u003eA retrospective chart review was conducted in patients with PST diagnosed during COVID-19 outbreak. Patients \u0026lt;18 years with pituitary stalk width of 3mm or more at pituitary insertion and/or 4mm or more at optic chiasm were included. In order to characterize and compare these cases with those already published, a review of the literature was performed.\u003c/p\u003e\n\u003cp\u003eResults\u003c/p\u003e\n\u003cp\u003eNine patients were diagnosed with PST. Seven were girls. Mean age at the onset of symptoms was 10.36 years (2.4-17). Germinal cell tumors (GCT) were diagnosed in 8 patients and Langerhans cell histiocytosis in one. All patients had negative tumor markers, arginine-vasopressin deficiency (AVD) and at least one anterior pituitary hormonal deficit at diagnosis.\u003c/p\u003e\n\u003cp\u003eDiagnoses were confirmed histologically in all patients, and four required a second biopsy. We found a frequency of 4 patients per year with PST due to GCT which is twice the one expected in the same population in Chile.\u003c/p\u003e\n\u003cp\u003eConclusion\u003c/p\u003e\n\u003cp\u003eA surprisingly high frequency of PST presented during the COVID-19 pandemic among Chilean pediatric patients, being GCT the most frequent etiology. The reasons behind this increase in reported cases are still to be elucidated.\u003c/p\u003e","manuscriptTitle":"Changes in the epidemiological profile of pituitary stalk thickening among pediatric population in Chile during COVID-19 pandemic","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-07-13 14:17:37","doi":"10.21203/rs.3.rs-3154962/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"e497d42c-bb83-44da-ab24-2bbc39654bad","owner":[],"postedDate":"July 13th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2023-07-25T11:29:19+00:00","versionOfRecord":[],"versionCreatedAt":"2023-07-13 14:17:37","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3154962","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3154962","identity":"rs-3154962","version":["v1"]},"buildId":"_2-kVJe1T_tPrBINL-cwx","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}