The clinical course of Rathke's cleft cysts in pediatric patients: impact on growth and pubertal development.
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ABSTRACT:
SUBMITTER: Higuchi Y
PROVIDER: S-EPMC8713062 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The transcription factor ISL1 is expressed in pituitary gland stem cells and the thyrotrope and gonadotrope lineages. Pituitary-specific Isl1 deletion causes hypopituitarism with increased stem cell apoptosis, reduced differentiation of thyrotropes and gonadotropes, and reduced body size. Conditional Isl1 deletion causes development of multiple Rathke's cleft-like cysts, with 100% penetrance. Foxa1 and Foxj1 are abnormally expressed in the pituitary gland and associated with a ciliogenic gene-expression program in the cysts. We confirmed expression of FOXA1, FOXJ1, and stem cell markers in human Rathke's cleft cyst tissue, but not craniopharyngiomas, which suggests these transcription factors are useful, pathological markers for diagnosis of Rathke's cleft cysts. These studies support a model whereby expression of ISL1 in pituitary progenitors drives differentiation into thyrotropes and gonadotropes and without it, activation of FOXA1 and FOXJ1 permits development of an oral epithelial cell fate with mucinous cysts. This pituitary-specific Isl1 mouse knockout sheds light on the etiology of Rathke's cleft cysts and the role of ISL1 in normal pituitary development.
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Project description:The epithelial cell adhesion molecule (EpCAM) is a type I glycoprotein located on the surface of epithelial cells. It is strongly expressed in many neoplasms and already used in the diagnosis and distinction of various tumour subtypes. Comparative studies about EpCAM expression in cystic sellar lesions are lacking. Therefore, we analysed its distribution pattern in adamantinomatous (aCP) and papillary (pCP) craniopharyngiomas (CP) and Rathke's Cleft Cysts (RCC) using immunohistochemistry and gene expression profiling. Whereas the protein was not detectable in pCP (n?=?10), all aCP (n?=?64) showed distinct staining patterns. The vast majority of RCC (n?=?10) also appeared positive, but these displayed notably lower labeling scores. Additionally, significantly higher mRNA levels were detectable in aCP (n?=?19) when compared to pCP (n?=?10) (p?=?9.985(-8)). Furthermore, pediatric aCP cases, in general, exhibited stronger EpCAM staining levels compared to adult ones (p?=?0.015). However, we were not able to verify this result on mRNA level. In summary, our findings demonstrate that EpCAM can be used as an additional distinction-marker for cystic lesions of the sellar region. Its unknown function in aCP and the presence of an approved monoclonal bispecific trifunctional antibody for cancer therapy are interesting starting points for further studies.
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Project description:Cilia are highly conserved organelles, which serve critical roles in development and physiology. Motile cilia are expressed in a limited range of tissues, where they principally regulate local extracellular fluid dynamics. In contrast, primary cilia are expressed by many vertebrate cell types during interphase, and are intimately involved in the cell cycle and signal transduction. Notably, primary cilia are essential for vertebrate hedgehog pathway activity. Improved detection of motile cilia may assist in the diagnosis of some pathologic entities such as Rathke's cleft cysts, whereas characterizing primary cilia in neoplastic tissues may implicate cilia-dependent signaling pathways as critical for tumorigenesis. We show that immunohistochemistry for the nuclear transcription factor FOXJ1, a master regulator of motile ciliogenesis, robustly labels the motile ciliated epithelium of Rathke's cleft cysts. FOXJ1 expression discriminates Rathke's cleft cysts from entities in the sellar/suprasellar region with overlapping histologic features such as craniopharyngiomas. Co-immunohistochemistry for FOXJ1 and markers that highlight motile cilia such as acetylated tubulin (TUBA4A) and the small GTPase ARL13B further enhance the ability to identify diagnostic epithelial cells. In addition to highlighting motile cilia, ARL13B immunohistochemistry also robustly highlights primary cilia in formalin-fixed paraffin-embedded sections. Primary cilia are present throughout the neoplastic epithelium of adamantinomatous craniopharyngioma, but are limited to basally oriented cells near the fibrovascular stroma in papillary craniopharyngioma. Consistent with this differing pattern of primary ciliation, adamantinomatous craniopharyngiomas express significantly higher levels of SHH, and downstream targets such as PTCH1 and GLI2, compared with papillary craniopharyngiomas. In conclusion, motile ciliated epithelium can be readily identified using immunohistochemistry for FOXJ1, TUBA4A, and ARL13B, facilitating the diagnosis of Rathke's cleft cysts. Primary cilia can be identified by ARL13B immunohistochemistry in routine pathology specimens. The widespread presence of primary cilia in adamantinomatous craniopharyngioma implicates cilia-dependent hedgehog signaling in the pathogenesis of adamantinomatous craniopharyngioma.
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Project description:Craniopharyngioma (CP) and Rathke's cleft cyst (RCC) are both suprasellar lesions. They are sometimes difficult to distinguish due to their similar findings. We report a case of papillary craniopharyngioma (pCP) with the clinical findings suggesting RCC. A 42-year-old female with intellectual disability presented to our hospital with severe visual dysfunction. Preoperative images revealed a suprasellar cystic lesion without calcification. We performed transsphenoidal surgery. Since the cyst had condensed-milk-like content suggesting RCC, we performed cyst fenestration and wash without removal of the cyst wall. Thereafter, we found fish-egg-like structures on the cyst wall. The histopathological analysis revealed that they had papillary structures surrounded by hyperplastic squamous epithelium with parakeratosis. Immunostaining for BRAF V600E was positive, leading to the diagnosis of pCP. After the surgery, her visual function improved and follow-up Magnetic resonance imaging at 18 months postoperatively showed no apparent recurrence. The presence of condensed-milk-like content suggests a likelihood of RCC indicating that aggressive resection may not be necessary. In contrast, the existence of fish-egg-like structures suggests pCP and requires careful follow-up.
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Project description:OBJECTIVE:The aim of this study was to investigate the relationship of BMI with subsequent statural growth among children born in the era of the obesity epidemic. METHODS:Among 18,271 children from Belarus (n?=?16,781, born 1996 to 1997) and the United States (n?=?1,490, born 1999 to 2002), multivariable linear and ordinal logistic regression was used to analyze associations of BMI z score from infancy to adolescence with subsequent standardized length and height velocity, standing height and its components (trunk and leg lengths), and pubertal timing. RESULTS:The prevalence of early adolescent obesity was 6.2% in Belarus and 12.8% in the United States. In both Belarusian and US children, higher BMI z scores in infancy and childhood were associated with faster length and height velocity in early life, while higher BMI z scores during middle childhood were associated with slower length and height velocity during adolescence. Associations with greater standing height and trunk length and earlier pubertal development in adolescence were stronger for BMI z scores at middle childhood than BMI z scores at birth or infancy. CONCLUSIONS:These findings in both Belarus and the United States support the role of higher BMI in accelerating linear growth in early life (taller stature and longer trunk length) but earlier pubertal development and slower linear growth during adolescence.
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Project description:The transcription factor ISL1 is expressed in pituitary gland stem cells and the thyrotrope and gonadotrope lineages. Pituitary-specific Isl1 deletion causes hypopituitarism with increased stem cell apoptosis, reduced differentiation of thyrotropes and gonadotropes, and reduced body size. Conditional Isl1 deletion causes development of multiple Rathke’s cleft-like cysts, with 100% penetrance. Foxa1 and Foxj1 are abnormally expressed in the pituitary gland and associated with a ciliogenic gene expression program in the cysts. We confirmed expression of FOXA1, FOXJ1 and stem cell markers in human Rathke's cleft cyst tissue, but not craniopharyngiomas, which suggests these transcription factors are useful, pathological markers for diagnosis of Rathke's cleft cysts. These studies support a model whereby expression of ISL1 in pituitary progenitors drives differentiation into thyrotropes and gonadotropes, and without it, activation of FOXA1 and FOXJ1 permits development of an oral epithelial cell fate with mucinous cysts. This pituitary-specific Isl1 mouse knockout sheds light on the etiology of Rathke's cleft cysts and the role of ISL1 in normal pituitary development.
2020-04-22 | GSE149019 | GEO
Project description:Adolescence is hallmarked by two parallel processes of sexual maturation and adult patterning of the brain. Therefore, adolescence represents a vulnerable postnatal period for neurodevelopment where exogenous factors can negatively impact adult brain function. For example, alcohol exposure during pubertal development can lead to long-term and widespread neurobiological dysfunction and these effects have been shown to persist even in the absence of future alcohol exposure. However, the molecular mechanisms mediating the persistent effects of alcohol are unclear. We propose that dysregulation of microRNAs (miR) could be a unifying epigenetic mechanism underlying these widespread long-term changes. We tested the hypothesis that repeated alcohol exposure during pubertal development would cause disruption of normal miR expression profiles during puberty and, subsequently, their downstream mRNA target genes in the ventral hippocampus using an established rat model of adolescent binge drinking. We found 6 alcohol-sensitive miRs that were all downregulated following alcohol exposure and we also investigated the normal age-dependent changes in those miRs throughout the pubertal period. Interestingly, these miRs were normally decreased throughout the process of puberty, but alcohol prematurely exacerbated the normal decline in miR expression levels. The work presented herein provides foundational knowledge about the expression patterns of miRs during this critical period of neurodevelopment. Further, this regulation of miR and mRNA expression by alcohol exposure presents a complex regulatory mechanism by which perturbation in this time-sensitive period could lead to long-term neurological consequences.
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Project description:ObjectiveRathke cleft cysts (RCC) are benign lesions of the sellar region that require surgical treatment in case of visual deterioration or progression of the cyst. However, the natural course is often stable and asymptomatic. We aimed to investigate the characteristics of patients with cyst progression during follow-up (FU) and to compare the natural history of patients with RCC with patients who underwent surgery.MethodsPatients with an MR morphologic cystic sellar lesion classified as RCC between 04/2001 and 11/2020 were included. Functional outcomes, including ophthalmologic, endocrinologic, and MRI data, were retrospectively analyzed and compared between surgically treated patients, patients on a "watch and wait" strategy (WWS), and patients on a WWS who underwent secondary surgery due to cyst progression.ResultsOne hundred forty patients (median age 42.8 years) with RCC on MRI were identified. 52/140 (37.1%) underwent primary surgery. Of 88 patients (62.9%) with initial WWS, 21 (23.9%) underwent surgery for secondary cyst progression. Patients on the WWS had significantly smaller cyst volumes (p = 0.0001) and fewer visual disturbances (p = 0.0004), but a similar rate of hormone deficiencies (p = 0.99) compared with surgically treated patients preoperatively. Postoperatively patients suffered significantly more often from hormone deficiencies than WWS patients (p = 0.001). Patients who switched to the surgical group were significantly more likely to have preoperative T1 hyperintense signals on MRI (p = 0.0001) and visual disturbances (p = 0.001) than patients with continuous WWS. Postoperatively, these patients suffered more frequently from new hormonal deficiencies (p = 0.001). Endocrine and ophthalmologic outcomes in patients with primary and secondary surgery were comparable. Multivariate analysis showed that WWS patients were at a higher risk of requiring surgery for cyst progression when perimetric deficits (p = 0.006), hyperprolactinemia (p = 0.003), and corticotropic deficits (p = 0.005) were present.ConclusionSurgical treatment of RCC may cause new hormonal deficiencies, which are rare in the natural course. Therefore, the indication for surgery should be carefully evaluated. Hyperprolactinemia and corticotropic deficits were significant indicators for a secondary cyst progression in patients with RCC. However, a significant amount of almost 25% of initially conservatively managed cysts showed deterioration, necessary for surgical intervention.
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Project description:ObjectivesTo determine the effects of foster care vs institutional care, as well as disruptions in the caregiving environment on physical development through early adolescence.Study designThis was a randomized controlled trial of 114 institutionalized, though otherwise healthy, children from 6 orphanages and 51 never institutionalized control children living in birth families (family care group) in Bucharest, Romania. Children were followed from baseline (21 months, range 5-31) through age 12 years for caregiving disruptions and growth trajectories and through age 14 years for pubertal development.ResultsChildren randomized to the foster care group showed greater rates of growth in height, weight, and body mass index (BMI) through age 12 years than institutionalized group. Tanner development was delayed in institutionalized group boys compared with foster care group and family care group boys at 12 but not 14 years. There were no differences in Tanner development and age of menarche among foster care group, institutionalized group, and family care group girls at ages 12 and 14 years. More disruptions in caregiving between 30 months and 12 years moderated decreases in growth rates of height in foster care group and weight in foster care group and institutionalized group across age. institutionalized group boys with ≥2 disruptions showed lower Tanner scores at age 12 vs institutionalized group and foster care group boys with <2 disruptions. foster care group girls with ≥2 disruptions had higher Tanner scores at age 14 vs foster care group girls with <2 disruptions. Age of menarche was not affected by caregiving disruptions.ConclusionsFor children who experienced early institutionalization, stable placement within family care is essential to ensuring the best outcomes for physical developmental.Trial registrationclinicaltrials.gov: NCT00747396.
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Project description:BackgroundThe American Board of Medical Specialties recognized Pediatric Hospital Medicine (PHM) for subspecialty certification in 2016, with the first certification exam in 2019. To address the need for exam preparatory materials, we designed and evaluated a novel PHM board review course that was offered both in-person and online.MethodsCourse content was based on the American Board of Pediatrics (ABP) PHM certifying exam outline. Course objectives were developed from published PHM core competencies and the 2012 ABP general pediatrics content objectives. National experts served as faculty, presenting didactic sessions, and contributing to a question bank for high-yield review. For program evaluation, we applied the Kirkpatrick Model, evaluating estimated exam pass rates (Level 4), participant learning (Level 2) via post-presentation practice questions, and participants' ratings of presenters (via five-point Likert scale) and satisfaction (Level 1).ResultsThere were 112 in-person and 144 online participants with estimated pass rates of 89 and 93%, respectively. The mean correct response for the post-presentation knowledge questions was 84%. Faculty effectiveness ratings ranged from 3.81 to 4.96 (median score 4.60). Strengths included the pace of the course, question bank, and printed syllabus. Suggestions for improvement included question bank expansion, focus on "testable" points rather than general information, and challenges with long days of didactic presentations.ConclusionsThis novel PHM board review course demonstrated effectiveness. Hospitalists preferred focused "testable" information, an active learning environment, and a robust question bank. Future preparatory courses should consider including more opportunities for practice questions, focused content review, and learner engagement.
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