United States

Introduction: Hormone-producing pituitary cell lineages are derived from a population of embryonic precursors expressing SOX2. These cells maintain multipotency into early postnatal life, acting as the resident population of pituitary stem cells (PSCs) and contributing extensively to all the endocrine cell lineages. In addition to this direct contribution to pituitary turnover, paracrine signalling from PSCs has been shown to be important for cell proliferation of neighbouring progenitors (PMC7803373). It is not known if SOX2+ PSCs are involved in the regulation of additional cell attributes during normal physiology and if there is functional heterogeneity among the SOX2+ PSC population.
Experimental Methods: We have carried out single-cell RNA-Sequencing of SOX2+ PSCs from Sox2Egfp/+ mouse pituitaries at three postnatal stages from P3 to P56 and used computational approaches to analyse their molecular signatures. A novel conditional mouse model expressing a constitutively active mutant form of the RNA binding factor BRF1 (R26stop-mBRF1) has been used to attenuate the expression of several cytokines and chemokines in SOX2+ cells embryonically and postnatally (PMC4589897).
Results: We show that the SOX2+ PSC population consists of three subgroups (SC1, SC2 and SC3). We reveal that SC1-SC2 express abundant cytokines and secreted factors, suggesting paracrine function. In contrast, SC3 is characterised by robust expression of Lef1, is identified as a committing PSC cluster, and its presence diminishes with age. Key markers of PSC clusters SC1-SC2 include the RNA binding factor BRF1. We show that BRF1 is highly expressed in PSCs and validate its expression by immunohistochemistry in both mouse and human pituitaries. Secondly, we show that the dysregulation of BRF1 in embryonic SOX2+ cells using the Hesx1-Cre driver (PMC3461924) results in pituitary hypoplasia and severe hypopituitarism due to a failure of the PIT1 and SF1 cell-lineage committed progenitors to terminally differentiate into hormone-producing cells. Additionally, there is a significant reduction of the stem cell compartment, manifested by lower numbers of SOX2/SOX9+ stem cells. This phenotype is recapitulated when using a Sox2-CreERT2 driver (PMID24094324). The differentiation failure can be rescued in vitro through co-culture of mutant cells with wild-type stem cells, as well as in vivo, in mutant pituitaries where activation of constitutively active BRF1 is restricted to few SOX2+ PSCs in a mosaic manner. Finally, we identify key ligands underlying this differentiation phenotype and demonstrate a partial restoration of terminal differentiation in the mutant, when cultured in the presence of these ligands.
Conclusion: We provide evidence indicating the presence of functionally distinct groups of SOX2+ pituitary stem cells and reveal a critical role for a PSC subset in the development of the stem cell compartment and in driving terminal differentiation of committed progenitors.

ENDO 2022

BRF1-Mediated Paracrine Signalling by a Subset of SOX2-Expressing Stem Cells is Required for Normal Development of the Stem Cell Compartment and Terminal Differentiation of Pituitary Committed Progenitors

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more than 30 oral sessions and a robust virtual poster hall for accepted scientific abstracts.

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ENDO’s comprehensive program provides attendees the opportunity to learn about the latest developments in hormone science and medicine from renowned investigators, expert clinicians, and educators from all over the world. 

technical paper

Context: Surgical removal is the primary treatment option for pituitary adenomas. However, pituitary surgery is frequently incomplete because of invasion of extrasellar cerebral structures. In particular, the vicinity with the carotid artery hinders the radical surgical excision of the adenoma portion invading the cavernous sinus. Our objective was to study the molecular bases of the cavernous sinus invasion by pituitary adenomas.
Methods: We obtained a unique tissue collection of 19 invasive pituitary adenomas with a sample from the intrasellar portion and a sample from the portion invading the cavernous sinus for each adenoma. We used RNA-sequencing to compare the gene expression patterns of the invading and intrasellar portions. The implication of one differentially expressed candidate gene in the invasive behavior was first analyzed in vitro using Transwell Assay to study the impact of its pharmacologic inhibition on cell migration and invasion. These experiments were conducted in murine lactosomatotroph GH3 cells and gonadotroph LbT2 cell. To further study the role of this gene on tumor growth and behavior in vivo, we elaborated a model of invasive pituitary adenomas by stereotactic injection of murine somatotroph GC cell into the lobes of the pituitary gland of female Wistar Furth rats. Twelve rats (10-12 week-old) received 20.000 GC cells in each pituitary lobe. After surgery, rats were monitored weekly, tumor development was assessed fortnightly by 3 successive 7Tesla MRI and analyzed by Horos software. Rats were sacrificed 7 weeks after GC cells injection. Six of the 12 rats were treated during this period with the pharmacological inhibitor of the candidate gene.
Results: RNA-sequencing identified 159 up-regulated genes and 11 down-regulated genes in the invasive adenoma portion. In vitro pharmacological inhibition of the candidate gene decreased cell migration and invasion in GH3 cells (p=0.0205 and p=0.0038) and LbT2 cell (p=0.0345 and p=0.0131). Amongst the 12 injected animals, 11 (92%) rats developed invasive pituitary tumors. Tumor growth was rapid, causing death from intracranial hypertensions before the theoretical end of the study protocol in 7 animals. Pharmacological inhibition tended to slow tumor growth from 30.3 mm³/week to 7.8 mm³/week (p=0.12) and decreased cumulative mortality (83% in untreated animals versus 33% in treated animals, p=0.08).
Conclusion: We described the molecular signature associated with the invasive behavior of pituitary adenomas and identified a therapeutic target, which is related to pituitary cells migration and invasion in functional in vitro studies. Pharmacologic inhibition of this target tended to decrease tumor growth and mortality from intracranial hypertension in vivo, however larger numbers of animals are necessary to confirm this observation. Our original approach of orthotopic cell injection into rat pituitaries resulting in tumor development provides a new tool for molecular studies of pituitary tumorigenesis and for the screening of new therapeutic agents.

Molecular determinants of cavernous sinus invasion by pituitary adenomas: functional in vitro studies and in vivo investigations in a rat model of invasive pituitary tumorigenesis obtained by stereotactic pituitary GC cells injection

Background
Oral octreotide capsules (OOC) are a treatment option for patients with acromegaly in the United States. The MPOWERED trial (NCT02685709) showed that OOC were noninferior to injectable somatostatin receptor ligands (iSRLs; octreotide or lanreotide) in maintenance of biochemical control in patients previously responding to both treatments, as well as demonstrated improvements in patient-reported outcomes among patients receiving OOC.
Objective
Report long-term safety and efficacy outcomes with OOC from the open-label extension (OLE) of MPOWERED.
Methods
Patients were eligible for and could voluntarily enroll into the OLE if they had completed the 15-month core treatment phase of MPOWERED (6-month Run-in phase plus 9-month randomized controlled treatment [RCT] phase or, for OOC nonresponders during/at end of Run-in at participating sites, combination sub-study evaluating OOC in combination with cabergoline) and were adequately biochemically controlled per investigator assessment. Maintenance of response (definition: IGF-I <1.3 x ULN; single timepoint) was assessed in each year of the OLE in patients responding at the start of that year. Additional analyses were performed on patients switching to OOC in the OLE from iSRLs in the core study.
Results
Sixty patients elected to enroll in the OLE (35 who received OOC and 19 who received iSRLs in the RCT phase, 6 from the combination sub-study). Median and maximal OOC exposure durations in the OLE were 2.2 and 3.5 years, respectively. A total of 94%, 90%, and 93% of patients receiving OOC monotherapy maintained biochemical response at the end of years 1, 2, and 3 of the OLE, respectively (using last observation carried forward imputation). Of patients switching from iSRLs to OOC during the OLE, 79% reported very good (47%) or excellent (32%) symptom control at the end of the OLE, compared with 47% (42% very good, 5% excellent) at the end of the RCT phase while receiving iSRLs. Patients switching from iSRLs also experienced significant improvements in the treatment convenience and treatment satisfaction domains (both P<0.05) of the Acromegaly Treatment Satisfaction Questionnaire. Median OOC compliance rate during the OLE was 99%. OOC safety during the OLE was consistent with that observed during the core study, with no new safety signals observed with long-term exposure.
Conclusions
The OLE of MPOWERED demonstrated a high percentage (≥90%) of patients maintaining biochemical response while receiving OOC monotherapy with a favorable long-term safety profile of OOC. Those who switched from iSRLs to OOC demonstrated improvements in symptom control, treatment convenience, and treatment satisfaction.

Long-term Efficacy and Safety Data for Oral Octreotide Capsules in Acromegaly: MPOWERED Trial Open-Label Extension Phase

Background: ACTH secreting pituitary adenomas are rare accounting for only 5-10% of pituitary adenomas. Most often these are sporadic, however there are rare associated familial disorders and genetic mutations. This case highlights a 41-year-old male with an ACTH secreting macroadenoma similar to one found in his brother previously.
Case: A 41-year-old male with no significant medical history presented to the hospital with headaches and visual changes for the past week and decreased libido, weight gain, and cold intolerance for the past year. Physical exam demonstrated left eye ptosis, proptosis, and pupillary dilation with intact visual fields, as well as Cushingoid features including BMI 35.1, abdominal obesity with striae, enlarged breasts and tanned skin. Family history revealed a brother diagnosed with an ACTH producing pituitary microadenoma requiring surgical resection 18 years prior.Brain MRI revealed a 2.6 x 2.5 x 3.7 cm sellar mass with optic chiasm compression and pituitary apoplexy. Labs revealed elevated ACTH 708 pg/mL (7.2–63 pg/mL) suggesting a functional macroadenoma, as well as signs of early hypopituitarism with TSH 0.37 uIU/mL (0.35-5.50 uIU/mL), free T4 0.5 ng/dL (0.5-1.3 ng/dL), free T3 2.6 pg/mL (2.3–4.2 pg/mL), prolactin 2.0 ng/mL (2.6-13.1 ng/mL), GH 0.2 ng/mL (</= 7.1 ng/mL).
He received Dexamethasone and Levothyroxine before undergoing transsphenoidal resection which confirmed an ACTH-secreting macroadenoma resulting in Cushing's disease. Given his family history, he underwent evaluation for MEN (multiple endocrine neoplasia) which revealed normal gastrin, calcium, calcitonin, PTH and chromogranin A. Furthermore, the patient and his brother underwent genetic testing which was negative for mutations associated with isolated familial pituitary adenomas (including MEN1, CDKN1A, PRKAR1A, AIP). After discharge, he was started on testosterone and transitioned to hydrocortisone with plans for ACTH stimulation test and steroid taper as tolerated.
Conclusion: Pituitary adenomas are fairly common, and most tend to be sporadic. ACTH secreting pituitary adenomas are rare and in rarer instances can be inherited as isolated tumors or as part of multiple endocrine neoplasia syndrome [1]. Early identification of genetic predisposition can allow for screening of associated comorbidities and early screening in family members. The patient and his brother both had rare ACTH-secreting adenomas, however genetic testing for genes associated with familial disorders was unrevealing in this case. While it is possible that the ACTH secreting tumors in both brothers were sporadic or due to environmental exposure, it is also possible that they share a genetic mutation not yet identified.
References: [1] Dworakowska D, et al. The pathophysiology of pituitary adenomas. Best Practice & Research Clinical Endocrinology & Metabolism. 2009;23(5): 525-541.

Chance or Pedigree?: A Rare Case of Familial ACTH Producing Pituitary Tumor

Methyl-CpG-binding protein 2 (MECP2) is a chromatin-associated protein that can both activate and repress transcription, playing an essential role in neuronal maturation. MECP2 is encoded by an X-linked gene (chromosome Xq28) with high expression in the brain, including the hypothalamic region. Loss-of-function mutations in MECP2 are usually associated with Rett syndrome, a rare genetic disorder characterized by normal early development followed by regression of acquired skills, such as purposeful hand movements and the ability to communicate, repetitive hand stereotypies, slowed brain growth, seizures, and intellectual disability with female predominance. Notably, early pubertal development (early thelarche, pubarche and, less often, menarche) has been demonstrated in girls with Rett syndrome. In this original study, a total of 329 CPP patients (308 girls and 21 boys) were investigated for MECP2 defects. Familial cases were identified in 38% of this CPP cohort. First, 129 CPP patients were enrolled for multigene sequencing studies (whole-exome sequencing n=58; targeted gene sequencing n=71) as part of genetic investigations based on large-scale approaches. Three rare heterozygous sequence variants predicted to be deleterious in MECP2 gene were identified in 5 girls from 4 unrelated families with CPP: the p.Arg97Cys de novo missense variant in two monozygotic twin sisters with CPP and microcephaly; the p.Ser176Arg de novo missense variant in one girl with sporadic CPP, obesity and autism; and the p.Ala6_Ala8dup insertion in two unrelated girls with sporadic CPP (one with a maternally inherited variant). To expand the investigation for potentially damaging sequence variants of MECP2, a larger multiethnic cohort of 200 CPP patients was further analyzed through Sanger sequencing. One rare heterozygous 3'UTR insertion in MECP2 (c.*36_*37insT) was identified in two unrelated girls with sporadic CPP (one with a maternally inherited variant and other with a de novo variant). None of these MECP2 variants have been previously reported in Rett syndrome cases. The girls with CPP associated with MECP2 defects did not manifest typical Rett syndrome. The three patients with more deleterious MECP2 variants, according to in silico prediction tools, had neurobehavioral phenotypes, likely corresponding to a genotype-phenotype correlation. Immunohistochemistry and immunofluorescence studies were performed in pubertal female mice. Abundant staining for Mecp2 was demonstrated in multiple hypothalamic nuclei (arcuate, suprachiasmatic, and paraventricular) and in the median eminence. Co-localization of Mecp2 and GnRH within GnRH neurons was suggested in double labelling experiments. Hence, Mecp2 expression was demonstrated in key hypothalamic nuclei responsible for GnRH regulation in female mice. In conclusion, we have identified rare dominant MECP2 defects in multiple unrelated girls with CPP with or without mild neurodevelopmental abnormalities, revealing a new X-linked form of premature reactivation of the hypothalamic-pituitary-gonadal axis.

X-Linked Central Precocious Puberty Associated with MECP2 Defects

Background
Pituitary cysts (PCs) may be related to the development of diminished growth hormone secretion because they may limit the proliferation of somatotrophs. This study seeks to investigate the mass effect of PCs on the pituitary function.

Methods
Patients aged 6-18 with cysts and follow-ups between 2007–21 were compared to normal controls (NCs) aged 6-18 from a neuroradiology center. Pituitary volume (PV) is the volume of the pituitary gland including the cyst, while net pituitary volume (netPV) is the volume of the pituitary gland excluding the cyst. Since NCs did not have PCs, only PV was utilized. PVs and netPVs are reported in mm3. Data were stratified into prepubertal (age < 11 yrs) and pubertal (age > 11 yrs). The Kruskal-Wallis One Way ANOVA on Ranks was utilized to compare multiple means, and the Kruskal-Wallis Multiple-Comparison Z Value test (with Bonferroni adjustment) was utilized for pairwise comparisons.

Results
The mean and median PVs of prepubertal GHD (n=37), ISS (n=5), and NCs (n=58) were 290.2 ± 109.7 and 305.0, 314.4 ± 100.8 and 299.8, and 246.8 ± 63.7 and 241.6, respectively. The difference between mean PVs of prepubertal GHD, ISS, and NCs was not significant.

The mean and median PVs of pubertal GHD (n=58), ISS (n=33), and NCs (n=112) were 391.5 ± 163.5 and 370.2, 409.2 ± 215.8 and 382.9, and 424.2 ± 138.9 and 402.7, respectively. The difference between mean PVs of pubertal GHD, ISS, and NCs was not significant.

For netPV, the mean and median values for prepubertal GHD and ISS patients were 252.2 ± 83.3 and 272.2, and 245.2 ± 85.7 and 244.9, respectively. The difference between mean netPVs of prepubertal GHD, ISS, and NCs was not significant.

For netPV, the mean and median values for pubertal GHD and ISS patients were 332.7 ± 121.3 and 346.4, and 333.9 ± 146.1 and 330.7, respectively. The mean netPVs of pubertal GHD and ISS patients were both significantly lower than the mean PV of pubertal NCs.

The mean and median PVs for cyst patients were 364.8 ± 170.0 and 347.8 which was not significantly different from the NCs. The mean and median netPVs for cyst patients were 307.3 ± 122.9 and 289.0 which was significantly different from the NCs (p<0.001).

Conclusion
When considering the functional component of the pituitary gland, cyst volume should be subtracted from the overall pituitary gland.

The Effect of Pituitary Cysts on Pituitary Volume in Patients with Growth Hormone Deficiency and Idiopathic Short Stature

Background: ROHHAD(NET) is a rare syndrome with a constellation of rapid-onset obesity, hypothalamic dysfunction, hypoventilation, autonomic dysregulation, and neural crest tumors. The endocrine disruptions can include obesity, growth hormone dysregulation, hyperprolactinemia, sodium/water imbalances, central hypothyroidism, adrenal insufficiency and puberty disorders. There have been just over 100 cases described thus far and only one adult patient described with severe insulin resistance. We present a pediatric patient diagnosed with ROHHAD(NET) with overgrowth and extremely elevated insulin concentrations
Case: Our patient initially presented with severe obesity, rapid linear growth, abnormal lipids, and elevated fasting insulin at the age of 2.5 years. He progressively developed breathing abnormalities, hypothalamic dysfunction, autonomic dysregulation, and a neural crest tumor. With this group of symptoms, criteria for ROHHAD (NET) was met. He progressed to develop insulin resistance, hyperprolactinemia, diabetes insipidus, central hypothyroidism and central adrenal insufficiency. He also required right adrenalectomy for a poorly differentiated neuroblastoma and ganglioneuroblastoma.
Results: Evaluation of his obesity included a negative monogenic obesity genetic panel (>30 genes tested) , normal leptin levels (11.6 ng/ml) and borderline elevated IGF-1 levels 166 ng/ml (z-score 2.5). Glucose levels were usually in the normal range but increased into the diabetes range when he was stressed or sick. HbA1c ranged from 5.6-6.2 % (Ref. range <6%) between age 2.5 and 4.5 years. A standard oral glucose tolerance test with blood draws performed at 0, 30, 60 and 120 minutes showed glucose levels of 78,118,123 and 122 mg/dl, insulin of 36,302, 338 and 449 mIU/L and c-peptide levels of 2.9,13.2,14.5 and 16.3 ng/ml respectively. Age at this time was 3.0 years and height, weight and BMI were on the 100% (Z-score 4.28,6.95 and 4.28 respectively) and HbA1c was 5.7%
Management: Although glucose tolerance was normal, insulin and C-peptide concentrations were extremely elevated for age and prepubertal status, suggestive of marked insulin resistance. Subsequently, he was started on liquid Metformin 250 mg BID as an adjunct to a calorie-restricted diet. He tolerated this well. His response to therapy has been hard to assess given frequent illnesses and hospitalizations for his various comorbidities; however, he has shown no progression to hyperglycemia, except during acute sickness.
Conclusion: To the best of our knowledge, this is the youngest patient with ROHADD(NET) reported to have very elevated insulin levels. In addition to rapidly progressing obesity, he had impressive linear overgrowth. Hyperglycemia and insulin resistance could be secondary to severe associated obesity and/or speculatively related to his underlying condition. This case expands the reported morbidities associated with this often-fatal disease

Early Onset of Insulin Resistance In a Patient with ROHHAD(NET) Syndrome

Introduction: Graves disease and Hashimoto thyroiditis represent the two ends of the autoimmune thyroid spectrum. Spontaneous conversion from one to the other is a rare phenomenon, especially in children, and the underlying mechanism is unknown. Changes in the predominance of stimulating versus blocking TSH receptor antibodies (TRAb) has been proposed as a potential etiology.Method: We describe a series of cases of autoimmune thyroid disease in children that converted from one end of the biochemical spectrum to the other Result: Eleven patients of whom 55% were girls and 36% had Down syndrome (DS) were identified. Five (46%) presented with hyperthyroidism (hyper) that spontaneously converted to hypothyroidism (hypo). Four patients (36 %) had hypo which converted to hyper while the remaining 2 (18%) presented with Hashitoxicosis (HT) with negative TRAb titers which later converted to hyper. In those who went from hyper to hypo, mean duration of antithyroid drug therapy was 1.8 ± 1.4 years and mean age at initial presentation was 11.0 ± 4.8 years (5-16). Before conversion, all 5 patients had positive TRAb titers with mean of 15.0 ± 4.2 and a mean thyroid peroxidase antibody level of 287.5 ± 389. A period of euthyroidism lasting 2.0 ± 0.8 years was present prior to the development of hypo with a mean TSH of 17.0 ± 25 mU/L (5.8-62). Mean duration of hypo in the second group was 5.0 ± 5.2 years and mean age at initial diagnosis was 6.7 ± 2.8 years (3-10). TSH became suppressed in all 4 patients, TRAb was elevated, and mean free T4 off levothyroxine was 3.3 ± 1.2 ng/dL (2.4-4.6). The two patients with initial HT were 12 ± 2.8 years at diagnosis and converted to hyper after 6.5 ± 0.7 months. Initial mean free T4 was 1.3 ± 0.2 ng/dL and after conversion was 4.6 ± 0.4 ng/dL along with strongly positive TRAb titers (mean of 6.9 ± 6.5). TSH became further suppressed after conversion to hyper (<0.01). More of our patients with DS converted from hypo to hyper than the other direction (75% vs 20%, p=0.01). However, two of them proceeded to have a wavering course between hyper and hypo requiring intensive monitoring and frequent changes in management. Conclusion: Although oscillating thyroid function in children with autoimmune thyroid disease is uncommon, it is important for parents and providers to be aware of this entity. The natural history of these cases is extremely variable and clinical management is challenging. Our findings suggest that DS may be a risk factor for the phenomenon of vacillating thyroid function in pediatric patients.

Conversion from one side of the autoimmune thyroid spectrum to the other: a pediatric clinical challenge

Introduction: Pediatric Graves' disease (GD) is associated with hyperthyroid symptoms broadly impacting psychosocial functioning. Total thyroidectomy (TT) is a definitive treatment option that replaces long-term antithyroid medication (ATD) for GD. While studies have examined health-related quality of life (hrQOL) in adults, there are no data describing impacts of definitive surgery in pediatrics. In this prospective, longitudinal study, we explored the impact of definitive surgery on hrQOL and psychosocial functioning in adolescent patients with GD. Methods: Patients 12-19 years old pursuing definitive surgery for GD and their parents were recruited to complete surveys before and at least six months following TT. Parents pre-operatively completed a demographic questionnaire, parent rating scale assessing perceived symptom severity, and motivations for pursuing TT questionnaire. Patients pre- and post-operatively completed the Pediatric Quality of Life Scales (PedsQL), Quality of Life Questionnaire for Patients with Thyroid Disease (ThyPRO), Perceived Stigmatization Questionnaire (PSQ), Body Esteem Scale for Adolescents and Adults (BESAA), and European Group on Graves' Orbitopathy GO Quality of Life Questionnaire (EUGOGO-QOL). Patients and parents post-operatively completed the Patient and Observer Scar Assessment Scale (POSAS) and a post-surgical satisfaction scale. Longitudinal paired scores were compared using Wilcoxon rank-sum test with Bonferroni-Holm correction. Survey subscore associations were assessed using Spearman tests with Benjamin-Hochberg correction. P-values < 0.10 for survey association analyses and all other p-values < 0. 05 were considered statistically significant. Results: Thirty-six patient/parent dyads completed baseline surveys, including 19 patient/parent dyads completing both pre- and post-TT surveys. Families reported that patients' GD and ATD significantly interfered with quality of life. Motivations for definitive surgery included ease of monitoring hypothyroidism as opposed to hyperthyroidism, access to a 'high-volume' surgeon, desire to reduce goiter symptoms, and opposition to radioactive medication. At baseline, patients reported high physical and cognitive GD symptomology via ThyPRO, specifically hyperthyroid symptoms, tiredness, anxiety, and emotional susceptibility. Psychosocial functioning via PedsQL, specifically in school settings, was depressed. Disease-specific hrQOL (ThyPRO) significantly improved following TT, with notable improvements in goiter (p=0. 002), hyperthyroid symptoms (p=0. 002), tiredness (p=0. 003), and anxiety (p=0. 003). Physical (p=0. 006) and school-related functioning (p=0. 003) improved post-TT (PedsQL), while variables captured by PSQ, BESAA, and EUGOGO-QOL were not significant pre- and post-TT. Reported GD-associated eye symptomology was minimal at baseline and further improved following surgery (p=0. 007). ThyPRO and PedsQL subscores were significantly associated at baseline and change after surgery, suggesting interconnectedness between disease-specific hrQOL and psychosocial functioning. Patients and parents reported median recovery of two months and high satisfaction with the outcomes of definitive surgery, with minimal scar appearance concerns. Conclusions: In the setting of a high-volume surgeon with low complication rates, definitive surgery for GD in pediatric populations has substantial, beneficial effects on disease-specific hrQOL and psychosocial functioning, with minimal adverse scar appearance complaints.

Impact of Definitive Surgery for Graves' Disease on Adolescent Health-Related Quality of Life and Psychosocial Functioning

Background: DICER1 syndrome, a rare autosomal dominant disorder, places affected individuals at risk for benign and malignant tumors of multiple organs, including thyroid, ovaries, lungs, kidneys, CNS. These tumors occur in childhood and usually before 40 years of age. Clinical Case: A 15-year old female presented with worsening abdominal pain and vomiting. She noted a "hard spot" on her abdomen and reported secondary amenorrhea with worsening acne and development of hirsutism over the previous 12 months. Imaging evaluation showed a 9 cm x 19 cm x 13 cm right ovarian mass with no enlarged lymph nodes. Initially, tumor markers and hormone levels were elevated: Alpha Fetoprotein 424 ng/mL [0-7], Testosterone 208 ng/dL [12-60], Free Testosterone 6.03 ng/dL [0.04-1.09], Inhibin A 129 pg/mL [97.5], Inhibin B 817 pg/mL [< 136], LDH 742 unit/L [370-645]. Patient underwent right salpingo-oophorectomy, lymph node and omentum biopsy; pathologic exam showed Stage 1C Sertoli-Leydig tumor of the right ovary (intermediate to poorly differentiated). She received chemotherapy with Cisplatin, Etoposide, Bleomycin. Genetic analysis revealed that she is heterozygous for a likely pathogenic variant, c.343del (p.Thr115Leufs*13) in DICER1, consistent with a diagnosis of autosomal dominant DICER1-associated disease. After therapy ended, her tumor markers and hormone levels normalized. Patient was found to have a multinodular goiter with benign pathology; her thyroid function remained normal. A 2 mm right middle lobe pulmonary nodule, stable, has been present on chest CT. Family history is significant for an euthyroid multinodular goiter with benign nodules in her 2-year older brother who has the same DICER1 pathogenic variant. Their mother and maternal grandmother also had total thyroidectomy for multinodular goiter. Conclusion: A cluster of certain tumors in family members involving successive generations, should prompt evaluation for a genetic cause, as early diagnosis, management and appropriate surveillance improve patients' quality of life.

Ovarian Malignancy, Familial Multinodular Goiter Associated with DICER1 Mutation

Growth hormone (GH) replacement therapy usually requires daily subcutaneous (s.c.) injections that can be burdensome for patients and their caregivers. Somapacitan, a long-acting reversible albumin-binding GH derivative, is in development for once-weekly s.c. administration in children with GH deficiency (GHD). REAL4 is a randomised, multi-national, open labelled, and active-controlled parallel group phase 3 trial, comprising a 52-week main phase and three-year extension period (NCT03811535). Two-hundred GH-treatment-naïve, prepubertal children with GHD (74.5% male) were randomly assigned in a 2: 1 ratio to receive 0.16 mg/kg/week s.c. somapacitan (n=132) or daily s.c. GH (0.034 mg/kg/day Norditropin®; n=68). The 52-week main trial results are presented here. The primary endpoint was annualized height velocity (HV) after 52 weeks of treatment. At week 52, the estimated mean HV was 11.2 cm/year for somapacitan compared to 11.7 cm/year for daily GH. The estimated treatment difference was -0.5 [95% CI -1.1 to 0.2] cm/year, confirming non-inferiority (non-inferiority threshold: -1.8 cm/year). Secondary height-related endpoints supported the primary endpoint. Insulin-like growth factor-I standard deviation score (IGF-I SDS) showed consistent increases for both somapacitan and daily GH over the 52 weeks, with change differences from baseline not statistically significant between treatment groups. At week 52, mean IGF-I SDS levels were similar between somapacitan (+0.28) and daily GH (+0.10) and within normal range (-2 to +2). Somapacitan was well tolerated, with no safety or local tolerability issues identified. There were no clinically relevant findings with respect to changes in glucose metabolism, no neutralizing anti-somapacitan or anti-GH antibodies were detected, and a low number of patients reported injection-site reactions, with similar proportions for somapacitan (5.3%) and daily GH (5.9%). In both treatment groups, 1.5% of patients reported injection site pain. Adherence was high for both treatments. The mean and median adherence for somapacitan treatment were 95.8% and 100%, respectively. The mean and median adherence for the daily GH group were 88.3% and 96.9%, respectively. In conclusion, once-weekly somapacitan has a similar efficacy and safety profile as daily GH with similar mean IGF-I levels in treatment-naïve children with GHD.

BRF1-Mediated Paracrine Signalling by a Subset of SOX2-Expressing Stem Cells is Required for Normal Development of the Stem Cell Compartment and Terminal Differentiation of Pituitary Committed Progenitors

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Molecular determinants of cavernous sinus invasion by pituitary adenomas: functional in vitro studies and in vivo investigations in a rat model of invasive pituitary tumorigenesis obtained by stereotactic pituitary GC cells injection

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