Children with multiple endocrine neoplasia type 2B: Not tall and marfanoid, but short with normal body proportions.

OBJECTIVE: Multiple endocrine neoplasia 2B (MEN2B) is characterised by early-onset medullary thyroid carcinoma (MTC), pheochromocytoma and several nonendocrine manifestations. Unfortunately, MEN2B is often diagnosed late, after the development of clinically significant MTC. Marfanoid habitus is considered an important related feature, which may lead to the assumption that patients with MEN2B have tall stature. Here, we describe the longitudinal growth and body proportions of eight MEN2B patients during childhood. DESIGN: It is a retrospective case series. METHODS: Patients were under the care of a Dutch MEN expertise centre. Growth patterns were assessed and interpreted in relation to body mass index (BMI), age at diagnosis and at thyroidectomy, extensiveness of disease manifestations and parental height. RESULTS: Seven patients were short during childhood, of whom four showed growth below target height range (THR) and three at the lowest margin of THR. Only one patient grew well within THR. All patients who attained final height (n = 4) ended within THR, despite short stature during childhood. Arm span/height ratio was not increased and upper segment/lower segment ratio was not reduced in any patient. Short stature in childhood in this study did not seem to be associated with age at diagnosis, age at thyroidectomy, extensiveness of MTC, endocrine deficiencies or BMI. CONCLUSIONS: This study shows that children with MEN2B may well present with short rather than tall stature. Thereafter, final height within THR was attained in those who already reached adulthood, but none had tall stature. Finally, body proportions were normal in all children and adults in this case series, not underlining a 'marfanoid' body habitus.

Electromagnetic-guided placement of nasoduodenal feeding tubes versus endoscopic placement: a randomized, multicenter trial.

BACKGROUND AND AIMS: Electromagnetic-guided placement (EMP) of a nasoduodenal feeding tube by trained nurses is an attractive alternative to EGD-guided placement (EGDP). We aimed to compare EMP and EGDP in outpatients, ward patients, and critically ill patients with normal upper GI anatomy. METHODS: In 3 centers with no prior experience in EMP, patients were randomized to placement of a single-lumen nasoduodenal feeding tube either with EGDP or EMP. The primary endpoint was post-pyloric position of the tube on abdominal radiography. Patients were followed for 10 days to assess patency and adverse events. The analyses were performed according to the intention-to-treat principle. RESULTS: In total, 160 patients were randomized to EGDP (N = 76) or EMP (N = 84). Three patients withdrew informed consent, and no abdominal radiography was performed in 2 patients. Thus, 155 patients (59 intensive care unit, 38%) were included in the analyses. Rates of post-pyloric tube position between EGDP and EMP were comparable (79% vs 82%, odds ratio 1.16; 90% confidence interval, 0.58-2.38; P = .72). Adverse events were observed in 4 patients after EMP (hypoxia, GI blood loss, atrial fibrillation, abdominal pain) and in 4 after EGDP (epistaxis N = 2, GI blood loss, hypoxia). Costs of tube placements were lower for EMP compared with EGDP: $519.09 versus $622.49, respectively (P = .04). CONCLUSIONS: Success rates and safety of EMP and EGDP in patients with normal upper GI anatomy were comparable. Lower costs and potential logistic advantages may drive centers to adopt EMP as their new standard of care. (Clinical trial registration number: NTR4286.).

Differences in checkpoint-inhibitor-induced hypophysitis: mono- versus combination therapy induced hypophysitis.

Objective: Immune checkpoint inhibitors (ICIs) are revolutionary in oncology but may cause immune-related (IR) side effects, such as hypophysitis. Treatment with anti-PD-(L)1, anti-CTLA-4 or anti-CLTA-4/PD-1 may induce hypophysitis, but little is known about the differences in clinical presentation or need for different treatment. We analyzed the differences of anti-PD-(L)1, anti-CTLA-4 and anti-CTLA-4/PD-1 induced hypophysitis. Methods: retrospective analysis of 67 patients (27 anti-PD-(L)1, 6 anti-CLTA-4 and 34 anti-CTLA-4/PD-1 induced hypophysitis). Results: The median time between starting ICIs and IR-hypophysitis was longer after anti-PD(L)-1) therapy (22 weeks versus 11 and 14 weeks after anti-CTLA-4 and anti-CTLA-4/PD-1 therapy, respectively). The majority of patients (>90%), presented with atypical complaints such as fatigue, nausea, and muscle complaints. Headache, TSH or LH/FSH deficiency were more common in anti-CTLA-4 and anti-CLTA-4/PD-1 versus anti-PD-(L)1 induced hypophysitis (83% and 58% versus 8%, 67% and 41% versus 11%, and 83% and 48% versus 7%, respectively). Pituitary abnormalities on MRI (hypophysitis or secondary empty sella syndrome) were only seen in patients receiving anti-CTLA-4 or anti-CTLA-4/PD-1 therapy. Recovery from TSH, LH/FSH and ACTH deficiency was described in 92%, 70% and 0% of patients after a mean period of 14 and 104 days, respectively, and did not differ between patients who did or did not receive high-dose steroids. Conclusion: The clinical presentation of IR-hypophysitis varies depending on the type of ICIs. MRI abnormalities were only seen in anti-CTLA-4 or anti-CTLA-4/PD-1 induced hypophysitis. Endocrine recovery is seen for LH/FSH and TSH deficiency but not for ACTH deficiency, irrespective of the corticosteroid dose.

Diagnostic Utility of Menin Immunohistochemistry in Patients With Multiple Endocrine Neoplasia Type 1 Syndrome.

A clinical diagnosis of multiple endocrine neoplasia type 1 (MEN1) syndrome is usually confirmed with genetic testing in the germline. It is expected that menin protein expression is lost in MEN1-related tumors. Therefore, we investigated the potential of menin immunohistochemistry in parathyroid adenomas as an additional tool in the recognition and genetic diagnosis of MEN1 syndrome. Local pathology archives were searched for parathyroid tumors from patients with MEN1 syndrome and without MEN1, including sporadic, patients with multiple endocrine neoplasia type 2A and hyperparathyroidism-jaw parathyroid tumors. Menin immunohistochemistry was performed and its use to identify MEN1-related tumors was assessed. Twenty-nine parathyroid tumors from 16 patients with MEN1 and 61 patients with parathyroid tumors from 32 non-MEN1 were evaluated. Immunohistochemical nuclear menin loss in one or more tumors was found in 100% of patients with MEN1 and 9% of patients with non-MEN1. In patients with multiple tumors, menin loss in at least one tumor was seen in 100% of 8 patients with MEN1 and 21% of patients with 14 non-MEN1. Using a cutoff of at least 2 tumors showing menin loss per patient, the positive and negative predictive values for the diagnosis MEN1 were both 100%. The practical and additional value of menin immunohistochemistry in clinical genetic MEN1 diagnosis is further illustrated by menin immunohistochemistry in 2 cases with a germline variant of unknown significance in the MEN1 gene. Menin immunohistochemistry is useful in the recognition of MEN1 syndrome as well as in the clinical genetic analysis of patients with inconclusive MEN1 germline testing.

Correction: Lebbink et al. Opposite Incidence Trends for Differentiated and Medullary Thyroid Cancer in Young Dutch Patients over a 30-Year Time Span. Cancers 2021, 13, 5104.

Error in Figure/Table [...].

Well-Differentiated Bronchopulmonary Neuroendocrine Tumors: More Than One Entity.

INTRODUCTION: Until now, well-differentiated bronchopulmonary neuroendocrine tumors (bpNET) occurring either sporadically (sp-bpNET) or in the context of multiple endocrine neoplasia type 1 (MEN1) and diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) are regarded as similar entities. However, in contrast to sp-bpNET: MEN1-related and DIPNECH-related bpNET rarely metastasize or lead to bpNET-related death. We aimed to describe and compare the course of the disease of sp-bpNET, DIPNECH- and MEN1-related bpNET. METHODS: All patients with histologically confirmed MEN1-related bpNET from the DutchMEN Study Group database (1990-2017), patients with resected sp-bpNET and DIPNECH patients referred to a Dutch European Neuroendocrine Tumor Society center between 2000 and 2018 were included. Fisher's exact test was used for comparison between groups. The primary end point was disease-specific mortality (DSM). Kaplan-Meier and logrank test were used to compare survival. Cox regression was used to identify risk factors for DSM in the sp-bpNET subgroup. RESULTS: We included 112 sp-bpNET, 29 MEN1, and 27 DIPNECH patients. Tumor classification was similar across subgroups. A total of 20 patients (18%) with sp-bpNET died because of bpNET, compared with none in the MEN1 group and DIPNECH group. Median disease-specific survival was 12.3 (confidence interval: 6.3-18.3) years for patients with sp-bpNET, and not estimable for the other subgroups (p < 0.001). Differences in baseline characteristics did not explain worse survival in sp-bpNET. Tumor classification and age at diagnosis were independent risk factors for DSM in sp-bpNET. CONCLUSIONS: Patients with sp-bpNET have a significantly higher DSM compared with MEN1 or DIPNECH-related bpNET, unexplained by differences in baseline characteristics. This implies that not all bpNET are similar entities.

Timely diagnosis of multiple endocrine neoplasia 2B by identification of intestinal ganglioneuromatosis: a case series.

BACKGROUND: Medullary thyroid carcinoma (MTC) in childhood is rare and has an unfavorable prognosis. To improve outcome, early diagnosis is essential. In patients with multiple endocrine neoplasia type 2B (MEN2B), MTC can occur already before the age of 1 year. Recognition of non-endocrine features of MEN2B may lead to timely diagnosis. PURPOSE: To describe how early recognition of non-endocrine features can lead to a timely diagnosis of MEN2B as well as the effect of recognition of premonitory symptoms on prognosis. METHODS: A retrospective case series from the University Medical Center Utrecht/Wilhelmina Children's Hospital, a Dutch national expertise center for MEN patients. All eight MEN2B patients in follow-up between 1976 and 2020 were included and medical records reviewed. RESULTS: Intestinal ganglioneuromatosis (IGN) as the cause of gastrointestinal (GI) symptoms was detected in seven patients. In three of them within months after birth. This led to early diagnosis of MEN2B, which allowed subsequent curative thyroid surgery. On the contrary, a MEN2B diagnosis later in childhood-in three patients (also) triggered by oral neuromas/neurofibromas-led to recurrent, persistent, and/or progressive MTC in five patients. CONCLUSIONS: Neonatal GI manifestations offer the most important window of opportunity for early detection of MEN2B. By accurate evaluation of rectal biopsies in patients with early onset severe constipation, IGN can be timely detected, while ruling out Hirschsprung's disease. MEN2B gene analysis should follow detection of IGN and-when confirmed-should prompt possibly still curative thyroid surgery.

Opposite Incidence Trends for Differentiated and Medullary Thyroid Cancer in Young Dutch Patients over a 30-Year Time Span.

Thyroid cancer is the most common endocrine malignancy in children. A rising incidence has been reported worldwide. Possible explanations include the increased use of enhanced imaging (leading to incidentalomas) and an increased prevalence of risk factors. We aimed to evaluate the incidence and survival trends of thyroid cancer in Dutch children, adolescents, and young adults (0-24 years) between 1990 and 2019. The age-standardized incidence rates of differentiated thyroid cancer (DTC, including papillary and follicular thyroid cancer (PTC and FTC, respectively)) and medullary thyroid cancer (MTC), the average annual percentage changes (AAPC) in incidence rates, and 10-year overall survival (OS) were calculated based on data obtained from the nationwide cancer registry (Netherlands Cancer Registry). A total of 839 patients aged 0-24 years had been diagnosed with thyroid carcinoma (PTC: 594 (71%), FTC: 128 (15%), MTC: 114 (14%)) between 1990 and 2019. The incidence of PTC increased significantly over time (AAPC +3.6%; 95%CI +2.3 to +4.8), the incidence rate of FTC showed a stable trend ((AAPC -1.1%; 95%CI -3.4 to +1.1), while the incidence of MTC decreased significantly (AAPC: -4.4% (95%CI -7.3 to -1.5). The 10-year OS was 99.5% (1990-1999) and 98.6% (2000-2009) in patients with DTC and 92.4% (1990-1999) and 96.0% (2000-2009) in patients with MTC. In this nationwide study, a rising incidence of PTC and decreasing incidence of MTC were observed. For both groups, in spite of the high proportion of patients with lymph node involvement at diagnosis for DTC and the limited treatment options for MTC, 10-year OS was high.

The Management of Neuroendocrine Tumors of the Lung in MEN1: Results From the Dutch MEN1 Study Group.

INTRODUCTION: Multiple endocrine neoplasia type 1 (MEN1)-related neuroendocrine tumors (NETs) of the lung are mostly indolent, with a good prognosis. Nevertheless, cases of aggressive lung NET do occur, and therefore the management of individual patients is challenging. AIM: To assess tumor growth and the survival of patients with MEN1-related lung NETs at long-term follow-up. METHODS: The population-based Dutch MEN1 Study Group database (n = 446) was used to identify lung NETs by histopathological and radiological examinations. Tumor diameter was assessed. Linear mixed models and the Kaplan-Meier method were used for analyzing tumor growth and survival. Molecular analyses were performed on a lung NET showing particularly aggressive behavior. RESULTS: In 102 patients (22.9% of the total MEN1 cohort), 164 lesions suspected of lung NETs were identified and followed for a median of 6.6 years. Tumor diameter increased 6.0% per year. The overall 15-year survival rate was 78.0% (95% confidence interval: 64.6-94.2%) without lung NET-related death. No prognostic factors for tumor growth or survival could be identified. A somatic c.3127A > G (p.Met1043Val) PIK3CA driver mutation was found in a case of rapid growing lung NET after 6 years of indolent disease, presumably explaining the sudden change in course. CONCLUSION: MEN1-related lung NETs are slow growing and have a good prognosis. No accurate risk factors for tumor growth could be identified. Lung NET screening should therefore be based on well-informed, shared decision-making, balancing between the low absolute risk of an aggressive tumor in individuals and the potential harms of frequent thoracic imaging.

Clues For Genetic Anticipation In Multiple Endocrine Neoplasia Type 1.

CONTEXT: Multiple endocrine neoplasia type 1 (MEN1) is a rare autosomal dominant hereditary disease caused by the loss of function of the MEN1 gene, a tumor-suppressor gene that encodes the protein menin. It is characterized by the occurrence of primary hyperparathyroidism (pHPT), duodenopancreatic neuroendocrine tumors (dpNET), pituitary tumors (PIT), adrenal adenomas, and bronchopulmonary (bp-NET), thymic, and gastric neuroendocrine tumors. More insight into factors influencing the age-related penetrance of MEN1 manifestations could provide clues for more personalized screening programs. OBJECTIVE: To investigate whether genetic anticipation plays a role in the largest known MEN1 families in the Netherlands. METHODS: All Dutch MEN1 families with ≥ 10 affected members in ≥ 2 successive generations were identified. Age at detection of the different MEN1-related manifestations were compared among generations using regression analyses adjusted for competing risks. To correct for the beneficial effect of being under surveillance, manifestations occurring during surveillance were also separately compared. RESULTS: A total of 152 MEN1 patients from 10 families were included. A significantly decreased age at detection of pHPT, dpNET, PIT, and bp-NET was found in successive generations (P < 0.0001). Adjusted analyses led to the same results. CONCLUSIONS: These results suggest the presence of genetic anticipation. However, due to a risk of residual bias, the results must be interpreted with caution. After independent validation in other cohorts and further translational research investigating the molecular mechanisms explaining this phenomenon in MEN1, the results might add to future, more personalized, screening protocols and earlier screening for future generations of MEN1 patients.

Clinical Relevance of Genetic Analysis in Patients With Pituitary Adenomas: A Systematic Review.

Pituitary adenomas (PA) are amongst the most prevalent intracranial tumors, causing complications by hormonal overproduction or deficiency and tumor mass effects, with 95% of cases occurring sporadically. Associated germline mutations (AIP, MEN1, CDKN1B, PRKAR1A, SDHx) and Xq26.3 microduplications are increasingly identified, but the clinical consequences in sporadic PA remain unclear. This systematic review evaluates predictors of a genetic cause of sporadic PA and the consequences for treatment outcome. We undertook a sensitive MEDLINE/Pubmed, EMBASE, and Web of Science search with critical appraisal of identified studies. Thirty-seven studies on predictors of mutations and 10 studies on the influence on treatment outcome were included. AIP and MEN1 mutations were associated with young age of PA diagnosis. AIP mutations were also associated with gigantism and macroadenomas at time of diagnosis. Xq26.3 microduplications were associated with PA below the age of five. AIP and MEN1 mutation analysis is therefore recommended in young patients (≤30 years). AIP mutation analysis is specifically recommended for patients with PA induced gigantism and macroadenoma. Screening for Xq26.3 microduplications is advisable in children below the age of five with increased growth velocity due to PA. There is no evidence supporting mutation analysis of other genes in sporadic PA. MEN1 mutation related prolactinoma respond well to dopamine agonists while AIP mutation associated somatotroph and lactotroph adenoma are frequently resistant to medical treatment. In patients harboring an Xq26.3 microduplication treatment is challenging, although outcome is not different from other patients with PA induced gigantism. Effective use of genetic analysis may lead to early disease identification, while knowledge of the impact of germline mutations on susceptibility to various treatment modalities helps to determine therapeutic strategies, possibly lowering disease morbidity.

No evidence for distinguishing bacterial from viral acute rhinosinusitis using symptom duration and purulent rhinorrhea: a systematic review of the evidence base.

OBJECTIVE: To evaluate the diagnostic value of symptom duration and purulent rhinorrhea in adults suspected of having acute bacterial rhinosinusitis. DATA SOURCES: PubMed, EMBASE, and the Cochrane Library. REVIEW METHODS: We performed a comprehensive systematic search on March 28, 2013. We included studies on the diagnostic value of duration of symptoms and purulent rhinorrhea in patients suspected of having acute bacterial rhinosinusitis. We assessed study design of included articles for directness of evidence and risk of bias. We extracted prevalence and positive and negative predictive values. RESULTS: Of 4173 unique publications, we included 1 study with high directness of evidence and moderate risk of bias. The prior probability of bacterial rhinosinusitis was 0.29 (95% confidence interval [CI], 0.24-0.35); we could not extract posterior probabilities. Odds ratios (95% CI) from univariate analysis were 1.03 (0.78-1.36) for duration of symptoms and 2.69 (1.39-5.18) for colored discharge on the floor of the nasal cavity. CONCLUSION AND RECOMMENDATION: We included 1 study with moderate risk of bias, reporting data in such a manner that we could not assess the value of symptom duration and purulent rhinorrhea in adults suspected of having acute bacterial rhinosinusitis. Recommendations to distinguish between a viral and a bacterial source based on purulent rhinorrhea are not supported by evidence, and the decision to prescribe antibiotic treatment should not depend on its presence. Based on judgment driven by theory and subsidiary evidence of a greater likelihood of bacterial rhinosinusitis after 10 days, antibiotic therapy may seem a reasonable empirical option.