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Objective: Cardiovascular complications and congenital malformations are known traits in Turner syndrome (TS), which increases mortality. Women with TS have varying phenotype and cardiovascular risks. A biomarker assessing the risk for cardiovascular complications could potentially reduce mortality in high-risk TS and reduce screening in TS participants with low cardiovascular risk.Design, patients, participants and measurements: As part of a study initiated in 2002, 87 TS participants and 64 controls were invited to magnetic resonance imaging of the aorta, anthropometry, and biochemical markers. TS participants were re-examined thrice lastly in 2016. The focus of this paper is the additional measurements of transforming growth factor beta (TGFβ), matrix metalloproteinase (MMP's), tissue inhibitor of matrix metalloproteinase (TIMP), peripheral blood DNA and their associations with TS and the cardiovascular risk and congenital heart disease.Results: TS participants had lower TGFβ1 and TGFβ2 values compared to controls. snp11547635 heterozygosity was not associated with any biomarkers but was associated with increased risk of aortic regurgitation. TIMP4 and TGFβ1 were correlated with the aortic diameter at several measuring positions. During follow-up, the antihypertensive treatment decreased the descending aortic diameter and increased TGFβ1 and TGFβ2 levels in TS.Conclusion: TGFβ and TIMP's are altered in TS and may play a role in the development of coarctation and dilated aorta. snp11547635 heterozygosity was not found to impact biochemical markers. Further studies should investigate these biomarkers to further unravel the pathogenesis of the increased cardiovascular risk in TS participants. Objective: Cardiovascular complications and congenital malformations are known traits in Turner syndrome (TS), which increases mortality. Women with TS have varying phenotype and cardiovascular risks. A biomarker assessing the risk for cardiovascular complications could potentially reduce mortality in high-risk TS and reduce screening in TS participants with low cardiovascular risk. Design, Patients, Participants and Measurements: As part of a study initiated in 2002, 87 TS participants and 64 controls were invited to magnetic resonance imaging of the aorta, anthropometry, and biochemical markers. TS participants were re-examined thrice lastly in 2016. The focus of this paper is the additional measurements of transforming growth factor beta (TGFβ), matrix metalloproteinase (MMP's), tissue inhibitor of matrix metalloproteinase (TIMP), peripheral blood DNA and their associations with TS and the cardiovascular risk and congenital heart disease. Results: TS participants had lower TGFβ1 and TGFβ2 values compared to controls. snp11547635 heterozygosity was not associated with any biomarkers but was associated with increased risk of aortic regurgitation. TIMP4 and TGFβ1 were correlated with the aortic diameter at several measuring positions. During follow-up, the antihypertensive treatment decreased the descending aortic diameter and increased TGFβ1 and TGFβ2 levels in TS. Conclusion: TGFβ and TIMP's are altered in TS and may play a role in the development of coarctation and dilated aorta. snp11547635 heterozygosity was not found to impact biochemical markers. Further studies should investigate these biomarkers to further unravel the pathogenesis of the increased cardiovascular risk in TS participants.

Context The long-term somatic and psychiatric consequences of Cushing’s syndrome are well-described, but the socioeconomic consequences are largely unknown. Objective We studied employment status, educational level, risk of depression, and other socioeconomic outcomes of Cushing’s syndrome in the years before diagnosis and after surgery. Design Nationwide register-based cohort study. Methods We used a validated algorithm to identify 424 patients operated for adrenal (n = 199) or pituitary Cushing’s syndrome (n = 225) in Denmark from January 1, 1986 to December 31, 2017. We obtained socioeconomic registry data from 10 years before diagnosis (year −10) to 10 years after surgery (year +10) and included a sex- and age-matched reference population. We identified prognostic factors for returning to work using modified Poisson regression. Results Compared to the reference population, the patients’ employment was permanently reduced from year −6 [relative risk (RR) 0.92, 95% CI 0.84-0.99] to year +10 (RR 0.66, 95% CI 0.57-0.76). Sick leave (RR 2.15, 95% CI 1.40-3.32) and disability pension (RR 2.60, 95% CI 2.06-3.27) were still elevated in year +10. Annual income, education, parenthood, relationship status, and risk of depression were also negatively impacted, but parenthood and relationship status normalized after surgery. Among patients, negative predictors of full-time employment after surgery included female sex, low education, comorbidity, and depression. Conclusion Cushing’s syndrome negatively affects a wide spectrum of socioeconomic variables many years before diagnosis of which only some normalize after treatment. The data underpin the importance of early diagnosis and continuous follow-up of Cushing’s syndrome and, not least, the pervasive health threats of glucocorticoid excess.

Objective Although the overall risk of cancer is not increased in Turner syndrome, the pattern of cancer occurrence differs from the general population. We aim to describe the cancer morbidity pattern in Turner syndrome and evaluate the effect of long-term hormone replacement therapy (HRT). Design Nationwide epidemiological study. Methods 1156 females with Turner syndrome diagnosed during 1960–2014, were linked with data from the Danish National Patient Registry. Statistics Denmark randomly identified 115 578 female controls. Stratified Cox regression was used to analyze cancer morbidity, mortality and effect of HRT. Results Overall risk of cancer was not elevated (hazard ratio 1.04 (95% CI: 0.80–1.36)). The risk of skin cancer and benign skin neoplasms was two-fold increased, while the risk of breast cancer was decreased (hazard ratio 0.4 (0.2–0.9)). Turner syndrome (45,X) had a two- to five-fold increased risk of benign CNS tumors, colon and rectal cancers, benign skin neoplasms and skin cancer. Turner syndrome women with a 45,X/46,XX karyotype had an increased risk of tongue cancer. HRT had no impact on the risk of any cancer investigated in this study. Conclusions The lack of one X chromosome might play a role in skin neoplasms, CNS tumors, colon and rectal cancers. The risk of breast cancer is lower than in the general population. Long-term HRT during the premenopausal age range seems not to exert a cancerous effect in Turner syndrome. Increased vigilance concerning specific types of cancer in Tuner syndrome harboring a 45,X karyotype is needed.

BackgroundOphthalmic complications are profound in Marfan syndrome (MFS). However, the overall burden is not well described. Our purpose was to evaluate the ocular morbidity in a nationwide perspective.MethodsWe identified the ocular morbidity in patients with MFS (n=407) by use of Danish national healthcare registers, using number and timing of hospital contacts related to ophthalmic diagnoses, to ophthalmic surgery and to prescriptions for ophthalmic medication. An age-matched and gender-matched background population (n=40 700) was used as comparator.ResultsAmong MFS, 56% (226/407) of the patients had at least one registration of an ophthalmic diagnosis as inpatient or outpatient during the study period (HR of 8.0 (95% CI 7.0 to 9.2)). Seven out of 11 main groups of diagnoses were affected, including ‘Lens’, ‘Choroid and retina’, ‘Ocular muscles, binocular movement, accommodation and refraction’, ‘Glaucoma’, Visual disturbances and blindness’, ‘Vitreous body and globe’, and ‘Sclera, cornea, iris and ciliary body’. The number of surgical procedures as well as the use of ophthalmic medication in patients with MFS was significantly increased.ConclusionThis nationwide epidemiological study of ocular morbidity in MFS demonstrates a profound burden and emphasises the need for thorough and experienced ophthalmological surveillance.

Background Marfan syndrome is associated with abnormalities in the musculoskeletal system including scoliosis, pectus deformities, protrusio acetabuli, and foot deformities. Over a life span, many patients with Marfan syndrome will need treatment; however, the musculoskeletal morbidity over a life span is not well described. The aim of the present study was to assess the overall burden of musculoskeletal disease in patients with Marfan syndrome. Materials and methods A registry-based, nationwide epidemiological study of patients with a Ghent II verified Marfan syndrome diagnosis from 1977 to 2014. Each patient was matched on age, and sex with up to 100 controls from the background population. Results We identified 407 patients with Marfan syndrome and 40,700 controls and compared their musculoskeletal diagnoses and surgical treatments using Cox proportional hazards ratio (HR). The risk of a registration of a musculoskeletal diagnosis in patients with Marfan syndrome was significantly increased compared to controls (HR: 1.94 (1.69–2.24). One out of six with Marfan syndrome was registered with scoliosis (HR: 36.7 (27.5–48.9). Scoliosis was more common in women with Marfan syndrome compared to men (HR: 4.30 (1.73–1.08)). One out of 11 were registered with a pectus deformity HR: 40.8 (28.1–59.3), and one out of six with a deformity of the foot. Primarily pes planus (HR: 26.0 (15.2–44.3). The proportion of patients with Marfan syndrome (94/407) that underwent musculoskeletal surgery was also significantly higher (HR: 1.76 (1.43–2.16)). The major areas of surgery were the spine, pectups correction, and surgery of the foot/ankle. Ten patients with Marfan syndrome had elective orthopedic surgery without being recognized and diagnosed with Marfan syndrome until later in life. None of these had scoliosis, pectus deformity or a foot deformity. Among patients with an aortic dissection, the age at dissection was 34.3 years in those with at least one major musculoskeletal abnormality. In patients without a major abnormality the age at dissection was 45.1 years (p Conclusions The extent of musculoskeletal disease is quite significant in Marfan syndrome, and many will need corrective surgery during their life span. Surgeons should be aware of undiagnosed patients with Marfan syndrome when treating patients with a Marfan syndrome like-phenotype.

PURPOSE: A systematic description of morbidity in 47,XYY syndrome based on nationwide registry data of hospital diagnoses and prescribed medication.METHODS: All males in Denmark diagnosed with 47,XYY syndrome during 1960-2014 were identified. Each was matched with 100 male controls from the general population. Diagnoses related to hospital encounters (1977-2014) and prescriptions (1996-2014) were analyzed by negative binominal regression and Cox regression, respectively.RESULTS: 47,XYY syndrome was associated with a significantly increased overall incidence of hospital diagnoses (incidence rate ratio = 2.30, confidence interval [CI]: 1.99-2.65), including a significantly increased incidence of diagnoses associated with congenital malformations and genetic disorders as well as with psychiatric, neurologic, respiratory, urogenital, endocrine, circulatory, gastrointestinal, and musculoskeletal system disorders. Diagnoses associated with infections, skin and eye disorders were significantly increased as well. 47,XYY syndrome was associated with a significantly increased occurrence of prescriptions overall (hazard ratio = 1.25, CI: 1.10-1.44), with sex hormones and medication related to the urogenital system, blood, and nervous system being most prominently increased.CONCLUSION: 47,XYY syndrome is associated with a significantly increased morbidity owing to a wide variety of diseases. Increased awareness of the diverse morbidity in 47,XYY syndrome may help guide clinicians assessing 47,XYY males, thereby improving long-term health outcomes.

Sex chromosome abnormalities (SCAs) are characterized by gain or loss of entire sex chromosomes or parts of sex chromosomes with the best-known syndromes being Turner syndrome, Klinefelter syndrome, 47,XXX syndrome, and 47,XYY syndrome. Since these syndromes were first described more than 60 years ago, several papers have reported on diseases and health related problems, neurocognitive deficits, and social challenges among affected persons. However, the generally increased comorbidity burden with specific comorbidity patterns within and across syndromes as well as early death of affected persons was not recognized until the last couple of decades, where population-based epidemiological studies were undertaken. Moreover, these epidemiological studies provided knowledge of an association between SCAs and a negatively reduced socioeconomic status in terms of education, income, retirement, cohabitation with a partner and parenthood. This review is on the aspects of epidemiology in Turner, Klinefelter, 47,XXX and 47,XYY syndrome.

PURPOSE: This study aimed to describe the comorbidity pattern in 47,XXX syndrome.METHODS: This was a registry-based study of hospital diagnoses and prescribed medication in a nationwide cohort of females with 47,XXX (n = 103) and 46,XX/47,XXX (n = 57) in which they were compared with 16,000 age-matched general population female controls.RESULTS: The overall occurrence of hospital diagnoses was significantly increased in females with 47,XXX when compared with controls (incidence rate ratio = 2.1, CI = 1.7-2.5), and when divided into 19 organ-specific groups, there was a significantly increased risk in the following 14 groups: infection, blood, endocrine and metabolism, mental, nervous system, eye, ear, respiratory, oral cavity and gastrointestinal, musculoskeletal, perinatal, congenital malformations, external factors, and "other." The risk of being prescribed any medication was not significantly increased in females with 47,XXX when compared with controls (hazard ratio = 1.2, CI = 0.9-1.4). However, when stratified according to medication groups, a significantly increased risk was detected in 4 of 13 groups. The overall occurrence of hospital diagnoses was also significantly increased when females with 46,XX/47,XXX were compared with controls (incidence risk ratio = 1.3, CI = 1.01-1.8), but generally, in comparison with controls, females with 46,XX/47,XXX were less severely affected than females with 47,XXX.CONCLUSION: The 47,XXX syndrome is associated with an increased occurrence of a wide variety of diseases. Increased awareness of this may contribute to improve counseling and clinical assessment of these patients.

The literature about eye, ear, nose, skin, and nervous system disorders in women with Turner syndrome is equivocal. Impaired vision and hearing in women with Turner syndrome have been described, and case reports of Turner syndrome girls suffering from epilepsy have been published, but no large population-based-studies have explored the occurrence of any of these disorders. We aimed to investigate the risk of admission with disorders related to the eye, ear, nose, skin, and nervous system, compared with background females, and the impact of hormone replacement therapy on these conditions. 1,156 females with TS diagnosed during 1960-2014 were identified using the Danish Cytogenetic Central Registry and linked with personal-level data from the National Patient Registry and the Medication Statistics Registry. Statistics Denmark randomly identified 115,577 age-matched background females. Negative binomial regression was used to analyze hospital discharge diagnoses, reporting incidence rate ratios (IRR). Women with Turner syndrome have an increased risk of developing eye disorders (IRR 4.3 (95% CI 3.5-5.4), including cataract, glaucoma, ocular movement, and accommodation. The risk of ear disorders (IRR 35.0 (27.9-43.9)) and nose (IRR 2.2 (1.4-3.6)) was increased in women with Turner syndrome, due to otitis media, cholesteatoma, and hearing loss. Disorders of the nervous system such as epilepsy were increased IRR 6.2 (2.4-15.9), along with skin conditions IRR 2.2 (95%CI 1.7-2.7) like psoriasis, atopic dermatitis, and ingrown nails.

Objectives: Studies indicate that other cardiovascular problems than aortic disease are a burden for patients with Marfan syndrome (MFS). The aim of the study was to assess the extent of this issue. Methods: A registry-based population study of patients with a Ghent II verified MFS diagnosis. Each patient was matched with up to 100 controls on age and sex. From the Danish healthcare system, we identified 407 MFS patients (from 1977 to 2014) and their cardiovascular events and compared them with those in 40,700 controls. Total follow-up time was 16,439 person years. Results: Mitral valve disease was significantly more common in MFS [HR: 58.9 (CI 38.1–91.1)] and happened earlier and more often in women than men with MFS [age at first registration: 22 vs. 38 years, HR: 2.1 (CI 1.0–4.4)]. Heart failure/cardiomyopathy was also more common in MFS [HR: 8.7 (CI 5.7–13.4)] and men were more affected than women, and at younger age [39 vs. 64 years, HR: 0.18 (CI 0.06–0.55)]. In all cases, atrioventricular block [HR: 4.9 (1.5–15.6)] was related to heart surgery. Supraventricular [HR: 9.7 (CI 7.5–12.7)] and ventricular tachycardia [HR: 7.7 (CI 4.2–14.3)] also occurred more often than in the control group. The risk of sudden cardiac death was increased [HR: 8.3 (CI 3.8–18.0)] but the etiology was unclear due to lack of autopsies. Conclusion: Non-aortic cardiovascular disease in patients with MFS is exceptionally prevalent and the range of diseases varies between women and men. Physicians caring for MFS patients must be aware of this large spectrum of cardiovascular diseases. Graphical abstract: [Figure not available: see fulltext.]

BACKGROUND: Survival of medullary thyroid carcinoma (MTC) subgroups in relation to the general population is poorly described. Data on the factors predicting long-term biochemical cure in MTC patients are nonexistent at a population level. A nationwide retrospective cohort study of MTC in Denmark from 1997 to 2014 was conducted, aiming to detect subgroups with survival similar to that of the general population and to identify prognostic factors for disease-specific survival and long-term biochemical cure.METHODS: The study included 220 patients identified from the nationwide Danish MTC cohort between 1997 and 2014. As a representative sample of the general population, a reference population matched 50:1 to the MTC cohort was used.RESULTS: Patients diagnosed with hereditary MTC by screening (hazard ratio [HR] = 1.5 [confidence interval (CI) 0.5-4.3]), patients without regional metastases (HR = 1.4 [CI 0.9-2.3]), and patients with stage I (HR = 1.3 [CI 0.6-3.1]), stage II (HR = 1.1 [CI 0.6-2.3]), and III (HR = 1.3 [CI 0.4-4.2]) disease had an overall survival similar to the reference population. On multivariate analysis, the presence of distant metastases (HR = 12.3 [CI 6.0-25.0]) predicted worse disease-specific survival, while the absence of regional lymph node metastases (odds ratio = 40.1 [CI 12.0-133.7]) was the only independent prognostic factor for long-term biochemical cure.CONCLUSIONS: Patients with hereditary MTC diagnosed by screening, patients without regional metastases, and patients with stages I, II, and III disease may have similar survival as the general population. The presence of distant metastases predicted worse disease-specific survival, while the absence of regional metastases predicted long-term biochemical cure.

Background The completeness of REarranged during Transfection (RET) testing in patients with medullary thyroid carcinoma (MTC) was recently reported as 60%. However, the completeness on a population level is unknown. Similarly, it is unknown if the first Danish guidelines from 2002, recommending RET testing in all MTC patients, improved completeness in Denmark. We conducted a nationwide retrospective cohort study aiming to evaluate the completeness of RET testing in the Danish MTC cohort. Additionally, we aimed to assess the completeness before and after publication of the first Danish guidelines and characterize MTC patients who had not been tested. Methods The study included 200 patients identified from the nationwide Danish MTC cohort 1997-2013. To identify RET tested MTC patients before December 31, 2014, the MTC cohort was cross-checked with the nationwide Danish RET cohort 1994-2014. To characterize MTC patients who had not been RET tested, we reviewed their medical records and compared them with MTC patients who had been tested. Results Completeness of RET testing in the overall MTC cohort was 87% (95% CI: 0.81-0.91; 173/200). In the adjusted MTC cohort, after excluding patients diagnosed with hereditary MTC by screening, completeness was 83% (95% CI: 0.76-0.88; 131/158). Completeness was 88% (95% CI: 0.75-0.95; 42/48) and 81% (95% CI: 0.72-0.88) (89/110) before and after publication of the first Danish guidelines, respectively. Patients not RET tested had a higher median age at diagnosis compared to those RET tested. Median time to death was shorter in those not tested relative to those tested. Conclusion The completeness of RET testing in MTC patients in Denmark seems to be higher than reported in other cohorts. No improvement in completeness was detected after publication of the first Danish guidelines. In addition, data indicate that advanced age and low life expectancy at MTC diagnosis may serve as prognostic indicators to identify patients having a higher likelihood of missing the compulsory RET test.

von Hippel Lindau disease (vHL) is caused by a hereditary predisposition to multiple neoplasms, especially hemangioblastomas in the retina and CNS, renal cell carcinomas (RCC), pheochromocytomas, neuroendocrine pancreatic tumours (PNET) and endolymphatic sac tumours. Evidence based approaches are needed to ensure an optimal clinical care, while minimizing the burden for the patients and their families. This guideline is based on evidence from the international vHL literature and extensive research of geno- and phenotypic characteristics, disease progression and surveillance effect in the national Danish vHL cohort. We included the views and preferences of the Danish vHL patients, ensured consensus among Danish experts and compared with international recommendations. Recommendations: vHL can be diagnosed on clinical criteria, only; however, in most cases the diagnosis can be supported by identification of a pathogenic or likely pathogenic variant in VHL. Surveillance should be initiated in childhood in persons with, or at risk of, vHL, and include regular examination of the retina, CNS, inner ear, kidneys, neuroendocrine glands, and pancreas. Treatment of vHL manifestations should be planned to optimize the chance of cure, without unnecessary sequelae. Most manifestations are currently treated by surgery. However, belzutifan, that targets HIF-2α was recently approved by the U.S. Food and Drug Administration (FDA) for adult patients with vHL-associated RCC, CNS hemangioblastomas, or PNETs, not requiring immediate surgery. Diagnostics, surveillance, and treatment of vHL can be undertaken successfully by experts collaborating in multidisciplinary teams. Systematic registration, collaboration with patient organisations, and research are fundamental for the continuous improvement of clinical care and optimization of outcome with minimal patient inconvenience.

Marfan syndrome (MFS), a rare genetic disease, has a prevalence of 6.5 in 100,000. Studies show that patients with MFS have reduced areal bone mineral density (BMD) compared with non-MFS individuals. We have previously shown that patients with MFS have reduced volumetric BMD and compromised trabecular and cortical bone microarchitecture. The present study was a registry-based, nationwide, population-based, cohort study using register data, aimed to evaluate fracture risk and fracture rates in MFS. We included 406 (196 women) patients with MFS through the Danish National Patient Register and 40,724 (19,327 women) persons, randomly selected and matched from the Civil Registry System. A total of 21.9% of the MFS and 18.9% of the reference population had experienced at least one fracture from 1995 to 2018. The fracture incidence rate was 27.5 per 1000 person-years in the MFS cohort (highest in young men and old women with MFS), and 20.3 per 1000 person-years in the reference population. The overall incidence rate ratio between the MFS and the reference population was 1.35 (95% confidence interval [CI ] 1.18-1.55) for all fractures. When evaluating the risk of being registered with an osteoporosis diagnosis in the Danish National Patient Register, starting relevant treatment for osteoporosis or experiencing a hip or spine fracture, 10.3% of the MFS cohort and 3.3% of the reference population could be classified as being osteoporotic. The between-group subhazard ratio was 3.97 (95% CI 2.56-6.25). Patients with MFS started treatment with an antiosteoporotic drug at a younger age than the reference population (57 [interquartile range 55-67] versus 71 [63-73]) years. The life expectancy in MFS is increasing, resulting in more patients facing diseases that are related to old age, such as age-related bone loss and increased risk of fractures. Our data suggest that bone health and fracture prevention needs to be part of the standard care for patients with MFS. © 2021 American Society for Bone and Mineral Research (ASBMR).

Context Pheochromocytoma and sympathetic paraganglioma (PPGL) are rare catecholamine-secreting tumors but recent studies suggest increasing incidence. Traditionally, PPGL are described to present with paroxysmal symptoms and hypertension, but existing data on clinical presentation of PPGL come from referral centers. Objective We aimed to describe time trends in clinical presentation and incidence of PPGL in a population-based study. Methods We conducted a nationwide retrospective cohort study of a previously validated cohort of 567 patients diagnosed with PPGL in Denmark 1977-2015. We collected clinical data from medical records of a geographic subcohort of 192 patients. We calculated age-standardized incidence rates (SIRs) and prevalence for the nationwide cohort and descriptive statistics on presentation for the subset with clinical data. Results SIRs increased from 1.4 (95% CI 0.2-2.5) per million person-years in 1977 to 6.6 (95% CI 4.4-8.7) per million person-years in 2015, corresponding to a 4.8-fold increase. The increase was mainly due to incidentally found tumors that were less than 4 cm and diagnosed in patients older than 50 years with no or limited paroxysmal symptoms of catecholamine excess. On December 31, 2015, prevalence of PPGL was 64.4 (CI 95% 57.7-71.2) per million inhabitants. Of 192 patients with clinical data, 171 (89.1%) had unilateral pheochromocytoma, while unilateral paraganglioma (n = 13, 6.8%) and multifocal PPGL (n = 8, 4.2%) were rare. Conclusion Incidence of PPGL has increased 4.8-fold from 1977 to 2015 due to a “new” group of older patients presenting with smaller incidentally found PPGL tumors and few or no paroxysmal symptoms.

Introduction: Aortic disease is the major cardiovascular disease in Marfan syndrome (MFS), however numerous studies indicate that other heart conditions may also be a major disease burden for patients with MFS Hypothesis: We hypothesized that the burden of non-aortic cardiovascular disease in MFS is considerable and the aim of the study is therefore to assess the extent of this issue in Danish patient with MFS. Methods: A register-based population study of Danish patients with a Ghent II verified Marfan Syndrome diagnosis. All patients were alive January 1st 1994, at the beginning of the ICD-10 system. Each patient was age-matched with up to 100 controls with the same sex. Results: We identified 407 MFS patients from the Danish healthcare system (1977-2014) and compared our findings with 40,700 persons from the background population. We found the following hazard ratios and confidence intervals: Mitral valve disease HR: 60.8 [39.5-93.5], pCardiomyopathy HR:12.7 [5.8-28.0], pHeart failure HR 8.2 [5.2-12.9], p Tachyarrhythmia HR: 9.7 [7.5-12.6], p AV-Block HR: 4.7 [1.5-15.1], pSudden cardiac death HR: 8.3 [3.8-18.0], pDiscussion: The registration of mitral valve disease occurred earlier and more often in women with MFS compared to men with MFS (age at registration: 22 vs. 38 years, HR: 2.2 (1.1-4.6) Among patients with arrhythmia 20 % had ventricular ectopics or tachycardia. Forty percent of the cases with tachyarrhythmia were unrelated to heart surgery and 37 % of the total cohort had tachyarrhythmia without having any surgery done. AV-block was in all cases related to heart surgery. Twenty patients with MFS had a registration with heart failure, whereof 9 were diagnosed unrelated to heart surgery. Looking only at registrations unrelated to heart surgery the HR was 4.8 (2.5-9.5). There was no difference in registration of heart failure between men and women. The sudden cardiac death etiology was unclear due to lack of autopsies. Conclusion: The burden of non-aortic cardiovascular disease is massive in patients with MFS and this must be in focus in the caretaking of patients with MFS

Liver and gastrointestinal diseases are frequent in women with Turner syndrome. However, their association with bleeding disorders, anaemia and the impact of hormone replacement therapy is unknown.To investigate the risk of liver and gastrointestinal diseases, haemorrhage and anaemia in women with Turner syndrome compared with the female background population, and the long-term impact of hormone replacement therapy on these conditions.One thousand one hundred and fifty-six women with Turner syndrome diagnosed during 1960-2014 were identified using the Danish Cytogenetic Central Registry and linked with personal-level data from the National Patient Registry and the Medication Statistics Registry. Statistics Denmark randomly identified 115 577 age-matched female controls. Negative binomial regression was used to analyse hospital discharge diagnoses. Medical prescriptions, mortality and the effect of hormone replacement therapy were estimated using stratified Cox regression.Liver disease increased 13-fold (IRR 12.9 (95% CI 5.8-28.8)), due to toxic liver disease (IRR 8.0 (95% CI 1.8-35.4)), liver insufficiency (IRR 6.7 (95% CI 1.7-26.9)), fibrosis/cirrhosis (IRR 16.5 (95% CI 2.2-122.1)) and unspecified liver disease (IRR 10.6 (95% CI 4.4-25.3)). Furthermore, presence of abnormal liver enzymes increased 12-fold (IRR 12.4 (95% CI 4.2-36.6)). The risk of gastrointestinal haemorrhage (IRR 3.4 (95% CI 1.8-6.2)), anaemia (IRR 3.2 (95% CI 2.0-5.0)) and coagulation disorders (IRR 2.9 (95% CI 1.1-7.1)) was increased. However these diagnoses were not associated with inflammatory bowel disease. Gastrointestinal mortality was increased three-fold (HR 3.1 (95% CI 1.5-6.2)), partly due to death by liver disease (HR 3.0 (95% CI 1.1-8.2)), gastrointestinal haemorrhage (HR 29.6 (95% CI 3.1-285.1)) and capillary malformations (HR 18.6 (95% CI 4.1-85.0)). There was no effect of hormone replacement therapy on gastrointestinal risk but a trend towards a beneficial impact on liver diseases.The risk of being diagnosed with liver disease was higher than previously reported. The occurrence of gastrointestinal haemorrhage and anaemia was increased in Turner syndrome. There was no effect of hormone replacement therapy on gastrointestinal risk but a trend towards a beneficial impact on liver diseases was detected.

Context Acromegaly is an insidious disease associated with severe somatic morbidity but data on socioeconomic status are scarce. Objective To study the socioeconomic status in acromegaly in a population-based follow-up study. Methods All incident cases of acromegaly (n = 576) during the period 1977-2010 were included. For every patient, 100 persons were sampled from the general population matched for date of birth and gender (comparison cohort). Cox regression and hazard ratios (HR), conditional logistic regression and linear regression with 95% confidence intervals (CI) were used. Outcome Measures Retirement, social security benefit, annual income, cohabitation, separation, parenthood and educational level. Results The proportion of retired individuals was significantly higher in patients with acromegaly after the time of diagnosis (HR, 1.43; 95% CI, 1.26-1.62) and also during the 5-year pre-diagnostic period (HR, 1.15; 95% CI, 1.03-1.28). More individuals with acromegaly received social security benefit compared with the comparison cohort during the initial period after the time of diagnosis. Among patients who maintained a job, the annual income was similar to the comparison cohort. Compared with the background population, cohabitation was lower (HR, 0.69; 95% CI, 0.50-0.95) as was parenthood (HR, 0.56; 95% CI, 0.39-0.80), whereas neither educational level (HR, 0.61; 95% CI, 0.35-1.06) nor separation (HR, 1.13; 95% CI, 0.86-1.47) were different. Female gender and insufficient disease control were associated with a significantly worse socioeconomic status. Conclusions 1) Socioeconomic status is impaired in patients with acromegaly even before a diagnosis of acromegaly. 2) Females and patients without disease remission have worse outcomes. 3) Early diagnosis and effective treatment of acromegaly could be important factors in mitigating the negative impact on socioeconomic factors.

Background: Gastrointestinal disorders, such as celiac disease, inflammatory bowel diseases and liver disease have previously been described with increased occurrence in women with Turner syndrome. However, evidence towards increased occurrence of bleeding disorders and anemia are sparse. Likewise, the impact of hormone replacement therapy on gastrointestinal disorders remains unknown. Aim: To investigate the risk of bleeding disorders, anemia, gastrointestinal and hepatological disease in women with TS compared with the female background population and to assess the effect of HRT on these conditions. Design: National cohort study Method: 1,156 females with TS diagnosed during 1960–2014 were identified using the Danish Cytogenetic Central Registry and linked with personal-level data from the National Patient Registry and the Medication Statistics Registry. Statistics Denmark randomly identified 115,577 age-matched female controls. Negative binomial regression was used to analyze hospital discharge diagnoses. Medical prescriptions, mortality and the effect of hormone replacement therapy were estimated using stratified Cox regression. Results: The risk of anemia, coagulation disorders and gastrointestinal hemorrhage were all increased three-fold in women with TS compared with controls. Gastrointestinal disorders were twice as frequent in TS individuals, with a three-fold increased risk of inflammatory bowel disease and a twelve-fold increased risk of liver disease and elevated liver enzymes. Both gastrointestinal and hepatological mortality were increased three-fold in TS women. Conclusion: Anemia, gastrointestinal hemorrhage, inflammatory bowel disease is more frequent in women with Turner syndrome compared with controls. The risk of liver disease may be higher than previously reported.

Context The long-term effects of female hormone replacement therapy (HRT) in Turner syndrome (TS) are unknown. Objective To examine morbidity, mortality and medicinal use in TS and the impact of HRT in 45,X women. Design and Setting National cohort study, following all TS individuals ever diagnosed in Denmark from 1977 to 2014. Patients and Methods In the Danish Cytogenetic Central Registry, we identified 1156 females diagnosed with TS from 1960 to 2014, and, subsequently, Statistics Denmark randomly identified 115 577 age-matched female controls. TS women and their matched controls were linked with person-level data from the National Patient Registry and the Medication Statistics Registry, and they were compared concerning mortality, hospitalizations, and medical prescriptions. Among 329 45,X women, 44 had never been HRT treated, and 285 had been treated at some point. HRT treated women were compared with untreated concerning mortality, hospitalizations, and medical prescriptions. Results Endocrine and cardiovascular mortality and morbidity were significantly increased in TS compared with the matched controls. Comparing HRT treated with nontreated 45,X women, we found a similar mortality (hazard ratio 0.83, 95% confidence interval 0.38–1.79). Among the HRT-treated 45,X women, we found a significantly lower use of antihypertensives, antidiabetics, and thyroid hormones and significantly reduced hospitalization rates for stroke and osteoporotic fractures. Conclusion Women with TS have an increased overall mortality and morbidity. HRT seems to have a beneficial effect on endocrine conditions, hypertension, and stroke in women with 45,X karyotype, with no clear impact on mortality.

Introduction Cowden syndrome is a cancer predisposition syndrome caused by pathogenic variants in PTEN. The affected patients possess an increased risk of breast, thyroid, renal, colorectal, endometrial cancers as well as malignant melanoma. Thus prophylactic surveillance and follow up is crucial for these patients. Methods A review of the literature including existing guidelines from the years 1996 until 2017 was carried out. In total, 2078 scientific papers were identified through database searches on Cowden syndrome. Among these, 11 manuscripts were included based on scientific relevance and quality. Expert consensus was reached to define management guidelines. Results The literature revealed a high risk of cancer in specific organs for patients diagnosed with Cowden Syndrome. Alternative management guidelines were proposed and discussed. Conclusions Here we propose a revised set of management guidelines for patients with Cowden syndrome in Denmark to address the increased risk of various cancer types.

Andreas Ebbehoj,1,2 Sarah Forslund Jacobsen,3 Christian Trolle,1 Maciej Grzegorz Robaczyk,4 Åse Krogh Rasmussen,3 Ulla Feldt-Rasmussen,3 Reimar Wernich Thomsen,5 Per Løgstrup Poulsen,1 Kirstine Stochholm,1 Esben Søndergaard1 1Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark; 2Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; 3Department of Endocrinology, Rigshospitalet, Copenhagen, Denmark; 4Department of Endocrinology, Aalborg University Hospital, Aalborg, Denmark; 5Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark Background: Pheochromocytoma and catecholamine-secreting paraganglioma (PPGL) are rare but potentially life-threatening tumors. We aimed to validate diagnosis codes for PPGL in the Danish National Patient Registry, the Danish National Pathology Registry, and the Danish Registry of Causes of Death and to create a national cohort of incident PPGL patients by linking these three registries. Patients and methods: We obtained data from the three abovementioned registries for all individuals registered with pheochromocytoma or catecholamine hypersecretion in Denmark during 1977–2016 (average population 5.30 million). We then reviewed health records for all individuals living in the North Denmark Region and Central Denmark Region (average population 1.75 million) to validate the diagnosis of PPGL. We tested a number of algorithms for accurately identifying true cases of PPGL to maximize positive predictive values (PPVs) and completeness. The best algorithm was subsequently validated in an external sample. Results: We identified 2626 individuals with a PPGL diagnosis code in Denmark, including 787 (30.0%) in the North Denmark Region and Central Denmark Region. In this subsample, we retrieved the health records of 771/787 (98.0%) individuals and confirmed 198 incident PPGL patients (25.3%). The PPV of PPGL diagnosis codes was 21.7% in the Danish National Patient Registry, 50.0% in the Danish Registry of Causes of Death, and 79.5% in the Danish National Pathology Registry. By combining patterns of registrations in the three registries, we could increase the PPV to 93.1% (95% confidence interval [CI]: 88.5–96.3) and completeness to 88.9% (95% CI: 83.7–92.9), thus creating a national PPGL cohort of 588 patients. PPV for the optimal algorithm was 95.3% (95% CI: 88.5–98.7) in the external validation sample. Conclusion: Diagnosis codes for pheochromocytoma had low PPV in several individual health registries. However, with a combination of registries we were able to identify a near-complete national cohort of PPGL patients in Denmark, as a valuable source for epidemiological research. Keywords: registry-based research, International Classification of Diseases, ICD, Systematized Nomenclature of Medicine, SNOMED, hospital register diagnoses, pathology register, cause of death register

Context: Little is known about long-term health outcomes in phenotypic females with 46,XY disorders of sex development (XY females) and the socioeconomic profile is not described in detail.Objective: To describe morbidity, mortality and socioeconomic status in XY females in a comparison to the general population.Design: A nationwide registry study with complete follow-up.Setting: A uniform public health care system.Patients or other participants: 123 XY females karyotyped in Denmark during 1960-2012 and a randomly selected age-matched control cohort of 12,300 females and 12,300 males from the general population.Interventions: None.Main outcome measures: combined mortality and morbidity as well as chapter-specific morbidity. Medicinal use and socioeconomic profile, including education, cohabitation and retirement.Results: Compared to female controls overall morbidity was increased in XY females (HR=1.72, CI: 1.43-2.08) but not when disregarding diagnostic chapters associated with either the specific DSD diagnosis or pregnancy and birth (HR=1.13, CI: 0.93-1.37). Mortality was similar to controls (HR=0.79, CI: 0.35-1.77). Cohabitation (HR=0.44, CI: 0.33-0.58) and motherhood (HR=0.10, CI=0.05-0.18) were reduced in XY females but educational level (HR=0.92, CI: 0.61-1.37) was similar to controls. Income diverged during life with XY females having respectively a lower and higher income in the younger and older years.Conclusions: Morbidity was not increased in XY females when disregarding diagnoses closely related to the DSD condition. Judged on educational level and income XY females perform well on the labor market. However, DSD seems to impact on the prospects of family life.​.

Study question What is the epidemiology and trajectory of health and socioeconomic status in males with 46,XX disorders of sex development (DSD)? Summary answer 46,XX DSD males had an increased overall morbidity compared to male background population controls, and the socioeconomic status was inferior on outcome parameters such as education and long-term income. What is known already 46,XX DSD males are rare and estimates of prevalence and incidence are limited. An increased morbidity and mortality as well as a negatively affected socioeconomic status are described in males with Klinefelter Syndrome. However, this has never been systematically studied in 46,XX DSD males. Study design, size, duration In this nationwide registry study including 44 males with a verified diagnosis of 46,XX DSD we aimed to estimate incidence, prevalence and diagnostic delay. Further, we aimed to study morbidity, mortality and socioeconomic outcome parameters using the Danish registries. The socioeconomic outcome parameters were education, income, retirement, parenthood and cohabitation. 46,XX DSD males were born during 1908-2012 and follow-up started at birth or at start of registration and ended in 2014. Participants/materials, setting, methods Potential cases (n = 69) were identified in the Danish Cytogenetic Central Registry and the diagnosis was verified by medical record evaluation (n = 44). A randomly selected age-matched control group of 100 males and 100 females per case was identified by Statistics Denmark. Main results and the role of chance Among newborn males the prevalence of diagnosed 46,XX DSD males was 3.5-4.7 per 100 000. Median age at diagnosis was 17.0 years (range: 0.0-62.8). Overall morbidity was increased compared to male controls (hazard ratio [HR] = 2.4, 95% CI: 1.8-3.3) but not when excluding endocrine and urogenital diseases as well as congenital malformations (HR = 1.2, 95% CI: 0.8-1.6). Mortality was not increased (HR = 0.6, 95% CI: 0.2-2.5) compared to male controls. 46,XX DSD males had poorer education (HR = 0.1, 95% CI: 0.0-0.9) and fewer fatherhoods (HR = 0.4, 95% CI: 0.2-0.7) than male controls, and their income was reduced for the following age groups; 45-49 years: odds ratio [OR] = 0.4 (95% CI: 0.2-0.7); 50-54 years: OR = 0.1 (95% CI: 0.0-0.6). Limitations, reasons for caution The study cohort is rather small, although it is large in comparison to other studies on 46,XX DSD males. Some 46,XX DSD males may have been excluded from the study owing to lack of data in medical records, making the diagnosis impossible to verify. As in all epidemiologic studies a risk of misclassification must be considered when interpreting the study results, and as the study included diagnosed 46,XX DSD males only, conclusions cannot be extended to non-diagnosed 46,XX DSD males. Wider implications of the findings This study provides a new insight into trajectory of health and socioeconomic status of 46,XX DSD males. Study funding/competing interest(s) This study was funded by research grants from the Health Research Fund of Central Denmark Region, the A.P. Moller Foundation 'Fonden til Laegevidenskabens Fremme', the Lundbeck Foundation and the Novo Nordisk Foundation (NNF13OC0003234 and NNF15OC0016474). The authors have nothing to declare. Trial registration number N/A.

BACKGROUND: Germline mutations of the REarranged during Transfection (RET) proto-oncogene cause multiple endocrine neoplasia 2 (MEN2). It is unclear whether the distribution of RET mutations varies among populations. The first nationwide study of the distribution of RET mutations was conducted, and the results were compared to those of other populations.METHODS: This retrospective cohort study included 1583 patients who underwent RET gene testing in one of three centers covering all of Denmark between September 1994 and December 2014. Primary testing method was Sanger sequencing, which included exons 8-11 and 13-16. Mutations were defined according to the ARUP database July 1, 2016.RESULTS: RET mutations were identified in 163 patients from 36 apparently unrelated families. Among the 36 families 13 (36.1%) carried mutations in codon 611, four (11.1%) in codon 618, three (8.3%) in codon 620, one (2.8%) in codon 631, six (16.7%) in codon 634, one (2.8%) in codon 790, one (2.8%) in codon 804, one (2.8%) in codon 852, one (2.8%) in codon 883, and five (13.9%) in codon 918. Among the 13 families with codon 611 mutations, 12 had the p.C611Y mutation.CONCLUSIONS: The distribution of RET mutations in Denmark appears to differ from that of other populations. Mutations in codon 611 were the most prevalent, followed by more frequently reported mutations. This might be due to a possible founder effect for the p.C611Y mutation. However, further studies are needed to find possible explanations for the skewed mutational spectrum in Denmark.

Gonadoblastoma and malignant transformations thereof can occur in females with Turner syndrome (TS) and Y chromosomal material. However, in females with TS and no Y chromosomal material, this is rarely seen. We report a female with an apparent 45,X karyotype (in blood and tumor) who was diagnosed with a metastatic embryonal carcinoma. Exome sequencing of blood and the tumor was done, and no Y chromosomal material was detected, while predicted deleterious mutations in KIT (likely driver), AKT1, and ZNF358 were identified in the tumor. The patient was treated with chemotherapy (first-line: cisplatin, etoposide, and bleomycin; second-line: paclitaxel and gemcitabine), and after that surgical debulking was performed. She is currently well and without signs of relapse. We conclude that embryonal carcinoma can apparently occur in 45,X TS without signs of Y chromosomal material.

Turner syndrome is a rare condition in women that is associated with either complete or partial loss of one X chromosome, often in mosaic karyotypes. Turner syndrome is associated with short stature, delayed puberty, ovarian dysgenesis, hypergonadotropic hypogonadism, infertility, congenital malformations of the heart, endocrine disorders such as type 1 and type 2 diabetes mellitus, osteoporosis and autoimmune disorders. Morbidity and mortality are increased in women with Turner syndrome compared with the general population and the involvement of multiple organs through all stages of life necessitates a multidisciplinary approach to care. Despite an often conspicuous phenotype, the diagnostic delay can be substantial and the average age at diagnosis is around 15 years of age. However, numerous important clinical advances have been achieved, covering all specialty fields involved in the care of girls and women with Turner syndrome. Here, we present an updated Review of Turner syndrome, covering advances in genetic and genomic mechanisms of disease, associated disorders and multidisciplinary approaches to patient management, including growth hormone therapy and hormone replacement therapy.

Background:Although the 47,XYY syndrome is one of the most common sex chromosome abnormalities in males, as being diagnosed in 18 per 100,000 newborns, little is known about the long-term health outcomes of this condition. Objective:To describe morbidity in a national cohort of 47,XYY males as compared to the general male population using complete data on hospital admissions and prescribed medication. Design and setting:A nationwide registry study with complete follow-up in a uniform public health care system. Participants:A total of 251 males with 47,XYY (n=205), 46,XY/47,XYY (n=28) or compatible karyotypes (n=18) diagnosed during 1965-2014 and a randomly selected age-matched control cohort of 25,100 males from the general population. Results:The risk of being admitted to hospital owing to any diagnosis was significantly increased in 47,XYY compared to controls (HR=1.8, CI:1.6-2.4). Dividing diagnoses into 18 diagnostic groups showed an increased risk of admission in all but three groups. The highest HR was observed for congenital malformations (HR=6.1, CI: 4.8-7.6); psychiatric diseases (HR=5.7, CI: 4.5-7.1); endocrine and metabolic disorders (HR=3.2, CI: 2.4-4.4); neurologic diseases (HR=3.0, CI:2.2-4.0); and urogenital system disorders (HR=3.0, CI: 2.4-3.7). Overall, 47,XYY had an increased risk of receiving medicinal prescriptions compared to controls (HR=1.3, CI:1.1-1.5), and it was significantly increased in 11 out of 14 medicinal prescription groups. The highest HR was observed for medication related to the blood (HR=2.5, CI:1.8-3.5) and the nervous system (HR=2.2, CI:1.9-2.7) as well as for urogenital system disorders and sex hormones (HR=2.7, CI: 2.0-3.7). Conclusions:This study of an unselected nationwide cohort of males affected by the 47,XYY syndrome shows that an additional Y chromosome is associated with an increased morbidity as interpreted from data of hospital admissions and medicinal prescriptions. Approximately 80% of males affected by the 47,XYY syndrome suffer from non-diagnosis, and it remains unknown whether these data extend to those not yet diagnosed.

Background: In Turner Syndrome (TS) it is recommended to induce puberty around 11-12 years of age, by initiating hormone replacement therapy (HRT), when premature ovarian failure is diagnosed. However, evidence for the long-term effects on morbidity and mortality is sparse and it is unknown how many TS receive HRT as recommended according to guidelines. Aim: To describe the incidence of cardiovascular and endocrine related morbidity and mortality, and the association with HRT in TS. Design: Nationwide epidemiological study using Danish registries on medications and healthcare contacts. Methods: We identified 1.156 women with Turner Syndrome diagnosed from 1960-2014 using The Danish Cytogenetic Central Registry and linked them with the Danish National Patient Register and the Medication Statistics Register. Statistics Denmark randomly identified 115.578 controls matched on gender and age. We used Stratified Cox regression to analyze morbidity, mortality and prescriptions, computing proportional hazard ratios (HR). Results: Women with TS had more than doubled risk of cardiovascular diseases such as arrhythmia, heart failure, hypertension, ischemic heart disease, stroke, and endocrine diseases such as thyroid disorders. Similar a 4-fold increase in the risk of diabetes type I and II and osteoporosis was seen. Many TS (17-33% depending on karyotype) never received HRT. Overall mortality in TS was 3-fold increased. Among TS with 45,X receiving HRT, mortality was lower than among HRT non-treated 45,X (HR 5.0 (3.0-8.2) vs. HR 3.0 (1.9-4.5)). We saw a significant reduction in use of antihypertensive medication (HR 0.5 (95% CI 0.4-0.7)), antidiabetics (HR 0.4 (95% CI 0.2-0.9)) and thyroid hormones (HR 0.5 (95% CI 0.3-0.9)) in HRT treated 45,X women compared to HRT non-treated 45,X women. Conclusion: 17-33% of TS women never received HRT. Mortality is increased 3-fold in all TS compared with controls, and 45,X women that did receive HRT had a lover mortality than those who did not. HRT have a beneficial effect on endocrine conditions, hypertension and stroke.

Background: Knowledge on the prevalence of sex chromosome abnormalities (SCAs) is limited, and delayed diagnosis or non-diagnosis of SCAs are a continuous concern. We aimed to investigate change over time in incidence, prevalence and age at diagnosis among Turner syndrome (TS), Klinefelter syndrome (KS), Triple X syndrome (Triple X) and Double Y syndrome (Double Y). Methods: This study is a nationwide cohort study in a public health care system. The Danish Cytogenetic Central Registry (DCCR) holds information on all karyotypes performed in Denmark since 1961. We identified all individuals in the DCCR with a relevant SCA during 1961-2014; TS: n = 1156; KS: n = 1235; Triple X: n = 197; and Double Y: n = 287. From Statistics Denmark, which holds an extensive collection of data on the Danish population, complete data concerning dates of death and migrations in and out of Denmark were retrieved for all individuals. Results: The prevalence among newborns was as follows: TS: 59 per 100,000 females; KS: 57 per 100,000 males; Triple X: 11 per 100,000 females; and Double Y: 18 per 100,000 males. Compared with the expected number among newborns, all TS, 38% of KS, 13% of Triple X, and 18% of Double Y did eventually receive a diagnosis. The incidence of TS with other karyotypes than 45,X (P < 0.0001), KS (P = 0.02), and Double Y (P = 0.03) increased during the study period whereas the incidence of 45,X TS decreased (P = 0.0006). The incidence of Triple X was stable (P = 0.22). Conclusions: The prevalence of TS is higher than previously identified, and the karyotypic composition of the TS population is changing. Non-diagnosis is extensive among KS, Triple X and Double Y, whereas all TS seem to become diagnosed. The diagnostic activity has increased among TS with other karyotypes than 45,X as well as among KS and Double Y.

Background Pheochromocytomas and catecholamine-secreting paragangliomas (PPGL) are rare catecholamine-producing tumors. Due to the rarity, limited data on prognosis exists. Here, we present national data on mortality for radically operated patients compared to the background population over a period of 40 years. Materials and methods We have previously identified a national cohort of 588 PPGL patients diagnosed in Denmark 1977-2016. After excluding 80 patients diagnosed post-mortem, we found that out of 508 patients diagnosed alive, 479 (94%) underwent radical surgery. Each operated patient was matched on birth year, age and sex with 100 random controls from the general population. PPGL patients and comparison cohort members were then followed from date of surgery (or matched index date) to date of death, emigration or 31st of December 2016. Mortality rate-ratios (MRR) were calculated in patient-comparisons strata using Cox regression and adjusted for Charlson Comorbidity Index (CCI). CCI was determined using diagnosis codes registered before time of PPGL diagnosis (or matched index date). To identify prognostic factors, we obtained health records and analyzed clinical data in a geographic subgroup of patients (N=162). Results Operated PPGL patients had a median age of 55 years (Q1-Q3 42-65) and 56% were female. 26% of PPGL patients had a Charlson Comorbidity Index of 2 or more, compared to only 9% in the comparison cohort, with a higher proportion of patients registered with cardiovascular disease (19% vs 7%), cancer (16% vs 5%) and with diabetes (12% vs 3%). Median follow-up time for patients was 7.2 years (Q1-Q3 3.4-15.6), with 10- and 20-year survival after surgery of 78% (95% CI 73-82) and 64% (95% CI 57-69), respectively. MRR for PPGL patients was 1.8 (95% CI 1.5-2.2) compared to the comparison cohort and 1.4 (95% CI 1.2-1.7) when adjusted for CCI. In the subcohort of PPGL patients with available clinical data (N=162), we found, that patients diagnosed with PPGL due to diagnostic work-up for secondary hypertension (N=27) had the highest mortality after surgery with an adjusted MRR of 3.1 (95% CI 1.7-5.8) compared to these patients’ matched comparison cohorts. Adjusted MRR was 0.9 (95% CI 0.4-1.8, N=49) for patients evaluated for paroxysmal symptoms, 1.0 (95% CI 0.2-4.6, N=16) for patients diagnosed due to hereditary PPGL in family or after syndromic presentation, 1.3 (95% CI 0.7-2.2, N=58) for adrenal incidentalomas, and 2.2 (95% CI 0.9-4.9, N=10) in patients diagnosed due to other causes. Conclusion PPGL patients undergoing radical curative surgery have a higher mortality compared to the background population even when considering their higher comorbidity index at time of diagnosis. Especially patients diagnosed due to work-up for secondary hypertension have an increased mortality. These results indicate that radical surgery might not completely reverse the harmful effects of PPGL.

Recombinant human GH (rhGH) has been in use for 30 years, and over that time its safety and efficacy in children and adults\ud has been subject to considerable scrutiny. In 2001, a statement from the GH Research Society (GRS) concluded that\ud ‘for approved indications, GH is safe’; however, the statement highlighted a number of areas for on-going surveillance of\ud long-term safety, including cancer risk, impact on glucose homeostasis, and use of high dose pharmacological rhGH\ud treatment. Over the intervening years, there have been a number of publications addressing the safety of rhGH with regard\ud to mortality, cancer and cardiovascular risk, and the need for long-term surveillance of the increasing number of adults who were treated with rhGH in childhood. Against this backdrop of interest in safety, the European Society of Paediatric\ud Endocrinology (ESPE), the GRS, and the Pediatric Endocrine Society (PES) convened a meeting to reappraise the safety of\ud rhGH. The ouput of the meeting is a concise position statement.

The acute metabolic actions of hGH were discovered in GH-deficient adults (GHDA) 60 years ago and placebo controlled trials of prolonged rhGH replacement therapy appeared 30 years after. Untreated GHDA causes excess morbidity and mortality from cardiovascular disease and the clinical features include fatigue, reduced aerobic exercise capacity, abdominal obesity, reduced lean body mass, osteopenia, and elevated levels of circulating cardiovascular risk biomarkers. Several of these abnormalities normalize with GH replacement. Frequent side effects are fluid retention and insulin resistance, which are reversible and dose-dependent. The dose requirement declines with age and is higher in women. Continuation of GH replacement into adulthood is indicated in some patients with childhood-onset disease so the diagnosis must be reassessed. Observational data show that mortality in GH replaced patients is reduced compared to untreated patients. Thus, GH replacement in GHDA has proven beneficial and safe.

The Marfan syndrome (MFS) is strongly associated with aortic disease causing a high prevalence of prophylactic aortic surgery, aortic dissection, and sudden death. The aim of the present study was to evaluate mortality in a nationwide Danish MFS population diagnosed by the Ghent II criteria. In a register-based setting, we identified all Danish patients with MFS (n = 412, men n = 215) by assessment of their medical records. We established a gender and age matched control cohort based on 41,000 control patients (men n = 21,500). MFS cases risk time was 6,669 patient years. We applied Cox regression using each case and his/her control as one stratum, adjusting for age and calendar time. We found a significantly decreased lifespan of 50 years compared with 60 years among controls. The mortality hazard ratio among MFS compared with controls was significantly increased to 3.6 (CI 2.8-4.7, p < 0.001); men 4.0 (CI 2.8-5.7, p < 0.001); women 3.2 (CI 2.1-4.8, p < 0.001). Aorta disease represented the main reason for the overall increased mortality with a hazard ratio of 194.6 (CI 67.4-561.7, p < 0.0001); men 208.7 (CI 53.8-809.1, p < 0.001); women 173.4 (CI 31.5-954.5, p < 0.001). In addition, an unexplained mortality due to respiratory illness was not attributed to pneumothorax. Excluding cardiovascular and respiratory causes of death, we found no indication that MFS is associated with increased mortality for other reasons.

Background: Pheochromocytomas and catecholamine-secreting paragangliomas (PPGL) are rare catecholamine-producing tumors. Due to the rarity, limited data on prognosis exists and data are mainly from tertiary centers with potential referral bias. Here, we present population-based mortality data over an observation period of 40 years.Materials and methods: We identified a cohort of 198 PPGL patients diagnosed 1 January 1977 to 31 December 2016 in North and Central Denmark (population 1.75 million). Data on tumor size, tumor location, surgery and recurrence were obtained from health records. Date of death or emigration was obtained from the Civil Registration System. Hazard rate-ratios (HRR) for death or tumor recurrence were calculated using Cox regression and adjusted for sex and age at diagnosis.Results: Radically operated (n=162, 81.8%) patients (median age 52.0 years (Q1–Q3: 39.3–63.0)) had an overall 5- and 10-year survival after surgery of 90.8% (CI95%: 84.5–94.6) and 78.7% (CI95%: 69.8–85.2) and a recurrence-free 5- and 10-year survival of 87.0% (CI95%: 80.1–91.7) and 75.7% (CI95%: 66.7–82.7), respectively. HRR for death or recurrence was not associated with tumor size or with extra-adrenal location of tumor. Twelve (6.1%) PPGL patients did not undergo radical surgery as they either died before surgery (n=2), had disseminated disease (n=4), abstained from surgery (n=4) or since radical surgery was not technically possible (n=2). For these patients, median time from diagnosis to death was 5.3 years (Q1–Q3: 0.3–16.4). Twenty-four (12.1%) PPGL patients were diagnosed at autopsy. Based on autopsy reports, PPGL was regarded the underlying cause of death in 5 (20.8%) patients, a contributing cause in 14 (58.3%) patients and an incidental finding in 5 (20.8%) patients.Conclusion: PPGL patients who undergo radical surgery have a good long-term prognosis with three-fourths of patients living more than ten years after surgery. Those who are not radically operated are a heterogeneous patient group with a relatively short life expectancy. This, combined with the fact that PPGL was considered a direct or contributing cause of death in many patients diagnosed at autopsy, underlines the importance of early diagnosis and treatment of PPGL.

Jes Sloth Mathiesen,1,2 Jens Peter Kroustrup,3 Peter Vestergaard,3,4 Kirstine Stochholm,5,6 Per Løgstrup Poulsen,5 Åse Krogh Rasmussen,7 Ulla Feldt-Rasmussen,7 Sten Schytte,8 Henrik Baymler Pedersen,9 Christoffer Holst Hahn,10 Jens Bentzen,11 Sören Möller,2,12 Mette Gaustadnes,13 Maria Rossing,14 Finn Cilius Nielsen,14 Kim Brixen,2 Anja Lisbeth Frederiksen,2,15 Christian Godballe1 1Department of ORL Head & Neck Surgery and Audiology, Odense University Hospital, Odense, Denmark; 2Department of Clinical Research, University of Southern Denmark, Odense, Denmark; 3Department of Clinical Medicine and Endocrinology, Aalborg University Hospital, Aalborg, Denmark; 4Steno Diabetes Center North Jutland, Aalborg, Denmark; 5Department of Internal Medicine and Endocrinology, Aarhus University Hospital, DK-8000 Aarhus, Denmark; 6Center for Rare Diseases, Aarhus University Hospital, Aarhus N, Denmark; 7Department of Medical Endocrinology, Copenhagen University Hospital, Copenhagen, Denmark; 8Department of ORL Head and Neck Surgery, Aarhus University Hospital, Aarhus, Denmark; 9Department of ORL Head and Neck Surgery, Aalborg University Hospital, Aalborg, Denmark; 10Department of ORL Head and Neck Surgery, Copenhagen University Hospital, Copenhagen, Denmark; 11Department of Oncology, Herlev Hospital, Herlev, Denmark; 12Odense Patient data Explorative Network (OPEN), Odense University Hospital, Odense, Denmark; 13Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark; 14Center for Genomic Medicine, Copenhagen University Hospital, Copenhagen, Denmark; 15Department of Clinical Genetics, Odense University Hospital, Odense, Denmark Background: The incidence and prevalence of multiple endocrine neoplasia 2A (MEN2A) have only been reported once in a nationwide setting. However, it is unclear whether the figures are representative of other populations, as the major component of the syndrome, hereditary medullary thyroid carcinoma (MTC), has been reported as rare in the same country. We conducted a nationwide retrospective cohort study of MEN2A in Denmark from 1901 to 2014, aiming to describe the incidence and prevalence. Methods: This study included 250 unique MEN2A patients born or resident in Denmark before December 31, 2014. Patients were identified through the Danish REarranged during Transfection (RET) cohort, linkage of MEN2A pedigrees, the Danish MTC cohort, a nationwide collaboration of MEN2 centers, cross-checking of other relevant cohorts, and a systematic literature search. Results: The incidence from 1971 to 2000 was 28 (95% CI: 21–37) per million live births per year. Incidence for the specific mutations or for the overall MEN2A group did not change significantly from 1901 to 2014 (P>0.05). Point prevalence at January 1, 2015, was 24 per million (95% CI: 20–28). Conclusion: The incidence and prevalence of MEN2A in Denmark seem higher than those reported in other countries. This is likely explained by the Danish C611Y founder effect. Also, our data indicate no significant change in MEN2A incidence during the last century. Keywords: multiple endocrine neoplasia 2A, incidence, prevalence, Denmark

Background: Multiple endocrine neoplasia (MEN) 2A and 2B are caused by REarranged during Transfection (RET) germline mutations. In a recent nationwide study, an unusually high prevalence (33%) of families with the C611Y mutation was reported, and it was hypothesized that this might be due to a founder effect. The first nationwide study of haplotypes in MEN2A families was conducted, with the aim of investigating the relatedness and occurrence of de novo mutations among Danish families carrying similar mutations. Methods: The study included 21 apparently unrelated MEN2A families identified from a nationwide Danish RET cohort from 1994 to 2014. Twelve, two, two, three, and two families carried the C611Y, C618F, C618Y, C620R, and C634R mutations, respectively. Single nucleotide polymorphism chip data and identity by descent analysis were used to assess relatedness. Results: A common founder mutation was found among all 12 C611Y families and between both C618Y families. No relatedness was identified in the remaining families. Conclusion: The data suggest that all families with the C611Y germline mutation in Denmark originate from a recent common ancestor, probably explaining the unusually high prevalence of this mutation. Additionally, the results indicate that the C611Y mutation rarely arises de novo, thus underlining the need for thorough multigenerational genetic work up in carriers of this mutation.

BACKGROUND: Data regarding the association between diabetes mellitus (DM) and tuberculosis (TB) in Africa are scare. We did a DM screening survey among TB patients and non-TB controls in Guinea-Bissau.METHODS: The study was conducted at the Bandim Health Project (BHP) in the capital Bissau. From July 2010 to July 2011, newly diagnosed TB cases were identified through a TB notification system. Concurrently, non-TB controls were selected randomly from the BHP's demographic surveillance database and visited at home. Participants were tested using fasting blood glucose (FBG) measurements. DM was diagnosed as FBG ≥ 7 mmol/l. Our survey was linked to the patient database at the only existing Diabetes Clinic in Bissau.RESULTS: TB patients (n=110) were older than the controls (n=572) (35 vs 31 years; p=0.02), more often male (55% vs 37%; pCONCLUSIONS: The prevalence of DM was low, also among TB patients. No association between DM and TB was found.

Pheochromocytoma is a rare disease but frequently poses a diagnostic dilemma due to the unspecific symptoms and its potentially life-threatening nature. There is a perception of an increase in the incidence of pheochromocytomas in recent years, but no data on time trends exist.We obtained data from The Danish National Registry of Patients, The Danish Registry of Causes of Death, and The National Pathology Registry for all persons registered with pheochromocytoma in 1977-2016. Health records were reviewed to validate the diagnosis for all patients in the Northern and Central Regions of Denmark (population 1.75 million). Incidence rates were calculated using Poisson regression. We identified 198 confirmed cases of pheochromocytoma. A significant increasing trend (pThe incidence of pheochromocytoma has increased significantly in recent years, presumably due to increased use of imaging studies. Incidentaloma patients appear to represent a new less symptomatic and older group of pheochromocytoma patients not previously diagnosed. Whether surgical treatment provides a health benefit in this group remains unknown.

Multiple endocrine neoplasia (MEN) 2A and 2B are caused by REarranged during Transfection (RET) germline mutations. In a recent nationwide study, an unusually high prevalence (33%) of families with the C611Y mutation was reported, and it was hypothesized that this might be due to a founder effect. The first nationwide study of haplotypes in MEN2A families was conducted, with the aim of investigating the relatedness and occurrence of de novo mutations among Danish families carrying similar mutations.The study included 21 apparently unrelated MEN2A families identified from a nationwide Danish RET cohort from 1994 to 2014. Twelve, two, two, three, and two families carried the C611Y, C618F, C618Y, C620R, and C634R mutations, respectively. Single nucleotide polymorphism chip data and identity by descent analysis were used to assess relatedness.A common founder mutation was found among all 12 C611Y families and between both C618Y families. No relatedness was identified in the remaining families.The data suggest that all families with the C611Y germline mutation in Denmark originate from a recent common ancestor, probably explaining the unusually high prevalence of this mutation. Additionally, the results indicate that the C611Y mutation rarely arises de novo, thus underlining the need for thorough multigenerational genetic work up in carriers of this mutation.