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Article ; Online: Incidence, Treatment, and Survival of Adrenocortical Carcinoma in Denmark 2003-2019.

Pedersen, Jens / Jarløv, Anne Elisabeth / Rasmussen, Åse Krogh / Stochholm, Kirstine

Journal of the Endocrine Society

2024 Volume 8, Issue 3, Page(s) bvae012

Abstract: Objectives: Adrenocortical carcinoma (ACC) is a malignant tumor originating from the adrenal cortex. The aim of the study was to report the incidence of ACC and survival of ACC in Denmark. The secondary objective was to describe the impact of treatment ... ...

Abstract	Objectives: Adrenocortical carcinoma (ACC) is a malignant tumor originating from the adrenal cortex. The aim of the study was to report the incidence of ACC and survival of ACC in Denmark. The secondary objective was to describe the impact of treatment with mitotane on survival. Design: Retrospective population study of patients diagnosed with ACC between 2003 and 2019 in Denmark. Methods: Individuals at risk for ACC were identified in the national Danish Health registries, and diagnosis of ACC was confirmed by review of the health records. Data on demographics, presentation, treatment, recurrence, and death was evaluated. Results: 138 patients were included in the study with more females (59.4%) than males (40.6%). Incidence rate was 1.4 per million per year. The incidence rate ratio significantly increased only in females by 1.06 [95% confidence interval (CI): 1.02-1.12] per year. Overall median survival was 1.93 (95% CI: 1.24-3.00) years with no differences between males and females. The proportion of patients treated with mitotane (either as adjuvant treatment or as part of a chemotherapeutic regime) was 72.3%. Survival was significantly decreased in women not treated with mitotane compared to women treated with mitotane (either as adjuvant or as part of a chemotherapeutic regime) hazards ratio .30 (95% CI: .10-.89), adjusted for European Network for the Study of Adrenal Tumours score, age at diagnosis, and year of diagnosis, but survival was unaffected by mitotane treatment in men. Conclusion: Incidence of ACC in Denmark was 1.4 per million per year and increased in women but not in males during the study period 2003-2019.
Language	English
Publishing date	2024-01-30
Publishing country	United States
Document type	Journal Article
ISSN	2472-1972
ISSN (online)	2472-1972
DOI	10.1210/jendso/bvae012
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Article: Morbidity, mortality, and socioeconomics in Klinefelter syndrome and 47,XYY syndrome: a comparative review.

Ridder, Lukas Ochsner / Berglund, Agnethe / Stochholm, Kirstine / Chang, Simon / Gravholt, Claus H

Endocrine connections

2023 Volume 12, Issue 5

Abstract: Context: Klinefelter syndrome (KS, 47,XXY) and 47,XYY syndrome are genetic conditions characterized by a supernumerary sex chromosome. The conditions share many traits, but considerable phenotypic differences are seen between the two. Focusing on ... ...

Abstract	Context: Klinefelter syndrome (KS, 47,XXY) and 47,XYY syndrome are genetic conditions characterized by a supernumerary sex chromosome. The conditions share many traits, but considerable phenotypic differences are seen between the two. Focusing on morbidity, mortality, and socioeconomics, this review highlights similarities and differences. Methods: Relevant literature was identified through PubMed with the following search terms; 'Klinefelter', '47,XXY', '47,XYY', and 'Jacobs syndrome'. Included journal articles were chosen at the authors' discretion. Results: KS and 47,XYY are the most common sex chromosome disorders in males, with an expected prevalence of 152 and 98 per 100,000 newborn males, respectively. Non-diagnosis is extensive, as only about 38% of KS and 18% of 47,XYY are diagnosed. Both conditions are associated with an increased mortality risk and increased risk of a variety of diseases and other health-related problems affecting virtually every organ system. Early diagnosis seems to predict a lesser comorbidity burden. Neurocognitive deficits as well as social and behavioral problems are commonly described. Both syndromes are associated with poor socioeconomicfor example, lower income and educational level and higher rates of crime. Infertility is a hallmark of KS, but fertility seems also reduced in 47,XYY. Conclusion: Being born as a boy with an extra X or Y chromosome is associated with increased mortality and excess morbidity, partially expressed in a sex chromosome-specific pattern.Both syndromes continue to be greatly underdiagnosed, even thoughearly intervention may improve the overall outcome. Earlier diagnosis to initiate timely counseling and treatment should be emphasized.
Language	English
Publishing date	2023-04-26
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2668428-7
ISSN	2049-3614
ISSN	2049-3614
DOI	10.1530/EC-23-0024
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Article ; Online: Incidence, prevalence, age at diagnosis, and mortality in individuals with 45,X/46,XY mosaicism: A population-based registry study.

Stochholm, Kirstine / Holmgård, Camilla / Davis, Shanlee M / Gravholt, Claus H / Berglund, Agnethe

Genetics in medicine : official journal of the American College of Medical Genetics

2023 Volume 26, Issue 1, Page(s) 100987

Abstract: Purpose: To assess the population-based incidence, prevalence, and age at diagnosis of individuals with 45,X/46,XY mosaicism (and associated variants) and describe the associated mortality pattern. In addition, a systematic literature review of papers ... ...

Abstract	Purpose: To assess the population-based incidence, prevalence, and age at diagnosis of individuals with 45,X/46,XY mosaicism (and associated variants) and describe the associated mortality pattern. In addition, a systematic literature review of papers providing prevalence data of 45,X/46,XY mosaicism was performed. Methods: A population-based epidemiological study of all individuals diagnosed with 45,X/46,XY mosaicism between 1960 and 2019. Mortality was analyzed using data from the Danish Causes of Death Register. One-hundred randomly age- and sex-matched general population controls per case were identified for comparison. Results: One-hundred-thirty-seven males and 46 females with 45,X/46,XY mosaicism were identified. The apparent prevalence was 5.6 per 100,000 liveborn males and 2.1 per 100,000 liveborn females. The incidence of males with 45,X/46,XY increased during the study (P > .0001) but was stable for females (P = .4). Males were significantly older than females when diagnosed (median age = 29.1, interquartile range: 3.4-41.3) years versus 13.3 (interquartile range: 2.1-19.1) years, P = .002). All-cause mortality was doubled in males with 45,X/46,XY (Hazard Ratio = 2.0, 95% confidence interval: 1.2-3.3) and quadrupled in females (Hazard Ratio = 4.0, confidence interval: 2.0-7.9). Conclusion: The apparent population-based prevalence of males and females with 45,X/46,XY is 5.6 and 2.1 per 100,000 liveborn males and females, respectively. Diagnosis of males with 45,X/46,XY males is increasing. 45,X/46,XY mosaicism is associated with an increased all-cause mortality.
MeSH term(s)	Male ; Female ; Humans ; Adult ; Mosaicism ; Incidence ; Prevalence ; Registries
Language	English
Publishing date	2023-09-28
Publishing country	United States
Document type	Systematic Review ; Journal Article
ZDB-ID	1455352-1
ISSN	1530-0366 ; 1098-3600
ISSN (online)	1530-0366
ISSN	1098-3600
DOI	10.1016/j.gim.2023.100987
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Article ; Online: The TGFβ system and TIMP1 and 3 genotypes in Turner syndrome-Relation with aortic congenital malformations.

Ridder, Lukas Ochsner / Stochholm, Kirstine / Mortensen, Kristian Havmand / Andersen, Niels Holmark / Gravholt, Claus Højbjerg

Clinical endocrinology

2023 Volume 99, Issue 6, Page(s) 545–551

Abstract: 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 ... ...

Abstract	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.
MeSH term(s)	Humans ; Female ; Turner Syndrome/complications ; Turner Syndrome/genetics ; Transforming Growth Factor beta/genetics ; Aorta ; Genotype ; Biomarkers ; Matrix Metalloproteinases/genetics ; Tissue Inhibitor of Metalloproteinase-1/genetics
Chemical Substances	Transforming Growth Factor beta ; Biomarkers ; Matrix Metalloproteinases (EC 3.4.24.-) ; TIMP1 protein, human ; Tissue Inhibitor of Metalloproteinase-1
Language	English
Publishing date	2023-03-15
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	121745-8
ISSN	1365-2265 ; 0300-0664
ISSN (online)	1365-2265
ISSN	0300-0664
DOI	10.1111/cen.14907
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Article ; Online: The comorbidity landscape of 47,XXX syndrome: A nationwide epidemiologic study.

Berglund, Agnethe / Stochholm, Kirstine / Gravholt, Claus Højbjerg

Genetics in medicine : official journal of the American College of Medical Genetics

2021 Volume 24, Issue 2, Page(s) 475–487

Abstract: 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 = ... ...

Abstract	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.
MeSH term(s)	Chromosomes, Human, X ; Comorbidity ; Epidemiologic Studies ; Female ; Humans ; Pregnancy ; Sex Chromosome Aberrations ; Sex Chromosome Disorders of Sex Development/diagnosis ; Trisomy
Language	English
Publishing date	2021-11-30
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1455352-1
ISSN	1530-0366 ; 1098-3600
ISSN (online)	1530-0366
ISSN	1098-3600
DOI	10.1016/j.gim.2021.10.012
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Article ; Online: The epidemiology of sex chromosome abnormalities.

Berglund, Agnethe / Stochholm, Kirstine / Gravholt, Claus Højbjerg

American journal of medical genetics. Part C, Seminars in medical genetics

2020 Volume 184, Issue 2, Page(s) 202–215

Abstract: 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 ... ...

Abstract	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.
MeSH term(s)	Chromosomes, Human, X/genetics ; Female ; Humans ; Karyotyping ; Klinefelter Syndrome/epidemiology ; Klinefelter Syndrome/genetics ; Klinefelter Syndrome/pathology ; Male ; Sex Chromosome Aberrations ; Sex Chromosome Disorders/genetics ; Sex Chromosome Disorders/pathology ; Sex Chromosomes/genetics ; Trisomy/genetics ; Trisomy/pathology ; Turner Syndrome/epidemiology ; Turner Syndrome/genetics ; Turner Syndrome/pathology ; XYY Karyotype/genetics ; XYY Karyotype/pathology
Language	English
Publishing date	2020-06-07
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2108622-9
ISSN	1552-4876 ; 0148-7299 ; 1552-4868
ISSN (online)	1552-4876
ISSN	0148-7299 ; 1552-4868
DOI	10.1002/ajmg.c.31805
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Article ; Online: Morbidity in 47,XYY syndrome: a nationwide epidemiological study of hospital diagnoses and medication use.

Berglund, Agnethe / Stochholm, Kirstine / Gravholt, Claus Højbjerg

Genetics in medicine : official journal of the American College of Medical Genetics

2020 Volume 22, Issue 9, Page(s) 1542–1551

Abstract: 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 ... ...

Abstract	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.
MeSH term(s)	Epidemiologic Studies ; Hospitals ; Humans ; Male ; Sex Chromosome Disorders ; XYY Karyotype
Language	English
Publishing date	2020-06-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1455352-1
ISSN	1530-0366 ; 1098-3600
ISSN (online)	1530-0366
ISSN	1098-3600
DOI	10.1038/s41436-020-0837-y
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Article ; Online: Disorders of the eye, ear, skin, and nervous system in women with Turner syndrome -a nationwide cohort study.

Viuff, Mette Hansen / Stochholm, Kirstine / Juul, Svend / Gravholt, Claus Højbjerg

European journal of human genetics : EJHG

2021 Volume 30, Issue 2, Page(s) 229–236

Abstract: 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 ... ...

Abstract	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.
MeSH term(s)	Cohort Studies ; Female ; Humans ; Incidence ; Nervous System ; Registries ; Turner Syndrome/complications ; Turner Syndrome/drug therapy ; Turner Syndrome/epidemiology
Language	English
Publishing date	2021-10-28
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1141470-4
ISSN	1476-5438 ; 1018-4813
ISSN (online)	1476-5438
ISSN	1018-4813
DOI	10.1038/s41431-021-00989-5
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Iversen, Peter / Kramer, Stine / Ebbehoj, Andreas / Søndergaard, Esben / Stochholm, Kirstine / Poulsen, Per Løgstrup / Hjorthaug, Karin

EJNMMI research

2023 Volume 13, Issue 1, Page(s) 108

Abstract: Background: Both [: Results: In total, 113 patients were included (97 suspected of primary PPGL and 16 suspected of recurrence). Of the 97 patients, 51 had pheochromocytomas (PCC) (in total 55 lesions) and 6 had paragangliomas (PGL) (in total 7 ... ...

Abstract	Background: Both [ Results: In total, 113 patients were included (97 suspected of primary PPGL and 16 suspected of recurrence). Of the 97 patients, 51 had pheochromocytomas (PCC) (in total 55 lesions) and 6 had paragangliomas (PGL) (in total 7 lesions). FDOPA detected and correctly localized all 55 PCC, while DOTATOC only detected 25 (sensitivity 100% vs. 49%, p < 0.0001; specificity 95% vs. 98%, p = 1.00). The negative predictive value (100% vs. 63%, p < 0.001) and diagnostic accuracy (98% vs. 70%, p < 0.01) were higher for FDOPA compared to DOTATOC. FDOPA identified 6 of 6 patients with hormone producing PGL, of which one was negative on DOTATOC. Diagnostic performances of FDOPA and DOTATOC were similar in the 16 patients with previous PPGL suspected of recurrence. Conclusions: FDOPA is superior to DOTATOC for localization of PCC. In contrast to DOTATOC, FDOPA also identified all PGL but with a limited number of patient cases.
Language	English
Publishing date	2023-12-18
Publishing country	Germany
Document type	Journal Article
ZDB-ID	2619892-7
ISSN	2191-219X
ISSN	2191-219X
DOI	10.1186/s13550-023-01056-4
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Article ; Online: Long-term safety of growth hormone-A combined registry analysis.

Stochholm, Kirstine / Kiess, Wieland

Clinical endocrinology

2017 Volume 88, Issue 4, Page(s) 515–528

Abstract: Objectives: Preliminary data from the French cohort of the Safety and Appropriateness of Growth hormone treatments in Europe (SAGhE) study raised concerns regarding the safety of recombinant human GH, suggesting that GH may increase mortality and ... ...

Abstract	Objectives: Preliminary data from the French cohort of the Safety and Appropriateness of Growth hormone treatments in Europe (SAGhE) study raised concerns regarding the safety of recombinant human GH, suggesting that GH may increase mortality and incidence of stroke in patients treated during childhood for GH deficiency or short stature. We evaluated published safety data, focusing on mortality, neoplasms, cerebrovascular events and diabetes across a number of large-scale pharmaceutical company GH registries. Design: A literature review was conducted using PubMed, EMBASE and Google Scholar to identify all relevant safety data from manufacturers' GH registries published between 1988 and April 2016. Results were hand-sorted to exclude nonrelevant publications; bibliographic references from retrieved articles were evaluated for any additional references. Results: The published data do not support an increased risk of mortality in children or adults treated with GH. There was no evidence of an increased risk of stroke, new malignancy, leukaemia, nonleukaemic extracranial tumours or recurrence of intracranial malignancy in patients without risk factors. The risk of a second neoplasm is increased, particularly if patients have received radiation therapy for a central nervous system tumour. There may be an increased risk of type 2 diabetes in GH-treated patients, but this appears to be confined to those with pre-existing risk factors. Conclusions: Patients with risk factors for malignancy or type 2 diabetes should be treated with caution and monitored during follow-up, but current published data provide reassurance on the long-term safety profile of GH in patients receiving GH treatment.
MeSH term(s)	Diabetes Mellitus, Type 2/chemically induced ; Growth Hormone/administration & dosage ; Growth Hormone/adverse effects ; Humans ; Mortality ; Neoplasms/chemically induced ; Product Surveillance, Postmarketing ; Registries
Chemical Substances	Growth Hormone (9002-72-6)
Language	English
Publishing date	2017-11-20
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	121745-8
ISSN	1365-2265 ; 0300-0664
ISSN (online)	1365-2265
ISSN	0300-0664
DOI	10.1111/cen.13502
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