Cushing’s Syndrome in Children and Adolescents: A Danish Nationwide Popu-
1 2 lation-Based Cohort Study
Johanne Marie Holst, MD1; Erzsébet Horváth-Puhó, PhD2; Rikke Beck Jensen, PhD3; Mariane Rix4, MD; Niels Thomas Hertel, PhD5; Olaf M. Dekkers, PhD2; Henrik Toft Sørensen, DMSc2; Anders Juul, DMSc3; and Jens Otto L. Jørgensen, DMSc1
Department of Internal Medicine and Endocrinology, Aarhus University Hospital, Aarhus, Denmark
2 Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark
3 Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, Copenhagen, Den- mark
4 Department of Pediatrics, Aalborg University Hospital, Aalborg, Denmark
5 Hans Christian Andersen Children’s Hospital, Odense University Hospital, Odense, Denmark
Key words: Cushing’s syndrome, Cushing’s disease, incidence
Department of Internal Medicine and Endocrinology Aarhus University Hospital
Phone: +45 28 25 48 82
24 25 E-mail: johahols@rm.dk
3 4 5 6 7 8 1 9 10 11 12 13 14 15 16 Word count: 3.243 without abstract 17 Number of figures and tables: 5 18 19 Corresponding Author: 20 Johanne Marie Holst, MD 21 22 23 Nørrebrogade 44, 8000 Aarhus C, Denmark
Abstract
Objective: Cushing’s syndrome (CS) affects all age groups, but epidemiologic data in young pa- tients are very limited. We therefore examined the incidence, prevalence, and hospital morbidity of CS in children and adolescents.
Design: In a nationwide cohort study we included all Danish citizens aged 0-20 years from 1977 to 2012. Data were obtained from the Danish National Patient Registry using the International Classi- fication of Diseases (ICD) codes and the Danish Civil Registration System. The diagnosis and treatment were validated by means of individual patient charts. Incidence rate of CS patients aged 0-20 years at diagnosis were computed (standardized to the age and sex distribution of the Danish population). The patients were followed for a maximum of 36 years. Standardized incidence ratios (SIRs) of different hospital-recorded outcomes based on the ICD codes in patients with CS com- pared to the general population were assessed.
Results: We identified a total of 40 pediatric patients with CS, yielding an annual incidence of 0.89 cases/10° population (95% confidence interval (CI) = 0.63-1.16). The median age at time of diagno- sis was 13.8 years (interquartile range 10.5-18.2 years), 58% were female, and 70% had adrenocor- ticotropic hormone-producing pituitary adenomas. During follow-up, CS patients (excluding three malignant cases) were at increased risk of being diagnosed with infections (standardized incidence ratio (SIR) 3.24, 95% CI 1.05-7.54) and infertility (SIR 4.56, 95% CI 1.48-10.63). The three pa- tients with an adrenocortical carcinoma died shortly after diagnosis, but mortality was not increased in the remaining patients.
Conclusions: CS is rare in the pediatric population. The risk of morbidity related to infections and infertility is elevated and merits further attention.
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Introduction
Cushing’s syndrome (CS), caused by prolonged exposure to excess glucocorticoids, is a serious condition associated with excess morbidity and mortality 1,2. Endogenous causes include adrenocor- 53 ticotropic hormone (ACTH)-dependent forms resulting from either an ACTH-secreting pituitary adenoma (i.e., Cushing’s disease [CD]) or an ectopic ACTH-secreting tumor. ACTH-independent forms include unilateral benign and malignant cortisol-producing adrenal tumors, as well as bilat- eral adrenal lesions. In contrast to iatrogenic CS, which is common, endogenous CS is a rare condi- tion with a reported annual incidence of ~ 2.0-2.5/106 population in Denmark 1. CD accounts for 60% and benign adrenal adenomas for 25% of endogenous CS 1. The mean age at diagnosis is 44 years and 75% of cases are women 2.
CS in children and adolescents is estimated to comprise 10% of diagnosed cases, but population- 62 based epidemiological data are lacking 3. As in adults, CD remains the most common cause of en- dogenous CS in children (85%), with a female predominance 4 (although a male predominance has been reported in prepubertal children 5-7). The onset of the disease is insidious, but its hallmark is 65 obesity combined with longitudinal growth retardation 4,5. The primary treatment of CS is surgery, 66 67 and the success rate in terms of remission of hypercortisolism appears to be high in both children and adults 5. Despite surgical control, CS in children is associated with somatic and psychosocial 68 complications 4 that warrant early diagnosis and meticulous follow-up.
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We therefore conducted a nationwide cohort study to examine the incidence and prevalence of CS in children and adolescents and the risk of subsequent hospital-recorded selected morbidity com- pared with the general population.
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Subjects and Methods
Source Population
The source population consisted of the age group of 0-20 years in Denmark between 1977 and 2012. Data were obtained from the Danish Civil Registration System (CRS) 8 and the Danish Na- tional Patient Registry (DNPR)9. The CRS has kept electronic records on gender, age, birth date, residence, emigration date, and vital status since 1968. The DNPR has recorded all hospital dis- charge diagnoses and surgical procedures since 1977 and all hospital outpatient specialty clinic and emergency room visits since 1995. The central personal registry number assigned to each Danish citizen at birth and to residents upon immigration allows accurate linkage of all Danish registries at the individual level. The Danish National Health Service provides universal tax-supported health care, guaranteeing free access to general practitioners and hospitals 10.
Study Population
All individuals aged 0-20 years at the time of a CS diagnosis during the study period (1977-2012) were identified from the DNPR. The cumulative population size of 0-20-year-old individuals in the study period was 4,678,038 persons. Patients diagnosed with adrenocortical carcinoma (ACC) were included in the incidence data but not in the analysis of outcomes. The International Classification of Diseases, Eighth Revision (ICD-8) and Tenth Revision (ICD-10) codes used in the study are pro- vided in the Supplemental Appendix (ICD-9 has never been used in Denmark). Throughout the pa- per, the term CS is used to describe the cohort of patients with Cushing’s syndrome except for the patients with ACC (unless otherwise specified).
The CS diagnosis is based on a combination of clinical characteristics, each of which are not path- ognomonic, and biochemical tests which are not infallible and prone to diagnostic misclassification
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11 1. To minimize misclassification, we added surgical intervention within three years after a CS di- agnosis as an additional eligibility requirement 12.
Hospital records were subsequently retrieved, and the authors performed a review of all patients’ individual medical records. A diagnosis of CS was made when laboratory testing, imaging, and treatment were in agreement. Uncertainties were discussed among the authors until consensus was reached.
Follow-up
Follow-up started on the date of initial CS diagnosis. Follow-up was censored when an outcome of interest occurred, when death or emigration took place, or on 31 December 2012, whichever came first. The patients were thus followed for a maximum of 36 years (maximum age at the end of fol- low-up was 54.5 years).
Study Outcomes
We computed the first hospital-recorded occurrence of infection, infertility, fracture or osteoporo- sis, cancer, epilepsy, diabetes, venous thromboembolism (VTE), acute myocardial infarction (AMI), stroke, and heart failure following the CS diagnosis. In- and outpatient diagnoses registered in the DNPR were used to identify these outcomes. Each hospital discharge or outpatient visit is recorded in the DNPR with one primary diagnosis and one or more secondary diagnoses classified according to ICD-8 until the end of 1993 and ICD-10 thereafter. Where possible, we examined available individual patient records to confirm the outcomes.
Statistical Analysis
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We characterized patients according to CS subtype, surgical intervention, sex, age, and year of CS
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diagnosis (1977-1990, 1991-2000, and 2001-2012).
We computed the standardized incidence rate of CS in children and adolescents (standardized to the age and sex distribution of the Danish population ≤ 20 years in the year 2000). The standardized in- cidence rate was calculated for the overall 1977-2012 study period. The point prevalence per 106 population was calculated on 1 January 2012 by dividing the number of prevalent CS cases by total number of Danish children and adolescents on the given date.
28 We then used the cumulative incidence (risk) function, accounting for death as a competing risk, to calculate the risk of outcomes based on ICD codes (infection, infertility, fracture or osteoporosis, cancer, epilepsy, diabetes, VTE, AMI, stroke, and heart failure) during the follow-up period. To compare the incidence of different outcomes in individuals with a diagnosis of CS with that of the 132 general population, we computed standardized incidence ratios (SIRs), i.e. the ratio of the observed to the expected number of CS. The expected number of cases with outcome was calculated by mul- tiplying national incidence rates of groups defined by age (five-year intervals), sex, and five-year calendar intervals by the corresponding person-years at risk in the CS cohort. For estimation of 95% 136 confidence intervals (CIs), we assumed that the number of outcomes followed a Poisson distribu- tion. Exact 95% CIs were used since the observed numbers were less than ten. Patients with an out- come diagnosis prior to or at the time of CS diagnosis were excluded from the calculation of SIR. All analyses were repeated after classifying CS patients according to their ACTH-dependency sta- tus. The information about hypopituitarism, permanent hydrocortisone replacement, and the dura- tion between first hospital admission and last surgery was retrieved from the patient records. Anal- yses were performed using SAS, version 9.2 (SAS Institute, Cary, North Carolina, US).
The study has been approved by the Danish Health and Medicines Authority (record no. 3-3013- 423/1/) and by the Danish Data Protection Agency (record no. 11-88-37-29).
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Results
Study Population
A total of 256 patients diagnosed with CS were identified initially from the DNPR. Of these, 33 pa- tients had a surgical intervention code. According to medical record review, three of these 33 pa- tients did not have CS. Of the 223 cases with a CS diagnosis code and no surgical intervention code in the DNPR, medical record review revealed ten patients who indeed had undergone a surgical in- tervention to treat CS (Figure 1A). One patient diagnosed with CS, who underwent a surgical inter- vention shortly after end of the follow-up period, was included in the analysis.
Patient Characteristics
In total, we identified 40 patients with CS meeting our inclusion criteria (Figure 1B). Twenty-nine patients had ACTH-dependent CS (72.5%), including one patient with ectopic disease (ACTH- secreting nephroblastoma). Eleven patients had ACTH-independent CS (27.5%) of whom four had a unilateral adenoma (10.0%), four had bilateral hyperplasia (10.0%), and three had ACC (7.5%). Three patients with CD had multiple endocrine neoplasia type 1 (MEN-1). One patient with CD al- so was diagnosed with Klinefelter syndrome, and one patient with bilateral adrenal disease was di- agnosed with primary pigmented nodular adrenocortical disease (PPNAD) as a component of the Carney complex. One patient with unilateral adrenal disease was diagnosed with craniofrontonasal syndrome. Prior to the CS diagnosis, one patient was diagnosed with anorexia nervosa. The three patients diagnosed with ACC (all females, median age at diagnosis: 18.4 years) were included in the estimation of the standardized incidence rate but excluded from other analyses. Demographic data on the CS patients at time of diagnosis are provided in Table 1. The median age of CS patients at diagnosis was 12.9 years (interquartile range 10.5-17.8 years) and 54% were female. In the ACTH-
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independent group, 88% were female (not including the three patients with ACC).
Incidence, Prevalence and Mortality
The standardized incidence rate of CS in children and adolescents are shown in Figure 2.
The annual incidence of pediatric CS in the overall study period (1977-2012) was 0.89 cases/106 population (95% CI = 0.63-1.16). The point prevalence in 2012 was 26 cases/10° population (95% CI = 18.9-35.8). The three CS patients who died during follow-up all had ACC.
Symptoms Prior to Diagnosis
Symptoms and signs prior to the CS diagnosis date were identified by medical record review of all patients with confirmed CS. Among those, 80% were obese and 53% had impaired linear growth. Additional symptoms and signs of CS included moon face and facial plethora (82.5%), truncal obe- sity (70%), buffalo hump (37.5%), hypertension (37.5%), striae (25%), myopathy (17.5%), easy bruising (17.5%), fatigue (15%), acne (15%), hirsutism (15%), psychiatric symptoms (15%), and headache (7.5%). Seven out of eight female patients aged ≥ 12 years at time of diagnosis had oli- gomenorrhea (the median age at time of CS diagnosis of these seven patients was 19.7 [interquartile range 16.3 - 20.1]).
Treatment
Twenty-four of the 28 patients with CD underwent transsphenoidal surgery (TSS) as first-line treatment, of which two were preoperatively treated with metyrapone and pasireotide for a short pe- riod. Six of the 24 patients undergoing TSS had a second pituitary operation, whereas one under- went bilateral adrenalectomy as second-line treatment. One of the 24 patients underwent bilateral adrenalectomy after a transsphenoidal re-operation; this patient also had a third transsphenoidal op-
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194 195 eration, stereotactic pituitary radiation therapy as subsequent treatment for Nelson’s syndrome and was briefly treated with ketoconazole. Of the remaining four patients with CD, two underwent radi- 196 ation as first-line treatment followed by TSS, which in one of the patients was preceded by short- term treatment with metyrapone and aminoglutethimide, one received stereotactic pituitary radia- tion therapy as monotherapy, and one underwent bilateral adrenalectomy followed by TSS for Nel- son’s syndrome. The patient with ectopic disease underwent nephrectomy, irradiation, and chemo- therapy. The eight patients with unilateral adrenal adenoma and bilateral hyperplasia underwent unilateral and bilateral adrenalectomy, respectively. The three patients with ACC all had surgery as part of their treatment. The median duration between first hospital admission and last surgery in all 40 patients was 5,0 months (interquartile range 2,0-18,0 months).
Study Outcomes
The cumulative incidence curves of the hospital-recorded outcomes (fracture and osteoporosis, in- fection, cancer, epilepsy, and infertility) are shown in Figure 3.
CS patients were at increased risk of being diagnosed with infertility (SIR 4.56, 95% CI 1.48-10.63) (Table 2). The median age of receiving an infertility diagnosis was 27.0 years, and four out of the five patients were women. Three patients had ACTH-dependent disease and were treated with ei- 211 ther TSS or stereotactic pituitary radiation. Neither the patient with Klinefelter nor the patient with anorexia nervosa received a diagnosis of infertility.
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CS patients were at increased risk of being diagnosed with infections (SIR 3.24, 95% CI 1.05-7.54) (Table 2), and when classified according to ACTH-dependency, the risk of infection was more pro- nounced in the ACTH-independent group (infections: SIR 5.72, 95% CI 1.18-16.71 vs. SIR 1.96, 95% CI 0.24-7.07). The risk of infection appeared to be higher among patients receiving hydrocor- tisone replacement. Thus, 28.6% (n=4) of patients on hydrocortisone replacement (n=14) were sub-
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sequently diagnosed with an infection, while only 4.3% (n=1) of patients not receiving hydrocorti- sone (n=23) had this diagnosis. None of the patients were diagnosed with infection more than twice. Four patients, of whom two were on hydrocortisone replacement, received a diagnosis indicative of acute adrenocortical failure, which in one case concurred with a diagnosis of infection.
Three patients were diagnosed with fractures or osteoporosis (SIR 1.76, 95% CI 0.36-5.15). Two patients were diagnosed with cancer (renal cell carcinoma and cervical adenocarcinoma in situ, re- spectively) (SIR 2.74, 95% CI 0.33-9.90). Epilepsy was diagnosed in one patient (SIR 2.98, 95% CI 0.08-16.62) and no patients were diagnosed with diabetes, VTE, AMI, stroke, or heart failure (data not shown).
Seventeen patients developed hypopituitarism as a consequence of either TSS or stereotactic pitui- tary radiation. Fourteen patients received permanent hydrocortisone replacement post-treatment, of which ten had ACTH-dependent disease.
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Discussion
In this nationwide population-based cohort study, we confirmed that CS is a rare disease with an annual incidence of 0.89 cases/106 population of CS in children and adolescents. We observed an increased risk of hospital-recorded infections and a hospital clinic code of infertility during long- term follow-up.
The strengths of our study include the population-based design and linkage among health-related registries. The study, however, also has limitations that merit attention. All patients with CS in Denmark between 1977 and 2012 were identified, but the absolute number of patients and outcomes was very low and the study had a maximum of 36 years of follow-up. Moreover, we did not include data on neuropsychiatric and cognitive complications, which have been reported to be frequent even among patients with biochemically controlled disease 4.
Data from the DNPR are used routinely in nationwide quality monitoring of treatment 13,14. Howev- er, data quality varies by ICD diagnosis 15. The majority of misclassified patients in our study were referred for suspected CS and the diagnosis was eventually discarded. To reduce misclassification, we included an additional eligibility criterion in terms of a pertinent surgical intervention diagnosis (adrenalectomy or pituitary surgery). The patients treated with nephrectomy and stereotactic radia- tion therapies were not captured by this eligibility criterion, and surgical interventions were incor- rectly recorded in nearly a quarter of patients diagnosed with CS. It is noteworthy that outpatient ICD diagnoses were not included until 1995, which may have impacted on the outcome diagnoses. However, the CS diagnosis and treatment of each individual patient ultimately included in our study were validated via patient charts, so we feel confident that the figures regarding incidence and dif- ferential diagnosis are accurate.
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The annual incidence of CS in this study is low as compared to those reported in populations in- cluding both children and adults 1,16. In accordance with earlier studies 1,5,12,16, we observed a pre- dominance of females. The gender distribution of our pediatric patients was more even than in adult CS patients. A male to female predominance among pediatric patients in general has previously been described in one study 17, and a male to female predominance among subgroups of pediatric patients has also been reported 5-7.
Our study showed that pediatric CS patients were at increased risk of being diagnosed with infec- tions in a hospital after the diagnosis, in line with adult data 12,18, but increased infection risk was not reported in a recent review of long-term outcomes in children treated for CS 4. The true inci- dence of infections in our cohort could be underestimated, as only hospital visits are reported to the DNPR. On the other hand, patients with CS are followed as outpatients on a regular basis, which may lead to increased diagnostic awareness and the risk of detection bias. It is also noteworthy that a diagnosis of infection was more frequent among patients receiving hydrocortisone replacement, which could suggest that relative adrenocortical failure could have been an underlying or contrib- uting cause of the hospitalization and subsequent diagnosis.
Menstrual irregularity and fertility problems are common in women with CS, most likely prompted by hypercortisolemia 19. Infertility became an ICD-10 diagnosis only in 1994, and due to left trun- cation some CS patients in our cohort may have had undiagnosed or non-recorded infertility, but our study did not measure infertility based on strict epidemiological measures. Still, we found an increased risk of diagnosed infertility post-treatment among adolescent CS patients. This observa- tion merits further investigation and attention from treating physicians.
Previous studies have showed that hypercortisolemia in children may also increase the long-term risk of osteoporosis 20, and our study also suggest an increased risk of osteoporosis and fractures.
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Recent meta-analyses report that adult CD is associated with increased mortality 21, even among pa- tients in biochemical remission 22. This increased mortality risk was not documented in the present CS population, but this may be due to inadequate statistical power and insufficient length of follow- up period. The risk of being diagnosed with cancer is increased in adult patients with CS 12, whereas 283 cancer as an outcome to our knowledge has not previously been examined in pediatric patients. Our data suggest that this group also is at an increased risk of being diagnosed with cancer; however, the absolute number was very low (n=2).
The medical history of some of our patient’s merits consideration. As previously published, one pa- tient was diagnosed with PPNAD as part of the Carney complex 23, a disorder characterized by an 288 increased risk of certain tumors due to mutations in the PRKAR1A gene 24. This observation ac- 289 290 291 cords with previous data on CS in children and adolescents 25. MEN-1 is a genetic disorder associ- ated with neoplastic lesions in the pituitary gland, the parathyroid glands, and the endocrine pancre- as 26. Three patients with CD in our cohort had MEN-1, which has previously been described 27. 292 One patient with CD also had Klinefelter syndrome, a sporadic genetic disorder in males character- ized by two or more X chromosomes, with a prevalence of 1-2 cases/1,000 males. The hallmark is hypogonadism and infertility. Apart from one instance of an ectopic ACTH-producing tumor in a patient with Klinefelter syndrome, no associations between the two syndromes have been reported previously 28. Craniofrontonasal syndrome is an X-linked malformation syndrome caused by muta- tions in the ephrin-B1 gene 29. One patient with adrenal CS suffered from this rare disease, which to our knowledge has not been reported previously. Prior to the CS diagnosis, one patient was diag- nosed with anorexia nervosa, which may have developed in response to glucocorticoid-induced weight gain. It is therefore important to be aware that an underlying disease such as CS may occa- sionally masquerade as an eating disorder 30,31
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In conclusion, this population-based cohort study provided new population-based estimates of the
303 304 incidence and prevalence rates of CS in children and adolescents. An elevated risk of certain condi- 305 tions attributable to complications of the syndrome was reported.
Declaration of Interest
Dr. Sørensen did not report receiving fees, honoraria, grants or consultancies. Department of Clini- cal Epidemiology is, however, involved in studies with funding from various companies as research grants to (and administered by) Aarhus University. None of these studies have relation to the pre- sent study. All other authors have nothing to declare.
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312 Funding
313 This study was supported by a grant from the Clinical Epidemiological Research Foundation in
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Denmark; and the Program for Clinical Research Infrastructure (PROCRIN) established by the Lundbeck Foundation and the Novo Nordisk Foundation.
Author Contributions
Johanne Marie Holst (MD), Erzsébet Horváth-Puhó (PhD), Rikke Beck Jensen (PhD), Mariane Rix (MD), Niels Thomas Hertel (PhD), Olaf M. Dekkers (PhD), Henrik Toft Sørensen (DMSc), Anders Juul (DMSc), and Jens Otto L. Jørgensen (DMSc) made substantial contributions to the study de- sign and the acquisition and interpretation of the data. Erzsébet Hováth-Puhó and Johanne Marie Holst completed all analyses. Johanne Marie Holst and Jens Otto L. Jørgensen drafted the manu- script. All authors contributed to the revision and completion of the article and provided their final approval of the version to be published. Johanne Marie Holst and Erzsébet Hovátg-Puhó had full access to all of the data in the study and take responsibility for the integrity of the data and the accu- racy of the data analysis.
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31. Sawicka N, Gryczyńska M, Sowiński J, Tamborska-Zedlewska M, Ruchała M. Two diagnoses become one? Rare case report of anorexia nervosa and Cushing’s syndrome. Neuropsychiatr Dis Treat. 2013;9:431-435.
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Figure Legends
Figure 1A. The Study Population Categorized According to Surgical Intervention Codes and Final Diagnosis.
CS: Cushing’s syndrome
420 Figure 1B. The Cushing’s Syndrome Cohort Categorized According to Subtypes CS: Cushing’s syndrome; ACTH: adrenocorticotropic hormone
Figure 2: Standardized Incidence Rate per 10° Person-Years According to Year (1977-2012)
Figure 3. The Cumulative Incidence Curve of the Outcomes Fracture or Osteoporosis, Infection, Cancer, Epilepsy, and Infertility
414 415 416 417 418 419
421 422 423 424 425 426
| Cushing Cohort (n =37) | ||
|---|---|---|
| N | Percent (%) | |
| Age | ||
| 0-14 | 21 | 56.8 |
| 15-20 | 16 | 43.2 |
| Gender | ||
| Female | 20 | 54.1 |
| Male | 17 | 45.9 |
| Year of Cushing's syndrome diagnosis | ||
| 1977-1990 | 14 | 37.8 |
| 1991-2000 | 13 | 35.1 |
| 2001-2012 | 10 | 27.0 |
| Person-Years at Risk | Observed No. | Expected No. | SIR (95% CI) | |
|---|---|---|---|---|
| Infection | 590.15 | 5 | 1.55 | 3.24 (1.05-7.54) |
| Fracture and osteoporosis | 555.50 | 3 | 1.70 | 1.76 (0.36-5.15) |
| Epilepsy | 641.43 | 1 | 0.34 | 2.98 (0.08-16.62) |
| Infertility | 618.66 | 5 | 1.10 | 4.56 (1.48-10.63) |
| Cancer | 666.71 | 2 | 0.73 | 2.74 (0.33-9.90) |
No: number
NA: not applicable
CI: confidence interval
SIR: standardized incidence ratio
n=256
n=33 Surgical intervention
n=223 No surgical intervention
n=3 Not CS
n=30 CS
n=10 CS
n=213 Not CS
B
CS n=40
ACTH dependent CS n=29
ACTH independent CS n=11
Morbus Cushning n=28
Ectopic CS n=1
Unilateral adenoma n=4
Bilateral Hyperplasia n=4
Carcinoma n=3
35
Fracture and osteoporosis
30
Infection
Cancer
25
Infertility
Cumulative risk (%)
Epilepsy
20
15
10
5
0
0
5
10
15
20
25
30
35
Years since Cushing diagnosis
10
Standardised incidence rate per 10^6 person-years
9
8
7
6
5
4
3
2
1
0
1977-1982
1983-1987
1988-1992
1993-1997
1998-2002
2003-2007
2008-2012
Year of Cushing diagnosis