1L.Chin Epidemiol Vol 51, No.2, pp. 147-158, 1998 ‘Coprright © 1998 Eleevier Science Ine. Al rights reserved 0895-4356/98/819.00 PIL $0895-4356(97900237-0 ELSEVIER Morbidity in Turner Syndrome Claus Hojbjerg Gravholt,"” Svend Jucul,? Rime Weis Naeraa,? and Jan Hansen* 'MepicaL Deparsuent M (ENpockinotocY axp Diaserss), Aarius Kosunenosorrat, AaRnUs UNWERSITY Hosrrrat, Aaritus, Devmank; ‘Deearrent oF EpipeqiolocY aNb Soctal, Mepiewe, Aaaius Untvenstry, Aanitus, DexMark; 'PaFDiATRIC Derartaent A, AaniUs KoMMUNEHOsrrtAL, AARHUS Univanstty Hosertat, ‘Aanivs, Denna; AND *CrrodENeric LanoraTORY, AARHUS PSYCHIATRIC HOSPITAL, ‘Aaanius University Hosprrat, Aannus, DENMARK ABSTRACT. Turner syndeome aflicts approximately 50 per 100,000 females and is characterised by rearded srowth, gonadal dysgenesis, and infertiliy. Much attention has heen focused on growth and growth promoting therapies, while les is known about the natural coune of the syndrome, especially in adulthood. We undertook this study to assess the incidence of diseases relevant in the study of Turner syndrome. The study period was from January 1, 1984 to December 31, 1993, and the study base was all women living in Denmark during the study period. We used data from the Danish Cytogenetic Central Register and the Danish National Registry of Patients to assess morbidity. This study supports several earlier studies reporting increased morbidity and confirms results ofa recent study on cancer in Turner syndrome. Women with Tumer syndrome seem to have an increased incidence of fractures, osteoporotic fractures in adulthood, and non-esteopototc factutes in childhood. Further ‘more, diabetes mellitus, both NIDDM and IDDM, was found with a markedly increased incidence in Turner syindrome, as well as ischemic heatr disease, hypertension, and stroke. The tsk of cancer, except cancer of the large bowel, does noe seem to be elevated in. Turner syndtome. Oue dara suggest chat patients with Turner syndrome are extraordinarily prone to abnormalities constituting the metabolic syndrome (e.g, hypertension, lslipidaemia, NIDDM, obesity, hyperinsulinemia and hyperuricemia). The present data may help t0 explain the decreased lifespan found in patienes with Tumer syndrome. | cLuN EPIDEMIOL 51;2:147, Elsevier Science Inc. 58, 1998. © 1998 KEY WORDS. Turner syndrome, morbidity, cancer, insulin dependent diabetes mellitus, non-insilin depen dent diabetes mellitus, osteoporosis, fractures, congenital malformations, thyroid diseases, metabolic syndrome INTRODUCTION Tumer syndrome is a condition involving total or partial absence of one X chromosome in all or part of the cells reduced final height, absence of female sex hormones, and in most cases infertility. Turner syndrome has been associ- ated with a numberof diseases including non-insulin depen- dent diabetes mellitus, abnormalities of glucose metabolism [1-8], and hypothyreosis and thyroid antibody formation, especially in a subgeoup with an isochromosome of the long arm of the X chromosome (i(Xq)), although islet cell auto- antibodies are not reported with increased frequency [9 21), Reduced bone mineral content (BMC) is often seen, as are other skeletal abnormalities [22-26]. An increased frequency of wrist fractures has been reported (27] whereas ‘others have not found excess fractures [23,28], Sex hormone replacement therapy is considered crucial to avoid a rapid decrease in BMC {29}. Increased circulating levels of he- patic enzymes have been reported in adult Turner patients ‘Aldro for corespondence: Dt. Claus Hajhere Grinholt, Medical De partment M (Endscinslogy and Diabetes), Aaehus Kommunehespial, University Hospital f Aarts, DK-8900 Aarhus Denmark “Accepted for publiation on 6 Cetohes 197, [30]. Gonadoblastoma has been reported with increased fre~ quency in mixed gonadal dysgenesis in some studies [31— 34], while not in others [35]. Turner syndrome is also associ- ated with congenital malformations such as coarctation of the aorta, horse shoe kidney and pterygium colli [36-38], especially with the 45,X karyotype [39-42]. Less severe con- genital malformations of the heart are also seen with in- ‘creased frequency [42-47]. The incidence of ischemic heart disease is normal, although one report found increased lev- els of cholesterol in acdolescents with Turner syndrome [48]. There are some case reports of patients with Tuer syn- drome with stroke [49-51]. ‘We undertook this study to obtain estimates of the inci- dence of associated chronic diseases in patients with Turner syndrome, and we used data from the Danish Cytogenetic Central Register and the Danish National Registry of Pa- tients to assess the morbidity. Only diseases leading to hos- pitalization were included in the analyses. MATERIALS AND METHODS: The study period covers 10 years, from January 1, 1984 to, December 31, 1995, and the study base includes all women148, living in Denmark during the study period (midpoint popu- lation, 2,594,036 women). Females with Turer syndrome (n = 594) were identified by the Danish Cytogenetic Cen- tral Register. Information about hospitalizations with the primary discharge diagnosis of interest was obtained from the Danish National Registry of Patients (1,007,502 admi sions), No outpatient data were included in the analyses. In Denmark seven laboratories perform postnatal karyo~ typing. The Danish Cytogenetic Central Register was founded in 1968 and has since collected information on constitutional chromosomal abnormalities throughout Denmark. Abnormalities diagnosed before 1968 were also included in the register. The Danish Cytogenetic Central Register has since 1978 issued an ancwal report [52]. We studied all possible Turner syndrome karyorypes, including phenotypical Turner females with karyotypes involving the Y chromosome. All hospital admnttances in Denmark since 1984 are rege istered in the Danish National Registry of Patients, with patient name, CPR number (Central Person Register num ber, which is unique to every inhabitant in Denmark), main discharge diagnosis and possible secondary discharge diag noses, and date of hospital admietance. The coding of di agnoses until 1993 was based on ICD-8 with a three-digit diagnostic level. In Denmark ICD-8 has been further elabo- rated into a five-ligit system [53]. In the present study the data are based on the three-digit system except for a few very specific diagnoses such as coarctation of the aorta, pte- rygium colli, and myasthenia gravis which are based on the five-digit diagnostic level ‘We received data from the Danish National Registry of Patients on the discharge diagnoses of interest among fee males during the 10-year study period from 1984 to 1995, Most diagnoses of interest have previously been proposed to be present in Turner syndrome in excess frequency (Ta- ble 1), but we also included diagnoses often seen on death certificates from Tumer patients [54]. Psychiatric diagnoses were not included in the analysis. ‘An incident case of a disease was operationally defined as the fist time during the 10-year period 1984-1993 when the diagnosis was given as primary discharge diagnosis for that woman. This applies both to the Turner patients and to the background population, When Turmer syndrome was recorded as the primary diagnosis (n = 162) for a person confirmed to have cytogenetically verified Turner syndrome in the Danish Cytogenetic Central Register, the secondary discharge diagnosis was used if recorded (n = 9), We used this approach because Turmer syndrome in itself rarely leads to hospitalization, but unfortunately the diagnosis of Turner syndrome is sometimes entered as the primary diagnosis, which is contrary co the recommendations in the ICD-8, according to whieh the primary diagnosis should be the di- agnosis actually leading to hospital ‘The original data set from the Danish National Registry of Patients describes 1,007,502 admissions. To identify “first CH, Gravhote er af TABLE 1. Diagnoses of interest in the study according to the 1cD8 Group of diagnoses! diagnosis ICD-8 number Cancer 149-209 Benign tumor 210-228 Unspecified tumor 330-239 Endocrine disease 240-258 ‘Anemia and other diseases of the blood. 280-289 Rheumatic heart disease 390-398 Hypertension 400-404 Heat disease 410-429 Vascular disease of the brain 430-438 Arteriosclerosis 440-448 Venous disease 450-458 Uleeroric colitis and Crohns disease 563 Diseases of the liver gall system, and pancreas 510-577 Pooriasis 66 Diseases of hair and hainses 04 Other skin diseases 709 Diseases of bone, locomotive system, and connective tissue 710-718 Osteoporosis 723.09 Myasthenia gravis 73.09 ‘Congenital malformation of the face, eas, and neck, m5 ‘Congenital malformation of the heart 746 Congenital malformation of the urinary stem 753 Fractures 800-829 admissions” we excluded admissions with the same dis- charge diagnosis as a prior admission. When excluding ad- missions with the same discharge diagnosis at the fiveigit level, 914,506 admissions remained in the data set. When eliminating admissions with the same discharge diagnosis at the three-tigi level, 886,482 admissions remained in the data set. The Turner cohort consisted of 594 women (karyotype distribution, see Table 2) and their contribution with age specific risk time during the 10-year study period was calcu- lated (Table 3). Since Turner syndrome is a congenital condition, risk time for the Tumer cohort was calculated from birth or from Jan 1, 1984 if born prior to that date, even though the actual cytogenetic diagnosis might have been established later (Table 3). The risk time for the background population (the entire female population of Denmark) was estimated from published demographic reports [55]. ‘A record linkage with the Danish National Registry of Patients showed that 272 women in the Tumer cohort (464%) had a total of 404 “frst admissions” in the study perio. The study was approved by the local ethical scientific committee, the directing board of doctors at the Danish Cy-Morbidity in Turner Syndrome 149. TABLE 2. Distribution of karyotypes in the study group Karyotype Number Percent 5x 284 48 5.X/46XX 96 16 5.X/46,X(Nq); 45.X/46,Xl (Xa) AT XXUCXq)s 45.X/46 XQ. OXX/46.XilXq); 46K Xq) 2 0 45.X/46.X dX): 46,X del(Xq): 46.X del(Xp) 4 6 5 XI46X idie(X), 45,X/46,X.c(-X); 45.146 X fra); $5XI4GXXp—j 45.X/46.% dup); 45/46. 46.X dup; 45.X/46.X.CXp); 45.X/46XKG~; 46,XXG~j 46.XXp— 2 4 45.X/46.X tring; 46X10) 26 4 45.X/46.X,+mar, 46.X,+mar, 46X,+mar/47.XX+ mae 10 2 45.X/46,XX/ATXXX: 45/47, XXX; 45.X/46 XXIST AXIS XAXK 33 6 45.X/46XV 4 2 AS X/46 XV )5 45 X/46 X diel VI; 45 XH46.X dell V; $5.X/46X AN AB XI4EXnw( Vs 45.X/46,X,ine IAT XK inv Ws ASXHOX AVY): 46.X,i0¥q): 46X00) 4 as Total 594 100 togenetic Central Register, and the national registry au- thorities. STATISTICAL METHODS The observed number of a diagnosis among Turner patients ‘was compared to the expected number calculated from the incidence in the study base by means of indirect age stan- dardization. The Poisson distribution was used to calculate 95% confidence limits for relative risks. Pearson chi test was used to test for differences between groups of karyo~ types; and the Mantel-Haenszel analysis for cohorts was used to compare incidence rates in categories of for different age groups: incidence rate ratios with 95% con- fidence limits were calculated as described by Breslow [56]. Below we describe and discuss significant as well as insig- nificant relative risks; because Turner syndrome is a rare syndrome, che combination of a rare syndrome and infte- TABLE 3. Time at risk among Turner patients and in the ‘Years at risk Turmer ‘Age groups syndrome cohort ‘Study base ot 289 1,402,080 5-14 946 3,082,500 15-24 1434 3,744,993 2534 1261 3.736343 5544 906 3.759.390 45-54 309 31079890, 197 2,668,770 a 2,437,800, 8 963,740 O79 540 24,875,507 quently encountered diseases can lead to few incident cases, but with a clear trend in the relative risk. The clinical sig- nificance of the findings is another issue. Because we con: sider a wide range of diseases, some common and some rate, wwe have not decided a priori on a general level of clinical significant increase in risk, since this in each case should depend upon the severity of the condition, as well as on the absolute risk of disease (see discussion). However, mod- erately elevated relative risks may be due to detection bias and thus the interpretation of relative risks below 1.5-2 should be cautious (see discussion). The statisties were done with SPSS for Windows version 6.1.3 (SPSS Ine., Chicago, IL) on a Pentium PC. RESULTS Population Figure 1 describes the observed prevalence of Turmer syn- drome for the birth cohorts 1913-1992, Until the 1940s the recorded prevalence was low while from 1950 to 1980 increasing to 30 to 40 cases per 100,000 females, From 1980 the recorded prevalence declined, probably reflecting both the short follow-up period and induced abortions of ascer tained Turner syndrome fetuses (approximately 10% of the pregnant population in Denmark underwent either chorion villus sampling or amniocentesis during this period) [57] IF the true prevalence of Turner syndrome is 50 per 100,000 liveborn females, about 70% of eases seem to have been identified from 1950 to 1980. Morbidity in Turner Syndrome ENDOCRINE DISEASES, The relative risk of getting an en- docrine diagnosis was 4.87 (Table 4). Hypothyreosis was seen significantly more often as was thyroiditis, insulin de-C,H. Gravhole et al 80 70 60 50 40 30-4 20 10 Prevalence of Turner syndrome per 100,000 liverborn girls, 1920 1930 1940 1950 1960 1970 1980 1990 Year of birth FIGURE 1. Recorded prevalence of Tumer syndrome per 100,000 liveborn girls by year of birth from 1913 to 1993. pendent diabetes mellitus, non-insulin dependent diabetes: FRACTURES. Osteoporosis and fractures occurred more mellitus, together with miscellaneous endocrine diseases; of frequently in Turner syndrome (Table 5). Some distinct the latter childhood hypoglycemia not connected to diabe- fractures were seen significantly more often, namely frac tes, and parathyroid disease presented an insignificant te tures of the metacarpal bones, of the femoral neck and of dency toward elevated relative risks. the femoral bone, as well as potentially osteoporotic frac- TABLE, Diagnoses (ICD-8) ‘Observed Expected RR (95% Cl) Endocrine diseases, overall (240-258) 5 1047 487 663-641) ‘Thyroid diseases, overall (240-246) 10 498 2.00 (0.96-3.69) ‘Thyreotoxicosis (242) 3 150 201 (@41-3.86) Hypothyreosis (244) 3 052 5.80 (1.20-16.94) Thyroidieis (245) 3 081 16.60 (3.42-48.50) Insulin dependent diabetes mellitus (IDDM) (249) 9 078 11,56 (5.29-21.95) Non-insulin dependent diabetes mellitus (NIDDM) (250) B 2.88 438 (2.40-7.72) Miscellaneous endoczine diseases (251-258 (~251.13-15)) 15 in 871 (487-1436) Parathyroid disease (252) 1 O14 7.25 (0.18-4037) Hypoglycemia’ (251.00) 2 os? 351 (043-1269) Bassd on diagnosis onthe five digit levelMorbidity in Tumer Syndrome 151 TABLE 5. Relative risk of disease in Turner syndrome (other than endocrine diseases and cancer) ‘Diagnoses (ICD-8) ‘Anemia and other diseases ef the blood (280-289) Rheumatic heart diseases (390-398) Hypertension (400-404) Hare diseases and arteriosclerosis (410-429, 440-448) ‘Vascular diseases of the brain, (430-438) ‘Venous diseases (450-458) Uleerotic colitis and Crohns disease (563) Diseases of the liver, gall system, and pancreas (570-57) Cirthosis of the liver (571) Gallstone diseases (574) Selected diseases affecting the skin (696, 704, 709) Psoriasis (696) Bone, locomotive system, and Connective tissue (710-718) Rheumatic arthritis (712) Osteoporosis? (723.09) Fractures, combined (800-829) Fractures of the spine (805) Fractures of the humeral bone (812) Fractures of the ulnar and radial ‘bones (813) Fractures of the metacarpal bones (615) Fractures of the phalangal bones (816) Fractures of the femoral neck (820) Fractures of the femoral hone (821) Fractures of the tibial an fibulal bone (823) Potential osteoporotic fractures* (805, 813, 820) ‘Myasthenia gravist (733.09) Congenital malformation of the heart (746) Coarctation of the aorta® (747.19) Congenital malformations of the urinary system (753) Congenital malformations of the face, ‘ears, and neck (745) Prervgiun colli? (745.59) Observed Expected 16 IRR (95% Cl) 419 167 (067-34) 043 4.62 (0.561667) 240 291 (1.17600) 758 241 (121-343) 2m 271 (1.04-5.33) 10.02 080 (0.34-1.57) 178 2.25 (0.61-5:15) 631 174 (087-3.12) 0.70 5.69 (1.55~14.56) 3B 161 (0:59-3.50) 093 3.22 (0.66-9.40) 045; 225 (0.06-12.51) 1056 0.95 (0.45-1.74) 126 3.18 (087-8.15) 028 10.12 (218-3093) 1623 2:16 (1:50-3.00) 082, 2.44 (030-882) 133 2.26 (047-660) 2.89 2.08 (0.76-4:52) 023 22.00 (7.14-51.33) 47 424 (051-1532) O8t 493 (134-1261) 060 9.93 (364-2161) 1.86 Lot (033-472) 452 2.66 (137-464) 007 S 1.05 13.35 (7.30-22.40) 006 367.13 (227.26-561.20) 0s7 8.78 (2-85-2048) 210 334 (134-688) 0.003 1158 (239-3385) Based om diagnos on the Gve dig level “These fractures include facture ofthe spine, facares ofthe ulnar and radial bones (including Calls! racine, and facares of the feral neck, tures which were: fractures of the spine, and of the ulnar and radial bones (including Colles’ fracture), and of the femoral neck. CONGENITAL MALFORMATIONS. Congenital malforma- tions of the heart, congenital malformations of the urinary system, and congenital malformations of the face, eas, and neck were more frequent among patients with Turer syn- drome (Table 5). Coarctation of the aorta was seen with a relative risk of 367 and pterygium colli was seen with a rela- tive risk of 1158, CANCER. The relative cancer risk among women with Turner syndrome was 1.35 with most of the individual rela- tive tisk for each neoplasm being insignificant, except the risk of getting cancer of the gut (RR: 4.36), particularly can-152 CH. Gravholt eral ‘TABLE 6. Relative risk of cancer in Turner syndrome Diagnoses (ICD-8) Cancer risk, overall (140-209) Buccal cavity (140-149) Digestive sytem (150-159) Colon and rectutn (153-154) Respiratory system (160-163) Skin, hone, and connective tissue (170-173) Breast (174) Female genieal tract (180-189) Ovary (183) (Other specified Locations (190-199) Lymphatic and hematopoietic visu (200-209) Benign tumor (210-228) Unspecitied rumors (230-239) Observed Expected __ RR (95% Cl) 2 8921.35 (0.70-235) 0 016 = 4 092 436 (1.19-11.16) 3 O61 494 (1.02-1445) 0 0.65 = o 0.80 = 2 259 O77 (009-279) 4 2131.88 (051-480) 0 oer = 1 OM — 1.10 (003-6.12) 1 079 126 (003-705) 18 2139 084 (050-133) 5 1046 048 (0.16-116) cer of the colon and the rectum (RR: 4.94) (Table 6). The relative risk of developing cancer of the breast was not dif ferent from the background population, and there were no recorded cases of cancer of the ovaries. ‘orner Diseases. We found a significantly increased rel- ative risk of 2.11 as regards heart diseases and arteriosclero- sis (Table 5). Hypertension and vascular disease of the brain appeared significantly more frequent. Insignificantly ele- vated relative risks were seen for a umber of conditions such as anemia and other diseases of the blood, rheumatic heart diseases, and diseases of the liver, gall system, and pan- creas. The relative risk of cirthosis of the liver was signif: cantly elevated. For diseases affecting bone, the locomotive system, and connective tissues the relative risk was identical to the background population, whereas the relative tisk in a sub- ‘group, theumacoid arthritis, was insignificantly elevated to 3.18 (Table 5). Influence of Karyotype Congenital malformations were most frequent among, women with 45,X, while a number of diseases were discov- ered considerably more often among women with other karyotypes (endocrine diseases, heart diseases, hyperten- sion, arteriosclerosis, venous diseases, and inflammatory gut diseases) (Table 7). In the other groups of diseases there ‘were no differences between the two karyotype groups, Influence of Age “The relative risk for endocrine diseases showed a maximum in young age groups with a subsequent decline toward a value of two in the age group 65+ years (data not shown). The same tendency was apparent for cardiovascular diseases (ICD-S numbers 390-458) (data not shown) and congeni- tal malformations (data not shown), although a very high relative rate for the oldest age group (35+) was recorded. In contrast, when pooling all fractures the relative risk in- creased with age, bur already in childhood females with Tuer syndrome had an increased risk of fractures (data not shown). The relative rate for cancer was in all age groups close to one and no fluctuations with age could be discerned (data not shown). Consistency between the Danish National Registry of Patients and the Danish Cytogenetic Central Register ‘The diagnosis of Turner syndrome in the Danish National Registry of Patients was encountered 272 times in 237 di ferent women. Only 161 could be found in the Danish Cytogenetic Central Register with a cytogenetic diagnosis ‘of Turner syndrome, and the remainder (76) seemed to be based solely on clinical features. Of these 42 had a nor imal cytogenetic examination, while two tumed out to be wrongly classified in the Danish Cytogenetic Central Reg- ister as having a normal karyotype when indeed having posible Tumer syndrome karyotypes (46,X.dup(X) and 46.X del inv(X)). These two cases were excluded from the statistical calculations. Three eases had the Karyotype 46,XY and henceforth probably Morris or Swyer syndrome. Two cases were mothers of girls with Tumer syndrome and had wrongly been classified in the Danish National Registry of Patients as having Tumer syndrome themselves. The re- maining 30 cases had ot been verified with cytogenetic examination. The average age at the time of hospitalization was not diferent for women with a diagnosis of Turner syn- drome in The Danish Cytogenetic Central Register com- pared to women with a diagnosis not verified in The Danish Cytogenetic Central Register or verified in The Danish Cy- togenetic Central Register as having a normal karyotype (average age 18.4 [SD: 19.4] versus 18.3 [SD: 13.5] years).Morbidity in Turner Syndrome 153 ‘TABLE 7. Distribution of diagnoses on karyotypes Diagnoses Cancers Endocrine diseases Anemia and other diseases ef the blocd Cardiovascular diseases Diseases of the liver, gall bladder, and pancreas Locomotor diseases ‘Congenital malformations Fractures All aryorypes All other 45X, karyotypes a (%) on (%) opt pee 42) eee Tee (50) ge 0 16 G30) 38 (70) 0.005, Sener 0 2 GO 287). 4G) 7) Og 5 G8) 8) OS 327) 6— 3) 006 7 4%) 18) 10 2 48) 510 (52) “Comparison of ene diagoosts with all other diagnoses. Pearson chi ‘Thus most of the inconsistencies scem to arise from prema- ture coding in the Danish National Registry of Patients with suspected Tumer syndrome, DISCUSSION Detection Bias Berkson identified a potential source of detection bias in hospital-based studies ifthe existence of one diagnosis af- fects the likelihood of another diagnosis being given [58] Pavients with Turner syndrome may be more likely than rnon-Tumer syndrome patients to be admitted to hospital simply because they already suffer from one condition and because they may have more encounters with the healch care system. This is obviously a potential drawback in the present study. Particularly for conditions that often remain undiagnosed (e.g, hypertension and NIDDM), or, when di- agnosed, often are treated without hospital admission (€85 rninor fractures, hypertension, and NIDDM) or when an association is already known to exist (eat, thyroid diseases and Tumer syndrome), the risk of detection bias seems high. For conditions thae invariably are diagnosed and usu- ally require hospital admission (e.g., [DDM and cancer) the risk of detection bias i smaller. On the other hand we iden- tified 153 cases in the data set where “Tumer syndrome” ‘was the only diagnosis. It is possible that this diagnosis was not the sole reason for hospital admission and that failure bby the discharging physician to properly record the relevant reason or diagnosis for admittance may lead to an underesti- ‘mation of the actual morbidity. Itis impossible to determine the magnitude of these offsetting sources of bias, but one should probably interpree the moderately increased relative risks with caution, and take into account the absolute risk of disease in each case Danish Cytogenetic Central Register The Danish Cytogenetic Central Register represents. a tunique opportunity for studying abnormal karyotypes, be- cause most cytogenetic examinations performed in. Den- mark are recorded here, whether normal or abnormal. The register can be considered complete, although technical er- rors can never be entirely excluded. Danish National Registry of Patients In the National Patient Reistry all hospital discharge diag- noses ae registered. No out-patient diagnoses were included as the registration of these data is not yet complete across Denmark. All patients hospitalized in public hospitals re- ceive upon discharge from hospital one or more diagnoses. As the hospital services in Denmark are completely run by local government we can assume thar we have knowledge of almost all relevant hospital diagnoses in this study. We have focused only on the primary diagnosis. A recent vali dation study of the quality of the diagnostic information (primary diagnosis) showed that the agreement between a recoder and the rexistry was between 73% and 89% on the three-digit level, depending on the clinical subspecialty Agreement between recoder and registry was 75-90% when the diagnosis in the registry was considered an acceptable alternative to the actual discharge diagnosis [59]. The infor- mation in the registry is obviously not optimal, but differen- tial misclassication of diagnoses is not likely to bias the ‘comparisons substantially ‘Age Distribution ‘The Turner population was hospitalized aca young age. This isshown in Table 3, where the age distribution of the hospi- talized Turner women is shown together with that of the background population. The hospital admission rate was in- creased at all ages (Fig. 2), especially among the young, Fig- tre [ illustrates that the diagnosis of Tumer syndrome was very tare before 1950 and that the prevalence again declines in the cohorts after 1980, probably due to the rather short follow-up period and to induced abortions of prenatally as-154 160 140 120 100 ‘Hospital admission rate / 1000 years 8 0-4 S14 15-24 25.34 35-44 CH. Gravhole et al 45-54 55-64 65-74 75-79 Age FIGURE 2. First hospital admission rates for diagnoses of interest. Hospital admission rates for specific age groups after indirect age standardization. Light hatched bars, Turner syndrome; dark hatched bars, background population. certained Turner syndrome karyotypes [57]. We established earlier that about 46% of all cases of postnatally diagnosed Turner syndrome from the birth cohorts 1970-1993 were diagnosed before the age of 5, 60% before 10, and 90% be fore 15 57]. Hypothetically, the women in the cohort might be the ones most severely affected phenotypically by the syndrome and therefore perhaps also the ones with the highest morbidity. On the other hand, many Turner syn- drome women born before 1950 were probably never diag- nosed before dying from congenital malformations, Turner related diseases, or other conditions. Furthermore, the awareness of Turner syndrome among clinicians has in- creased during recent years, contributing to the much higher prevalence recorded since 1950 (Fig. 1). Morbidity in Turner Syndrome ENDOCRINE DISEASES. The relative risk of endocrine dis- case was increased in Turner syndrome. This was apparent for all groups of endocrine diseases except for thyrotoxicosis This is in accordance with other studies, which have also found an increased frequency of thyroid autoantibodies [9- 16,21), A new and unexpected association was that not only NIDDM, but also IDDM is more prevalent in Turner syn- drome. Most reports so far have focused on the increased insulin resistance and chus a presumed increased risk of de- veloping NIDDM [1-3,5,10], whereas IDDM has not been associated with Turner syndrome, Moreover, autoantibodies against pancreatic islet cells are not present in excess fre ‘quency when screening populations of females with Turner syndrome (13,18-20]. These results, however, confirm our recent work on mortality in Turner syndrome where diabe- tes mellitus was reported as an underlying cause of death in 25% of the eases [54]. There is of course a rsk of misclassifi- cation of the type of diabetes (i.e, an admission classified as IDDM may be a case of NIDDM, either early onset or treated with insulin), but we have no reason to suspect @ differential misclassification between Turner patients and rnon-Turner patients. The relative risk of endocrine disease is high early in life, declining somewhar with age, but never below a relative risk of two. FRACTURES. Osteoporosis, osteoporotic fractures, and. fractures overall were more frequent among women with Tumer syndrome (Table 5). This was expected since we know that many older women with Tumer syndrome in Denmark either do nor receive sex hormones or have started substitution late in life, Reduced bone mineral con-Morbidity in Turner Syndrome tent has been found by others [22,25]. Two groups did not report any increased frequeney of fractures [23,28], whereas one study reported increased frequency of wrist fractures in young girls [27]. One study advocated that there seemed to be no scientific evidence fr lifelong sex hormone treatment to women with Tumer syndrome since they could show no reduction in bone mineral content with time [28], while others have found that treatment with sex hormones is cru- cial in order to avoid a rapid decrease in bone mineral con- tent in Turner females 26,29]. The elevated relative tisk of fractures in general was present already in childhood, and the risk can hardly be ascribed to lack of sex hormones, but pethaps can be explained by the numerous bone abnormali- ties known to be present in Tumer syndrome [22-26], and an additional defect in bone development. We lack infor- ‘mation on sex hormone substitution therapy in this cohort. CONGENITAL MALFORMATIONS. The risk of congenital malformations is increased in Turner syndrome. This has been known since Turner published his original report [60] and has been repeatedly shown by others [36,37.42]. Here ‘we present, to our knowledge for the first time, relative risks and incidence rates (Table 5). As shown by others there ‘were more congenital malformations among che group of 45.X versus all other karyotypes (37,61) ‘CANCER. Tumer syndrome has previously been reported to be associated with an increased risk of ulcerative colitis [62-64], which again is associated with an increased risk of cancer of the colon and the rectum [65]. In line with previ- ‘ous reports we found an increased relative risk of inflamma- tory bowel disease (2.25 (0.61-5.75)); this was statistically insignificant, pethaps due to the rarity of the disease. In a recent stucly of cancer in Turner syndrome in Denmark it ‘was found that the relative risk of cancer of the colon and the rectum was 69 (2.2~16.2), corresponding well to our data (4.94 (1.02-14.45)) [35]. In that stady, none of the ppetsons with cancer of the colon and the rectum had any inflammatory diseases prior to the cancer [35]. More dara are needed on this subject before any definite association between Tumer syndrome and inflammatory bowel disease can be established, ‘An association between Tumer syndrome and cancer of the colon and the rectum has been reported previously {66— 68]. No other cancers were found with excess frequency (Table 6). Today most women with Tumer syndrome re- ceive lifelong sex hormone substitution and concerns have been raised about a possible increased risk of cancers of the reproductive organs due to this [69,70]. Sex hormone substi- tution may lead to an increased risk of cancer of the breast and reproductive organs [71,72]. Particularly in this context it is noteworthy and reassuring that we did not detect any excess risk of cancer of the breast, or the urinary system and genital organs. Surely one has to be cautious in the interpretation of these results, as we do not know exactly how many females with Tumer syndrome in this cohort 155 have received sex hormone substitution and, if so, for how long. Previously an association between leukemia and Tumer syndrome has been suggested in case reports [73,74]. This could not, however, be supported in this study (RR: 1.26 {0.03~7.05)), AAs in the recent study by Hasle etal. [35] of the Danish Cancer Register, no cases of gonadoblastoma or dysgermi- noma were found, despite the fact that 29 of the women with Turner syndrome had cytogenetically verified Y chro- ‘mosomal material in their karyotype. Furthermore, recent studies imply that a large proportion of women with Turner syndrome and karyotypes without Y chromosomal material has so-called “hidden” Y chromosomal mosaicism, only de- tectable with the use of PCR {75,76], even though the clini- cal and practical implications of this finding are disputed [77-79], The relative rate of cancers was low in all age groups. This means that the tisk of cancer in Tumer syn- drome is close to the general population OTHER DISEASES. We found significantly increased risks for hypertension, cardiovascular heart disease and arterio- sclerosis, and vascular diseases of the brain. The increased risk of heare disease and arteriosclerosis confirms our recent finding from death certificates, demonstrating that approxi: mately 50% of all deaths were caused by cardiovascular dis- ceases occurring 6-13 years earlier than expected [54]. The increased risk of cardiovascular disease in Turner syndrome ‘could be due to chronic estrogen deficiency and to inappro- priately treated hypothyreosis; conditions associated with coronary artery disease, clevated LDL cholesterol, and apo- lipoprotein B levels [80-82]. The increased risk of heart disease could also relate to the elevated frequency of con- genital malformations of the heart; yet it is intriguing that Congenital malformations were more frequent among fe. males with 45,X, whereas cardiovascular diseases were found considerably more often among females with “other karyo- types” (Table 7). In a recent population-based study, 26% of all Turner syndrome females (N = 179) had malforma- tions of the heart, By far the most frequent malformations ‘were coarctation of the aorta (10%) and aortic valve abnor- malities (18%), with malformations occurting significantly more often among females with the 45,X karyotype (45,X: 38% versus mosaic monosomy: 119) [42]. These results im- ply that factors other than congenital malformations of the heart are involved in the pathogenesis of heart disease in adult Turner syndrome. We are not aware of any other re- ports of increased frequency of hypertension and only case reports have suggested an association between increased risk of stoke and Tumer syndrome [49-51]. Since we found statistically significant relative risks for heart diseases, hy- pertension, and diabetes mellitus (NIDDM) it is tempting to suggest that women with Turner syndrome are exquisitely prone to develop the abnormalities of the metabolic syn- drome (syndrome X), such as hypertension, dyslipidemia156 (high triglycerides and low HDL cholesterol), NIDDM, obesity, hyperinsulinemia, and hyperuricemia [83]. When pooling all cardiovascular diseases (ICD-8 numbers 390 458), a high relative risk was noted in the younger age ‘groups with a decline in relative morbidity with age Circhosis of the liver was found with a relative risk of 5.69 (1.55-14.56), while the relative risk of diseases of the liver, gall system, and pancreas was not increased. In a re- cent study of 49 middle-aged women with Turner syndrome, liver enzymes were found to be elevated, though no overt liver disease was recorded in that group, and liver biopsies in three patients were normal [84]. Previously two case 1e- ports have observed cirthosis of the liver in one patient and intrahepatic bile stasis and hepatomeyaly in another patient [85,86]. ‘Sex Hormones and Turner Syndrome In this study we found an increased frequency of a range of diseases known to be alleviated to some extent by sex hor- rmione substitution, particularly estrogens. The relative risks of fractures, of heart diseases, hypertension, and vascular insults of the brain, of NIDDM and other endocrine diseases were all increased. From other studies in adult women with Turner syndrome itis known that overweight and perhaps frank obesity is widespread [87]. A picture emerges from the present study of a risk profile very much like that of post menopausal women, just occurring at a much earlier time in life. Numerous reports have emphasized the benefits of ‘estrogen replacement therapy in healthy postmenopausal women with respect to osteoporosis, heart disease, insulin sensitivity, and possibly NIDDM [88-92]. We found no in- ‘creased risk of cancer, especially cancer of the breast; this hhas been found by some and not by others in postmen pausal women receiving estrogens with or without gestagens [71,72]. On these grounds we see no reasons to discontinue sex hormone substitution in patients with Tuer syndrome at the rime of normal menopause (e.g., 55 years) CONCLUSIONS This seudy confirms several earlier studies reporting in- creased morbidity due to a number of conditions and sub- stantiates results of a recent study on cancet in Turner syn: drome. Women with Tumer syndrome seem to have an increased incidence of fractures, osteoporotic fractures in adulthood, and non-osteoporatic fractures in childhood. Furthermore, diabetes mellitus, both NIDDM and IDDM, had a markedly increased incidence in Turner syndrome, 28 well as ischemic heart disease, hypertension, and stroke. We ‘consider these findings of elinical significance and they may ‘explain part of the decreased life span seen in Turner syn~ drome. These data furthermore suggest that women with Tumer syndrome have a risk profile like postmenopausal ‘women, and a close link to the metabolic syndrome seems to be present, CH. 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