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* Department of Growth and Reproduction GR, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
National Centre for Register-Based Research, University of Aarhus, Aarhus, Denmark
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Methods. The age- and gender-specific incidence rates as well as prevalence rates of precocious pubertal development in Denmark were estimated using data from the Danish National Patient Registry and Statistics Denmark from 1993 to 2001.
Results. Overall, 670 children with precocious pubertal development were registered with a diagnosis of precocious puberty (PP) from 1993 to 2001, corresponding to 50 to 70 new cases of PP per year in Denmark. The incidence of PP was constant during the study period from 1993 to 2001. The incidence of PP subdivided by gender and age at diagnosis was 
0.5 per 10000 in girls who were younger than 2 years, decreasing to levels below 0.05 per 10000 in girls aged 2 to 4 years, thereafter gradually rising to 8 per 10000 for girls aged 5 to 9 years. For boys who were younger than 8 years, the incidence was very low (<1 per 10000) and increased only slightly to 1 to 2 per 10000 in boys aged 8 to 10 years. The prevalence of PP was 20 to 23 per 10000 in girls, whereas the prevalence was fivefold lower for boys (<5 per 10000).
Conclusions. From this first epidemiologic study based on national registries, we estimated that 0.2% of all Danish girls and <0.05% of Danish boys had some form of precocious pubertal development.
Key Words: precocious puberty • premature thelarche • premature pubarche • Denmark • epidemiology • incidence • prevalence • register-based study
Abbreviations: PP, precocious puberty • CPP, central precocious puberty • ICD-10, International Classification of Diseases, Tenth Revision • GnRH, gonadotropin-releasing hormone
Early development of secondary sexual characteristics may significantly influence psychosocial development and statural growth.1–4 Furthermore, early or precocious puberty (PP) has been associated with increased risk for breast cancer in adult life.5 Isosexual precocity is defined as the development of secondary sexual characteristics in girls who are younger than 8 years and in boys who are younger than 9 years.6 The cause of PP in girls who are older than 6 years is most commonly idiopathic (ie, without demonstrable central nervous system lesions or peripheral hormone secretion), whereas boys are more likely to have a pathologic cause at any age. Girls are affected much more frequently than boys.7–9
During the past 2 centuries, an earlier sexual maturation, indicated by an earlier age at menarche, has been observed in European countries, but this downward trend in the age of puberty seems to have leveled off in the last decades.10 The stabilization of age at onset of puberty in most European countries contrasts recent epidemiologic studies from the United States in which onset of puberty (as determined by age at breast development) in girls seems to occur much earlier11–13 than it did 20 years ago.14 However, the age at menarche was only slightly lower compared with previous studies in the United States,12,15 suggesting lack of appreciation of early signs of puberty in previous studies or an altered timing and progression of female puberty. In American boys, a similar tendency toward earlier onset of puberty has been suggested, although not as evident as for girls.15,16 This evidence prompted the Lawson Wilkins Pediatric Endocrine Society to review the current guidelines for the ages at which the cause of PP should be searched for, and it was recommended to lower the prevailing standards from 8 to 7 years for white girls and to 6 years for black girls,17 whereas no changes in the current guidelines for evaluating boys were suggested. Midyett et al18 critically reviewed these recommendations, and the risk of overlooking serious endocrine pathology as a consequence of lowering the age limit was emphasized. In Europe, the definitions of PP and diagnostic guidelines have remained unchanged as no major changes in the onset of puberty have been shown.19,20 In addition, it was shown recently that the suggested American guidelines applied to a European child population would not be safe to select girls with central PP (CPP) who require brain imaging.20
The understanding of these studies and possible implications of the suggested American recommendations are strongly limited by the sparse knowledge about the epidemiology of PP in the general child population. Studies from Belgium and the United States have suggested that PP occurs in 0.005% to 0.01% of children, but it is not clear whether these estimates are prevalence or incidence data.21,22 We therefore studied the prevalence as well as the gender- and age-specific incidence of PP in Denmark using nationwide registries to establish valid epidemiologic data on this relatively rare disease.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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5.3 million inhabitants. All inhabitants are included in the Danish Civil Registration system, in which they are registered with a unique 10-digit personal identification number (central person registry number), enabling accurate follow-up from birth throughout life. All Danish patients who are admitted to Danish hospitals are registered with discharge diagnoses according to the World Health Organization’s International Classification of Diseases, Tenth Revision (ICD-10) and central person registry number in the National Registry of Patients. The National Registry of Patients was established in 1977, and from 1995, all diagnoses from hospital outpatient clinic visits have also been included. We included both outpatient visits and inpatient admittances registered with an ICD-10 diagnosis of PP (E30.1 or E22.8 according to ICD-10) from 1993 to 2001. ICD-10 codes were introduced in 1993 in Denmark. In this study, we included only patients who were registered with ICD-10 codes as PP registration in the ICD-8 classification is very rare.
Data Limitations
In Europe, the generally accepted diagnostic age limit for PP is onset of puberty before 8 years of age for girls and 9 years for boys.6 In principle, this means that girls are at risk for developing PP until their eighth birthday and boys until their ninth birthday. However, the existence of a lag time between the first observation of signs of puberty reported by the parents and the establishment of the diagnosis of PP at the first consultation of a pediatric endocrinologist is widely known and was found to be 1.5 years in a Belgian study.3 This is well in accordance with our clinical experience; therefore, we included only girls who were registered with the diagnosis of PP before 9 years of age and boys who were registered before 10 years of age. The ideal follow-up period for girls then would be from 0 to 9 years of age and for boys from 0 to 10 years of age. That we could include only patients who received a diagnosis from 1993 means that no children could be followed for PP in the register through their entire risk period. Data of children who were born before 1993 were left censored as a result of late entry in the study (ie, the children were too old). This means that girls who were born in 1984 could be followed for PP for only 1 year (their ninth year of age, which was the calendar year 1993), girls who were born in 1985 for 2 years (from 8 to 9 years of age; calendar years 1993–1994), girls who were born in 1986 for 3 years (from 7 to 9 years of age; calendar years 1993–1995), and so on. Similarly, data on boys who were born after 1991 and girls who were born after 1992 were right censored as a result of premature termination of follow-up (ie, the children were too young).
From Statistics Denmark, we obtained information on the number of girls who were in the age group 0 to 9 years and number of boys who were in the age group 0 to 10 years and alive and living in Denmark on January 1 for each year from 1984 onward and on the number of children born each year. In this study, we followed 1.15 million children, 610000 of whom were followed from birth.
Calculation of Incidence and Prevalence
For each calendar year, age, and gender, we calculated the incidence of PP in Denmark as the number of children who at that age and calendar year received a diagnosis of PP for the first time divided by the total number of children alive and living in Denmark at that age and year. Furthermore, for each year of birth and gender, we calculated the prevalence as the number of children who were born that year and had ever received a diagnosis of PP divided by the total number of children born that year.
Validation of the Diagnosis
Patients who are referred for PP may present with a variety of disorders associated with early sexual maturation. This means that a registered diagnosis of PP may encompass patients with true CPP; premature adrenarche as well as patients with premature thelarche; and even patients with normal, although early, pubertal development.7,13 We therefore reviewed 100 randomly selected cases among all patients who were registered with PP in the National Registry of Patients to validate the diagnosis and to estimate the time from patient-observed development of secondary sex characteristics to subsequent registration of the diagnosis in the National Registry of Patients. All case notes were reviewed by the same investigator (G.T.) during site visits at the relevant local pediatric departments. Validation showed that 96 of 100 registered cases were classified correctly, as the file records contained examinations for pubertal maturation in files of 9 boys and 87 girls. Evaluation revealed that 46% of the patients had true PP, characterized by appearance of secondary sex characteristics combined with growth acceleration, advanced bone age, and/or a pubertal response to gonadotropin-releasing hormone (GnRH) challenge, with a striking female preponderance (female to male ratio: 15:1). Premature thelarche (isolated breast development in association with normal growth rate, and bone age corresponding to chronological age and/or prepubertal response to GnRH challenge) and premature adrenarche (isolated growth of pubic hair in association with normal growth rate, and bone age corresponding to chronological age and/or prepubertal response to GnRH challenge) were registered in files from 36 children with PP. Pubertal development was found early but within the normal age limits in the remaining 14 children. One case record could not be identified, and 3 case records were misclassified. Mean age at onset of puberty (according to patient history) was 6.7 years (range: 0.8–8.8 years) in girls and 6.7 years (range: 2.5–8.9 years) in boys in all diagnostic subgroups. The diagnosis was registered at a mean age of 7.3 years (range: 0.8–9.0 years) in girls and 7.1 years (range: 2.4–9.96 years) in boys, which resulted in a mean time from onset of puberty to registration of diagnosis of 0.6 years in girls (range: 0–5.5 years) and 0.3 years in boys (range: 0–1.0 year).
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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0.5 per 10000 in girls who were younger than 2 years, decreasing to levels below 0.05 per 10000 in girls aged 2 to 4 years, thereafter gradually rising to 8 per 10000 for girls aged 5 to 9 years. For young boys, the incidence was very low (<1 per 10000) and increased only slightly to 1 to 2 per 10000 in boys aged 8 to 10 years.
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20 to 23 per 10000 in girls, whereas the prevalence was fivefold lower for boys (<5 per 10000). None of the birth cohorts had a complete follow-up period (see "Methods") because the diagnosis of PP was recorded only from 1993 to 2001 as seen from Fig 3B.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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In a study from Belgium, it was calculated that children with PP represented 0.01% of the cumulated child population in a 9-year period.21 However, it is difficult to compare the occurrence of PP in Belgium with our study, because the size of the total Belgian child population was only roughly estimated, and it is not clear whether the given estimate is an incidence or prevalence measure. An American study cited in the Journal of the American Medical Association in 1982 reported the incidence of PP to be 1 in 5000 to 10000 in American children.22 Unfortunately, we are unable to compare these data with our findings, because the methods that were originally used in the American study were never published. The only existing Danish data for comparison originate from a study published in 1961,1 when it was estimated that 4 to 5 cases of PP could be expected every year in the Danish population (4.5 million people in 1961). This obviously is much lower than our estimated 50 to 70 cases per year. We cannot rule out the possibility that methodologic differences between the 2 studies may explain some of the differences: Thamdrup1 examined diagnostic lists in all Danish hospitals from 1917 to 1954 of all diagnoses imagined to include PP. Approximately 800 records were reviewed, and 70 patients fulfilled the criteria (PP defined as onset of puberty in girls younger than 8 years and in boys younger than 9 years). The material was extended by including 8 cases of premature pubarche found by examining all girls and boys in 7 institutions for mental defectives and by another 22 children examined in 1954–1956 in 2 Copenhagen University Hospitals, and in a total of 100 cases were included in his study.1 Thus, it is likely that some underestimation of the prevalence of PP in Denmark has occurred in the ascertainment of cases in that study, because patients were selected from a subset of Danish institutions for mentally disabled and only from 2 hospitals in the period 1954–1956. Hypothetically, our finding of an increased occurrence of PP compared with the historical Danish data could reflect a general decline in age at onset of puberty. During the past 2 centuries, an earlier age at menarche has been observed in European countries, but this downward trend seems to have leveled off in the last decades.10 In Denmark, the mean age at menarche declined from 13.8 years of age in 195423 to 13.03 in 198324 and has remained at this level afterward (13.0 years in 1997).25 The same trend was found in a preliminary report on timing of female puberty in Denmark,26 in which no evidence of earlier onset of breast development or menarche in 1990 compared with a study from 1964 was found.27 The apparent increased occurrence of PP therefore most likely could be explained by improved treatment options, increased awareness of the condition, and an increased systematic registration in the Danish National Registry of Patients.
The crude incidence of girls with premature breast development (including premature thelarche, PP, and infant mammoplasia; n = 66) was 2.9 per 10000 person-years among girls aged 0.5 to 8 years in Olmsted, Minnesota, studied in the period 1940–1984.28 This is comparable to the calculated incidence of PP in girls in our study, which varied from 1.5 to 2.9 per 10000 person-years during the study period. In girls who were younger than 2 years, we found an incidence of PP of 0.5 per 10000, whereas the incidence of premature breast development was 12-fold higher in Olmsted (6 per 10000). These 2 studies are not directly comparable as different methods were used to select patients. In the Olmsted study, all recorded diagnoses "referable to the breast" were included, whereas only the ICD-10 diagnosis E30.1 and E22.8 were used to identify patients in our study. However, palpable breast tissue is a common physiologic condition, occurring in 84% of 3-month-old Danish girls,29 and our data show that only a few cases of premature breast development in Danish infants are registered with the ICD-10 diagnosis of PP. It therefore is difficult to determine whether the incidence of premature breast development really is higher in Olmsted, Minnesota, compared with Denmark.
There are some limitations in our data that need to be addressed. First, our calculated prevalence and incidence of PP may be overestimated because validation of the diagnoses revealed that true PP was found in only 46% of the cases, whereas the remaining cases represented children with benign variants (ie, premature thelarche or premature adrenarche) or early normal pubertal development. The ICD-10 diagnostic codes do not have a specific code for variants of sexual precocity, and patients with these conditions therefore are registered with the same diagnosis of "precocious puberty." Our results are in accordance with a series of 223 American children who were referred for signs of PP, in which 47% were found to have true CPP.18 It is strikingly higher, however, than recently reported by Kaplowitz, who found that only 9% of 104 patients who were referred for evaluation of early pubertal development had true CPP.30 That 46% had true PP, a much higher number than reported by Kaplowitz,30 suggests an underreporting of incomplete forms of puberty to this database (or, less likely, a significantly lower incidence of partial forms of puberty in Denmark compared with the United States). The comparable percentage of true PP reported by Midyett et al18 in the United States represents the percentage of patients with early pubertal changes seen in their endocrine clinic. Patients with partial forms, in which treatment would not be indicated, were screened by primary care physicians and not referred. Thus, it is likely that the Danish database is enriched for patients with true and complete PP and includes only a part of the young population with early secondary sexual development. Second, girls were followed until 9 years of age and boys until 10 years of age. This is an extension from the generally accepted age limits of PP that as well could contribute to an overestimation. However, our validation study showed that median age at onset of puberty was below 8 years for girls and 9 years for boys and that the mean lag time from appearance of physical signs of puberty until registration was 0.6 years in girls. These findings support that the selected age limits were useful to identify patients with precocious onset of puberty in the register. In addition, a substantial number of patients are referred after 9 or 10 years of age but had developed secondary sex characteristics several years earlier. The latter could result in an underestimation of the calculated occurrence of PP in our study. Pubertal maturation is not routinely assessed in Danish children; therefore, children with precocious sexual maturation probably are seen only in the health care sector if the concern is raised by the parents or other caregivers. Some parents will have experienced their own history of early pubertal development and interpret it as a normal (inherited) phenomenon when the same happens to their offspring. Some cases that present to general practitioners or pediatricians in the primary the health care sector will not be referred to the pediatric departments of the Danish hospitals if the cases are considered to be normal-early pubertal development and not "precocious puberty"; the true occurrence of precocious pubertal development therefore may be higher.
Third, inclusion of patients who were seen in outpatient clinics in the years before 1995 could potentially result in misclassifying a pool of previously prevalent cases of PP as incident cases, when visits in outpatient clinics became registered in the Danish National Registry of Patients from 1995. However, the observed incidence of PP was fairly constant by calendar year, giving the evidence that we register only incident (ie, new) cases of PP during the study period. This has the implication that the unregistered prevalent cases remain unregistered in the population. The slightly lower incidence of PP observed in the end of the study period may be explained by the fact that children who were admitted in 2001 and have not received a diagnosis of PP yet may lead to an underreporting of children who received a diagnosis of PP at the end of our study.
Finally, none of the included birth cohorts could be followed in the whole period when they were at risk for developing PP. Registration was started in 1993 and ended in 2001. To have a complete follow-up period, girls have to be followed from birth to 9 years of age and boys until 10 years of age, which was not possible in our study. In general, data on children who were born before 1993 were left censored as a result of late entry in the study, and data on boys who were born after 1991 and girls who were born after 1992 were right censored as a result of premature termination of follow-up. Consequently, the calculated prevalence of PP will be underestimated. However, on the basis of our data, the most complete follow-up period, which included the oldest ages, was on girls who were born in 1991 and boys who were born in 1992. Our conservative estimate of the prevalence of precocious pubertal development among these children is 20 to 23 per 10000 girls, whereas it is <5 per 10000 for boys.
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CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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ACKNOWLEDGMENTS |
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We thank I. Bjerrum-Bach and J. Nordhoeck for inspiration to conduct this study. We are grateful to our helpful Danish colleagues who allowed us to review their case notes.
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FOOTNOTES |
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Reprint requests to (G.T.) Department of Growth and Reproduction GR, Rigshospitalet Section 5064, Blegdamsvej 9, DK-2100 Copenhagen Ø, Denmark. E-mail: gteilmann{at}rh.dk
No conflict of interest declared.
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  G. Teilmann, C. B. Pedersen, N. E. Skakkebaek, and T. K. Jensen Increased Risk of Precocious Puberty in Internationally Adopted Children in Denmark Pediatrics, August 1, 2006; 118(2): e391 - e399. [Abstract] [Full Text] [PDF]
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 L. Aksglaede, A. Juul, H. Leffers, N. E. Skakkebaek, and A.-M. Andersson The sensitivity of the child to sex steroids: possible impact of exogenous estrogens Hum. Reprod. Update, July 1, 2006; 12(4): 341 - 349. [Abstract] [Full Text] [PDF]
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) and girls (•) shown by year of diagnosis from 1993 to 2001.
