Congenital adrenal hyperplasia due to 21-hydroxylase deficiency results in cortisol and aldosterone deficiency and is, in its most severe form, lethal. We aimed to assess the effect of historical medical improvements in the care of patients with this disorder over time and to assess the effects of neonatal screening in Sweden.
For this retrospective, population-based cohort study, we collected data for all known patients with congenital adrenal hyperplasia in Sweden between Jan 1, 2010, and Dec 31, 2011. Data sources included the registry at the Swedish national screening laboratory, patients identified via the Swedish neonatal screening programme, late-diagnosed patients reported to the laboratory, and patients who underwent genetic diagnostics or became known to us through clinical contacts. All known patients were included in a population-based cohort study of the distribution of clinical severity, genotype, sex, and the effect of nationwide neonatal screening.
We identified 606 patients with the disorder, born between 1915 and 2011. The CYP21A2 genotype (conferring deficiency of 21-hydroxylase) was known in 490 patients (81%). The female-to-male ratio was 1·25 in the whole cohort, but close to 1 in patients detected by the screening. We noted a sharp increase in the number of patients diagnosed in the 1960s and 1970s, and after the introduction of neonatal screening in 1986 the proportion of patients with the salt-wasting form of congenital adrenal hyperplasia increased in both sexes, from 114 (47%) of 242 individuals between 1950 and 1985 to 165 (57%) of 292 individuals between 1986 and 2011 (p=0·038). On average, five to ten children were missed every year before 1970. The non-classic form of the disorder was diagnosed more often in women than in men, which accounts for the female preponderance in our cohort.
Our findings suggest that, contrary to current belief, boys and girls with salt-wasting congenital adrenal hyperplasia were equally missed clinically. Neonatal screening improved detection of the salt-wasting form in girls as well as boys, saving lives in both sexes. The non-classic form was diagnosed more often in women than it was in men, leading to the female preponderance in this cohort.
Our findings show a substantial increase in the apparent incidence of congenital adrenal hyperplasia during the past century, with increases in line with improvements in diagnosis and treatment over time. The absence of a female preponderance has previously been interpreted as a sign of good medical care and diagnosis. However, our data show that both male and female patients with the salt-wasting form are missed clinically—even in a country such as Sweden with a developed health-care system—and that neonatal screening improves survival in both sexes. A large proportion of patients were not detected by neonatal screening. Non-classic congenital adrenal hyperplasia is diagnosed more often in women than it is in men, explaining the overall female preponderance despite the fact that male and female patients with salt-wasting congenital adrenal hyperplasia are diagnosed equally via screening.
To our knowledge, this study is the most extensive description of the changing apparent incidence of the different clinical forms of the disorder over time (panel). The sharp rise in the apparent incidence during the 1960s (figure 1) can be interpreted as the effect of not only the introduction of treatment with glucocorticoids in the 1950s, but also the concomitant increasing awareness of the disorder and its symptoms. Availability of a treatment generally results in increasing motivation among physicians to identify and diagnose a disease. However, in 1950, when glucocorticoids were introduced, there was only one active paediatric endocrinologist in Sweden, and little knowledge and awareness of congenital adrenal hyperplasia. Despite the obstacles, a few patients in the country were identified and started on glucocorticoid supplementation in the early 1950s. Laboratory diagnosis was difficult in both the 1950s and the 1960s, relying on measurements of urinary steroids. The amount of 17-ketosteroids was used as a measure of the level of androgens, and 17-hydroxysteroids as a measure of cortisol. Gonadotropins were measured with a mouse bioassay:extract from urine was given to prepubertal female mice and the uterine weight was subsequently measured as an indirect indication of the amount of gonadotropins.33
Research in context
We searched PubMed and Web of Science for research articles and reviews written in English with no restriction to year of publication. We used the search terms “congenital adrenal hyperplasia”, “21-hydroxylase deficiency”, and “CYP21A2”. We also searched the reference lists of retrieved articles. We identified no other studies describing the incidence of congenital adrenal hyperplasia related to the progress of diagnostics and treatment covering the past 100 years. The first effective treatment with glucocorticoids was introduced in the 1950s and improved patients’ survival. Mineralocorticoid treatment for patients with salt-wasting forms of the disorder was introduced shortly thereafter. Diagnosis has developed from clinical examination to laboratory markers and genetic analyses. Most publications report a skewed sex ratio, with more girls than boys diagnosed, in the prevalence of congenital adrenal hyperplasia, which is widely interpreted as more girls surviving the neonatal period.
Our findings show how medical development during the past 100 years has improved the survival of patients with congenital adrenal hyperplasia, first by the introduction of glucocorticoid and mineralocorticoid treatment and later with the introduction of neonatal screening. Our findings contradict previous ideas about the disorder: many have postulated that the female preponderance among patients with congenital adrenal hyperplasia is caused by missed diagnosis and increased mortality in boys. However, our data show that both male and female babies with the severe form of the disorder were missed clinically and that neonatal screening improved survival in both sexes equally. Non-classic congenital adrenal hyperplasia is diagnosed more often in women than in men, which accounts for the female preponderance in this cohort.
Since the 1950s, once diagnosis was made, treatment was still difficult. Treatment for congenital adrenal hyperplasia has changed little over time, with the exception of the introduction of mineralocorticoid treatment. The first mineralocorticoid, 11-desoxycorticosterone acetate, was given as sublingual tablets or subcutaneous implants that lasted for 3 months, at which point patients were at risk of adrenal crisis. Improved surgical techniques and more centralised surgical care have led to better surgical outcomes. However, these modern techniques also have shortcomings, such as strictures, reduced sensitivity, and impaired sexual function.15, 34, 35
We detected no substantial decrease in the female-to-male ratio after the introduction of screening in our population. However, and more importantly, the proportion of salt-wasting forms of congenital adrenal hyperplasia increased substantially after the introduction of the nationwide neonatal screening programme. This finding should be taken into consideration when assessing the need for neonatal screening in a population. Specifically, the incidence of the salt-wasting form seems to be a more important and adequate measure for improvement of the situation for patients with congenital adrenal hyperplasia compared with the sex ratio alone. In the cohort of patients identified through the neonatal screening programme the female-to-male ratio was close to one. Mild forms of the disorder, presenting later in life and with no risk of salt loss, are detected more often in women. Hence, the female preponderance among the late-diagnosed patients is largely the reason for the high proportion of female patients in the whole cohort (figure 1), and there is a time lag before these patients contribute to the incidence. This occurrence explains the drop in apparent incidence as well as the equal sex ratio after the year 2000 (figure 1). The classification of patients by genotyping—81% had a known genotype—in combination with the nationwide coverage since 1986 made these conclusions possible.
The carrier frequency, and therefore the actual incidence of congenital adrenal hyperplasia has probably been stable over time because available data do not suggest a large global variance in the incidence of the salt-wasting form, with the exception of a few populations.3 On the assumption that all patients with salt-wasting congenital adrenal hyperplasia born after screening began have been diagnosed, the number of patients not identified in the pre-screening era can be reliably calculated because the birth rate in Sweden since 18th century is known (figure 3). Patients with the salt-wasting form of the disorder most likely did not survive the neonatal period whereas patients with the simple virilising form might have had adrenal crises during later infections,35 or might not have been diagnosed at all, as would also have been the case with patients with the non-classic form of the disorder. However, the estimated number of non-salt-wasting patients might be less reliable, because these individuals might have been missed in the screening and not all patients with a non-salt-wasting form of the disorder might have been reported to the registry. Additionally, the proportion of non-classic cases could have increased with the increasing immigration to Sweden since the late 1960s.
The apparent increase in incidence in the 1970s might suggest, to some extent, increased interest in the disorder and the fact that one of the investigators of this paper (AT) made a concurrent survey to identify all diagnosed patients. Neonatal screening could, in itself, have increased awareness of the disease and thereby also improved clinical diagnoses in patients with milder forms of the disease. More identified patients and an increased apparent incidence result in better awareness of the disease.
With screening in combination with the possibility of doing CYP21A2 mutation analyses, physicians no longer have to await electrolyte disturbances in a newborn baby to be able to assess the severity of their disease. Hence, the patients might escape the possible negative effects on brain development. The oldest patients mostly underwent CYP21A2 genotyping, which might be indicative of the fact that they are followed up more often at specialised clinics at university hospitals.
Some of the patients born before 1950 with congenital adrenal hyperplasia were initially assigned a male sex, with or without a hypospadias diagnosis. A physically detectable symptom, the virilisation of external genitalia, aided diagnosis and increased survival. In the 1950s, our knowledge of chromosomes and chromosomal determination of sex increased, and the analysis of Barr bodies became routine clinical practice in the 1950s.36 This development led to the general idea that all 46XX individuals with congenital adrenal hyperplasia should be raised as girls when the patients were diagnosed early.
In the middle of the 20th century, the focus was on the survival of the patients. With improved treatment, other aspects of the patients wellbeing can be addressed. The many patients with a known CYP21A2 genotype has enabled retrospective analyses of treatment outcomes in relation to disease severity—ie, cortisol deficiency and extent of androgen exposure.11,13, 34 The increased awareness of the psychological effects of prenatal exposure to androgens and disappointing surgical results in the more virilised patients, even using improved, modern techniques, have led to discussions about how treatment should be optimised and what sex the more virilised patients should be brought up as. The discussion about sex assignment has just begun.37
The integration of clinical work with molecular genetics and improved specialised care has been instrumental in improving the medical competence and the outcome for patients with congenital adrenal hyperplasia. Improvements in surgical and psychological care are some of the main challenges for the future.