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Endocrine Care |
Department of Pediatrics (J.K., H.F., F.W.), University of Vienna, A-1090 Vienna, Austria; Department of Pediatrics (F.V., J.L.), 3rd Faculty of Medicine, Charles University, CZ-10081 Prague, Czech Republic; Department of Medical Computer Sciences (G.H.), University of Vienna, A-1000 Vienna, Austria; 2nd Department of Pediatrics (J.S.), Semmelweis University, H-1094 Budapest, Hungary; 2nd Department of Pediatrics (Z.P.), Comenius University, SK-83340 Bratislava, Slovakia; University Children’s Hospital (T.B.), University Medical Center, SLO-61104 Ljubljana, Slovenia; and Department of Pediatrics (J.K.), University of Szeged, H-6720 Szeged, Hungary
Address all correspondence and requests for reprints to: Franz Waldhauser, M.D., Department of Pediatrics, University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria.
Abstract
Despite the fact that congenital adrenal hyperplasia (CAH) is one of the most common inborn endocrine disorders, some patients are not identified, or may even die, in an acute salt-losing crisis. In a retrospective study covering the last 30 yr, we examined the time elapsing before diagnosis of CAH patients, in 5 Middle European countries, and the mortality rate in diagnosed patients and their siblings during childhood; we also attempted to estimate how many patients are not diagnosed clinically each year.
Basic and follow-up clinical data and the family histories of 484 patients with classical forms of CAH diagnosed between 1969 and 1998 were collected and recorded in 5 Middle European countries. The sex-ratio, time elapsing before diagnosis, and mortality among siblings and patients were calculated, and the number of undiagnosed patients was estimated.
We found significantly fewer genetic males (43.0%) than females (57.0%) among 484 classic CAH patients, and the percentage of diagnosed boys did not increase with time; 64.7% of them suffered from the salt-wasting (SW) form, and 35.3% from the simple virilizing (SV) form, of the disease. The diagnosis of CAH was established significantly later in males than in females in both forms [SW: 26 vs. 13 days (median), P < 0.0001; SV: 5.0 vs. 2.8 yr, P = 0.03]. Infant mortality in the general population was significantly lower than in either siblings (1.8% vs. 7.0%; P < 0.0001) or in SW (2.29% vs. 11.3%; P < 0.0001). According to our calculations, by our current praxis of clinical ascertainment, 2–2.5 SW and up to 5 SV stay undiagnosed, out of 40 expected CAH patients per year in the countries investigated. Both clinical detection and treatment of CAH patients, at least in males, were insufficient in the five Middle European countries examined during the last 30 yr. Neonatal mass screening and/or greater awareness of the medical community are discussed as ways of improving the efficacy of CAH management. Our experience may be applicable to other countries with similar health care systems.
CONGENITAL ADRENAL HYPERPLASIA (CAH) is one of the most common inborn endocrine disorders inherited in an autosomal recessive manner (1, 2). In 90–95% of cases, it is caused by a mutation of the CYP21 gene, which is located on the short arm of chromosome 6 (6p21.3) and encodes the enzyme, 21-hydroxylase (21-OH), which is required for normal adrenal steroid biosynthesis (2, 3, 4). A deficiency in the activity of this enzyme results in reduced cortisol production and an excess of adrenal androgens, often with diminished aldosterone biosynthesis. Depending on the type of gene mutation, on the subsequent degree of reduction in 21-OH activity, and on the sex of affected subjects, the severity and the pattern of clinical symptoms may differ considerably among patients (2, 5).
From a clinical point of view, three subtypes of 21-OH deficiency (21-OHD) have been identified (4, 6): 1) The salt-wasting (SW) form of CAH is characterized by a life-threatening metabolic crisis, typically presenting in the first weeks after birth, with salt-loss, hyponatremia, hyperkalemia, dehydration, shock, and signs of ambiguous genitalia in females but not in males. The simple virilizing (SV) form is usually recognized by a variable degree of clitoris hypertrophy, posterior labial fusion in females and pseudoprecocious puberty in males. The nonclassical form is rarely diagnosed before the onset of puberty and usually is suspected in females because of hirsutism and cycle irregularities (4, 7). 21-OH activity is reduced to 0–1% of normal in SW, some 1–2% in SV, and 20–50% in nonclassical forms (8). However, an exact classification of CAH subtypes is sometimes difficult, owing to substantial overlaps in clinical symptoms and laboratory findings caused, in part, by compound heterozygosity (9, 10), thus supporting the concept that CAH is basically a disease continuum (11, 12).
From the therapeutic point of view, minimal goals would be to detect all SW before the occurrence of a life-threatening SW crisis and to diagnose and treat all SV patients early in life as to avoid acceleration in bone maturation and eventual short adult stature. Whereas it is believed that most of the female SW patients are diagnosed as a result of their ambiguous genitalia before the occurrence of an SW crisis, male SW may not be identified until the first signs of the crisis appear or may stay undiagnosed and not survive this episode. Similarly, female SV may be suspected and diagnosed early in life as a result of the mild symptoms of genital masculinization. Male SV with signs of pseudoprecocious puberty may attract attention at a later time in life or remain undiagnosed (4, 12). Although these problems in the diagnosis of CAH are well known in principle (6, 12, 13), there are few quantitative data on their clinical relevance in a population with an advanced health care system.
In a retrospective study covering the last 30 yr, we investigated the length of time until diagnosis and the mortality rate in detected CAH patients and their siblings during childhood. Finally, we attempted to estimate how many CAH patients fail to be diagnosed annually in the five Middle European countries studied.
Subjects and Methods
Patients
Pediatric endocrinologists from 5 Middle European countries (Austria, Czech Republic, Hungary, Slovakia, and Slovenia, with a total population of approximately 35 million) pooled data from the CAH patients they had treated over the previous 35 yr, to create a common data bank. Depending on the country, approximately 40–90% of the pediatric units joined the study. Participation depended mainly on geographical and personal factors. In all 5 countries more than 99% of the population benefits from public health insurance. In addition, throughout almost the whole observation period, all these countries had some kind of governmental program which sponsored up to 4 supervisions by pediatricians or family practitioners annually in infants and small children. The infant mortality, an indicator of the quality of a health care system, ranged from 4.7–10 deaths per 1000 newborns in 1997 (14), similar to figures in other European countries or in the United States.
As a first step, a questionnaire regarding the family history, as well
as basic clinical and laboratory data at diagnosis and during follow-up
was provided by the endocrinologist caring for the patient. A national
scientific coordinator checked the data for completeness and sent it to
the study center to establish the data bank. In this way, information
was collected and registered on 598 CAH patients. The data on the
patients’ family structure was double-checked by means of a second
form requesting the precise date of birth and possible death of all
siblings. Only forms filled in with all the required data and signed by
the endocrinologist caring for the individual patient were used (Table 1
).
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The diagnosis was based on typical clinical symptoms of CAH (classical forms) and elevated urinary 17-ketosteroid or pregnanetriol excretion (early observation period) or elevated blood 17-hydroxyprogesterone (17-OHP) amid normal or low serum deoxycorticosterone (late observation period) (4). In most cases in the early observation period, the diagnosis was confirmed by elevated blood 17-OHP levels during follow-up.
The SW form of CAH was considered if an SW crisis occurred during the first 4 weeks of life, i.e. dehydration and serum Na less than 125 mmol/L and serum K more than 6 mmol/L, requiring glucocorticoid and mineralocorticoid treatment (10). The SV form was diagnosed if clinical symptoms of CAH without SW were present before the age of puberty onset, i.e. 8 yr; whereas the nonclassical form was considered if these symptoms occurred during and after puberty (6, 7, 9).
Methods
To obtain a homogeneous study cohort, we selected only patients with 21-OHD diagnosed between January 1, 1969 and December 31, 1998 (n = 513) from the data bank. Of these individuals, 29 suffered from the nonclassical form of the disease and were excluded from further analysis, because pediatric endocrinologists do not usually have representative samples of these patients, many of whom may see a gynecologist directly. The remaining 484 SW and SV patients may be considered as a representative sample of all the classical CAH patients diagnosed over the 30-yr investigation period in the 5 countries participating. The sample contains approximately 50% of all classical CAH patients diagnosed in these countries during that time (see below). A certain bias cannot be completely ruled out, because patients in a study cohort may experience better diagnosis and care than those on routine management. However, this statement may apply to prospective (rather than to retrospective) studies such as the present one.
The following topics were investigated in the cohort studied: 1) The
actual sex ratio was determined and broken down according to the type
of CAH and investigation period (Table 2). The number of missing patients was
estimated from the difference between the values found and those
expected. 2) The length of time until diagnosis was determined and
explored for differences in sex and type of CAH. 3) Mortality was
determined in siblings of CAH patients and compared with the mortality
of the age-appropriate general population. Only double-checked data
from CAH patients’ families (approximately 60% of enrolled
individuals) from all 5 countries were used for this topic. A possible
bias, e.g. physicians/parents may report more easily if a
child is lost, cannot be excluded. However, we have no evidence for
such an inclination, and it seems unlikely that a bias of this nature
might distort the picture. By the case collection date, 229 subjects
had passed their 1st birthday, and 181 had passed their 14th. This
information was used for the calculation of the mortality rate. 4)
Mortality was determined in the diagnosed CAH patients and was compared
with the mortality in the age-appropriate general population. In
addition, the age at the time of each patient’s death was scrutinized.
Only Hungarian data were used for the latter topic, because no other
cases were continuously followed or had a complete follow-up by one
person (J. Sólyom). By the data collection date, all the patients
(n = 235) had passed their first birthday, and 130 had passed
their 14th. This information was also used for the calculation of the
mortality rate.
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Statistical methods
Proportions were compared using Fisher’s exact test and exact
-square tests. The proportion of males was statistically compared
with the population proportion of 51.3% using an exact confidence
interval for proportions. The time till diagnosis was described by the
median and 25th and 75th percentiles (denoted by Q1 and Q3,
respectively) and compared using Wilcoxon’s rank-sum test.
P-values <0.05 were considered statistically significant.
The statistical software package StatXact (1996; Cytel Software Corp.,
Cambridge, MA) was employed for exact tests. The software
package SAS (1996; SAS Institute, Inc., Cary, NC) was used
for all other purposes.
Results
Of the 484 classical CAH patients examined, roughly two
thirds (64.7%) suffered from the SW, and one third (35.3%) from the
SV, form of the disease. About one third (38.6%) of the cohort was
diagnosed during the first half of the observation period and two
thirds (61.4%) in the second half (Table 2
).
Sex ratio in CAH
We found markedly fewer genetic males (43.0%) than females
(57.0%) among the classical 21-OHD CAH patients studied in the five
countries (Table 2). This male/female ratio differs statistically from
that in the general population (51.3/48.7%; P =
0.0003).
The male/female ratio was 41.2/58.8% from 1969–83 and 44.1/55.9% from 1984–98. This means that the percentage of diagnosed boys did not increase significantly during the second 15-yr period (P = 0.57).
The male/female ratio was 47.0/53.0% in the SW form and 35.7/64.3% in SV patients (P = 0.01).
Length of time to diagnosis
The exact date of diagnosis was available in 404 patients. Analysis of these data revealed that it took twice as long to establish the diagnosis of SW in males as in females (median, 26 vs. 13 days; P < 0.0001). Similarly, in the SV form of the disease, the length of time before diagnosis was much greater in boys than in girls (median, 5.0 vs. 2.8 yr; P = 0.03).
The speed of diagnosis in males, however, improved significantly during
the 30-yr observation period (Table 3).
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Furthermore, when we investigated the 41 families with more than 1 affected sibling, we found that, out of 15 instances where a male was the first-born and a female the second-born patient, the diagnosis in 4 boys (26.7%) was established only after previous diagnosis of the younger sister. The numbers for the complementary sex distribution showed that, out of 11 families with an affected female as the first and a boy as the second child, no females (0.0%) were diagnosed after diagnosis of the younger brother. Although not significant (P = 0.11), these data may support the impression from clinical practice that CAH boys are often diagnosed only after a younger sister has been previously diagnosed.
Mortality in CAH siblings
The precise family structure, with the date of birth of all the
siblings and the date of their eventual death, was available in 250
families with at least 1 classical CAH patient diagnosed between 1969
and 1998. Of the 231 siblings, 16 [12/1/3 = males/females
(M/F)/ambiguous genitalia] died within the first year of life, at a
mean age of 63.5 days (Q1–Q3: 28–104 days), and 1 boy at age 9.2 yr
as the result of a nonadrenal/nontesticular tumor (Fig. 1). The infant mortality in the general
population was significantly lower than among siblings of CAH patients
(1.8% vs. 7.0%; P < 0.0001).
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Postmortem examination of the cause of death in infant siblings revealed that 2 out of 16 had a definitive diagnosis of CAH, and another 10 out of 16 had possible connections with the disease. Three patients showed clear signs of ambiguous genitalia, and 3 had typical clinical symptoms (vomiting, dystrophy) and laboratory signs of an SW crisis (low sodium, high potassium in serum, hypovolemia, acidosis). Pathological findings characteristic for CAH were found by autopsy in 7 out of 16 siblings, making a postmortem diagnosis probable. In one subject, CAH was ruled out by normal 17-OHP levels. In 3 cases, the cause of death was unclear, and no connection with CAH was suspected.
Mortality in CAH patients
Of 235 Hungarian patients, 17 SW (8/9; M/F) and 2 SV (2/0; M/F)
died. Sixteen of the SW (6.8% of 235, 11.3% of 142 SW) patients died
within the first year of life, one at age 3 yr. One of the SV patients
died as a result of sepsis at age 1.2 yr; and the other, with a
malignant thymoma at age 8.6 yr (Fig. 2). The mortality rate during the
first year of life was significantly higher in the SW group than in the
Hungarian general population (11.3% vs. 2.29%;
P < 0.0001). Thus, the probability of dying within the
first year of life for SW patients is approximately 5 times higher than
for the general population. When this period has elapsed, such patients
apparently are not more endangered than the general population.
Increased mortality was not detectable in SV patients.
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The disease was diagnosed at a median age of 16.5 (range, 12–36.5)
days in SW survivors and 21 (12–36) days in SW nonsurvivors
(P = 0.82). Among the nonsurvivors, the diagnosis was
established at age 22 (13.5–28) days in males and 14.5 (10–31.5) days
in females (P = 0.4302). Males died at the median age
of 101 (84–125) days; and females, at 91 (35–121.5) days (Fig. 2).
Because all the other proportions investigated among CAH patients from the other four countries were very similar to the Hungarian ones, it may be assumed that the mortality rate in Hungary is more or less representative for the other four Middle European countries studied.
Estimation of the annual number of undiagnosed CAH patients in five Middle European countries
In our sample of CAH patients, we found 166 female and 147 male
SW. Because an equal gender distribution has to be expected for genetic
reasons, we missed 19 males (Fig. 3). In
line with the assumption that almost all female SW are diagnosed
because of their genital malformation soon after birth (3, 12), we observed a ratio of 1–1.5 females to 5 males in our
siblings who died unexpectedly (see above). Thus, if a real sex ratio
of 1/5 (females/males) in undiagnosed SW is assumed, it follows that: x
female undiagnosed SW/(19 + x) male undiagnosed SW = 1/5. This
relationship indicates that we may have missed some 4.75 female and an
additional 4.75 male SW subjects in our sample. Similarly, among the SV
group, 49 males are missing in our sample for equal sex distribution
(Fig. 3).
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that from 40 expected CAH patients annually,
0.3 female SW, 1.7 male SW, and 3.5 male SV subjects remain
undiagnosed. Should we fail to detect up to 10% of the SV females during childhood, the estimate of undetected SV persons would marginally increase to 0.8 females and 4.2 males (calculations not shown).
Discussion
In our cohort of classical CAH patients, we found a sex ratio of
approximately 40% boys to 60% girls, which was independent of the
participating country and the observation period, i.e. first
vs. second half of the 30-yr observation period (Table 2).
The male/female disparity was even more pronounced in SV than in SW
patients. This demonstrates the difficulty in identifying male CAH
patients and the lack of significant progress in the diagnostic ability
of our health care systems in recent years. The data are in accordance
with previous observations from other communities where similar sex
ratios were described (13, 17, 18, 19).
The problems in detecting male CAH patients are also apparent from the observations that it took twice as long to diagnose male as it did to identify female SW subjects, and that male SV subjects are recognized more than 2 yr later than their female counterparts. However, in our sample, SV females became obvious at a median age of 2.8 yr, with a wide age range from 0.4–6.5 yr (25th –75th percentile). This indicates the general difficulties accompanying the diagnosis of CAH.
According to our data, the assumption that almost all SW females are detected soon after birth owing to their genital malformation (4, 12) seems too optimistic. Of the 231 siblings of our CAH patients, 12 boys, 1 girl, and 3 infants with ambiguous genitalia died during infancy, even though only 4 were to be expected, from the general infant mortality of the region. Thus, 12 subjects too many died. Because most deaths took place in early infancy and because, in 12 of the 16 deceased infants, evidence for CAH was detected postmortem, it is likely that they were undetected SW subjects who did not survive the salt-losing crisis. From these data, it would seem that some SW females are not identified despite genital malformation and that the sex ratio in undiagnosed SW would be around 1–1.5 to 5 (females to males).
From the sex ratios obtained and from the assumption that the incidence of classical CAH in Middle Europe is in the order of 1 in 10,000, one can approximate that in our countries with around 400,000 births annually at present, 2–2.5 SW subjects, with a female/male ratio of 1–1.5 to 5, are not detected and probably die undiagnosed in a salt-losing crisis. The data also indicate that annually, up to 1 female and approximately 4 male SV subjects are not diagnosed during childhood. Some of these SV subjects, particularly females, will be diagnosed later in life because of infertility or cycle irregularities, whereas others will probably never be noticed. In any case, they will not reach their target height and probably will suffer from short stature and hirsutism (6, 7).
The real number of undiagnosed patients may be up to one third higher or lower than the estimation above, depending on the real incidence of classical CAH in Middle Europe and on the actual birth rate. Reports on the incidence of classical CAH range from 1 in 5,000 to 1 in 18,000, depending on race (16) and on the mode of estimation, i.e. genetic screening (10, 15, 20) vs. case survey (17, 18) vs. hormone screening (11, 16). Each method has its pros and cons, but the real incidence is not known (16).
However, our estimate, based on the largest cohort of CAH patients examined, to our knowledge, permits a rough quantification of undetected CAH patients. Because most of the ratios were similar to those found in other cohorts, our estimate may be basically representative for other countries with health care systems similar to ours.
One strategy for reducing the number of undiagnosed CAH patients has been the introduction of newborn screening for CAH by particular countries or regions (11, 16, 18, 21). Neonatal screening based on the measurement of 17-hydroxyprogesterone (17-OHP) level in filter paper blood samples collected by heel-stick was started in 1977 (22). Results derived from more than 7.5 million newborns world-wide (16) demonstrated its effectiveness in the early recognition of SW, usually preventing the life-threatening salt-losing crisis and psychological stress deriving from prolonged incorrect gender assignment (11, 21, 23). However, the interpretation of 17-OHP levels in premature and sick infants, as well as borderline values resulting from different laboratory techniques, are difficult (23, 24), usually requiring a second hormone test after recall (11) or mutation analysis of the CYP21 gene (25). The latter method detects only 85% of cases owing to rare or still unknown gene mutations. Nevertheless, avoidance of any delay in the diagnosis is mandatory for the usefulness of the screening, which requires almost perfect organization and an excellent health care system (11, 21). Even then, identification of all SV subjects is not feasible without having an unacceptably high false-positive rate. Thus, 17-OHP screening seems to be a difficult, but successful, tool for the early diagnosis of almost all SW patients, but it may be less suitable for identification of all SV subjects.
According to Swedish data, the costs of CAH screening were U.S. dollars 2.7 per newborn (21), which would amount to approximately 1.1 million U.S. dollars for the 5 Middle European countries annually.
Another major result of our study is that, within the current framework of our health care systems, a considerable number of identified CAH patients die unnecessarily during infancy. Because the diagnosis in these patients was established between 2 and 3 weeks, similar to the time for the survivors, and most of them died after the age of 2 months, the increased mortality cannot be attributed to delayed diagnosis. In fact, the main cause of death remained severe concurrent infections and/or sepsis, mostly confirmed by autopsies. Inadequate steroid substitution during the stress of infection must be suggested as a possible reason for the increased mortality (26). Fortunately, most of the cases occurred during the first part of our observation period, indicating that knowledge of the correct treatment of CAH in stress situations improved with time. In contrast to a previous report (26), we did not observe conspicuous mortality among the older CAH children.
From the two major problems encountered in the treatment of our CAH patients, namely increased mortality during infancy and late diagnosis of SV, only the latter may be partly improved by the introduction of CAH screening. However, campaigns to increase the awareness of CAH among physicians and parents might be effective. In addition to continuous medical education, with special courses for practitioners (26, 27), both postnatal examination of female genitalia for virilization and examination for accelerated growth rate during early childhood, with respect to CAH, should be added to child health documents. In addition, a special monetary prize, widely publicized in the medical community, could be granted annually to those physicians who identify a male infant with classical CAH as the first patient in a family. Such measures could increase medical attention to a level that might permit even more male SW to be detected in time.
Based on the sex ratio of our classical CAH patients and their deceased siblings, our findings provide an estimate of the number of undiagnosed CAH patients in 5 Middle European countries, which may be in the range of approximately 2 SW and 5 SV annually. These figures are based on the present annual birth rate of around 400,000. If the birth rate continues to drop, as it has during the last 30 yr, the numbers will need to be adjusted accordingly. Unfortunately, we also found a 5 times higher infant mortality rate in SW subjects than in the general population. Whereas CAH screening has the potential for timely identification of undiagnosed SW and probably for saving lives, early diagnosis of SV and reduction in the increased mortality among SW may be improved by measures that stimulate the medical community’s awareness of this disease. The experience of 5 Middle European countries may also be valid for other countries with similar health care systems.
Footnotes
1 This study was supported by the Central European
Program for University Studies–SLO-013 Project and in part by the
Slovenian Ministry of Science and Technology (Grant J3-7880). 
2 The MEWPE-CAH study group consists of the following
physicians who contributed patients’ data—Austria: P. Blümel,
H. Frisch, K. Kapelari, E. Plöchl, K. Schmitt, and F. Waldhauser;
Czech Republic: O. Hníková, B. Kalvachová, J.
Klabochová, S. Kolou
ková, J. Lebl, L. Lisá, V.
Procházková, 
. Pr
hová, R.
Prsa, J. kvor, M. najderová,
J. Venhá
ová, F. Votava, J. Zapletalová, and J.
Zeman; Hungary: É. Erhardt, Z. Halász, I. Ilyés, J.
Kovács, K. Láng, E. Nagy, T. Niederland, F. Péter, L.
Ságodi, G. Soltész, E. Sólyom, J. Sólyom, L.
Szabó, and P. Szûts; Slovakia: S. Bielikova, M. Debreova,
J. Javorkova, L. Kostalova, M. Kusekova, Z. Misikova, Z. Pribilincova,
J. Strnova, Z. Simekova, and D. Trezova; Slovenia: T. Battelino, N.
Bratani, V. Dol
an, C. Krsinik, B.
Repi-Lampret, M. Stopar, K. Trebuak, N.
Uri-Bratina, and M. 
erjav-Tanek.
Received November 8, 2000.
Revised February 15, 2001.
Accepted March 12, 2001.
References
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