No evidence of an increase in early infant mortality from congenital adrenal hyperplasia in the absence of screening

To analyze the mutational spectrum of steroid 21-hydroxylase (CYP21) and the genotype- phenotype correlation in patients with congenital adrenal hyperplasia (CAH) registered in the Middle European Society for Pediatric Endocrinology CAH database, and to design a reliable and rational approach for CYP21 mutation detection in Middle European populations. Molecular analysis of the CYP21 gene was performed in 432 CAH patients and 298 family members. Low-resolution genotyping was performed to detect the eight most common point mutations. High-resolution genotyping, including Southern blotting and sequencing was performed to detect CYP21 gene deletions, conversions, point mutations or other sequence changes. CYP21 gene deletion and In2 and Ile172Asn mutation accounted for 72.7% of the affected alleles in the whole study group. A good genotype-phenotype correlation was observed, with the exception of Ile172Asn and Pro30Leu mutations. In 37% of patients low resolution genotyping could not identify the causative mutation or distinguish homozygosity from hemizygosity. Using high-resolution genotyping, the causative mutations could be identified in 341 out of 348 analyzed patients. A novel mutation Gln315Stop was found in one simple virilising CAH (SV-CAH) patient from Austria. In the remaining seven patients polymorphisms were identified as the leading sequence alteration. The presence of elevated basal and ACTH-stimulated 17-hydroxyprogesterone, premature pubarche, advanced bone age and clitoral hypertrophy directly implicated Asn493Ser polymorphism in the manifestation of nonclassical- (NC) and even SV-CAH. By genotyping for the most common point mutations, CYP21 gene deletion/conversion and the 8 bp deletion in exon 3, it should be possible to identify the mutation in 94-99% of the diseased alleles in any investigated Middle European population. In patients with a mild form of the disease and no detectable mutation CYP21 gene polymorphisms should be considered as a plausible disease-causing mutation.

The aim of this study was to evaluate the benefits of neonatal screening for congenital adrenal hyperplasia (CAH). All children with CAH born in Sweden from January 1989 to December 1994 were subjected to a systematic follow-up. Clinical symptoms were recorded and laboratory data collected. The clinical diagnosis versus diagnosis by screening was investigated. The results were compared with those of a retrospective study of all patients diagnosed during 1969-1986 (before the introduction of neonatal screening). The prevalence of CAH in Sweden was 1:9800 with screening. Patients with CAH were identified earlier by screening. Half of the infants (47%) were not diagnosed at the time of recall, which was 8 days (median). In the study population, 25% of the girls and 73% of the boys were diagnosed by screening alone. The median age at the time of the definite diagnosis in boys was 21 days before screening as compared with 9 days (median) during the last part of the screening period. During the screening period, only 1 boy had a severe salt loss crisis, which occurred at the age of 8 days. Before screening, (1969-1986) 2 boys had died in the neonatal period because of an adrenal crisis. The lowest serum sodium recorded at the time of diagnosis was 124 mmol/L (median; range, 93-148) before, as compared with 134 mmol/L (median; range, 115-148) after the introduction of screening. The number of girls who were initially considered to be boys was not reduced by screening (17% vs 18%). The period of uncertainty regarding gender attributable to virilization was shortened considerably, as well as the time it took to make a correct gender assignment: 23 days (median) before screening versus 3 days (median) with screening. The maximum time it took to make the correct gender assignment was 960 days before screening and 14 days with screening. The number of patients diagnosed late, ie, after the first year of life, decreased considerably after the introduction of screening. The false-positive rate (when a new filter paper blood sample was requested or when a child was referred to a pediatrician for follow-up) was <0.05% and in about 60% of the cases, it was attributable to preterm infants. The cost of screening was US dollar 2.70 per screened infant. The main benefits of screening were avoidance of serious salt loss crises, earlier correct gender assignment in virilized girls, and detection of patients who would have otherwise been missed in the neonatal period. Deaths in the neonatal period were prevented by screening. The aim of the screening program was to identify patients with the severe forms of CAH. Nevertheless, it must be considered a distinct benefit that a number of patients with milder forms of CAH were detected earlier, because earlier therapy results in decreased virilization, normalized growth and puberty, and, in all probability, an improved psychosocial situation for these children. We conclude that, in the Swedish health care system, the benefits of screening for CAH outweigh the costs.

Background/Aims: Congenital adrenal hyperplasia (CAH) is increasingly being included in newborn screening programs. Screening can prevent neonatal mortality in children with salt-wasting CAH, but the number of deaths prevented is not known. Cost-effectiveness analyses of screening require estimates of the probability of mortality in CAH. Methods: We reviewed the literature to identify cohort studies of children with CAH ascertained clinically in the absence of screening. We abstracted the numbers of infant deaths attributable to CAH. We also addressed sex ratios among children with clinically detected CAH and the contribution of ascertainment bias to unbalanced ratios. Results: The evidence suggests a probability of infant death due to adrenal crises in salt-wasting CAH of 4% or less in contemporary advanced economies without screening for CAH. This is lower than previous estimates, although the rate of mortality could be considerably higher in populations with limited clinical awareness or access. Conclusion: Although screening for CAH is conducted in a number of countries, further research is still needed to provide reliable estimates on the numbers of prevented deaths, along with evidence-based assessments of the potential benefits, harms, and costs of screening.