Early Diagnosis of Children with Classic Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency by Newborn Screening

Abstract

Congenital adrenal hyperplasia (CAH) comprises a group of rare autosomal recessively inherited disorders of cortisol biosynthesis in the adrenal cortex. More than 95% are based on a defect in the CYP21A2 gene causing 21-hydroxylase deficiency. Newborn screening (NBS) for CAH by means of 17-hydroxy-progesterone (17-OHP) determination in dried whole blood on filter paper has been introduced as part of the NBS in many countries worldwide. The goals of CAH screening are early detection of the severe, salt-wasting form, therefore prevention of adrenal crisis or death, early detection of the simple virilizing form, and prevention or shortening of the period of incorrect gender assignment in females. Methodological problems of false-positive samples, especially in pre-term infants, can be corrected by adapting the cut-off values for 17-OHP to birth weight, gestational age and age at the time of collection and by performing a second tier screening. Despite a positive voting for newborn CAH screening by the European Society for Pediatric Endocrinology and the Lawson Wilkins Pediatric Endocrine Society, it is obvious that the acceptance of CAH screening varies worldwide.

A genetic epidemiology study of congenital adrenal hyperplasia in Italy

“…Here, q was derived through an alternative genetic epidemiology approach called HI method, which makes it possible to estimate the pathogenic allele frequency of a given autosomal recessive disorder using mutational spectra and genotype data that are commonly available in medical genetics units worldwide. Our q estimates of 21OHD-CAH were in line with previous assumptions on CAH prevalence in Caucasian populations, 5 but were much higher than those derived from previous observational studies carried out in the same regions where our cohorts had been recruited. 4 This is mostly due to the fact that such screenings were mainly aimed at the detection of the most severe forms of CAH and were based on the detection of 13 is reported for the cohort from mainland Italy.…”

“…17OHP serum levels right after birth, 4 a method that has already been suspected of being prone to type I error and not very sensitive to detect some simple virilizing and most non-classical CAH forms. 5,14 Initially, the potential of NSPs to detect all clinical forms of CAH was not fully predictable. Today, we know that it is not possible to detect all individuals with CAH in such screenings, [15][16][17] since increasing the sensitivity for SV-/NC-CAH would result in an increased recall rate and a high false positive rate.…”

“…6 Consequently, it is much more difficult to estimate the frequency of NC-CAH, which is assumed to be approximately 1/1000 in Caucasian populations. 5 In the present paper, we used an epidemiological approach that makes it possible to estimate the pathogenic allele frequency (q)hence the prevalence (P = q 2 )-of an autosomal recessive disorder using the proportion of homozygous patients (homozygosity index, HI), the mutational spectrum and the inbreeding coefficient estimate (F) in a sample of affected individuals. This formula-which we named HI method 7 -was developed from a previous theoretical work 8 and allows to compute q for a given autosomal recessive disorder, through the formula…”

Phenotypic Variation of 46,XX Late Identified Congenital Adrenal Hyperplasia among Indonesians

“…12 This discrepancy suggests that more of SW type CAH patients died from adrenal crises before being diagnosed. Identifying newborn girls with signs and symptoms of CAH is not difficult because of genital ambiguity and salt wasting symptoms in the SW type.…”

Hetero sexual precocious puberty: Case report and literature review

“…[2] Incidence is 1:5,000 to 1:15,000 live births, prevalence is as high as 1:27 in Ashkenazi Jews, Male: Female 1:1, mortality rate is 3%-13%. [3] Clinical presentation of CAH due to 21-hydroxylase deficiency depend on severity of the enzyme deficiency. In females the spectrum can vary from very severe form (classic virilizing adrenal hyperplasia) presenting at birth with ambiguous genitalia, milder form (simple virilizing adrenal hyperplasia) can present in childhood with precocious pubic hair, clitoromegaly, accelerated growth and skeletal maturation, while mildest form (non-classic adrenal hyperplasia) can present in adolescence or adulthood with oligomenorrhea, hirsutism, and/or infertility.…”