Clinical and molecular profile of newborns with confirmed or suspicious congenital adrenal hyperplasia detected after a public screening program implementation

Kopacek, Cristiane; Prado, Mayara Jorgens; Silva, Cláudia Maria Dornelles da; Castro, Simone Martins de; Beltrão, Luciana Amorim; Vargas, Paula Regla; Grandi, Tarciana; Rossetti, Maria Lúcia Rosa; Spritzer, Poli Mara

doi:10.1016/j.jped.2018.03.003

Cited by 13 publications

(22 citation statements)

References 26 publications

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“…Although often plagued by ambiguous results and false calls, the CAH screening is generally successful in identifying affected patients with classic CAH, especially if combined with a secondtier follow-up. 3,27 Second-tier genetic screening has been proposed as an adjunct to hormonal measurements, but genotyping remains costly and time-consuming and thus has not been widely used. The high-throughput screening assay presented here is cost-effective and may be combined with other genotyping to create a more costeffective and efficient second-tier screening test.…”

Section: Discussionmentioning

confidence: 99%

High-Throughput Screening for CYP21A1P-TNXA/TNXB Chimeric Genes Responsible for Ehlers-Danlos Syndrome in Patients with Congenital Adrenal Hyperplasia

Lao

Brookner

Merke

2019

The Journal of Molecular Diagnostics

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Many patients with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency have CAH-X syndrome, a connective tissue dysplasia consistent with hypermobility-type Ehlers-Danlos syndrome due to a contiguous gene deletion involving the adjacent CYP21A2 and TNXB genes. CAH-X syndrome is caused by carrying CYP21A1P-TNXA/TNXB chimeric genes [CAH-X chimera 1 (CH-1) and chimera 2 (CH-2)] on one or more alleles. Genetic analysis is cumbersome due to pseudogene interference. We developed a PCR-based CAH-X high-throughput screening method to assess the copy numbers of TNXB exons 35 and 40; this method is amenable to either real-time quantitative PCR or droplet digital PCR (ddPCR). The assay was validated in a cohort of 278 subjects from 146 unrelated CAH families. Results were confirmed by a validated Sanger sequencing platform. A total of 44 CAH-Xepositive calls were made, with 42 (26 CH-1 and 16 CH-2) confirmed. The assay had 100% sensitivity (42 true/42 positives), 99.2% specificity (234 true/236 negatives), and an overall 99.3% accuracy (276/278). Calls made by real-time quantitative PCR and ddPCR were consistent (100%), and ddPCR offered easier data interpretation. The CAH-X prevalence was 15.6% (21/135 probands), higher than the previously estimated 8.5%, and was particularly high (29.2% or 21/72) in those with a 30-Kb deletion. This assay is suitable for high-throughput CAH-X screening, especially in subjects testing positive for CAH in neonatal screening.

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Section: Discussionmentioning

confidence: 99%

High-Throughput Screening for CYP21A1P-TNXA/TNXB Chimeric Genes Responsible for Ehlers-Danlos Syndrome in Patients with Congenital Adrenal Hyperplasia

Lao

Brookner

Merke

2019

The Journal of Molecular Diagnostics

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“…Italian study describes three girls with slightly elevated 17OHP levels (18.2-35.3 nmol/L) detected during NBS and transient clitoromegaly were later identified as heterozygous cases (for all cases were detected c.293-13C > G pathogenic variant in one allele of CYP21A2 gene). In these cases, spontaneous regression of clitoromegaly was observed during the follow-up through the first six months of life [34]. In other studies, higher levels of mean stimulated 17OHP in the carriers of CYP21A2 mutation presented with premature pubarche and late-onset hyperandrogenemia [35][36][37].…”

Section: Discussionmentioning

confidence: 57%

Impact of Newborn Screening on Clinical Presentation of Congenital Adrenal Hyperplasia

et al. 2021

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Background and Objectives: The main reason for Newborn screening (NBS) for congenital adrenal hyperplasia (CAH) is to prevent adrenal insufficiency that can lead to life-threatening conditions. On the other hand, screening programs are not always sensitive and effective enough to detect the disease. We aimed to evaluate impact of the national NBS on the clinical presentation of patients with CAH in Lithuania. Materials and Methods: A retrospective study was performed on data of 88 patients with CAH from 1989 to 2020. Patients with confirmed CAH were divided into two groups: (1) 75 patients diagnosed before NBS: 52 cases with salt-wasting (SW), 21 with simple virilising (SV) and two with non-classical (NC) form; (2) 13 patients diagnosed with NBS: 12 cases with SW and 1 case with SV form. For the evaluation of NBS effectiveness, data of only male infants with salt-wasting CAH were analysed (n = 36, 25 unscreened and nine screened). Data on gestational age, birth weight, weight, symptoms, and laboratory tests (serum potassium and sodium levels) on the day of diagnosis, were analysed. Results: A total of 158,486 neonates were screened for CAH from 2015 to 2020 in Lithuania and CAH was confirmed in 13 patients (12 SW, one–SV form), no false negative cases were found. The sensitivity and specificity of NBS program for classical CAH forms were 100%; however, positive predictive value was only 4%. There were no significant differences between unscreened and screened male infant groups in terms of age at diagnosis, serum potassium, and serum sodium levels. Significant differences were found in weight at diagnosis between the groups (−1.67 ± 1.12 SDS versus 0.046 ± 1.01 SDS of unscreened and screened patients respectively, p = 0.001). Conclusions: The sensitivity and specificity of NBS for CAH program were 100%, but positive predictive value—only 4%. Weight loss was significantly lower and the weight SDS at diagnosis was significantly higher in the group of screened patients.

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“…In the past, NBS programs have been somewhat hampered by limitations of statistical assessments and the ability to account for multiple factors. It is likely that molecular analysis would also increase specificity [36]. However, not all mutations can be reliably detected in the screening setting and therefore may ultimately limit the sensitivity [37].…”

Section: Discussionmentioning

confidence: 99%

Wisconsin’s Screening Algorithm for the Identification of Newborns with Congenital Adrenal Hyperplasia

Bialk¹,

Lasarev

Held

2019

IJNS

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Newborn screening for congenital adrenal hyperplasia (CAH) has one of the highest false positive rates of any of the diseases on the Wisconsin panel. This is largely due to the first-tier immune assay cross-reactivity and physiological changes in the concentration of 17-hydroxyprogesterone during the first few days of life. To improve screening for CAH, Wisconsin developed a second-tier assay to quantify four different steroids (17-hydroxyprogesterone, 21-deoxycortisol, androstenedione, and cortisol) by liquid chromatography–tandem mass spectrometry (LC–MSMS) in dried blood spots. From validation studies which included the testing of confirmed CAH patients, Wisconsin established its own reporting algorithm that incorporates steroid concentrations as well as two different ratios—the birth weight and the collection time—to identify babies at risk for CAH. Using the newly developed method and algorithm, the false positive rate for the CAH screening was reduced by 95%. Patients with both classical forms of CAH, salt-wasting and simple virilizing, were identified. This study replicates and expands upon previous work to develop a second-tier LC–MSMS steroid profiling screening assay for CAH. The validation and prospective study results provide evidence for an extensive reporting algorithm that incorporates multiple steroids, birth weight, and collection times.

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Clinical and molecular profile of newborns with confirmed or suspicious congenital adrenal hyperplasia detected after a public screening program implementation

Cited by 13 publications

References 26 publications

High-Throughput Screening for CYP21A1P-TNXA/TNXB Chimeric Genes Responsible for Ehlers-Danlos Syndrome in Patients with Congenital Adrenal Hyperplasia

High-Throughput Screening for CYP21A1P-TNXA/TNXB Chimeric Genes Responsible for Ehlers-Danlos Syndrome in Patients with Congenital Adrenal Hyperplasia

Impact of Newborn Screening on Clinical Presentation of Congenital Adrenal Hyperplasia

Wisconsin’s Screening Algorithm for the Identification of Newborns with Congenital Adrenal Hyperplasia

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