Impact of Newborn Screening on Clinical Presentation of Congenital Adrenal Hyperplasia
Abstract
:1. Introduction
2. Materials and Methods
2.1. Newborn Screening
2.2. Biochemical Diagnosis of Salt-Wasting CAH
2.3. Molecular Diagnostics
2.4. Subjects
- (1)
- Before NBS: 75 patients; 52 cases with SW form, 21-with SV, and 2-with NC form.
- (2)
- After NBS: 13 patients; 12 cases with SW, and 1 case with SV form (Figure 1).
2.5. Statistical Analyses
2.6. Bioethics
3. Results
3.1. Newborn Screening for CAH
3.2. Clinical and Laboratory Assessment of Patients with SW CAH
3.3. Phenotype and Genotype Correlation in Patients of CAH Diagnosis in Lithuania Cohort
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Gestational Age (Weeks) | Cut-Off of 17OHP Serum Concentrations (ng/mL Serum *) | Reference Value to Recall for a Second Sample (ng/mL Serum *) | Reference Value to Urgent Medical Evaluation (ng/mL Serum *) |
---|---|---|---|
>38 | 28 | >28 <33.6 | ≥33.6 |
35–37 | 39 | >39 <46.8 | ≥46.8 |
32–34 | 53 | >53 <63.6 | ≥63.6 |
29–31 | 80 | >80 <96 | ≥96 |
<29 | 198 | >198 <237.6 | ≥237.6 |
Numbers of Newborns | |
---|---|
Screened newborns (2015–2020) | 158,486 |
Positive tests (>cut off 17OHP): Recalled for the 2nd sample Notifications of positive case: Referrals for urgent medical evaluation after 1st DBS Referrals for medical evaluation after 2nd DBS | 320 204 118 116 2 |
False-positive tests | 307 |
True positive tests: From recalled for the 2nd sample From referred for urgent medical evaluation | 13 2 11 |
False-negative tests * | 0 |
Variables | Screened Cohort (n = 12) | Unscreened Cohort (n = 52) | Screened Males (n = 9) | Unscreened Males (n = 25) |
---|---|---|---|---|
Age at diagnosis in days, mean ± SD | 14.6 ± 9.6 | 16.5 ± 11.6 | 15.44 ± 7.79 | 19.13 ± 7.156 |
p = 0.603 | p = 0.19 | |||
Weight change (%), mean ± SD | −0.31 ± 4.9 | −6.2 ± 6.9 | 5.42 ± 17.72 | −7.81 ± 8.58 |
p = 0.007 | p = 0.023 | |||
Potassium mmol/L, mean ± SD | 6.7 ± 1.3 | 6.9 ± 1.6 | 6.89 ± 1.5 | 7.7 ± 1.5 |
p = 0.79 | p = 0.33 | |||
Sodium, mmol/L, mean ± SD | 127.5 ± 7.9 | 127.6 ± 11.6 | 126.31 ± 8.99 | 124.5 ± 9.7 |
p = 0.67 | p = 0.64 | |||
Sodium < 132 mmol/L, n (%) | 9 (75%) | 29 (56.4%) | 7 (78%) | 20 (80%) |
p = 0.22 | p = 0.89 | |||
Sodium < 130 mmol/L, n (%) | 5 (42%) | 25 (48%) | 5 (55%) | 18 (72%) |
p = 0.67 | p = 0.59 |
Pahtogenic Variant | Identification No. (dbSNP [10], HGMD [11]) | Expected Phenotype | Allele No. (Frequency) (n = 94) | |
---|---|---|---|---|
cDNA Level (NM_000500.9, NG_007941.3) | Predicted Protein Change (NP_000491.4) | |||
c.1A > C | p.(Met1Leu) | SW | 1(0.01) | |
c.293-13C > G | New splice acceptor site | rs6467 | SW | 16 (0.17) |
c.[293-13C > G;1360C > T] | p.[(?);(Pro454Ser)] | - | SW | 3 (0.03) |
c.[293-13C > G;332_339delGAGACTAC] | p.[(?);(Gly111Valfs) | SW | 1 (0.01) | |
c.329T > A | p.(Leu110Ter) | - | SW | 2 (0.02) |
c.332_339delGAGACTAC | p.(Gly111Valfs) | 1 (0.01) | ||
c.518T > A | p.(Ile173Asn) | rs6475 | SV | 9 (0.10) |
c.525C > A | p.(Tyr175Ter) | - | SW | 1 (0.01) |
c.844G> | p.(Val282Leu) | rs6471 | NC | 4 (0.04) |
c.916del | p.(Val306PhefsTer17) | - | - | 1 (0.01) |
c.923dupT | p.(Leu308Phefs) | rs267606756 | SW | 1 (0.01) |
c.[923dupT;955C > T] | p.[(Leu308Phefs); (p.Gln319Ter)] | - | SW | 1 (0.01) |
c.955C > T | p.(Gln319Ter) | rs7755898 | SW | 3 (0.03) |
c.1069C > | p.(Arg357Trp) | rs7769409 | SW | 4 (0.04) |
c.1294G > A | p.(Glu432Lys) | rs1245238711 | NC | 1 (0.01) |
c.1360C > T | p.(Pro454Ser) | rs6445 | NC | 2 (0.02) |
~30 kb deletion 1 | p.(0) | - | SW | 20 (0.21) |
Deletion of exons 1–3 | p.(0) | - | SW | 7 (0.07) |
Deletion of exons 1–7 | p.(0) | - | SW | 10 (0.11) |
Unidentified pathogenic variant | - | 6 (0.06) |
Genotype 1 | Age at Diagnosis | Clinical Manifes-Tation | Expected Phenotype | Gender |
---|---|---|---|---|
1989–2014 | ||||
c.[CYP21A1P(NR_040090.1)n.877+?_CYP21A2 (NM_000500.9)c.477+?del)];[CYP21A1P(NR_040090.1)n.877+?_CYP21A2(NM_000500.9)c.477+?del)], p.[(0)];[(0)] 2 | 1–5 days | SW | SW | 2 females |
c.[CYP21A1P(NR_040090.1)n.877+?_CYP21A2(NM_000500.9)c.477+?del)];[(?-8)_(447+1_448-1)del], p.[(0)];[(0)] 3 | 6–20 days | SW | SW | 2 females, 3 males |
c.[CYP21A1P(NR_040090.1)n.877+?_CYP21A2(NM_000500.9)c.477+?del)];[(?-8)_(939+1_940-1)del], p.[(0)];[(0)] 4 | 0 day | SW | SW | 1 female |
c.[923dupT];[1451G>C], p.[(Leu308PhefsTer6(;)Arg484Pro)] | 17 days | SW | SV | 1 male |
c.[CYP21A1P(NR_040090.1)n.877+?_CYP21A2(NM_000500.9)c.477+?del)];[(?-8)_(939+1_940-1)del], p.[(0)];[(0)] 4 | 13 days | SW | SW | 1 male |
c.[CYP21A1P(NR_040090.1)n.877+?_CYP21A2(NM_000500.9)c.477+?del)];[(?-8)_(939+1_940-1)del], p.[(0)];[(0)] 4 | 34 days | SW | SW | 1 male |
c.[CYP21A1P(NR_040090.1)n.877+?_CYP21A2(NM_000500.9)c.477+?del)];[293-13C>G], p.[(0)];[(?)] | 0–17 days | SW | SW | 1 female, 2 males |
c.[(?-8)_(549+1_550-1)del];[293-13C>G], p.[(0)];[(?)] | 13 days | SW | SW | 1 male |
c.[(?-8)_(939+1_940-1)del];[293-13C>G;518T>A;1360C>T], p.[(0)];[(?;Ile173Asn;Pro454Ser)] | 15 days | SW | SW | 1 male |
c.[CYP21A1P(NR_040090.1)n.877+?_CYP21A2(NM_000500.9)c.477+?del)];[955C>T], p.[(0)];[(Gln319Ter)] | 42 days | SW | SW | 1 female |
c.[CYP21A1P(NR_040090.1)n.877+?_CYP21A2(NM_000500.9)c.477+?del)];[1069C>T], p.[(0)];[(Arg357Trp)] | 30 days | SW | SW | 1 male |
c.[(?-8)_(447+1_448-1)del];[293-13C>G], p.[(0)];[(?)] | 26 days | SW | SW | 1 male |
c.[(?-8)_(447+1_448-1)del];[923dupT], p.[(0)];[(Leu308PhefsTer6)] | 27 days | SW | SW | 1 male |
c.[(?-8)_(447+1_448-1)del];[923dupT; 955C>T], p.[(0)];[(Leu308PhefsTer6;Gln319Ter)] | 12 days | SW | SW | 1 female |
c.[1A>C];[293-13C>G], p.[(Met1Leu)];[(?)] | 22 days | SW | SW | 1 male |
c.[293-13C>G];[293-13C>G;1360C>T], p.[(?)];[(?;Pro454Ser)] | 1 day | SW | SW | 1 female |
c.[293-13C>G];[c.332_339del], p.[(?)];[(Gly111ValfsTer21)] | 21 days | SW | SW | 1 male |
c.293-13C>G(;)332_339del(;)518T>A, p.(?)(;)(Gly111ValfsTer21)(;)(Ile173Asn) | 6 days | SW | SW/SV | 1 male |
c.293-13C>G(;)332_339del(;)1360C>T, p.(?)(;)(Gly111ValfsTer21)(;)(Pro454Ser) | 15 days | SW | SW/NC | 1 female |
c.[293-13C>G];[518T>A], p.[(?)];[(Ile173Asn)] | 11 days–12.9 years | SV | SV | 3 females, 1 male |
c.293-13C>G(;)955C>T(;)1069C>T, p.(?)(;)(Gln319Ter)(;)(Arg357Trp) | 30 days | SW | SW | 1 male |
c.[293-13C>G];[1069C>T], p.[(?)];[(Arg357Trp) | 7 days | SW | SW | 1 female |
c.844G>T(;)955C>T, p.(Val282Leu)(;)(Gln319Ter) | 6,2 years | SW | NC | 1 female |
c.955C>T(;)1360C>T(;)1455del, p.(Gln319Ter)(;)(Pro454Ser)(;)(Met486TrpfsTer56) | 3 days | SW | SW/NC | 1 female |
c.[518T>A];[518=], p.[(Ile173Asn)];[(Ile173=)] | 6.3 years | SW | SV? | 1 female |
c.[(?-8)_(939+1_940-1)del];[518T>A], p.[(0)];[(Ile173Asn)] | 5 years | SV | SV | 1 female |
c(?-8)_(939+1_940-1)del];[518T>A], p.[(0)];[(Ile173Asn)] | 9 years | SV | SV | 1 male |
c.[(?-8)_(939+1_940-1)del];[844G>T], p.[(0)];[(Val282Leu)] | 7 days | SV | NC | 1 female |
c.[(?-8)_(939+1_940-1)del]];[1294G>A], p.[(0)];[(Glu432Lys)] | 5 years | SV | NC | 1 female |
c.[293-13C>G;1360C>T];[1360C>T], p.[(?;Pro454Ser)];[(Pro454Ser)] | 22.7 years | NC | NC | 1 female |
c.293-13C>G(;)518T>A(;)1360C>T, p.(?)(;)(Ile173Asn)(;)(Pro454Ser) | 27 years | SV | SV/NC | 1 male |
Heterozygous duplication of CYP21A2 gene. Homozygous or heterozygous genotype for c.955C>T, p.(Gln319Ter) variant | 5 years | SV | SW | 1 male |
c.[CYP21A1P(NR_040090.1)n.877+?_CYP21A2(NM_000500.9)c.477+?del)];[844G>T] | 16 years | NC | NC | 1 female |
c.[844G>T];[=], p.[(Val282Leu)];[(Val282=)] | 56 days | NC | - | 1 female |
2015–2020 | ||||
c.[CYP21A1P(NR_040090.1)n.877+?_CYP21A2(NM_000500.9)c.477+?del)];[CYP21A1P(NR_040090.1)n.877+?_CYP21A2(NM_000500.9)c.477+?del)], p.[(0)];[(0)] | 8 days | SW | SW | 1 male |
c.CYP21A1P(NR_040090.1)n.877+?_CYP21A2(NM_000500.9)c.477+?del)(;)(?-8)_(939+1_940-1)del], p.[(0)];[(0)] | 8 days | SW | SW | 1 male |
c.CYP21A1P(NR_040090.1)n.877+?_CYP21A2(NM_000500.9)c.477+?del)(;)(c.293-13C>G), p.[(0)];[(?)] | 8 days | SW | SW | 1 female |
c.(?-8)_(939+1_940-1)del(;)293-13C>G, p.[(0)];[(?)] | 10 days | SW | SW | 1 male |
c.(?-8)_(939+1_940-1)del(;)329T>A, p.[(0)];[(Leu110Ter)] | 20 days | SW | SW | 1 male |
c.293-13C>G(;)(293-13C>G) | 5 days | SW | SW | 1 female |
c.[293-13C>G];[518T>A], p.[(?)];[(Ile173Asn)] | 32 days | SW | SV | 1 male |
c.[293-13C>G];[1069C>T], p.[(?)];[(Arg357Trp) | 15 days | SW | SW | 1 male |
c.329T>A(;)525C>A, p.(Leu110Ter)(;)(Tyr175Ter) | 14 days | SW | SW | 1 male |
c.[518T>A];[916del], p.[(Ile173Asn)];[(Val306PhefsTer17)] | 43 days | SW | SV | 1 male |
c.[518T>A];[916del], p.[(Ile173Asn)];[(Val306PhefsTer17)] | 15 days | SW | SV | 1 male |
c.955C>T(;)1069C>T p.(Gln319Ter)(;)(Arg357Trp) | 2 days | SW | SW | 1 female |
c.[518T>A];[518=], p.[(Ile173Asn)];[(Ile173=)] | 71 days | SV | 1 female |
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Navardauskaitė, R.; Banevičiūtė, K.; Songailienė, J.; Grigalionienė, K.; Čereškevičius, D.; Šukys, M.; Mockevicienė, G.; Smirnova, M.; Utkus, A.; Verkauskienė, R. Impact of Newborn Screening on Clinical Presentation of Congenital Adrenal Hyperplasia. Medicina 2021, 57, 1035. https://doi.org/10.3390/medicina57101035
Navardauskaitė R, Banevičiūtė K, Songailienė J, Grigalionienė K, Čereškevičius D, Šukys M, Mockevicienė G, Smirnova M, Utkus A, Verkauskienė R. Impact of Newborn Screening on Clinical Presentation of Congenital Adrenal Hyperplasia. Medicina. 2021; 57(10):1035. https://doi.org/10.3390/medicina57101035
Chicago/Turabian StyleNavardauskaitė, Rūta, Kornelija Banevičiūtė, Jurgita Songailienė, Kristina Grigalionienė, Darius Čereškevičius, Marius Šukys, Giedrė Mockevicienė, Marija Smirnova, Algirdas Utkus, and Rasa Verkauskienė. 2021. "Impact of Newborn Screening on Clinical Presentation of Congenital Adrenal Hyperplasia" Medicina 57, no. 10: 1035. https://doi.org/10.3390/medicina57101035