ESPE2024 Poster Category 2 Adrenals and HPA Axis (25 abstracts)
Genotype-Phenotype correlations in three patients with CYP21A2 picked up by 17- ɑ OHP screening
Iva Stoeva 1 , Kalina Mihova 2 , Kunka Kamenarova 2 , Daniela Kostova 2 , Raliza Georgieva 3 , Margarita Arshinkova 4 , Natasha Yaneva 4 & Radka Kaneva 2,5
1University Pediatric Hospital "Prof. Ivan Mitev" Screening and Functional Endocrine Diagnostics, Sofia, Bulgaria. 2Molecular Medicine Center, Department of Medical Chemistry and Biochemistry, Medical Faculty, Medical University of Sofia, Sofia, Bulgaria. 3University Pediatric Hospital "Prof. Ivan Mitev" Neonatology, Medical Faculty Sofia, Sofia, Bulgaria. 4University Pediatric Hospital "Prof. Ivan Mitev" Endocrinology&Diabetes, Sofia, Bulgaria. 5Medical University, Sofia, Bulgaria
Introduction: Systematic newborn screening (NBS) based on 17 ɑ OHP, followed by molecular analysis for the most frequent adrenal enzyme steroid abnormalities in newborns at high risk for congenital adrenal hyperplasia (CAH), allowed to reveal the nature of genotype-phenotype correlations in most of the patients (pts) presented as “classical CAH” – salt wasters (SW) or simple virilizers (SV). According to the enzyme rest activity they could be grouped and investigated. Personalized future treatment strategies are focused on the molecular etiology. Patients with common molecular deteriorations but different phenotypes are attracting special attention.
Material and Methods: DNA extraction from peripheral blood, Sanger sequencing and MLPA (MLPA P050) analysis were performed.
Case Presentations: All three pts (table1) were unrelated, non - consanguine, born at term, with classical 21OHD (simple virilizing and salt wasting), differences in 17 OHP screening levels, clinical manifestations and therapeutic answer to glucocorticoids and mineralocorticoids. Despite early diagnosis and treatment pt 2 died.
| Sex | 17 OHP (nmol/l) | Age (d) | ISNS 17 OHP Cut off | Form | Genotype | |
| Pat 1 | f | 69.9 | 4 | 20 | SV | Heterozygous deletion ex 2-7; Homozygous deletion promotor and ex 1; Homozygous variants: c.-126C>T, c.-113G>A, c.-110T>C, c.-103A>G, c.92C>T (p.Pro31Leu), rs9378251; Heterozygous variants c.518T>A (p.Ile173Asn), rs6475; c.710T>A (p.Ile237Asn) rs1554299737; c.713T>A (p.Val238Glu), rs12530380; c.719T>A (p.Met240Lys), rs6476; c.923dup (p.Leu308fs), rs267606756; Chimeria type: CH-5. |
| Pat 2 | m | >324 | 3 | 23 | SW | Homozygous del of CYP21A2 gene and ex 35 of TNXB gene; Homozygous variants c.92C>T (p.Pro31Leu), c.293-13C>G, rs6467, c.332_339delGAGACTAC (p.Gly111Valfs), rs387906510, c.518T>A (p.Ile173Asn), rs6475, E6 cluster [I236N (c.710T>A), V237E(c.713T>A), M239K (c.719T>A)], V281L (c.844G>T), c.844G>T (p.Val282Leu) rs6471, c.923dup (p.Leu308fs), rs267606756, c.955C>T (p.Gln319Ter) rs7755898. Chimeria type: CAH-X CH-1. |
| Pat 3 | f | >324 | 1 | 28 | SW | Heterozygous deletion ex. 1-7 CYP21A2 gene and ex 35 TNXB; Heterozygous deletion ex 1-3 CYP21A2 gene; Homozygous variants c.92C>T (p.Pro31Leu) rs9378251, c.332_339delGAGACTAC (p.Gly111Valfs), heterozygous - c.-126C>T, rs6470, in promotor and in exons c.710T>A (p.Ile237Asn) rs1554299737; c.713T>A (p.Val238Glu), rs12530380; c.719T>A (p.Met240Lys), rs6476; c.923dup (p.Leu308fs), rs267606756. Chimeria type: CH-2. |
| The prenatal molecular genetic diagnosis offered to the parents of pat 1 helped to provide the family with a healthy boy. | ||||||
Conclusion: The extensive molecular analysis not restricted to reveal only homozygous or compound heterozygous mutations of CYP21A2 is important and should include adjacent to CYP21A2 structures. It contributes to the possible explanation of the phenotypic variability in CAH due to 21 OHD. Difficulties in obtaining and interpreting the precise underlying abnormalities require team work and experience.
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