Paola Concolino1, Rosa Maria Paragliola2,3. 1. Department of Laboratory and Infectious Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Largo A. Gemelli 8, 00168, Rome, Italy. paola.concolino@policlinicogemelli.it. 2. Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Rome, Italy. 3. Unit of Endocrinology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy.
Abstract
BACKGROUND AND OBJECTIVE: Congenital adrenal hyperplasia involves a series of autosomal recessive disorders where adrenal steroidogenesis is affected. We present a detailed molecular investigation of 13 newborns affected from the severe form of congenital adrenal hyperplasia related to 21-hydroxylase deficiency. METHODS: All patients were diagnosed with classical congenital adrenal hyperplasia in the neonatal period due to adrenal crisis and/or ambiguous genitalia presentation. None of the infants was identified through a congenital adrenal hyperplasia newborn screening program. A molecular analysis of the CYP21A2 gene and a familiar segregation analysis were performed. RESULTS: Adrenal crisis was the most severe manifestation in the male salt-wasting newborns while all female patients presented with atypical genitalia. Newborns were correctly genotyped and no genotype-phenotype divergences were found. Two novel severe genotypes, not previously reported, were identified. The novel CYP21A2 frameshift mutations (c.793delG and c.297dupG) were added to the other 45 variants recently reported in the literature, leading to a total count of 279 pathogenic variants affecting the gene. CONCLUSIONS: We have successfully genotyped 13 infants diagnosed with classical congenital adrenal hyperplasia after birth. Our molecular approach led to the identification of two novel frameshift CYP21A2 pathogenic variants related to the salt-wasting form of congenital adrenal hyperplasia.
BACKGROUND AND OBJECTIVE: Congenital adrenal hyperplasia involves a series of autosomal recessive disorders where adrenal steroidogenesis is affected. We present a detailed molecular investigation of 13 newborns affected from the severe form of congenital adrenal hyperplasia related to 21-hydroxylase deficiency. METHODS: All patients were diagnosed with classical congenital adrenal hyperplasia in the neonatal period due to adrenal crisis and/or ambiguous genitalia presentation. None of the infants was identified through a congenital adrenal hyperplasia newborn screening program. A molecular analysis of the CYP21A2 gene and a familiar segregation analysis were performed. RESULTS: Adrenal crisis was the most severe manifestation in the male salt-wasting newborns while all female patients presented with atypical genitalia. Newborns were correctly genotyped and no genotype-phenotype divergences were found. Two novel severe genotypes, not previously reported, were identified. The novel CYP21A2 frameshift mutations (c.793delG and c.297dupG) were added to the other 45 variants recently reported in the literature, leading to a total count of 279 pathogenic variants affecting the gene. CONCLUSIONS: We have successfully genotyped 13 infants diagnosed with classical congenital adrenal hyperplasia after birth. Our molecular approach led to the identification of two novel frameshift CYP21A2 pathogenic variants related to the salt-wasting form of congenital adrenal hyperplasia.
Authors: Lina Schiffer; Lise Barnard; Elizabeth S Baranowski; Lorna C Gilligan; Angela E Taylor; Wiebke Arlt; Cedric H L Shackleton; Karl-Heinz Storbeck Journal: J Steroid Biochem Mol Biol Date: 2019-07-27 Impact factor: 4.292
Authors: Sebastian Gidlöf; Anna Wedell; Claes Guthenberg; Ulrika von Döbeln; Anna Nordenström Journal: JAMA Pediatr Date: 2014-06 Impact factor: 16.193
Authors: Phyllis W Speiser; Wiebke Arlt; Richard J Auchus; Laurence S Baskin; Gerard S Conway; Deborah P Merke; Heino F L Meyer-Bahlburg; Walter L Miller; M Hassan Murad; Sharon E Oberfield; Perrin C White Journal: J Clin Endocrinol Metab Date: 2018-11-01 Impact factor: 5.958