title: Five new cases of 46,XX aromatase deficiency: clinical follow-up from birth to puberty, a novel mutation, and a founder effect.
abstract: BACKGROUND
  Aromatase is the key enzyme for estrogen biosynthesis and is encoded by the CYP19A1 gene. Since 1991, several molecular CYP19A1 gene alterations associated with aromatase deficiency have been described in both sexes.
  
  
  OBJECTIVE
  The objective of the study was to detect CYP19A1 mutations in five aromatase-deficient 46,XX patients, to describe the clinical follow-up from birth to puberty and to perform haplotype analysis associated with the high-frequency c.628G>A splice mutation in Argentinean patients.
  
  
  METHODS
  The design of the study was the sequencing of the coding and flanking intronic regions of the CYP19A1 gene in all patients and parents. Haplotype analysis of patients carrying the c.628G>A mutation was also performed.
  
  
  METHODS
  Clinical and biochemical findings in five new cases and one previously reported female aromatase-deficient patient (46,XX) are described. All patients presented with ambiguous genitalia at birth. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency as well as other steroidogenic defects were ruled out.
  
  
  RESULTS
  Phenotypic variability among the affected patients was found during follow-up. Direct sequencing of the CYP19A1 gene from genomic DNA revealed one novel mutation (c.574C>T) in two patients. In silico analysis predicted the c.574C>T mutation to be probably damaging. Four of six nonrelated patients presented with the c.628G>A splice mutation. Haplotype analysis showed that the c.628G>A splice mutation is associated with the same haplotype in our population.
  
  
  CONCLUSIONS
  Increased knowledge on phenotypical variability found in female aromatase-deficient patients is useful to improve the detection rate in this disorder. In our population, a genetic founder defect has probably contributed to an increase in the incidence of the c.628G>A splice mutation.
authors.affiliation: Endocrinology Service (R.M., N.P.G., M.Co., G.G., M.J., P.R., D.M.W., M.Ci., M.A.R., A.B., N.S.), Laboratory of Cellular Biology and Retrovirus (C.R.), Hospital de Pediatria Garrahan, C1245AAM Buenos Aires, Argentina; Endocrine Service (G.P.), Hospital Infantil Municipal de Córdoba, 5000 Córdoba, Argentina; Endocrine Service (J.G.F.), Hospital Regional de Concepcion, CPT4146GXD Tucuman, Argentina; and Endocrine Service (M.M.), Hospital de Niños de la Santísima Trinidad de Córdoba, 5000 Córdoba, Argentina.
authors.forename: Roxana
authors.initials: R
authors.lastname: Marino
authors.forename: Natalia
authors.initials: N
authors.lastname: Perez Garrido
authors.forename: Mariana
authors.initials: M
authors.lastname: Costanzo
authors.forename: Gabriela
authors.initials: G
authors.lastname: Guercio
authors.forename: Matías
authors.initials: M
authors.lastname: Juanes
authors.forename: Carlos
authors.initials: C
authors.lastname: Rocco
authors.forename: Pablo
authors.initials: P
authors.lastname: Ramirez
authors.forename: Diana M
authors.initials: DM
authors.lastname: Warman
authors.forename: Marta
authors.initials: M
authors.lastname: Ciaccio
authors.forename: Gladys
authors.initials: G
authors.lastname: Pena
authors.forename: José García
authors.initials: JG
authors.lastname: Feyling
authors.forename: Mirta
authors.initials: M
authors.lastname: Miras
authors.forename: Marco A
authors.initials: MA
authors.lastname: Rivarola
authors.forename: Alicia
authors.initials: A
authors.lastname: Belgorosky
authors.forename: Nora
authors.initials: N
authors.lastname: Saraco
mesh_terms: D058489:46, XX Disorders of Sex Development / Q000235:genetics*; D000293:Adolescent; D001141:Aromatase / Q000172:deficiency* / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D005500:Follow-Up Studies; D018703:Founder Effect; D006177:Gynecomastia / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D007248:Infertility, Male / Q000235:genetics*; D008661:Metabolism, Inborn Errors / Q000235:genetics*; D009154:Mutation
chemical_list: D001141:Aromatase; C561410:CYP19A1 protein, human