title: Monogenic and polygenic models detected in steroid 21-hydroxylase deficiency-related paediatric hyperandrogenism.
abstract: OBJECTIVE
  Hyperandrogenism, although mostly due to polygenic interactions, is monogenic for some enzymatic adrenal deficiencies. This study evaluates mono- and biallelic 21-hydroxylase deficiency (21OHD)-related hyperandrogenism in pediatric patients. Sensitizing and protective polymorphisms were investigated in carriers and cryptic forms of 21OHD.
  
  
  METHODS
  The study involved a monogenic analysis of CYP21A2 in patients (375 nonclassical 21OHD [NC21OHD] children; 306 hyperandrogenic 21OHD carriers, n = 306) and a polygenic association study (CAPN10-UCSNP44, PON1-108, TNFR2-M196R, IGF2-ApaI and IRS1-G972R polymorphisms) of 170 hyperandrogenic carriers plus 277 family members (control groups). The metabolic marker 17OH progesterone defined the degree of deficiency; clinical expressivity was determined by pediatric endocrinologists.
  
  
  RESULTS
  The group of 21OHD carriers manifesting hyperandrogenism was enriched in the CAPN-UCSNP44 rare variant in homozygosity (4.9 vs. 0.4%, NCBI data for the general population; p = 0.004). In our patients and controls, contrasting distributions were observed for this and another polymorphism, TNFR2-196R. In a recessive model, their rare variants were more frequently detected among the forms with high (p = 0.048) and low (p = 0.034) expressivity respectively.
  
  
  CONCLUSIONS
  21OHD-related pediatric hyperandrogenism follows monogenic and polygenic models. The opposite behaviors in terms of clinical expressivity detected for CAPN-UCSNP44 and TNFR2-M196R rare variants suggest these variants to be sensitizing and protective factors respectively in adrenal hyperandrogenism.
authors.affiliation: Laboratorio Diagnóstico Molecular Bioquímica, Hospital General Universitario Gregorio Marañón, Madrid, Spain. bezquieta@vodafone.es
authors.forename: B
authors.initials: B
authors.lastname: Ezquieta
authors.forename: M
authors.initials: M
authors.lastname: Oyarzabal
authors.forename: R
authors.initials: R
authors.lastname: Barrio
authors.forename: C
authors.initials: C
authors.lastname: Luzuriaga
authors.forename: F
authors.initials: F
authors.lastname: Hermoso
authors.forename: J L
authors.initials: JL
authors.lastname: Lechuga
authors.forename: S
authors.initials: S
authors.lastname: Quinteiro
authors.forename: A
authors.initials: A
authors.lastname: Rodríguez
authors.forename: J I
authors.initials: JI
authors.lastname: Labarta
authors.forename: A
authors.initials: A
authors.lastname: Gutierrez Macias
authors.forename: M
authors.initials: M
authors.lastname: Gallego
authors.forename: J M
authors.initials: JM
authors.lastname: Bellón
mesh_terms: D000312:Adrenal Hyperplasia, Congenital / Q000201:enzymology* / Q000235:genetics; D000483:Alleles; D043303:Aryldialkylphosphatase / Q000235:genetics; D002154:Calpain / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D004247:DNA / Q000737:chemistry / Q000235:genetics; D005260:Female; D006801:Humans; D017588:Hyperandrogenism / Q000201:enzymology* / Q000235:genetics; D007223:Infant; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics; D007335:Insulin-Like Growth Factor II / Q000235:genetics; D008297:Male; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000235:genetics; D013255:Steroid 21-Hydroxylase / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism
chemical_list: C035170:IGF2 protein, human; C526297:IRS2 protein, human; D055504:Insulin Receptor Substrate Proteins; D047889:Receptors, Tumor Necrosis Factor, Type II; D007335:Insulin-Like Growth Factor II; D004247:DNA; C531510:CYP21A2 protein, human; D013255:Steroid 21-Hydroxylase; D043303:Aryldialkylphosphatase; C468406:PON1 protein, human; D002154:Calpain; C415197:calpain 10