ESPE Abstracts (2019) 92 FC14.2

Pubertal Onset in 1572 Girls with Short, Normal and Tall Stature: Associations to Height, Serum IGF-I and PAPP-A2 Genotypes

Emmie N Upners1,2, Alexander S. Busch1,2, Kristian Almstrup1,2, Jørgen Holm Petersen1,2, Katharina Main1,2, Rikke Beck Jensen1,2, Anders Juul1,2


1Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. 2International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), University of Copenhagen, Copenhagen, Denmark


Background: Sexual maturation is closely linked to growth, suggesting common pathways between the reproductive development and the growth hormone/insulin-like growth factor-I (GH/IGF-I) axis. IGF-I bioavailability is regulated by Pregnancy associated plasma protein-A (PAPP-A), Pregnancy associated plasma protein-A2 (PAPP-A2) and Stanniocalcin 2 (STC2). A large genome-wide association study (GWAS) identified PAPP-A, PAPP-A2 and STC2 to represent loci strongly associated with adult height.

Aims: The aim of this study was to explore the association between height, serum IGF-I, genotypes of PAPP-A, PAPP-A2, STC2 and pubertal timing in a large cohort of healthy girls and in a cohort of girls diagnosed with short and tall stature.

Method: 1572 girls were recruited from two population-based cohorts of healthy Danish children (n=1382), a cohort of patients with short stature (n=124) and tall stature (n=67). Anthropometrics, assessment of pubertal stages and IGF-I SDS were included. The girls were genotyped for PAPPA (rs751543), PAPPA2 (rs1325598) and STC2 (rs889014). A Mendelian randomization approach was used to assess the association between height and puberty.

Results: A dose-dependent association between the minor allele of PAPPA2 and height was observed. Girls homozygous for the minor allele (TT) were -0.27 [-0.47; -0.08] SDS shorter and CT heterozygotic girls were -0.09 [-0.25; 0.06] SDS shorter compared to CC major allele carriers (P=0.03). The association remained significant after correcting for IGF-I. We found no significant association between PAPPA and STC2 and height.

Age of pubertal onset was significantly later in girls with short stature (11.19 [10.86;11.52] years) and earlier in the tall girls (9.25 [8.82;9.69] years) compared to girls with normal stature 9.96 [9.85;10.07] years (P<0.01). Age at menarche was significantly later in girls with short stature 13.96 [13.55;14.37] years compared to girls with normal stature 13.09 [13.00;13.18] years (P<0.01). Adjusting for BMI did not essentially change the estimates. The genotypes were not associated with pubertal onset and menarche.

Girls within the highest IGF-I SDS quintile (Q5) had earlier pubertal onset (B2) and age at menarche compared to girls in Q1-Q4 (P<0.01).

Conclusion: We found a significant association between PAPPA2 genotype and height in this large well-characterized cohort of girls. Height and IGF-I SDS, but not PAPP-A, PAPP-A2 and STC2 genotypes, were negatively associated with age at pubertal onset and menarche.

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