Most patients with Turner syndrome (TS) need hormone replacement therapy because of hypergonadotropic hypogonadism; individual outcomes, however, are highly variable. Our objective was to assess the influence of five estrogen receptor 1 gene (ESR1) polymorphisms (rs543650, rs1038304, rs2046210, rs2234693 and rs9340799) on adult height, breast development, uterine volume and bone mineral density (BMD). We studied 91 TS patients from a tertiary hospital using adult estrogen dose. In our group, ESR1 rs2234693 was associated with femoral neck and total hip BMD, and it accounted for around 10% of BMD variability in both sites (P < 0.01). Patients homozygous for C allele in this polymorphism had significantly lower femoral neck BMD (0.699 ± 0.065 g/cm² vs 0.822 ± 0.113 g/cm², P = 0.008) and total hip BMD (0.777 ± 0.118 g/cm² vs 0.903 ± 0.098 g/cm², P = 0.009) than patients homozygous for T allele. The other four ESR1 polymorphisms were not able to predict any of the above estrogen therapy outcomes in an isolated manner. Patients homozygous for the haplotype GCG formed by polymorphisms rs543650, rs2234693 and rs9340799 had an even more significantly lower femoral neck BMD (0.666 ± 0.049 vs 0.820 ± 0.105 g/cm², P = 0.0047) and total hip BMD (0.752 ± 0.093 vs 0.908 ± 0.097 g/cm², P = 0.0029) than patients homozygous for haplotypes with a T allele in rs2234693. In conclusion, homozygosity for C allele in ESR1 rs2234693 and/or for GCG haplotype appears to be associated with lower femoral neck and total hip BMD. We believe that the identification of polymorphisms related to estrogen outcomes may contribute to individualization of treatment in TS.

The genetic aetiology of congenital hypopituitarism (CH) is not entirely elucidated. FGFR1 and PROKR2 loss-of-function mutations are classically involved in hypogonadotrophic hypogonadism (HH), however, due to the clinical and genetic overlap of HH and CH; these genes may also be involved in the pathogenesis of CH. Using a candidate gene approach, we screened 156 Brazilian patients with combined pituitary hormone deficiencies (CPHD) for loss-of-function mutations in FGFR1 and PROKR2. We identified three FGFR1 variants (p.Arg448Trp, p.Ser107Leu and p.Pro772Ser) in four unrelated patients (two males) and two PROKR2 variants (p.Arg85Cys and p.Arg248Glu) in two unrelated female patients. Five of the six patients harbouring the variants had a first-degree relative that was an unaffected carrier of it. Results of functional studies indicated that the new FGFR1 variant p.Arg448Trp is a loss-of-function variant, while p.Ser107Leu and p.Pro772Ser present signalling activity similar to the wild-type form. Regarding PROKR2 variants, results from previous functional studies indicated that p.Arg85Cys moderately compromises receptor signalling through both MAPK and Ca^{2 +} pathways while p.Arg248Glu decreases calcium mobilization but has normal MAPK activity. The presence of loss-of-function variants of FGFR1 and PROKR2 in our patients with CPHD is indicative of an adjuvant and/or modifier effect of these rare variants on the phenotype. The presence of the same variants in unaffected relatives implies that they cannot solely cause the phenotype. Other associated genetic and/or environmental modifiers may play a role in the aetiology of this condition.