Background: Estrogen insensitivity syndrome is a form of functional estrogen deficiency which is caused by a defect in the estrogen receptor type α (ESR1). As a result of the receptor mutation, estrogens cannot be recognized and hence initiate their biological action on pubertal growth, skeletal maturation, and accrual of bone mass. A mutation in the gene encoding ESR1 has been described in only 2 cases (one man and one woman). We now describe the first family with ESR1 mutation to be identified in Algeria in whom both male and female offspring were affected.
Family study: Our index patient is a 21-year-old female, one of four children (three sisters and a brother) born to parents who are second cousins. She presented aged 16 years with absent breast development, primary amenorrhea and hirsutism. Clinical assessment showed height (Ht) 170 cm (+1.09 SDS), weight (Wt) 70 kg (+1.45 SDS), Tanner stage B1A3P5, acne and severe hirsutism (Ferriman-Gallwey score 22). Bone age was 11 years. Laboratory studies revealed serum oestradiol 9526 pmol/l (N 110 280 pmol/l), elevated gonadotrophins - FSH 15 IU/L (N 211), LH 18 IU/l (N 2 9) with normal 46,XX karyotype, and multicystic ovaries on pelvic ultrasound. Genetic studies showed a c.1181G>A mutation in the fifth coding exon of ESR1, causing an arginine to histidine substitution at residue 394 (Arg 394His) of the ESR1 ligand-binding domain. Family screening revealed that both parents and one healthy sister are heterozygous for the mutation while an older sister aged 25 years and a brother aged 18 years are homozygotes. Similar to the index case they have pubertal delay with hypergonadotrophic hypogonadism. The brothers Ht is 165 cm (−1.65 SDS), Wt 73 kg (+0.56 SDS), and he has bilateral cryptorchidism, Tanner stage G1A1P1, with LH: 13 and FSH:55 IU/l, serum AMH 0.6 ng/ml (N 1.551) and Inhibin B: 5 pg/ml (N >100). The older sister had hirsutism and primary amenorrhea, Ht:156 cm (−1.29 SDS), Wt:67 kg (+0.95 SDS), Tanner stage B1A3P5, LH: 21 IU/l, FSH: 20 IU/l. E2: 9476 pmol/l
Conclusion: This family, the first to demonstrate clinical features of complete estrogen insensitivity in both male and female sexes, illustrates the range of pathology in estrogen resistance, and the challenge in terms of finding therapeutic solutions.
10 - 12 Sep 2016
European Society for Paediatric Endocrinology