Table 1: Summary of clinical studies in male patients with aromatase excess syndrome (modified from [4]).

(a)

Family Family A Family B Family C Family D Family E Mutation types Duplication Duplication Deletion Deletion Deletion The promoter involved in CYP19A1 overexpression CYP19A1 CYP19A1 CYP19A1 DMXL2 DMXL2 1 2 3 4 5 6 7 8 9 10 Age at examination (year) 66 15 20 15 15 13 42 9 12 13 <Phenotypic findings> Gynecomastia (tanner breast stage) 2 2 2 3 4 4 4 3 4 4 Onset of gynecomastia (year) 13 13 10 11 12 11 11 7 9 10 Mastectomy (year) No Yes (15) No Yes (15) Yes (15) Yes (13) No No Yes (12) Yes (13) Testis (ml) N.E. 12 12 12 12 12 N.E. 3 12 20 Pubic hair (tanner stage) N.E. 2-3 4 5 4 3 N.E. 1 3 4 Facial hair Normal Scarce Scarce Normal Absent Absent N.E. Absent Absent Absent Height (SDS)a −1.2 −0.3 +0.4 +0.8 −2.0 −1.0 −1.6 +2.7 ±0 +1.8 Bone age (year)b N.E. N.E. N.E. 16.0 16.0 13.5 N.E. 13.0 15.0 17.0 Fertility (spermatogenesis) Yes ? (Yes)h ? ? ? Yes ? ? ? <Endocrine findings>c B B S B S B S B S B S B B S B S B S <At Dx> Stimulus LH (mIU/mL) GnRHe 3.8 2.3 14.3 2.1 17.0 2.4 29.4 1.9 40.6 1.8 69.2 1.1 11.5 0.6 39.5 6.7 14.8 LH (mIU/mL) GnRH (after priming)f 1.8 9.5 1.3 10.7 FSH (mIU/mL) GnRHe 1.7 3.1 5.3 <0.5 1.2 0.9 2.4 1.4 4.2 2.0 7.8 3.2 6.6 0.6 2.9 0.7 1.0 FSH (mIU/mL) GnRH (after priming)f 2.6 3.2 <0.5 0.9 Prolactin (ng/ml) 4.3 5.3 8.2 9.1 11.3 18.8 Δ4A (ng/mL) 0.5 1.1 1.2 0.6 0.7 2.4 2.9 T (ng/mL) hCGg 2.9 1.6 2.2 4.0 2.6 7.2 1.4 7.9 0.6 3.6 2.4 3.2 9.7 DHT (ng/mL) 0.4 0.2 0.4 1.2 Inhibin B (pg/mL) 61.6 74.6 83.5 75.2 E1 (pg/mL) 157 120 124 57 63 53 E2 (pg/mL) 29 15 22 59 56 38 24 19 25 58 E2/T ratio (×103) 10.0 9.4 10.0 14.8 21.5 27.1 31.7 10.4 18.1

(b)

Family Family F Family G Family H Sporadic Mutation types Deletion Inversion Inversion Inversion The promoter involved in CYP19A1 overexpression DMXL2 CGNL1 MAPK6 TMOD3 TLN2 11 12 13 14 15 16 17 18 19 20 21j 22 23 Age at examination (year) 69 35 44 45 9 8 13 10 35 7 13 17 36 <Phenotypic findings> Gynecomastia (tanner breast stage) Yes i Yes i Yes i Yes i 2 3 3 3 Yes 3 5 N.E. Yes Onset of gynecomastia (year) ? ? ? ? 8 8 11 10 5 5 8 7 ? Mastectomy (year) Yes i Yes i Yes i Yes i No No Yes (?) Yes (?) Yes (16) No Yes (?) Yes (?) Yes (19) Testis (ml) N.E. N.E. N.E. N.E. 2 1.5 2 2 N.E. N.E. N.E. Normal N.E. Pubic hair (tanner stage) N.E. N.E. N.E. N.E. 1 1 2 1 Normal 1 2-3 (at 21.0) N.E. N.E. Facial hair N.E. N.E. N.E. N.E. Absent Absent Absent Absent Absent Absent N.E. Scarce N.E. Height (SDS)a N.E. ~−1.5 ~−1.5 ~−1.5 +1.4 N.E. +2.0 +2.4 Short >+2.5 −1.6 (at 21.0) Short N.E. Bone age (year)b N.E. N.E. N.E. N.E. 12.5 13.0 15.0 14.5 (at 12.5) N.E. 13.0 (at 5.5) 17.0 N.E. N.E. Fertility (spermatogenesis) Yes Yes Yes Yes ? ? ? ? Yes ? ? ? ? <Endocrine findings>c B B B B B B B S B B B B S B <At Dx> Stimulus LH (mIU/mL) GnRHe 0.2 3.5 1.7 3.0 0.2 <0.1 2.6 6.3 1.5 1.7 0.1 2.6 10.0 4.3 LH (mIU/mL) GnRH (after priming)f FSH (mIU/mL) GnRHe 1.4 2.3 0.8 0.8 1.4 0.5 0.8 1.2 1.2 1.5 0.3 <0.1 <0.1 2.7 FSH (mIU/mL) GnRH (after priming)f Prolactin (ng/ml) Δ4A (ng/mL) 1.4 0.4 1.7 0.5 0.3 <0.3 0.9 1.5 1.3 0.8 0.3 2.4 0.9 T (ng/mL) hCGg 2.6 2.5 2.1 2.5 <0.1 <0.1 2.7 9.2 2.7 3.2 <0.1 1.2 3.8 2.3 DHT (ng/mL) 0.2 0.5 Inhibin B (pg/mL) E1 (pg/mL) 32 34 59 34 26 41 77 86 903 119 544 556 E2 (pg/mL) 10 19 24 31 11 7 25 40 223 15 178 392 E2/T ratio (×103) 3.8 7.6 11.4 12.4 9.3 14.8 69.6 148.3 170.4

SDS: standard deviation score; Dx: diagnosis; Tx: therapy; LH: luteinizing hormone; FSH: follicle stimulating hormone; Δ4A: androstenedione; T: testosterone; DHT: dihydrotestosterone; E1: estrone; E2: estradiol; GnRH: gonadotropin-releasing hormone; hCG: human chorionic gonadotropin; N.E.: not examined; B: basal; and S: stimulated. Abnormal clinical findings are boldfaced. Abnormally low hormone values are boldfaced, and abnormally high hormone values are underlined. aEvaluated by age- and ethnicity-matched growth references; heights ≥+2.0 SD or below ≤−2.0 SD were regarded as abnormal. bAssessed by the Tanner-Whitehouse 2 method standardized for Japanese or by the Greulich-Pyle method for Caucasians; bone age was assessed as advanced when it was accelerated a year or more. cEvaluated by age-matched male reference data, except for inhibin B and E1 that have been compared with data from 19 adult males. dTreated with aromatase inhibitors (anastrozole). eGnRH 100 μg/m2 (max. 100 μg) bolus i.v.; blood sampling at 0, 30, 60, 90, and 120 minutes. fGnRH test after priming with GnRH 100 μg i.m. for 5 consecutive days. ghCG 3000 IU/m2 (max 5000 IU) i.m. for 3 consecutive days; blood sampling on days 1 and 4. hAlthough 3 has not yet fathered a child, he has normal spermatogenesis with semen volume of 2.5 ml (reference value: >2 ml), sperm count of 105 × 106/ml (>20 × 106/ml), total sperm count of 262.5 × 106 (>40 × 106), motile cells of 70% (>50%), and normal morphological sperms 77% (>30%). iThese four patients allegedly had gynecomastia that required mastectomy (age unknown). jThe sister has macromastia, large uterus, and irregular menses; the parental phenotype has not been described. The conversion factor to the SI unit: LH 1.0 (IU/L), FSH 1.0 (IU/L), E1 3.699 (pmol/L), E2 3.671 (pmol/L), Δ4A 3.492 (nmol/L), and T 3.467 (nmol/L).