Molecular Bases and Phenotypic Determinants of Aromatase Excess Syndrome
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).