(b) (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
Case		Case 11	Case 12	Case 13	Case 14	Case 15	Case 16	Case 17		Case 18	Case 19	Case 20	Case 21j		Case 22	Case 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 Case 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).