Aromatase, the product of CYP19A1, catalyzes the conversion of androgens to estrogens. 46, XX infants with aromatase deficiency, due to androgen excess, present with ambiguous genitalia at birth. In 46, XY individuals, however, the subtle phenotypic features make the diagnosis even more difficult. Less than 15 male cases were reported in the literature and we present the first case of aromatase deficiency diagnosed in Taiwan.
A 23-year-old man, Burman overseas student of Chinese descent, presented to an orthopedist with a two-year history of left ankle pain, which was diagnosed as gout by his previous physician. Unexpectedly, unfused growth plates were discovered so he was referred to our pediatric endocrine clinic for evaluation. Reviewing his past history, we learned he is the third child of consanguineous parents. His mother experienced deepening of voice during this pregnancy which resolved following parturition. He was 177 cm tall at the age of 19. At the time he presented to our clinic, he weighed 95.3 kg and was 183 cm tall. Physical exam showed the ratio of U/L segment to be 0.82, stretched penile length 6.5 cm, bilateral testes > 25 mL, pubic hair at Tanner stage V, and presence of genu valgum. The skeletal age was 14 years and 6 months. Labs showed FSH 19.7 IU/L (0.7–11.1), LH 8.18 IU/L (0.8–7.6), total testosterone 1335 ng/dL (240–871), estradiol <20 pg/mL, DHEA-S 13.41 μmol/L (6.5–14.6), androstenedione 5.73 nmol/L (3.5–9.8) and 17-OH progesterone 6.55 nmol/L (2–10). GnRH (100 μg i.v) stimulation test showed a supranormal basal FSH level and a normal to higher LH response (FSH at baseline/peak were 23.0/38.6 IU/L; LH at baseline/peak were 8.81/47.7 IU/L). Under the clinical suspicion of aromatase deficiency, we performed genetic sequencing of CYP19A1 (NM_031226) and found a homozygous missense variant c.1108G>A (V370M), a previously reported pathogenic mutation.
A diagnosis of aromatase deficiency was made. He also had hypertension (156/87 mmHg), dyslipidemia (T-cholesterol 236 mg/dL, LDL-C 175 mg/dL) and insulin resistance (AC glucose 87 mg/dL, insulin 23.5 μU/mL, HOMA-IR 5.0, Hb1Ac 5.6%). Bone mineral density of lumbar spine (DXA) showed a T-score of -2.8, consistent with the diagnosis of osteoporosis.
Estrogen is pivotal for epiphyseal closure in both sexes. As demonstrated in this case, estrogen deficiency in men results in tall stature and eunuchoid habitus, while it is also associated with low bone density and metabolic syndrome. The gonadotropin response in this report suggests the inhibitory role of estrogen in the male HPG axis. Clinicians may consider this rare diagnosis for men in their late teens or early twenties, who have spontaneous initiation of puberty, presenting with bone pain and continued linear growth.