Table 1.
Summary of all reported human CYP19A1/aromatase mutations and their characteristics
| No. of patients | Familial | Consanguinity | Mutation Allele 1 | Mutation Allele 2 | Karyotype | Sex of rearing | Age at Presentation | Phenotype | Virilization of Baby at Birth | Virilization of Mother | Spontaneous Puberty | Ovary/Testis Phenotype | Functional Testing | Ref. |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 2 | Yes | NK | M85R | c.629-2G>A | 46,XX | F | Birth | Ambiguous genitalia at birth, puberty absent and bone age delayed, virilizing signs at pubertal age | Yes | NK | NK | NK | M85R: no activity | (8) |
| 2 | Yes | Likely | R115X | R115X | 46,XX | M + F | 14/8 | P1 (M): At 14 y, undescended testes and hypospadias, presence of ovaries with cysts and small uterus. P2 (F): At 8 y, 1 cm phallus, 2 urogenital openings, pubic pilosity | Yes (Prader III in P1 and II in P2) | No | Yes | Histo P1: ovarian follicle cysts | ND | (9) |
| 2 | Yes | Yes | W141X | P1: W141X; P2: missing allele/deletion | 46,XX | F | 2/5 | Hypertrophic clitoris and prepuce with single urogenital opening; low estradiol, elevated LH and FSH | Yes (Prader IV) | Yes | No | Normal at presentation | ND | (10) |
| 2 | No | No | E210K | E210K | 46,XX | F | Birth | P1: Ambiguous genitalia at birth, spontaneous pubertal development Tanner 4 with virilization signs; menarche at 12 y. P3: Clitorial enlargement with complete labial fusion and urogenital sinus with single phalloscrotal opening; gonads nonpalpable. Spontaneous puberty starting at 9 y, Tanner 3 at 12 y with signs of virilization and elevated gonadotropins | Yes (Prader II in P1; IV in P3) | No | Yes | Multiple cysts in both ovaries at age 18 y (P1) and at 9 y (P3) | ND | (11) |
| 1 | No | No | E210K | E210K | 46,XY | M | 25 | 29 y, tall, eunuchoid habitus, cryptorchidism, bone pain, metabolic syndrome | NA | NK | Yes | Histo: hypotrophic seminiferous tubules with mature Sertoli cells. Germ cell depletion without spermatogenic development. Scarce, mature Leydig cells in small groups. | ND | (12) |
| 1 | No | No | E210K | c.1235delA | 46,XX | F | Birth | Ambiguous genitalia and virilization (Prader V), PCOS in childhood; spontaneous breast development at age 8 y | Yes (Prader V) | Yes | Yes (partial) | Large ovarian follicles at 5 mo; Histo: normal stroma, numerous follicles. At 7.7 y: increased size of uterus with multiple ovarian cysts | c.1235delA: no activity | (11) (13- 15) |
| 1 | No | No | E210K | Y81C | 46,XX | M to F | Birth | Phallic enlargement, hypospadias, nonpalpable gonads. Delayed bone age at 6 y | Yes (Prader IV) | Yes | NA | Bilateral ovaries with cysts | ND | (11) |
| 1 | No | No | R192C | R192C | 46,XX | F | Birth | Ambiguous genitalia, 2 cm phallus | Yes (Prader IV) | Yes | NA | Normal by ultrasound at years 3 | ND | (11) |
| 1 | No | No | R192C | R457X | 46,XX | F | Birth | Ambiguous genitalia, 1 cm phallus and complete labial fusion. Single phalloscrotal opening. No gonads palpable. | Yes | No | Yes | At 10 y, enlarged ovaries by ultrasound | ND | (11) |
| 2 | Yes | Yes | R192H | R192H | 46,XX and 46,XY | F + M | F at birth; M at 15 mo | F: Clitoral hypertrophy and labial fusion; M: hypospadia and cryptorchidism | F: yes (Prader IV) | No | NK | Histo of ovary at 1 year: normal. | 19% of WT | (1) |
| 1 | No | Yes | R365Q | R365Q | 46,XY | M | 28 | 28 y, continuous growth and unfused epiphysis, infertility, skeletal pain, metabolic syndrome | NA | NK | Yes | Histo: hypospermatogenesis and germ cell arrest | 0.4% of WT | (16) |
| 1 | No | Likely | V370M | V370M | 46,XX | F | Birth | Ambiguous genitalia (small phallic structure without hypospadias); not palpable gonads. Urogenital sinus | Yes (Prader V) | Yes | NA | Ovaries not visualized at birth | ND | (17) |
| 2 | Yes | Yes | R375C | R375C | 46,XX and 46,XY | F + M | Birth | P1, 46,XX, F, 28 y: DSD at birth, sexual infantilism and virilization, PCOS, tall stature. P2, 46,XY, M, 24 y: tall, osteopenia, delayed bone maturation, eunuchoid, macroorchidism | Yes (P1) | Yes | No in P1 (F), yes in P2 (M) | Histo: ovaries with PCOS phenotype | 0.2% of WT | (18) |
| 2 | Yes | Yes | R375H | R375H | 46,XY | M | 27 | Bone pain and recurrent forearm fractures, progressive overgrowth | NA | NK | Yes | Borderline sperm count and motility | ND | (19) |
| 1 | No | No | R375H | M127R | 46,XY | M | 25 | Continuing linear growth, eunuchoid body habitus, adiposity, and diffuse bone pain | NA | NK | Yes | Histo: hypospermatogenesis | R375H: 7% of WT; M127R: 0% | (20) |
| 1 | No | No | R435C | R435C | 46,XX | F | Birth | Ambiguous genitalia; sexual infantilism, PCO | Yes (Prader IV) | Yes | Yes, partial | Bilateral cystic ovaries at age 13.5 y | 1.5% of WT | (21) |
| 2 | Yes | Yes | F234del | F234del | 46,XX | M + F | Birth | P1, m: Ambiguous genitalia (phallic enlargement and hypospadia). Gynecomastia at puberty caused gonadectomy. P2, F: Ambiguous genitalia. 2 cm phallus, partial labial fusion. | Yes (Prader IV) | Yes | Yes | Histo: cystic ovaries | 19% of WT | (21) |
| 1 | Yes | Yes | c.452-621-c.628 + 803del | c.452-621-c.628 + 803del | 46,XX | F | Birth | Labial fusion, excess of clitoral skin | Yes | Yes | No | Small ovaries observed with MRI | 0% | (21) |
| 1 | No | NK | C437Y | R435C | 46,XX | F | Birth | Ambiguous genitalia at birth; 14 y: primary amenorrhea, no breast development, enlarged clitoris, pubic hair Tanner stage III, sexual infantilism, PCO | Yes | Only acne | No | Multiple bilateral cysts | C437Y: 0% of WT R435C: 1.1% of WT | (22, 23) |
| 1 | No | No | L451P | Y81C | 46,XY | M | 24 | Eunuchoid proportions, bilateral genua valga, incomplete fused epiphyses, osteopenia | NA | No | Yes | Testes of normal size and consistency | L451P: 3.1% of WT Y81C:14.3% of WT | (24) |
| 1 | NK | NK | R457X | R457X | 46,XX | F | NK | F, virilization | Yes | NK | NK | NK | ND | (25) |
| 1 | No | NK | N411S | c.–41C>T | 46,XX | F | Birth | At birth ambiguous genitalia, clitoral hypertrophy, thin dividing wall between urethral opening and a normal vaginal introitus with a hymen altus | Yes | Yes | NA | Normal by ultrasound | N411S: 0% of WT c.-41C>T: 50% of WT | (26) |
| 1 | No | Yes | c.629-1453_744- 486_del | c.629- 1453_744- 486_del | 46,XX | M + F | Birth | At 1 mo: ambiguous genitalia, gonads not palpable, phallus 1 cm, uterus by ultrasound | Yes (Prader III) | No | NA | Small ovaries by ultrasound | ND | (27) |
| 1 | No | Yes | c.1263 + 1G>T | c.1263 + 1G>T | 46,XX | M | Birth | Ambiguous genitalia of unknown cause at birth. At 21 y: undescended testes, hypoplastic scrotum, hypoplastic uterus | Yes (Prader V) | No | Abnormal | Histo: streak gonads | ND | (28) |
| 1 | No | Yes | c.469C_del | c.469C_del | 46,XY | M | Birth | Investigated after birth because of severe maternal virilization. Found low estrogen levels, high androstenedione, normal free testosterone. | NA | Yes | NA | Normal | ND | (29) |
| 1 | No | Yes | c.264G_del | c.1036_1037ins 23bp | 46,XX | F | Birth | Ambiguous genitalia, 3 cm clitoromegaly; PCOS later | Yes (Prader IV) | Yes | NA | Large ovaries with cysts | c.264G_del < 0.3% of WT; 23bp_del < 0.3% of WT | (30) |
| 1 | No | Yes | Ala306_Ser314_ dup | Ala306_ Ser314_dup (likely) | 46,XX | F | Birth | At birth ambiguous genitalia. Lack of pubertal development. Streak ovaries. At 32 y, osteopenia and fracture, tall stature, central obesity, borderline hypertension, impaired fasting glucose | Yes (Prader III) | NK | No | Streak ovaries | ND | (31) |
| 1 | No | No | c.1263 + 5G>A | c.1263 + 5G>A | 46,XX | F | 4 | At 4, labioscrotal fusion, 1.5 cm clitoromegaly, perineal urethra. At 13.5 y, delayed bone age, small uterus, follicular cysts in ovaries. | Yes | No | Abnormal (B1, P4) | PCOS | ND | (32, 42) |
| 1 | No | Yes | c.743 + 2T>C | c.743 + 2T>C | 46,XX | F | Birth | At birth: ambiguous genitalia, enlarged phallus, gonads not palpable | Yes (Prader IV-V) | Yes | NA | ND | 0.3% of WT | (7, 33) |
| 1 | No | No | V445X | c.296 + 1G>A | 46,XX | F | Birth | At birth: masculine- appearing external genitalia, enlarged phallus, complete fusion of posterior labioscrotal folds | Yes (Prader V) | Yes | Yes (Tanner 4) | At birth: slightly enlarged ovaries. At 2 y: enlarged ovaries with several cysts, fallopian tubes and uterus normal in appearance, histopathology showed many normal-appearing large tertiary follicles with an oocyte within a cumulus oophorus projecting into antrum. | ND | (34, 35) |
| 2 | Yes | Yes | c.469C_del | c.469C_del | 46,XY and 46,XX | M + F | 16 (M | P1 (M): 16 y, no gynecomastia or other abnormalities, open epiphyses, congenital hearing loss of 85%, delayed bone age | NA and NK (F) | No | M: yes and F: no | Normal by clinical exam | ND | (36) |
| 1 | No | Yes | c.629-3C>A– frameshift and stop codon 8 nt after exon 5 | c.629-3C>A– frameshift and stop codon 8 nt after exon 5 | 46,XY | M | 27 | Normal sex characteristics, spontaneous erections sufficient for intercourse, genua valga, kyphoscoliosis, pectus carinatus. Retarded bone maturation. Abnormal glucose and lipid metabolism. | NA | Yes | Yes | Below threshold sperm count (1 mL/ mL), 100% immotile spermatozoa. Oligoazoospermia | ND | (37) |
| 1 | No | NK | c.311-334_del | c.1263 + 1G>T → Y361X | 46,XY | M | 27 | At 27 y, height 193 cm, eunuchoid, unfused epiphyses, osteopenia, increase fasting insulin, mild astenozoospermia and history of right cryptorchidism | NA | NK | Yes | History of cryptorchidism. Borderline FSH and inhibin B at age 27 y | ND | (38) |
| 1 | No | Yes | c.744-2A>G | c.744-2A>G | 46,XX | F | Birth | Ambiguous genitalia at birth; 19 mo: gonads not palpable, penis-like phallus 1.5 cm, single penoscrotal urethral opening, labioscrotal fusion defect | Yes (Prader IV) | Yes | NA | Very small ovaries by ultrasound | ND | (39) |
| 1 | NK | NK | c.1058insT | c.1058insT | 46,XY | M | 26 | 190 cm tall, hypertension, hyperuricemia, hypercholesterolemia | NA | NK | Yes | NK | ND | (40) |
| 3 | Yes | Yes | c.568insC → L190P leading to S199X | c.568insC → L190P leading to S199X | 46,XX | F | Birth | Clitoromegaly, partial to complete labial fusion | Yes (Prader II-III) | Yes | NA | Hypoplastic ovaries by imaging studies | ND | (41) |
Abbreviations: DSD, disorder of sex development; F, female; FSH, follicle-stimulating hormone; LH, luteinizing hormone; M, male; MRI, magnetic resonance imaging; NA, not applicable; ND, not determined; NK, not known; P1, patient 1; P2, patient 2 etc; PCOS, polycystic ovary syndrome; WT, wild-type.