Early and accelerated puberty boy with a homozygous R192C mutation in CYP19 (aromatase) gene

1. Early and accelerated puberty boy with a homozygous R192C mutation in CYP19 (aromatase) gene Costanzo M, Guercio G, Garcia-Feyling J1, Saraco N, Marino R, Perez Garrido N, Lazzati JM, Maceiras M, Rivarola MA, Belgorosky A. 1 Hospital Regional de Concepción, Tucumán, Argentina Servicio de Endocrinologia, Hospital de Pediatria Garrahan, C.A.B.A., Argentina MON060

2. CYP19A1 Aromatase P450 Aromatase I II III IV V VI VII VIII IX X Non-coding exon CYP19A1 Conley et al. J Steroid Biochem Mol Biol, 2001

3. Aromatase deficiency FEMALE (46,XX) BOTH MALE (46,XY) • Ambiguousgenitalia • Absence of breastdevelopment and menarche • Partialformswithincompletepubertaldevelopment • Ovariancysts • Hyperandrogenism • Abnormalserumgonadotropins • Maternal virilization • Delayedboneage • Lowbone mineral density • Metabolicsyndrome • Normal genitalia • Continuous linear growth • Tallstature • Eunychoidbodyproportions • Normal toincreased FSH, normal toincreased T • Azoospermia Belgorosky et al. Horm Research, 2009 Bulun SE. Fertil Steril, 2014

4. Case report: Molecular Analysis CYP19A1 gene V370M6 Homozygous for a c.574C>T missense mutation in exon 5 g.IVS3+1G>A1 1Mullis PE et al. (1997) 2Deladoëy et al. (1999) 3Belgorosky A et al. (2003) 4Conte FA et al. (1994) 5Portrat-Doyen S et al. (1996) 6Ludwig M et al. (1998) 7Harada N et al. (1992) 8Morishima A et al. (1995) 9Carani C et al. (1997) 10Hermann BL et al. (2002) 11Maffei L et al. (2004) 12Lanfranco F et al. (2008) 13Richter-Unruh A et al. (2008) 14Lin L et al. (2007) 15Maffei L et al. (2007) 16Pura et al. (2003) 17Hauri-Hohl A et al. (2011) 18Verma et al. (2012) 19 Ludwikowski et al. (2013) 20Baykan et al. (2013) 21Gagliardi et al. (2014) 22Bouchoucha et al. (2014) 23Marino et al (2014) R375H15, 20 Ex5del14 P408fsX4451 M85R13 g.IVS5-3C>A10 p.Arg192Cys 23 R435C4,14, 18 g.IVS5-1G>A13 R192H22 R457X5,23 V306_S314dup21 I II III IV V VI VII VIII IX X W141X19 C437Y4 Non-coding exon CYP19A1 M127R15 g.IVS9+1G>T12 c.312_334del12 E412fsX4453 g.IVS6+2T>C7 L157fsX1782 N411S17 R375C8 c.628G>A3,11,23 F234del14 ins1058T16 R365Q9 Y81C23 Argentinian cases

5. Case report: First evaluation Maternal virilization was present during both pregnancies HEIGHT BOYS x Clinicalevaluation Chronologicalage (CA): 7.9 ys Height 134.2 cm (1.63 SDS) Weight 28.3 kg (0.95 SDS) Normal externalmalegenitalia Tannerstage G1 PH1 Scrotal testes (2ml) CA, years Boneage: 5 ys (G&P)

6. Case report: Studies

7. Case report follow-up: Pubertal onset HEIGHT Chronologicalage: 9.8 ys Height 144.5 cm (1.51 SDS) Weight 31 kg (0.95 SDS) Normal externalmalegenitalia Tannerstage G1 PH1 Scrotal testes (4/3ml) BOYS x x CA: 9.8 ys T 4/3 Basal testosterone: 0.57 ng/ml Boneage: 6.9 ys (G&P) CA, years

8. Case report follow-up: Rapid pubertal progression HEIGHT Chronologicalage: 11.3 ys Height 157.5 cm (2.38 SDS) Weight 46.5 kg (0.95 SDS) Normal externalmalegenitalia Tannerstage G4 PH3 Scrotal testes (10/10ml) BOYS x x x x CA: 11.3 T 10/10 CA, years

9. Case report follow-up: Studies

10. Discussion Estrogen restrain on gonadotropin secretion has been demonstrated in animal and human models of estrogen deficiency In normal boys, estrogens are the main sex steroid involved in the negative feedback control of gonadotropin secretion during early and mid-puberty (Wickman 2001)

11. Discussion The use of aromatase inhibitors increases serum gonadotropin levels with a consequent supraphysiological rise in testosterone concentrations, raising concern regarding pubertal progression (Hero, 2005) Interestingly, our patient presented with accelerated puberty and apparently normal pituitary gonadal function

12. Conclusion The accelerated pubertal progression observed in this aromatase deficient boy supports the role for aromatase activity in the regulation of the pubertal tempo in boys