Testotoxicosis: Report of Two Cases, One with a Novel Mutation in LHCGR Gene

Testotoxicosis is a rare disorder which presents as isosexual peripheral precocious puberty in males. Despite the pattern of autosomal dominant inheritance, sporadic cases also may occur. Due to activating mutation in luteinizing hormone (LH))/choriogonadotropin receptor (LHCGR) gene, early virilization and advancement in bone age are common with increased serum testosterone levels above adult ranges, despite low LH and follicularstimulating hormone (FSH) levels. There are different treatment regimens, such as combination of bicalutamide (antiandrogen agent) and a third-generation aromatase inhibitor, that are reported to be well-tolerated and successful in slowing bone age advancement and preventing progression of virilization. We report here two patients who presented with peripheral precocious puberty and an activating mutation in the LHCGR gene: one with a family history and previously determined mutation and the other without family history and with a novel mutation (c.830G>T). Combination of bicalutamide+anastrozole was ineffective in slowing pubertal progression and bone age. Short-term results were better with ketoconazole

Kaynakça

Schedewie HK, Reiter EO, Beitins IZ, Seyed S, Wooten VD, Jimenez, JF, Aiman EJ, DeVane GW, Redman JF, Elders MJ Testicular Leydig cell hyperplaisa as a cause of familial sexual precocity. J Clin Endocrinol Metab 1981; 52:271-278.

Rosenthal SM, Grumbach MM, Kaplan SL. Gonadotropin- independent familial sexual precocity with premature Leydig and germinal cell maturation (familial testotoxicosis): Effects of a potent luteinizing hormone-releasing factor agonist and medroxyprogesterone acetate therapy in four cases. J Clin Endocrinol Metab 1983;57:571-579.

Laue L, Chan WY, Hsueh AJ, Kudo M, Hsu SY, Wu SM, Blomberg L, Cutler GB Jr. Genetic heterogeneity of constitutively activating mutations of the human luteinizing hormone receptor in familial male-limited precocious puberty. Proc Natl Acad Sci USA 1995;92:1906-1910.

Shenker A, Laue L, Kosugi S, Merendino JJ Jr, Minegishi T, Cutler GB Jr. A constitutively activating mutation of the luteinizing hormone receptor in familial male precocious puberty. Nature 1993;365:652-654.

Gondos B, Egli CA, Rosenthal SM, Grumbach MM. Testicular changes in gonadotropin-independent familial male sexual precocity. Familial testotoxicosis. Arch Pathol Lab Medi 1985;990-995.

Leschek EW, Chan WY, Diamond DA, Kaefer M, Jones J, Barnes KM, Cutler GB Jr. Nodular Leydig cell hyperplasia in a boy with familial male-limited precocious puberty. J Pediatr 2001;138:949-951.

Bertelloni S, Baroncelli GI, Lala R, Cappa M, Matarazzo P, De Sanctis C, Saggese G. Long-term outcome of male-limited gonadotropin-independent precocious puberty. Horm Res 1997;48:235-239.

Latronico AC, Shinozaki H, Guerra G Jr, Pereira MA, Lemos Marini SH, Baptista MT, Arnhold IJ, Fanelli F, Mendonca BB, Segaloff DL. Gonadotropin-independent precocious puberty due to luteinizing hormone receptor mutations in Brazilian boys: a novel constitutively activating mutation in the first transmembrane helix. J Clin Endocrinol Metab 2000;85:4799-4805.

Teles M, Brito VN, Arnhold IJ, Mendonca BB, Latronico AC. Preclinical diagnosis of testotoxicosis in a boy with an activating mutation of the luteinizing hormone receptor. J Pediatr Endocrinol Metab 2006;19:541-544.

Nagasaki K, Katsumata N, Ogawa Y, Kikuchi T, Uchiyama M. Novel C617Y mutation in the 7th transmembrane segment of luteinizing hormone/choriogonadotropin receptor in a Japanese boy with peripheral precocious puberty. Endocr J 2010;57:1055-1060.

Gromoll J, Partsch, CJ, Simoni, M., Nordhoff, V, Sippell WG, Nieschlag E, Saxena B. A mutation in the first transmembrane domain of the lutropin receptor causes male precocious puberty. J Clin Endocr Metab 1998;83: 476-480.

Laue L, Wu SM, Kudo M, Hsueh AJ, Cutler GB Jr, Jelly DH, Diamond FB, Chan WY. Heterogeneity of activating mutations of the human luteinizing hormone receptor in male-limited precocious puberty. Biochem Mol Med 1996; 58:192-198.

Rosenthal SM, Grumbach MM, Kaplan SL. Gonadotropin- independent familial sexual precocity with premature Leydig and germinal cell maturation (familial testotoxicosis): effects of a potent luteinizing hormone-releasing factor agonist and medroxyprogesterone acetate therapy in four cases. J Clin Endocrinol Metab 1983;57:571-579.

Holland FJ, Kırsch SE, Selby R. Gonadotropin-Independent Precocious Puberty ("Testotoxicosis"): Influence of maturational Status on response to ketoconazole. J Clin Endocrinol Metab 1987;64:328-333.

Soriano-Guillén L, Lahlou N, Chauvet G, Roger M, Chaussain J L, Carel JC. Adult height after ketoconazole treatment in patients with familial male-limited precocious puberty. J Clin Endocrinol Metab 2005;90:147-151. Epub 2004 Nov 2

Babovic-Vuksanovic D, Donaldson MD, Gibson NA, Wallace AM. Hazards of ketoconazole therapy in testotoxicosis. Acta Paediatr 1994;83:994-997.

Almeida MQ, Brito VN, Lins TS, Guerra-Junior G, de Castro M, Antonini SR, Arnhold IJ, Mendonca BB, Latronico AC. Long- term treatment of familial male-limited precocious puberty (testotoxicosis) with cyproterone acetate or ketoconazole. Clin Endocrinol (Oxf) 2008;69:93-98. Epub 2008 Jul 1

Itoh K, Nakada T, Kubota Y, Suzuki H, Ishigooka M, Izumi T.Testotoxicosis proved by immunohistochemical analysis and successfully treated with cyproterone acetate. Urol Int 1996;57:199-202.

Eyssette-Guerreau S, Pinto G, Sultan A, Le Merrer M, Sultan C, Polak M. Effectiveness of anastrozole and cyproterone acetate in two brothers with familial male precocious puberty. J Pediatr Endocrinol Metab 2008;21:995-1002.

Mitre N, Lteif A. Treatment of familial male-limited precocious puberty (testotoxicosis) with anastrozole and bicalutamide in a boy with a novel mutation in the luteinizing hormone receptor. J Pediatr Endocrinol Metab 2009;22:1163-1167.

Lenz AM, Shulman D, Eugster EA, Rahhal S, Fuqua JS, Pescovitz OH, Lewis KA. Bicalutamide and third- generation aromatase inhibitors in testotoxicosis. Pediatrics 2010;126:728-733. Epub 2010 Aug 16

Reiter EO, Mauras N, McCormick K, Kulshreshtha B, Amrhein J, De Luca F, O'Brien S, Armstrong J, Melezinkova H. Bicalutamide plus anastrozole for the treatment of gonadotropin-independent precocious puberty in boys with testotoxicosis: a phase II, open-label pilot study (BATT). J Pediatr Endocrinol Metab 2010;23:999-1009.

Wit J M, Hero M, Nunez SB. Aromatase inhibitors in Pediatrics. Nat Rev Endocrinol 2011;8:135-147.

Martin MM, Wu SM, Martin AL, Rennert O M, Chan WY. Testicular seminoma in a patient with a constitutively activating mutation of the luteinizing hormone/chorionic gonadotropin receptor. Eur J Endocrinol 1998;139:101-106.

Ganem JP, Workman KR, Shaban SF. Testicular microlithiasis is associated with testicular pathology. Urology 1999;53:209- 213.

Thomas D, Vlachopapadopoulou E, Papadakis V, Sklavou R, Stefanaki K, Polychronopoulou S, Michalacos S. Testicular microlithiasis in siblings: clinical implications. Pediatric radiol 2008;38:688-690. Epub 2008 Feb 2

Dutra RA, Perez-Bóscollo AC, Melo EC, Cruvinel JC. Clinical importance and prevalence of testicular microlithiasis in pediatric patients. Acta Cir Bras 2011;26:387-390.

Gougoudi E, Zachariou Z, Kogia E, Zavitsanakis A. Testicular microlithiasis and Leydig cell proliferation in Wistar rats underwent Fowler-Stephens procedure. Pediatr Med Chir 2012;34:192-197.

Chien RN, Yang LJ, Lin PY, Liaw YF. Hepatic injury during ketoconazole therapy in patients with onychomycosis: a controlled cohort study. Hepatology 1997;25:103-107.

Kim TH, Kim BH, Kim YW, Yang DM, Han YS, Dong SH, Kim HJ, Chang YW, Lee JI, Chang R. Liver cirrhosis developed after ketoconazole-induced acute hepatic injury. J Gastroenterol Hepatol 2003;18:1426-1429.

Kaynak Göster