Abstract


Introduction: Testotoxicosis (OMIM176410) is an autosomal dominant, male limited disorder causing constitutive activation of the LH receptors in the Leydig cells, resulting in highly increased autonomous testosterone synthesis.

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Introduction: Testotoxicosis (OMIM176410) is an autosomal dominant, male limited disorder causing constitutive activation of the LH receptors in the Leydig cells, resulting in highly increased autonomous testosterone synthesis.

Medical history: /The patient presented at 10 months of age with pubic hair and growth of genitals. Bone age was advanced by 3.5 years. Testosterone was markedly elevated to 35.1 nmol/L, the GnRH test showed a prepubertal response. The ACTH test and s-17-OH-progesterone were normal. Bilateral testis biopsy at 1.5 years showed extensive Leydig cell hyperplasia with fully differentiated Leydig cells, some tubules with partially differentiated Sertoli cells, spermatogonia and a few primary spermatocytes which had entered meiosis, but no visible spermatids(1). He was diagnosed with testotoxicosis at 1.5 years (heterozygous for c.1732G>T, p.Asp578Tyr mutation in the LHCGR gene).

Treatment: Throughout infancy and childhood, he underwent available anti hormonal therapies (GnRH agonist, Ketoconazole, MPA, Cyproterone Acetate, Testolactone, Tamoxifen and Letrozole). Daily growth hormone was administered from 7.3 years to 12.7 years. All medication was discontinued from 12.7 years.

Adult outcome: Final adult height was 164 cm (target height 172.6 cm). Bone mineral density (BMD) was normal (T-score -0.8 SD (L1-L4)).Testicular volume by orchidometry was 8 mL. Testosterone was 24 nmol/L, Estradiol 117 pmol/L, Inhibin B 22 pg/ml, AMH 23 pmol/L, FSH < 0.05U/l and LH <0.05 U/l. Semen analysis showed sperm concentration: 3.4 mill/mL, semen volume: 2.2 mL, sperm motility A+B (14%), C (7%), D (79%). A heterogeneous irregular testicular echo pattern was observed by ultrasonography, which was repeated every 6-12 months. At age 25 ultrasound of testes revealed a tumor suspicious mass, biopsy showed benign Leydig cell tumor but with extensive germ cell neoplasia in situ.
Despite life-long undetectable levels of LH and FSH, the patient fathered a son by natural conception at 23.8 years. The son virilized in infancy (Testosterone 18.4 nmol/L at 9 months), was diagnosed with an identical mutation, and therapy with Bicalutamide and Letrozole was initiated.

Conclusion: We present detailed clinical and biochemical parameters from childhood, adolescence and adulthood of a young man with severe testotoxicosis presenting in infancy. Despite anti hormonal therapy the patient ended up with reduced height but normal BMD. We observed meiotic entry of some germ cells already in infancy, spermatogenic activity in adulthood and an ability to conceive despite documented undetectable levels of LH and FSH throughout life. Development of Leydig cell tumor with extensive germ cell neoplasia in situ, in our patient, suggest the need for regular follow up of such patients. Long term consequences of lifelong increased concentration of sex steroids and LH receptor activation remain to be seen. 

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