Endocrine Abstracts

JOINT2946

Introduction: Precocious puberty is rare in boys with McCune-Albright syndrome (MAS). Cases of unilateral or bilateral macroorchidism, along with elevated inhibin B and anti-Müllerian hormone (AMH) levels but normal androgen levels, have been reported due to the autonomous hyperfunction of Sertoli cells. Management is challenging and focuses on suppressing gonadal steroidogenesis and mitigating the peripheral effects of androgens.

Case Report: Our patient first presented at age 5 years and 6 months with macroorchidism, increased height (135.8 cm, +1.82 SDS) and growth velocity (10.96 cm/year, +7.03 SDS), as well as accelerated bone age (+49 months). Tanner staging showed PH2, G2-3; testicular volumes were 8 mL and 10 mL, and penile length was 9.0 cm. Laboratory evaluation revealed normal basal and stimulated (Synacthen) androgen levels and a normal urine steroid profile. LH and FSH were at prepubertal levels. Alpha-fetoprotein and beta-HCG levels were normal. Inhibin B levels were markedly elevated (367 ng/l), while AMH was within the normal range (15 ng/l). Ultrasound imaging showed enlarged but homogeneous testes without microlithiasis. Genetic testing ruled out fragile X syndrome, and karyotyping confirmed a 46, XY genotype. Whole-exome (blood) sequencing did not reveal any pathogenic variants. The patient was lost to follow-up but presented again at 7 years and 4 months. After LH-RH stimulation, LH increased from <0.5 to 4.5 U/l, while FSH remained unchanged. We initiated treatment with leuprorelin acetate. However, pubertal signs and growth acceleration progressed, prompting us to perform a testicular biopsy. Genetic analysis of testicular tissue revealed somatic hypomethylation of all four GNAS differentially methylated regions (DMRs): exon A/B (GNAS-A/B: TSS DMR = A/B), GNAS antisense (GNAS-AS1: TSS DMR = AS1), extra-large stimulatory G protein (GNAS-XL: Ex1 DMR = XL), and neuroendocrine secretory protein 55 (GNAS-NESP: TSS DMR = NESP), compared to normal methylation results in DNA from blood sample of the same patient. No further mutation has been detected in both tissues. Following this diagnosis, we initiated combination therapy with spironolactone and anastrozole and discontinued leuprorelin acetate.

Conclusion: Precocious puberty in boys with McCune-Albright syndrome is rare and requires a testicular biopsy for diagnosis. Given the underlying etiology, GnRH agonists are ineffective; however, a combination of third-generation aromatase inhibitors and antiandrogens may be the preferred therapeutic approach. ¹Aversa T, Zirilli G, Corica D, De Luca F, Wasniewska M. Phenotypic testicular abnormalities and pubertal development in boys with McCune-Albright syndrome. Ital J Pediatr. 2018 Nov 19;44(1):136.