Clinical characteristics and management of gonadotropin-independent precocious puberty in McCune–Albright syndrome in children – A case series from a tertiary care center, Sri Lanka

INTRODUCTION

The reported prevalence of McCune–Albright syndrome (MAS) is between 1 in 100,000 and 1 in 1,000,000.^[1-3] The clinical spectrum was originally characterized in 1963 with the triad of monostotic/polyostotic fibrous dysplasia (FD), café-au-lait spots, and precocious puberty.^[2,3] Nonetheless, it is now known to have a significantly more complex phenotype, with many hyperfunctioning endocrinopathies.^[1,3,4] Activating somatic mutations of the GNAS1 gene encoding the alfa subunit of the G protein receptor cause MAS.^[3,5,6] As a result, the intrinsic GTPase activity of the alfa subunit is eliminated, resulting in constitutive receptor activation and aberrant cyclic AMP generation.^[3] MAS is characterized by hyperfunctioning endocrinopathies caused by constitutive, ligand-independent communication through the luteinizing hormone, follicle-stimulating hormone, thyroid-stimulating hormone, growth hormone (GH)-releasing hormone, and adrenocorticotropic hormone receptors.^[4] The same constitutive Gs activation impairs the development of skeletal stem cells, resulting in the replacement of normal bone and marrow with immature woven bone and fibrotic stroma, leading to FD.^[4] The activation of gonadotropin receptors in the gonads results in gonadotropin-independent precocious puberty (GIPP), which is typically accompanied by the development of ovarian cysts and episodes of estrogen release that cause vaginal bleeding in females.^[7,8] In addition, different endocrinopathies occur with varying frequency.^[1]

Here, we report four cases of MAS who were actively being followed up in a leading children’s hospital in Sri Lanka with a combination of clinical features and various hyperfunctioning endocrinopathies.

CASE REPORT

We present the profile of four cases with MAS. The age at presentation ranged from 3 to 7 years with an M: F ratio of 2:2. The café-au-lait spots and body deformities were consistently seen in all four cases. The salient clinical features of the four patients who presented with MAS and their subsequent management are tabulated below [Tables 1 and 2]. Two cases had GIPP, and one case had hypophosphatemic rickets at the time of presentation. [Table 1] summarizes the initial presenting features of the patients, and [Table 2] shows the subsequent clinical features and management. In the follow-up, all four cases developed GIPP; three cases had hypophosphatemic rickets, and two cases had hyperprolactinemia. Thyrotoxicosis was seen in one case who required thyroidectomy after medical management failed.

DISCUSSION

The MAS is clinically characterized by the triad of café-aulait skin color, peripheral precocious puberty, and polyostotic FD of bone.^[1] However, the clinical presentation and progression in individual cases are variable.^[1] The utility of GNAS1 mutation analysis is restricted in Sri Lankan settings with limited facilities; the clinical picture serves as the foundation for diagnosis. The most prevalent endocrine symptom of MAS is GIPP, which frequently manifests first and occasionally is the only clinical symptom of MAS.^[5,8] This is also the common feature shared by all four of our described patients.

The GIPP associated with MAS was treated with several medicines in both sexes.^[7] Currently, aromatase inhibitors (AIs) that inhibit estrogen biosynthesis have also been utilized successfully in both girls as well as in boys.^[2,3,7,8] These drugs competitively inhibit the enzyme aromatase binding to the enzyme’s cytochrome P450 component, reducing the production of estrogen.^[3,7,8] In a small number of girls with MAS, testolactone, a first-generation AI, demonstrated promising outcomes in a preliminary study.^[7] Third-generation AIs, including anastrozole, Letrozole, and fadrozole, have the advantages of a once-daily dose and greater efficacy.^[1,8] Letrozole has demonstrated efficacy in a modest number of studies.^[1,8]

GIPP has been successfully treated with ketoconazole in the short term, which acts by inhibiting cytochrome P450 enzymes and the formation of steroids.^[9] Ketoconazole is reported to have stopped vaginal bleeding, lowered estradiol levels, and slowed bone age development in two girls with MAS over the course of a year without any adverse reactions.^[9] Antiandrogens such as bicalutamide and spironolactone have been used in the management of peripheral precocious puberty in boys with MAS earlier.^[4] It has been demonstrated that a combination of first-generation AIs (such as testolactone) and antiandrogens (such as spironolactone or flutamide) can control virilization symptoms and growth rate.^[3] Different combination strategies that included the antifungal agent ketoconazole and the androgen receptor inhibitor cyproterone acetate have been used to treat boys with MAS. However, the documented link between ketoconazole and hepatic damage is viewed as a significant restriction for the use of this antifungal medication.^[3]

In our cohort of four patients, there were 2 boys (patients 1 and 2). Patient 1 was diagnosed with GIPP at the age of 7 years. He was started on spironolactone initially as letrozole was not available in Sri Lanka at that time. He is now 19 years old, and the main concern is the GH excess, for which he is on long-acting octreotide. Possibly due to the concurrent GH excess, his final height has not been compromised even though he has had GIPP. Patient 2 developed GIPP 2 years after presentation and was started on letrozole and spironolactone. The treatment resulted in the deceleration of the bone age advancement.

Patients 3 and 4 were girls who had concerns about GIPP. Patient 3 developed GIPP with the development of a unilateral ovarian cyst 9 months after the presentation, and patient 4 came with GIPP due to a unilateral ovarian cyst for which both started on letrozole. Initiation of letrozole leads to cessation of vaginal bleeding as well as regression of ovarian cysts and deceleration of the bone age advancement. However, long-term follow-up is needed to comment on the final heights of this cohort of patients. Even in the absence of a genetic diagnosis in the Sri Lankan setting, clinical diagnosis aids in the identification of these patients.

Hypophosphatemic rickets were one of the other common features shared by three of our patients, even though it was reported as a rare entity.

CONCLUSION

MAS is characterized by the triad of monostotic/polyostotic FD, café-au-lait spots, and precocious puberty. GIPP is frequently the presenting feature amongst many hyperfunctioning endocrinopathies seen in MAS. Management options are varied with AIs showing promising results. It is of utmost importance to follow up children with MAS regularly for the development of other hyperfunctioning endocrinopathies with regular biochemical assessment as they can develop other hyperfunctioning endocrinopathies.