Abstract
Background: Peripheral precocious puberty of ovarian origin is a very rare condition compared to central form. It may be associated with an isolated ovarian cyst (OC). The causes of OC in otherwise healthy prepubertal girls is currently unknown.Methods: Exome sequencing was performed on a cohort of 18 unrelated girls presenting with prenatal and/or prepubertal OC at pelvic ultrasonography. The presenting symptom was prenatal OC in 5, breast development in 7 (with vaginal bleeding in 3) and isolated vaginal bleeding in 6. All had OC ≥ 10 mm. The girls had no other anomalies. Four patients had a familial history of ovarian anomalies and/or infertility.Results: In 9 girls (50%), candidate or known pathogenic variants were identified in genes associated with syndromic and non-syndromic forms of hypogonadotropic hypogonadism including PNPLA6, SEMA3A, TACR3, PROK2, KDM6A, KMT2D, OFD1, GNRH1, GNRHR, GLI3, INSR, CHD7, CDON, RNF216, PROKR2, GLI3, LEPR. Basal plasma concentrations of gonadotropins were undetectable and did not increase after gonadotropin-releasing hormone test in 3 of them whilst 5 had prepubertal values. The plasma estradiol concentrations were prepubertal in 6 girls, high (576 pmol/L) in one and not evaluated in 2 of them.Conclusions: In the first study reporting exome sequencing in prepubertal OC, half of the patients with OC carry either previously reported pathogenic variants or potentially pathogenic variants in genes known to be associated with isolated or syndromic forms of congenital hypogonadotropic hypogonadism. Functional studies and studies of other cohorts are recommended to establish the causality of these variants.
Highlights
Precocious puberty (PP) in girls is defined by the development of sexual characteristics before 8 years-of-age [1]
This suggests that variants in genes associated with hypogonadotropic hypogonadism (HH) may contribute to the etiology of ovarian cyst (OC)
Eight of 16 girls had a basal plasma concentrations of gonadotropins which were undetectable and did not increase after gonadotropin releasing hormone (GnRH) test. Five of these 8 had high levels of estradiol suggesting a retrocontrol effect but 3 had prepubertal concentrations. These data reflect previous studies which indicated that the majority of girls with precocious pseudopuberty associated with an OC had basal plasma concentrations of luteinizing hormone (LH) and follicle stimulating hormone (FSH) that are either low or undetectable and that do not increase after the GnRH test, whilst the others had a prepubertal response [4, 5]
Summary
Precocious puberty (PP) in girls is defined by the development of sexual characteristics (development of breast, pubic or axillary hair and/or menstrual bleeding) before 8 years-of-age [1]. Isosexual peripheral PP is characterized by the development of breast and/or menstrual bleeding due to primary estradiol secretion originating from either the ovaries or from adrenals in the absence of hypothalamic-pituitary-gonadal axis activation. Central and peripheral PP can be distinguished by measuring basal and gonadotropin releasing hormone (GnRH)-stimulated luteinizing hormone (LH) and follicle stimulating hormone (FSH) peaks concentrations. These concentrations increase in central forms [3], whilst they are low and do not increase in peripheral PP. Peripheral precocious puberty of ovarian origin is a very rare condition compared to central form. It may be associated with an isolated ovarian cyst (OC). The causes of OC in otherwise healthy prepubertal girls is currently unknown
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