RASopathies Are Associated With Delayed Puberty; Are They Associated With Precocious Puberty Too?

Abstract

RASopathies, such as Noonan, Costello, and cardio-facio-cutaneous syndromes, are developmental disorders caused by mutations in rat sarcoma-mitogen-activated protein kinase pathway genes. Mutations that cause Noonan syndrome have been associated with delayed puberty. Here we report 4 patients with either Costello or cardio-facio-cutaneous syndrome who developed precocious puberty, suggesting complex regulation of the hypothalamic-pituitary-gonadal axis and the timing of puberty by the rat sarcoma-mitogen-activated protein kinase pathway. Additional study of the timing of puberty among patients with RASopathies is warranted to ascertain the incidence of delayed and precocious puberty in these conditions and to examine genotype-phenotype correlations, which may provide insight into pathways that regulate the timing of puberty.

Endocrine abnormalities in cardiofaciocutaneous syndrome: a case of precocious puberty, hyperprolactinemia and diabetes insipidus

“…Compared with girls, boys have a higher incidence of precocious puberty due to central nervous system disorders, including tumours and hamartomas 14. However, the four patients with CFCS with precocious puberty for whom brain imaging information was available, had no structural abnormalities, apart from one patient with mild ventricular asymmetry and non-specific thinning of the corpus callosum, as well as the imaging findings of our patient, which have been previously described in CFCS 9 11 12. The possibility of increasing the understanding of the control of pubertal timing through the study of patients with RASopathies has already been recognised 12.…”

“…However, the four patients with CFCS with precocious puberty for whom brain imaging information was available, had no structural abnormalities, apart from one patient with mild ventricular asymmetry and non-specific thinning of the corpus callosum, as well as the imaging findings of our patient, which have been previously described in CFCS 9 11 12. The possibility of increasing the understanding of the control of pubertal timing through the study of patients with RASopathies has already been recognised 12. The preponderance of precocious puberty among male patients with CFCS, pointed for the first time here, may provide additional clues towards the understanding of the sex difference seen in the prevalence of precocious puberty.…”

“…In 2016, a retrospective chart review of two patients with CFCS and two patients with Costello syndrome who presented with precocious puberty was performed. One of the patients with CFCS was a 4-year-old boy with a BRAF mutation and the other was a 3-year-old girl with a KRAS mutation 12…”

High prevalence of syndromic disorders in patients with non-isolated central precocious puberty

“…Other complex developmental syndromes involving genetic or epigenetic abnormalities have been shown to be associated with CPP in case reports. Such associations were found in this study for patients with Silver-Russell and Temple syndromes (maternal uniparental disomy of chromosome 7 and paternal imprinted disruption or maternal uniparental disomy on chromosome 14, respectively) (42), Williams-Beuren syndrome (7q11.23 microdeletion) (17) and Kabuki syndrome (MLL2 gene mutation) (18). In other chromosomal abnormalities, incidental association could not be excluded, but rare clinical cases have already been reported (15,16,43).…”

“…A few groups have reported the epidemiology of non-isolated CPP either at their own institutions (7,8,9,10,11) or over multiple institutions (12,13,14). These studies were limited by the inclusion solely of patients with CNS lesions only, with other associated disorders being evaluated imprecisely, mostly through case reports (15,16,17,18,19).…”