ISSN 1662-4009 (online)

ESPE Yearbook of Paediatric Endocrinology (2021) 18 1.7 | DOI: 10.1530/ey.18.1.7

Nat Commun. 2021 Apr 1;12(1):2028. doi: 10.1038/s41467-021-21712-4. PMID: 33795686.

The authors describe 5 patients with Cardio-Facio-Cutaneous (CFC) syndrome with features of septo−optic dysplasia (SOD), and GH/IGF−1 deficiency of variable degree. All were identified to carry a gain−of−function mutation in BRAF.

RASopathies encompass Noonan syndrome, Cardio−Facio−Cutaneous (CFC) syndrome, and neurofibromatosis type 1. They are a class of developmental syndromes that result from germline mutations in the genes encoding the components of the ERK/MAPK pathway. One of these genes is BRAF, in which mutations have been described to cause various RASopathies.

The authors found that BRAF is expressed along the developing human hypothalamus−pituitary axis. Activation of the ERK/MAPK pathway in mouse pituitary progenitors (Prop1:Cre;BrafV600E/+) resulted in the absence of terminally differentiated somatotroph, thyrotroph, and gonadotroph cells at E17.5. Murine knock−in of a CFC−causing human BRAF mutation (Q241R) also led to deficient differentiation of pituitary hormone−producing cells. Finally, activation of the ERK/MAPK pathway by expressing both the BrafV600E and the BrafQ241R alleles reduced Pit1−dependent terminal differentiation of the somatotrophs (GH) and thyrotrophs (TSH), while increasing the number of ACTH+ve and PRL+ve cells.

The authors conclude that these findings show a critical role of BRAF in hypothalamo−pituitary−axis development both in mouse and human. For the clinician, it is important to look for pituitary hormone deficiencies in patients with RASopathies.

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