ESPE Abstracts (2015) 84 FC11.1

Mutations in BRAF are Associated with Septo-Optic Dysplasia and Cardiofaciocutaneous Syndrome

Rachel Bessera, Louise Gregorya, Justin Daviesb & Mehul Dattania


aUniversity College London, Institute of Child Health, London, UK; bUniversity Hospital Southampton, Southampton, UK


Background: Mutations in BRAF are a rare cause of cardiofaciocutaneous syndrome (CFC). Recently, BRAF mutations have been reported in papillary craniopharyngiomas, but have not been described in patients with other hypothalamo-pituitary abnormalities. We describe three patients with CFC and septo-optic dysplasia (SOD) associated with heterozygous BRAF mutations.

Cases: Patients presented in childhood with clinical features of genetically proven CFC, short stature (height <0.4th centile) and MRI features of SOD. In 2/3 (Cases 1 and 2), GH deficiency was initially observed (see Table 1). Case 1 subsequently developed low normal T4 and TSH requiring Levothyroxine replacement, and gonadotrophin deficiency, Case 2 TSH deficiency and primary gonadal failure and Case 3 partial ACTH deficiency.

In situ hybridisation performed on human embryonic brain and hypothalamo-pituitary sections showed strong BRAF mRNA transcript expression at Carnegie stages (CS) 19, 20, 23 and 8 post-conception weeks in the hypothalamus/ventral diencephalon, Rathke’s pouch, trigeminal ganglia, retina, spinal cord and ganglia, and partially at CS16.

Table 1 (for abstract FC11.1)
Case/gender (M/F)Case 1 (M)Case 2 (F)Case 3 (F)
BRAF mutationc.770 A>G (p.Q257R)c.1403T>C (p.Phe468Ser)c.721 A>C (p.T241P)
GH peak (μg/l) (age/years) IGF1 (μg/l), NR5.9 (2.5 years)* 61, 20–1805.1 (9.7 years)** 69, 111–55111 (6.2 years)** 74, 88–474
fT4 (pmol/l age/years), NR TSH mU/l (age/years), NR16.6 (3.4 years), 10.3 (3.8 years) 7.3–21.1 0.7 (3.4 years), 0.58 (3.8 years) 0.34–0.569.4 (9.8 years) 10.8–19.0 3.0 (9.8 years) 0.4–4.6Normal
LH, FSH (IU/l (age/years) Tanner stageStimulated: 4.1, 8.0 (14.1 years) Testosterone 0.5 (nmol/l) 1Basal: 44.5, 53.5 (13 years) Oestradiol: <44 pmol/l 1
Cortisol peak (nmol/l)433***
NR, normal range; *, clonidine; **, glucagon stimulation; ***, modified synacthen.

Conclusion: We report the first novel association of SOD and CFC secondary to BRAF mutations. Unifying features include GH deficiency, with evolution of other pituitary abnormalities. Patients with CFC should be screened for pituitary abnormalities as these may be associated with morbidity. BRAF therefore appears to be implicated in normal pituitary function.

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