BSPED2015 ORAL COMMUNICATIONS Oral Communications 6 (10 abstracts)
1UCL Institute of Child Health, London, UK; 2Faculty of Medicine, University of Southampton, Southampton, UK; 3Department of Paediatric Endocrinology, Southampton Childrens Hospital, 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 cases 1 and 2, GH deficiency was initially observed (see Table 1), with case 1 subsequently developing gonadotrophin deficiency and a low-normal T4 and TSH, requiring levothyroxine replacement. Case 2 developed TSH deficiency 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, Rathkes pouch, trigeminal ganglia, retina, spinal cord, and ganglia.
Case/gender (M/F) | Case 1 (M) | Case 2 (F) | Case 3 (F) |
BRAF mutation | c.770 A>G (p.Q257R) | c.1403T>C (p.F468S) | c.721 A>C (p.T241P) |
GH peak (μg/l) (age/year) | 5.9 (2.5 years)a | 5.1 (9.7 years)b | 11 (6.2 years)b |
IGF1 (μg/l), NR | 61, 20180 | 69, 111551 | 74, 88474 |
fT4 (pmol/l) (age/year) | 16.6 (3.4 years), 10.3 (3.8 years) | 9.4 (9.8 years) | Normal |
NR | 7.321.1 | 10.819.0 | |
TSH (mU/l) (age/year) | 0.7 (3.4 years), 0.58 (3.8 years) | 3.0 (9.8 years) | |
NR | 0.340.56 | 0.44.6 | |
LH and FSH (IU/l) (age/year) | Stimulated: 4.1, 8.0 (14.1 years) | Basal: 44.5, 53.5 (13 years) | - |
Testosterone 0.5 nmol/l | Oestradiol: <44 pmol/l | ||
Tanner stage | 1 | 1 | |
Cortisol peak (nmol/l) | - | - | 433c |
MRI features | Small anterior pituitary | Reduction in white matter | Pending |
Absent corpus callosum | Enlarged lateral ventricles | ||
Hypoplastic optic nerves | Hypoplastic corpus callosum | ||
Hypoplastic optic nerves | |||
Normal anterior and posterior pituitary and stalk | |||
NR, normal range; a, clonidine; b, glucagon stimulation; c, modified Synacthen. |
Conclusion: We report the first novel association of SOD and CFC secondary to BRAF mutations. Endocrine features include GH deficiency, with evolution of other pituitary abnormalities. Patients with CFC should be screened for pituitary defects as these may be associated with morbidity. BRAF therefore appears to be implicated in normal hypothalamo-pituitary function.