Endocrine Abstracts

Background: Cardiofaciocutaneous (CFC) syndrome is a rare disorder characterised by multiple abnormalities including congenital heart disease, craniofacial dysmorphology, ectodermal abnormalities, developmental delay, and epilepsy. Case reports of growth hormone (GH) deficiency, hyperprolactinemia, and precious puberty have been reported in association with CFC syndrome. A recent case series and gene knockout study highlighted the mechanistic role of CFC syndrome-causing gene, B-Raf proto-oncogene (BRAF), in pituitary gland development and subsequent hypopituitarism. Here, we present a case showing the involvement of BRAF in hypopituitarism associated with CFC syndrome.

Case presentation: Our patient was diagnosed with CFC syndrome caused by a heterozygous missense variant (c.770A>G) in exon 6 (p.Q257R mutation) of the BRAF gene. His phenotype includes distinctive facial features, left ventricular hypertrophy, developmental delay, hypotonia, feeding problems, undescended testis, and epilepsy. Ophthalmological investigations identified bilateral optic atrophy. He was referred to endocrinology for short stature at 4.6 years of age (ht SDS −4.00). GH deficiency was diagnosed following an inadequate GH peak of 4.76 mU/L during a glucagon stimulation test and undetectable serum IGF-1. ACTH and TSH deficiency were excluded. Additionally, he experiences symptoms characteristic of hypothalamic syndrome including sleep disturbance and social-communication difficulties. Treatment with 0.025 mg/kg per day of GH led to marked improvements in gross motor skills and mobility. His height centile and serum IGF-1 concentrations however only improved after gradually increasing the dose to 0.05 mg/kg per day. His current height at 12.3 years lies on the 5th centile (MPH between the 9th and 25th centile). Serum IGF-1 concentrations have remained in lower quartile (23.4 nmol/l; 6.4–68.1) despite relatively high GH doses, suggesting possible GH insensitivity. Magnetic resonance imaging identified hydrocephalus which was treated with a ventriculoperitoneal shunt, but showed otherwise normal brain and pituitary gland.

Conclusion: We describe the second report of BRAF mutation in association with GH deficiency in a patient with CFC syndrome. The response to GH therapy is similar to the previous report, suggesting possible co-existent GH insensitivity. Along with GI and cardiac defects, GH deficiency must be considered as a cause of short stature in CFC syndrome.