J was born at term (2.62 kg). She presented aged six months with severe faltering growth, (weight 5.1 kg, length 57.3 cm, OFC 39.0 cm). Investigations showed elevated prolactin (1838 mIU/l) and undetectable IGF1 but were otherwise normal. Her karyotype was 46XX. A brain MRI was normal. By 11 months of age she had evident developmental delay and dysmorphic features (triangular face; hypertelorism; synophrys; broad nasal root; short nose with rounded tip; carp like mouth; short neck and low anterior hairline) and bilateral conductive hearing loss. Aged 2 years she underwent an insulin tolerance test (peak GH 88.9 mU/l, Peak Cortisol 1196 nmol/l). Russell-Silver syndrome was initially considered, before a clinical diagnosis of Cornelia de Lange Syndrome (CdLS) was made. Her skeletal features were considered very characteristic of CdLS, however, her face was considerably less characteristic. 3D facial analysis suggested that she just fell into the CdLS spectrum. Aged 7y a de novo mutation in HDAC8 (Xq13.1) was found confirming CdLS.
CdLS is a dominantly inherited congenital malformation disorder. In ~60% of cases, NIPBL mutations are identified, with mutations in SMC1A (5%) and SMC3 (<1%) also recognised. Histone Deacetylase 8 (HDAC8) mutations were first identified as a cause of CdLS in 2012 (1). Reversible acetylation of histone is a key regulator of gene expression. Loss of HDAC8 activity results in increased SMC3 acetylation (SMC3-ac) and consequent abnormal gene expression.
23 - 25 Nov 2016
British Society for Paediatric Endocrinology and Diabetes