Macrocephaly, epilepsy, autism, dysmorphic features, and mental retardation in two sisters: A new autosomal recessive syndrome?

Abstract

We report two sisters with macrocephaly, epilepsy, and severe mental retardation. The first child was a 14 year old girl born at term after a normal pregnancy, with birth weight 3600 g and occipitofrontal circumference (OFC) 36 cm (75th centile). Her head size increased markedly during the first six months of life, and was later stable at 2-3 cm above the 97.5th centile. Her development was characterised by psychomotor delay, epilepsy, and autistic features. Her face appeared mildly dysmorphic with a large forehead, short philtrum, and bushy eyebrows. Her younger sister was also born at term with birth weight 2600 g and OFC 34 cm (25th centile). She also developed postnatal macrocephaly with OFC 2 cm above the 97.5th centile and the same mild dysmorphic facial features as her sister. Her development was also characterised by psychomotor delay, autistic features, and epilepsy. In addition, she suffered from coeliac disease. She died unexpectedly at the age of 5 years, probably from an epileptic attack. Necropsy confirmed megalencephaly but no other pathological changes were found. The clinical features in these two sisters do not fit with any known syndrome and may represent a previously unrecognised autosomal recessive disorder.