Abstract 424 Clinical Genetics/Dysmorphology Platform, Tuesday, 5/4

Based on cases excluded from a clinical study of Sotos syndrome, Cole and Hughes ( Am J Med Genet 41:115-124, 1991) reported a unique syndrome associated with progressive postnatal macrocephaly, marked obesity, distinctive facial features, mental retardation, and positive family history for macrocephaly. Subsequently, Stevenson et al ( Lancet 349:1744-1745, 1997) emphasized the association of progressive postnatal macrocephaly with autism, and they suggested that this might comprise a recognizable autism syndrome. We report a child with Cole-Hughes syndrome and associated autistic features, who appears to have a distinctive behavioral phenotype associated with this syndrome. His size at birth was normal, but lack of speech at 22 mos, with preservative behavior and a very brief attention span, led to diagnosis of mental retardation with autistic features. At age 22 mos, his weight was +6 S.D. above mean for age, with head circumference +2 S.D. A brain MRI revealed mild prominence of ventricles. By 4 1/2 yrs, his height was +2 S.D., head circumference was +3 S.D., and weight was +5 S.D. Repeat MRI at 8 yrs revealed an enlarged posterior corpus callosum with hypoplastic superior cerebellar vermis. At 14 yrs, his height was 90th centile, head circumference was +4.2 S.D., and weight was +5 S.D. He used a few idiosyncratic gestures and had severely limited speech production, with many self-stimulating, repetitive behaviors and limited interest in school activities. Parental stature was 25th-50th centile, with mom's head circumference 50th-75th centile and dad's head circumference at the 97th centile. Autism is thought to be a genetic disorder with male predominance. There is associated mental retardation in 75% of cases, and associated macrocephaly in 23-24% of cases (more common in males and more often inherited from fathers.) These observations suggest that autism may be a newly-recognized behavioral manifestation of Cole-Hughes macrocephaly-mental retardation syndrome, and that autosomal dominant macrocephaly is not always benign. We are investigating several similar cases of Cole-Hughes syndrome for autistic features, and we feel this unique behavioral manifestation may be part of this syndrome.