Adams-Oliver syndrome: Refining the diagnostic phenotype. S. Hassed, S. Li, J. Mulvihill, S. Palmer Dept Pediatrics/Gen, Univ Oklahoma HSC, Oklahoma City, OK.

   Adams-Oliver syndrome (AOS) is a rare genetic disorder defined as aplasia cutis congenita (ACC) and limb reduction defects; fetal vasculopathy has been proposed as the pathogenesis. Associated anomalies are not well characterized. Four genes are known: DOCK6 [MIM 614219, 614194], EGOT [MIM 615297, 614789], ARHGAP31 [MIM 100300, 610911], and RBPJ [MIM 614814, 147183]; the last previously reported by one author (SH). We describe 15 unreported individuals with AOS; none have identifiable mutations, so additional genes remain to be found. A total literature review of 270 cases from 155 families was analyzed for anomalies; 17 have known genotype. Great variability is observed regardless of genotype. As expected, 94% of probands had ACC with limb defects; 34% of affected relatives had both cardinal manifestations. Other limb defects included syndactyly, ectrodactyly, and polydactyly. All but 1% of ACC were on the scalp, and only 52% of scalp lesions had underlying bone aplasia. The third most common finding was brain abnormalities, 22%, higher than previously reported. These were quite varied and many could not be attributed to vascular events. Various brain malformations were seen (common hypoplasias, microcephaly, hydrocephalus, with few vascular malformations), but some sequelae of vascular dysfunction (ischemia, infarct, periventricular leukomalacia and calcifications) also occurred. Most unexpected was a high rate, 22%, of CNS migration defects (pachygyria, polymicrogyria, heterotopia, colpocephaly). A deformation mechanism from cranial defects is not likely a major cause of brain abnormalities; half of patients with brain anomalies had intact skulls, though focal hypoplasia or abnormal ventricles were twice as common in cases where calvarial defects were present. There were no consistent associations between vascular anomalies or events and brain malformations. A wide variety of congenital heart defects was seen in 21%. Cutis marmorata telangiectasia congenital was present in 19%. Other vascular anomalies were seen in 13%; most involved scalp vessels (7%), but internal vascular anomalies were seen in 5%, and 2% involving hepatoportal disease. The remaining anomalies had no predictable pattern, with intraocular anomalies in 3%, cleft lip/palate in 2%, and renal anomalies in 1%. Fourteen childhood deaths were reported from complications, including 3 from hemorrhage. Defining clinical diagnostic criteria seems feasible.

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