ORPHA: 974;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 15q15.1 | Adams-Oliver syndrome 6 | 616589 | Autosomal dominant | 3 | DLL4 | 605185 |
A number sign (#) is used with this entry because of evidence that Adams-Oliver syndrome-6 (AOS6) is caused by heterozygous mutation in the DLL4 gene (605185) on chromosome 15q15.
Adams-Oliver syndrome is a rare developmental disorder defined by the combination of aplasia cutis congenita of the scalp vertex and terminal transverse limb defects (e.g., amputations, syndactyly, brachydactyly, or oligodactyly). In addition, vascular anomalies such as cutis marmorata telangiectatica congenita, pulmonary hypertension, portal hypertension, and retinal hypervascularization are recurrent findings. Congenital heart defects have been estimated to be present in 20% of AOS patients; reported malformations include ventricular septal defects, anomalies of the great arteries and their valves, and tetralogy of Fallot (summary by Stittrich et al., 2014).
For a discussion of genetic heterogeneity of Adams-Oliver syndrome, see AOS1 (100300).
Meester et al. (2015) reported 23 individuals from 9 families with Adams-Oliver syndrome and mutation in the DLL4 gene. The severity of the clinical features varied widely, but all affected individuals had scalp involvement including aplasia cutis congenita (with an underlying skull defect in 3 cases) or a bald area. Limb abnormalities, including syndactyly, brachydactyly, and short distal phalanges, were present in 9 individuals; 1 individual was also missing toes on one foot. Cardiovascular features were reported in 3 individuals, with ventricular septal defect in 2, 1 of whom also had truncus arteriosus.
The transmission pattern of AOS6 in family 5 reported by Meester et al. (2015) was consistent with autosomal dominant inheritance.
The heterozygous mutation in the DLL4 gene that was identified in a patient (family 8) with AOS6 by Meester et al. (2015) occurred de novo.
Meester et al. (2015) screened 91 families with Adams-Oliver syndrome for mutations in the candidate gene DLL4 and identified heterozygous nonsense and missense mutations in 9 families (see, e.g., 605185.0001-605185.0006). Noting the marked intrafamilial variability in phenotypic expression, with some parents exhibiting isolated aplasia cutis congenita whereas their offspring were severely affected, Meester et al. (2015) suggested that other genetic, epigenetic, or environmental factors might be involved in the clinical expression of the disease. Incomplete penetrance was also observed in some families.
Meester, J. A. N., Southgate, L., Stittrich, A.-B., Venselaar, H., Beekmans, S. J. A., den Hollander, N., Bijlsma, E., Helderman-van den Enden, A., Verheij, J. B. G. M., Glusman, G., Roach, J. C., Lehman, A., and 12 others. Heterozygous loss-of-function mutations in DLL4 cause Adams-Oliver syndrome. Am. J. Hum. Genet. 97: 475-482, 2015. [PubMed: 26299364] [Full Text: https://doi.org/10.1016/j.ajhg.2015.07.015]
Stittrich, A.-B., Lehman, A., Bodian, D. L., Ashworth, J., Zong, Z., Li, H., Lam, P., Khromykh, A., Iyer, R. K., Vockley, J. G., Baveja, R., Silva, E. S., Dixon, J., Leon, E. L., Solomon, B. D., Glusman, G., Niederhuber, J. E., Roach, J. C., Patel, M. S. Mutations in NOTCH1 cause Adams-Oliver syndrome. Am. J. Hum. Genet. 95: 275-284, 2014. [PubMed: 25132448] [Full Text: https://doi.org/10.1016/j.ajhg.2014.07.011]