Adams-Oliver syndrome (AOS) is an extremely rare inherited disorder characterized by defects of the scalp and abnormalities of the fingers, toes, arms, and/or legs. The physical abnormalities associated with this disorder vary greatly among affected individuals. Some cases may be very mild while others may be severe. In infants with Adams-Oliver syndrome, scalp defects are present at birth and may include one or multiple hairless scarred areas that may have abnormally wide blood vessels directly under the affected skin. In severe cases, an underlying defect of the bones of the skull may also be present. In addition, infants with this disorder typically have malformations of the hands, arms, feet, and/or legs. These range from abnormally short fingers and toes to absent hands and/or lower legs. In some cases, additional abnormalities may also be present. Most cases of AOS appear to follow autosomal dominant inheritance but autosomal recessive inheritance has also been reported.
We provide testing for the genes listed below that are known to be associated with Adams-Oliver syndrome.
The encoded protein is a GAP shown to regulate two GTPases involved in protein trafficking and cell growth. ARHGAP31 mutations disrupt actin cytoskeletal structures, causing syndromic cutis aplasia and limb anomalies and the autosomal dominant form of Adams-Oliver syndrome.
Autosomal recessive multiple congenital anomaly syndrome that is characterized by aplasia cutis congenita and terminal transverse limb defects, in association with variable involvement of the brain, eyes, and cardiovascular systems.
Autosomal dominant form of Adams-Oliver syndrome involving characteristic vertex scalp defects and terminal limb defects, but without congenital heart defects, other associated defects, or immune defects.
Autosomal recessive form characterized by cutis aplasia of the scalp, terminal transverse defects of the toes, and atrial septal defect.
||Caused by heterozygous mutation in the NOTCH1 gene on chromosome 9q34.defined by the combination of aplasia cutis congenita of the scalp vertex and terminal transverse limb defects, in addition, vascular anomalies such as cutis marmorata telangiectatica congenita, pulmonary hypertension, portal hypertension, and retinal hypervascularization are recurrently seen. Congenital heart defects have been estimated to be present in 20% of AOS patients.
||Caused by heterozygous mutation in the DLL4 gene on chromosome 15q15. Autosomal dominant disorder characterized by cutis aplasia and terminal transverse limb defects as well as congenital heart defects
Methodology: Sequencing of entire coding region
Purpose:Confirmation of Clinical Diagnosis
Test Requisition: Sequencing Requisition
ARHGAP31 CPT Code: 81479 Cost: $500.00
RBPJ CPT Code: 81479 Cost: $500.00
DOCK6 CPT Code: 81479 Cost: $500.00
EOGT CPT Code: 81479 Cost: $500.00
DLL4 CPT Code: 81479 Cost: $500.00
NOTCH1 CPT Code: 81407 Cost: $500.00
Panel CPT Code: 81407 Cost: $3000.00
Turn-around-time: 5-6 weeks each test
1. Bandyopadhyay S, Chiang CY, Srivastava J, et al. (2010). "A human MAP kinase interactome". Nat. Methods 7 (10): 801–5.
2. Southgate L, et al. (2011). "Gain-of-Function Mutations of ARHGAP31, a Cdc42/Rac1 GTPase Regulator, Cause Syndromic Cutis Aplasia and Limb Anomalies". Am. J. Hum. Genet. 88 (5): 574–85.Shaheen, R., Faqeih, E., Sunker, A., Morsy, H., Al-Sheddi, T.,
3. Shamseldin, H. E., Adly, N., Hashem, M., Alkuraya, F. S. (2011) “Recessive mutations in DOCK6, encoding the guanidine nucleotide exchange factor DOCK6, lead to abnormal actin cytoskeleton organization and Adams-Oliver syndrome”. Am. J. Hum. Genet. 89: 328-333.
4. Hassed, S. J., Wiley, G. B., Wang, S., Lee, J.-Y., Li, S., Xu, W., Zhao, Z. J., Mulvihill, J. J., Robertson, J., Warner, J., Gaffney, P. M. (2012) “RBPJ mutations identified in two families affected by Adams-Oliver syndrome”. Am. J. Hum. Genet. 91: 391-395.
5. Shaheen, R., Aglan, M., Keppler-Noreuil, K., Faqeih, E., Ansari, S., Horton, K., et al. (2013) "Mutations in EOGT confirm the genetic heterogeneity of autosomal-recessive Adams Oliver syndrome". Am. J. Hum. Genet. 92: 598-604.
6. Aguirre, A., Rubio, M.E., Gallo, V.(2010) "Notch and EGFR pathway interaction regulates neural stem cell number and self-renewal". Nature 467:323-327.
7. Meester, J. A. N., Southgate, L., Stittrich, A.-B., Venselaar, H., et al..(2015) "Heterozygous loss-of-function mutations in DLL4 cause Adams-Oliver syndrome". Am. J. Hum. Genet. 97: 475-482.