Adams–Oliver syndrome

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Adams–Oliver syndrome
Classification and external resources
OMIM 100300
DiseasesDB 32741

Adams–Oliver syndrome (AOS) is a rare congenital disorder characterized by defects of the scalp and cranium (cutis aplasia congenita), transverse defects of the limbs, and mottling of the skin.


One of the specific features of AOS is cutis aplasia congenita (missing hair and/or skin) affecting the posterior part of the skull, with or without an underlying defect of the cranial bone. The size of the lesion is variable and may range from solitary round hairless patches to complete exposure of the cranial contents. There may also be varying degrees of terminal transverse defects (for example, shortened digits) of either the upper extremities, lower extremities, or both. Individuals with AOS may have mild growth deficiency, with height in the lower normal percentiles. The skin is frequently observed to have a mottled appearance (cutis marmorata). Other congenital anomalies, including cardiovascular malformations, cleft lip and/or palate, abnormal renal system, and mental retardation are observed in a fraction of affected individuals. Variable defects in blood vessels have also been described, including hypoplastic aortic arch, middle cerebral artery, pulmonary arteries. Other vascular abnormalities described in AOS include absent portal vein, portal sclerosis, arteriovenous malformations, abnormal umbilical veins, and dilated renal veins.


AOS was initially described as having autosomal dominant inheritance due to the reports of families with multiple affected family members in more than one generation. The severity of the condition can vary between family members, suggestive of variable expressivity and reduced penetrance of the disease-causing allele. Subsequently, it was reported that some cases of AOS appear to have autosomal recessive inheritance, perhaps with somewhat more severe phenotypic effects. Three AOS genes have been identified, ARHGAP31, DOCK6, and RBPJ. The first two genes listed regulate proteins CDC421 and RAC1.

Another gene that has been associated with this condition is Notch1.[1]


The precise mechanism underlying the congenital abnormalities observed in AOS is unknown. Similar terminal transverse limb anomalies and cardiovascular malformations are seen in animal models of hypoxic insults during the first trimester.[2][3] Combined with the common association of cardiac and vascular abnormalities in AOS, it has been hypothesized that the spectrum of defects observed in AOS could be due to a disorder of vasculogenesis.

So far, the disease-causing genetic defect in AOS has not been definitively identified. In rare cases, AOS can be associated with chromosomal translocations. A panel of candidate genes (including ALX4, ALX1, MSX1, MSX2, P63, RUNX2 and HOXD13) have been tested but no disease-causing mutations have been identified.[4][5]


The diagnosis of AOS is a clinical diagnosis based on the specific features described above. A system of major and minor criteria was proposed.[6]

Major features Minor features
Terminal transverse limb defects Cutis marmorata
Aplasia cutis congenita Congenital heart defect
Family history of AOS Vascular anomaly

The combination of two major criteria would be sufficient for the diagnosis of AOS, while a combination of one major and one minor feature would be suggestive of AOS. There is currently no genetic testing that can be performed in order to confirm or rule out this condition.


Management of AOS is largely symptomatic and aimed at treating the various congenital anomalies present in the individual. When the scalp and/or cranial bone defects are severe, early surgical intervention with grafting is indicated.


The overall prognosis is excellent in most cases. However, individuals with more severe scalp and cranial defects may experience complications such as hemorrhage and meningitis, leading to long-term disability.


AOS is a rare genetic disorder and the annual incidence or overall prevalence of AOS is unknown. Approximately 100 individuals with this disorder have been reported in the medical literature.


AOS was first reported in a family with eight affected members[7]

Research Directions[edit]


  1. ^ Stittrich AB, Lehman A, Bodian DL, Ashworth J, Zong Z, Li H, Lam P, Khromykh A, Iyer RK, Vockley JG, Baveja R, Silva ES, Dixon J, Leon EL, Solomon BD8, Glusman G1, Niederhuber JE9, Roach JC1, Patel MS (2014) Mutations in NOTCH1 cause Adams-Oliver Syndrome. Am J Hum Genet pii: S0002-9297(14)00320-6
  2. ^ Webster
  3. ^ Ghatpande
  4. ^ Verdyck et al., 2003
  5. ^ Verdyck et al., 2006
  6. ^ Snape et al. 2009
  7. ^ Adams and Oliver, 1945.


Jones, Kenneth L (1997). Smith's Recognizable Patterns of Human Malformation (5th ed. ed.). Saunders. ISBN 0-7216-6115-7. 

James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology (10th ed. ed.). Saunders. ISBN 0-7216-2921-0. 

Adams FM, Oliver CP (1945). "Hereditary deformities in man due to arrested development". J Hered. asia .london 36: 3–7. 

Baskar S, Kulkarni ML, Kulkarni AM, Vittalrao S, Kulkarni PM (2009). "Adams–Oliver syndrome: Additions to the clinical features and possible role of BMP pathway.". Am J Med Genet A 149 (8): 1678–1684. doi:10.1002/ajmg.a.32938. PMID 19606482. 

Bonafede RP, Beighton P (1979). "Autosomal dominant inheritance of scalp defects with ectrodactyly". Am J Med Genet 3 (1): 35–41. doi:10.1002/ajmg.1320030109. PMID 474617. 

Maniscalco M, Zedda A, Faraone S, de Laurentiis G, Verde R, Molese V, Lapiccirella G, Sofia M (2005). "Association of Adams–Oliver syndrome with pulmonary arterio-venous malformation in the same family: a further support to the vascular hypothesis.". Am J Med Genet A 136 (3): 269–274. doi:10.1002/ajmg.a.30828. PMID 15948197. 

McGoey RR, Lacassie Y (2008). "Adams–Oliver syndrome in siblings with central nervous system findings, epilepsy, and developmental delay: refining the features of a severe autosomal recessive variant.". Am J Med Genet A 146 (4): 488–491. doi:10.1002/ajmg.a.32163. PMID 18203152. 

Snape KM, Ruddy D, Zenker M, Wuyts W, Whiteford M, Johnson D, Lam W, Trembath RC (2009). "The spectra of clinical phenotypes in aplasia cutis congenita and terminal transverse limb defects.". Am J Med Genet A 149 (8): 1860–1881. doi:10.1002/ajmg.a.32708. PMID 19610107. 

Verdyck P, Holder-Espinasse M, Hul WV, Wuyts W (2003). "Clinical and molecular analysis of nine families with Adams–Oliver syndrome.". Eur J Hum Genet 611 (6): 457–463. doi:10.1038/sj.ejhg.5200980. PMID 12774039. 

Verdyck P, Blaumeiser B, Holder-Espinasse M, Van Hul W, Wuyts W (2006). "Adams–Oliver syndrome: clinical description of a four-generation family and exclusion of five candidate genes.". Clin Genet 69 (1): 86–92. doi:10.1111/j.1399-0004.2006.00552.x. PMID 16451141. 

Whitley CB, Gorlin RJ (1991). "Adams–Oliver syndrome revisited". Am J Med Genet. 40 (3): 319–326. doi:10.1002/ajmg.1320400315. PMID 1951437. 

Zapata HH, Sletten LJ, Pierpont ME (1995). "Congenital cardiac malformations in Adams–Oliver syndrome.". Clin Genet 47 (2): 80–84. PMID 7606848. 

Further reading[edit]

External links[edit]

There is an online support group for families affected by Adams–Oliver syndrome at [1]