Recommended panel testing at Breda Genetics for this condition:
Summary
Adams-Oliver syndrome (AOS) is a rare genetic condition, which may affect both males and females. The main features are aplasia cutis (an abnormality of skin development, which leads to missing skin on the scalp) and malformations of the limbs (terminal transverse limb defects). In few cases, the skull under the skin is also underdeveloped. This disorder is believed to occur due to interrupted blood flow in certain blood vessels during the fetal development stage. Deficient hair growth and scarring is seen individuals with this condition. Cutis marmorata can also be found in some cases. Limbs defects are consistent with abnormalities of the arms, hands, fingers and/or legs and feet. Fingers may be hypoplastic and even fused together. In severe cases, fingers, feet and/or hands may be absent, resembling an amputation. Most cases of Adams-Oliver syndrome are autosomal dominant, but also autosomal recessive inheritance is reported.
Detailed clinical description
In Adams-Oliver syndrome signs and symptoms and degree of severity (from mild to severe) may vary from one individual to another. Signs and symptoms include:
- Growth deficiency;
- Aplasia cutis congenita, with abnormal skin patches on scalp, which may be bleeding, scarred, or ulcerated;
- Hands and feet defects, with possible absence of some bones;
- Heart and vascular defects. Ventricular septal defect (VSD) is the most common heart defect;
- Eye, liver, central nervous system or pulmonary artery of the lungs may be affected in some individuals.
Prevalence
Adams-Oliver syndrome is a rare condition with an estimated incidence of approximately 1 in 225,000 individuals.
Molecular genetics
Adams-Oliver syndrome is genetically heterogeneous and may show an autosomal dominant or autosomal recessive pattern of inheritance. Mutations can be found in the NOTCH1, DLL4, RBPJ, and ARHGAP31 genes (autosomal dominant cases) or in the EOGT and DOCK6 genes (autosomal recessive cases). Notably, ARHGAP31 mutations are dominant pathogenic truncating variants resulting in a gain of function (whereas truncating mutations usually cause loss-of-function). The pathogenic mutations described in the other genes are loss-of-function variants (either in case of autosomal dominant or autosomal recessive inheritance). Adams-Oliver syndrome associated genes are involved in various aspects of the embryonic development of skull, limbs, bones, nerves, muscles, blood vessels and heart.
Differential diagnosis
The following disorders may show partial clinical overlap with Adams-Oliver syndrome and should be considered in the differential diagnosis.
- Scalp-ear-nipple syndrome, caused by mutation in KCTD1. Clinical findings include hypothelia, mammary hypoplasia, ear anomalies and variable combinations of aplasia cutis congenita. Occasional hypodontia, renal hypoplasia or ocular anomalies are also observed. Digital anomalies include distal hypoplasia, camptodactyly and syndactyly.
- Focal dermal hypoplasia (Goltz, PORCN mutations): This syndrome can feature both aplasia cutis and limb anomalies. It is a multisystem disorder primarily characterized by involvement of the skeletal system, skin, eyes, and face. A distinguishing feature is that the dermal hypoplasia follows the lines of Blaschko.
- Cutis marmorata telangiectatica congenita (CMTC): it is characterized by unusual discolored patches of skin caused by widened blood vessels. In many affected individuals, complete absence of the skin in affected areas and large lesions are apparent.
- Bart type epidermolysis bullosa dystrophica (COL7A1 mutations, Bart syndrome): The major feature is congenital absence of the skin. Sometimes, affected individuals may have fragile skin that blisters upon exposure to minor trauma, absence or malformation of the fingernails and toenails.
- Dominant dystrophic epidermolysis bullosa (also caused by COL7A1 mutations): aplasia cutis congenita lesions are restricted to the limbs. Persistent skin fragility and blistering postnatally are clinical diagnostic features.
There are also other congenital disorders (e.g. Johanson-Blizzard syndrome, trisomy 13 syndrome, and amniotic bands syndrome) that may be characterized by skull and scalp defects and other abnormalities of the hands and feet. These disorders usually have other physical features which helps differentiating them from Adams-Oliver syndrome.
Genetic testing strategy
Considering the genetic heterogeneity of Adams-Oliver syndrome and its differential diagnosis with other genetic disorders, it is highly recommended to proceed to a multigene panel, possibly based on whole exome or whole genome sequencing.
Recommended panel testing at Breda Genetics for this condition:
References:
Adams-Oliver syndrome review of the literature: Refining the diagnostic phenotype. Hassed S, Li S, Mulvihill J, Aston C, Palmer S. Am J Med Genet A. 2017 Mar;173(3):790-800. PMID 28160419
Mutations in NOTCH1 cause Adams-Oliver syndrome. 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 BD, Glusman G, Niederhuber JE, Roach JC, Patel MS. Am J Hum Genet. 2014 Sep 4;95(3):275-84. PMID 25132448
