November 16, 2021
Years published: 1988, 1989, 1997, 1998, 2004, 2007, 2009, 2021
NORD gratefully acknowledges Jay Qiu, MMSc, NORD Editorial Intern from the Emory University Genetic Counseling Training Program and Cecelia A. Bellcross, PhD, MS, CGC, Associate Professor, Director, Genetic Counseling Training Program, Emory University School of Medicine, for assistance in the preparation of this report.
Adams-Oliver syndrome (AOS) is a rare inherited condition present at birth that involves changes to the limbs and scalp. Symptoms may include areas of missing skin on the scalp, limb abnormalities, heart defects, neurological concerns, and issues with the eyes. AOS is caused by harmful changes (mutations) in the ARHGAP31, DLL4, DOCK6, EOGT, NOTCH1, or RBPJ genes. Some people with AOS do not have a mutation in one of these genes AOS has different inheritance patterns based on the gene involved. Mutations in these genes can follow either an autosomal dominant or recessive inheritance pattern. There is no cure for AOC. However, it can be managed by monitoring for and treating the symptoms. This is typically done by several different healthcare providers such as pediatricians, cardiologists, and plastic surgeons.
People with AOS may have the following symptoms: absence of areas of skin (aplasia cutis congenita); shortened or missing fingers, hands, toes and/or feet; heart problems present at birth; neurological concerns such as developmental delays and learning disabilities; kidney issues and eye problems.
Symptoms can vary widely based on the gene involved. The most common symptom of AOC is an absence of areas of skin, which most commonly occurs around the scalp but can occur in other parts of the body. It can range from mild to severe. These areas of absent skin will often heal without treatment a couple of months after birth. However, in severely affected patients, there is a greater chance for infection, excessive bleeding (hemorrhage), seizures, high pressure within the skull (brain herniation) and cerebrospinal fluid leakage.
In about 20% of patients, there may be long-lasting enlarged small blood vessels. This can create a marbled-like appearance on the skin. These fragile dilated blood vessels may bleed. In severely affected patients, there may be an issue with the skull due to a bone defect that causes areas of absent bone. This can lead to excessive bleeding and bacterial infections.
Infants with AOS may have changes of the fingers, toes, hands and/or feet. Some infants may have very short fingers and/or toes. In severely affected patients, the fingers, toes, hands, feet and/or lower legs may be partially or completely missing. Also, there may be webbing of the toes (syndactyly) and/or underdeveloped toenails. In general, the lower half of the body (i.e., lower legs, feet, and toes) is more severely affected.
About 23% of people with AOS have structural heart problems. These include incomplete development of the left side of the heart (hypoplastic left ventricle) or a hole in the heart (septal defects) that affects how the blood flows. Also, patients can experience high blood pressure in the arteries of the lungs (pulmonary hypertension).
Around 35% of people with AOS have problems with brain development such as a much smaller head than expected (microcephaly), sac-like protrusion of the brain (encephalocele), and structural issues in the brain that can lead to epilepsy and seizures. These can be associated with developmental and intellectual problems.
Less than 10% of people with AOS experience eye problems which may include clouding of the lens of the eyes (cataracts), eye misalignment (esotropia), and decline of the optic nerve (optic atrophy).
Other symptoms such as a hole in the lip or roof of the mouth and extra nipples occur rarely in patients with AOS.
AOS is known to be caused by harmful changes (mutations) in several genes: ARHGAP31, DLL4, DOCK6, EOGT, NOTCH1, or RBPJ. Symptoms vary based on which gene is involved. In about 50% of patients, no mutations in these genes are found.
Most cases follow an autosomal dominant inheritance pattern through mutations in the ARHGAP31, DLL4, NOTCH1, and/or RBPJ gene. The ARHGAP31, DLL4, and NOTCH1 genes have shown incomplete penetrance. This means that people who carry mutations in these genes may not display symptoms for AOS. For the RBPJ gene, incomplete penetrance has not been shown. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular genetic condition. The non-working gene can be inherited from either parent or can be the result of a new harmful gene change (de novo mutation) in the affected individual that was not inherited from the parents. The chance of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.
AOS that involves the EOGT or DOCK6 genes follow an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.
Some researchers suspect that the physical features associated with AOS may result from interrupted blood flow through certain arteries during fetal development. These features are seen in a group of developmental conditions called “subclavian artery supply disruption sequence (SASDS).” Other conditions in this group include Poland syndrome, Klippel-Feil syndrome, Moebius syndrome and Sprengel deformity.
AOS affects males and females in equal numbers. AOS occurs in about 44 out of every 10 million people and is present at birth.
The diagnosis of Adams-Oliver syndrome can be made when an infant has both the absence of skin of the scalp and changes of the fingers, hands, toes, and/or feet. Also, a diagnosis can be made if an individual both has aplasia cutis congenita or changes of the fingers, hands, toes and/or feet, and has a first-degree relative with AOS. Lastly, a diagnosis can be made when an individual has either of these two main features: the absence of skin or malformation of the fingers, hands, toes, and/or feet, and a single mutation in the autosomal dominant related gene (ARHGAP31, DLL4, NOTCH1, or RBPJ) or two mutations in an autosomal recessive related gene (DOCK6 or EOGT).
The treatment of Adams-Oliver syndrome is directed towards the specific symptoms that are apparent in an individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, orthopedic and plastic surgeons, cardiologists, ophthalmologists, physical therapists, and other health care professionals may be needed for an individual’s treatment and surveillance of skin, limb, cardiovascular, neurological and eye concerns.
In many patients, scalp defects may heal without treatment within the first few months of life. Skin grafting, skull surgery and/or other surgical procedures may be required for individuals with AOS who have skull problems. Wearing helmets may be recommended for some children with AOS to prevent trauma to the head and potential damage to the wide blood vessels.
Physical therapy, surgery, and/or the use of artificial limbs may be recommended for children who have a partial or complete absence of fingers, toes, hands, feet and/or lower legs.
A complete medical evaluation should be done to look for potential concerns with the heart. Cardiovascular issues such as structural heart problems may require surgery.
Monitoring for symptoms on a yearly basis is recommended for infants with AOS. Echocardiographs should be done every year until the age of three for signs of pulmonary hypertension. For neurological concerns, affected children should have a neurological exam and assessment of psychomotor development every year. For eye concerns, affected children should see a pediatric ophthalmologist up until the age of three to look for any problems with the eyes.
Genetic counseling is recommended for individuals with AOS and their families. Other treatments for this disorder are symptomatic and supportive.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222 TTY: (866) 411-1010 Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact: www.centerwatch.com
For information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
(Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder [e.g., skin abnormalities, limb, and skull defects, etc.].)
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