Adams-Oliver Syndrome

Adams-Oliver Syndrome

Overview

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 changes (variants) in the ARHGAP31, DLL4, DOCK6, EOGT, NOTCH1, or RBPJ genes. Some people with AOS do not have a variant in one of these genes. AOS has different inheritance patterns based on the gene involved and can follow either an autosomal dominant or recessive inheritance pattern. There is no cure for AOS. However, it can be managed by monitoring and treating the symptoms. This is typically done by several different healthcare providers such as pediatricians, cardiologists and plastic surgeons.

Signs & Symptoms

Symptoms can vary widely based on the gene change (variant) that causes the disease, which is known as phenotype-genotype correlation, meaning that the signs and symptoms (phenotype) vary based on the gene variant that is involved. The most common symptom of AOC is an absence of areas of skin (aplasia cutis congenita) and malformations of the limbs.

Aplasia cutis (75%-85% of the cases) most commonly occur around the scalp, especially on the top of the head (skull vertex) and can range from mild to severe.

These areas of absent skin will often heal without treatment a couple of months after birth, but may be complicated by infection, excessive bleeding (hemorrhage), seizures, high pressure within the skull (brain herniation) and cerebrospinal fluid leakage.

Aplasia cutis can occur in other parts of the body and, in some people, the bone under the skin is also underdeveloped.

Bone defects with absent bone can occur in certain areas of the skull, which can lead to bleeding and infections

Limb defects (85% of the cases) usually affect the outermost lower part of the body (terminal transverse limb defects) more and may include:

Shortened or missing fingers, hands, toes and/or feet

Partial or complete absence of fingers, toes, hands, feet and/or lower legs

Webbing of the toes (syndactyly) and/or underdeveloped toenails

Other signs and symptoms may include:

Vascular and heart problems present at birth (congenital heart defects) in about 23% of people with AOS including:

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

High blood pressure in the arteries of the lungs (pulmonary hypertension)

Neurological problems (in around 35% of people with AOS) such as:

Smaller than normal head circumference (microcephaly)

Sac-like protrusion of the brain (encephalocele)

Epilepsy and seizures due to structural issues in the brain

Developmental delays and learning disabilities due to structural issues in the brain

Kidney problems

Skin birthmark, called cutis marmorata telangiectatica congenita (in about 20% of people) that appears as a marbled, lace-like, or fishnet pattern of widened blood vessels on the skin

This birthmark may bleed in severe cases

Eye problems (in less than 10% of people) which may include:

Clouding of the lens of the eyes (cataracts)

Eye misalignment (esotropia)

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

Each of the six subtypes, AOS1 through AOS6, has a unique genetic cause and a distinct pattern of symptoms that sets it apart from the others.

AOS1

It is often the mildest subtype. Signs and symptoms are relatively limited to skin and limb findings.

AOS2

It is usually the most severe and multisystemic form. It frequently includes both microcephaly and macrocephaly (an abnormally large head circumference), profound neurological involvement and more extensive limb reduction anomalies and broader internal organ involvement. This subtype also shows more severe nail and skin findings.

AOS3

It is distinct for its isolated neurological involvement without heart abnormalities. People often present with microcephaly, scalp defects and significant central nervous system anomalies, including brain malformations. Limb defects and nail anomalies are present but not usually as severe as in AOS2. The absence of cardiac involvement helps differentiate AOS3 from most other types.

AOS4

It is characterized by facial and eye abnormalities not commonly seen in other subtypes. These include microphthalmia, short palpebral fissures, cleft lip or palate and distinct nasal features like a depressed bridge or bulbous tip. It also includes vascular skin anomalies and congenital heart defects and mild developmental delay. These vascular and craniofacial features make AOS4 stand out.

AOS5

It is the subtype characterized by the most cardiac involvement, including serious heart defects such as valve abnormalities (tricuspid and mitral), atrial or ventricular septal defects, and right-sided heart enlargement, and by serious eye abnormalities. It is also associated with vascular brain complications, such as strokes, thromboses and cerebellar malformations. This type is very complex because of the combined presence of cardiac, eye and vascular and neurological findings.

AOS6

It is defined by the presence of truncus arteriosus, not reported in other subtypes. It also has distinct limb defects such as symbrachydactyly, syndactyly and missing toes are prominent and often asymmetric. Scalp defects and microcephaly are typical, while facial features may include a depressed nasal bridge and bulbous nasal tip. It is also the only subtype where low amniotic fluid (oligohydramnios) has been noted prenatally. These features, rare heart defects, prenatal findings and distinct limb anomalies, differentiate AOS6 from the other types.

In summary, while all forms of Adams-Oliver syndrome share core skin and limb features, they diverge significantly in systemic involvement. AOS1 is limited and mild, AOS2 is severe and affects multiple organs, AOS3 affects the neurologic system more without heart involvement, AOS4 features vascular and craniofacial anomalies, AOS5 combines heart, eye and vascular brain issues, and AOS6 is distinguished by truncus arteriosus and prenatal problems.

Meningitis may occur in some children with Adams-Oliver syndrome who have severe defects of the scalp and skull. Meningitis is characterized by swelling of the membranes (meninges) around the brain or spinal cord.

Causes

AOS is known to be caused by disease-causing changes (known as pathogenic variants) in several genes: DOCK6, ARHGAP31, RBPJ, NOTCH1, EOGT and DLL4. AOS can be divided into six types according to the causative gene: type 1, caused by ARHGAP31 gene variants; type 2, caused by DOCK6 gene variants; type 3, caused by RBPJ gene variants; type 4, caused by EOGT gene variants; type 5, caused by NOTCH gene variants; and AOS, caused by DLL4 gene variants. In about 50% of people with AOS, no variants in these genes are found.

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.

Subtypes 1, 5 and 6 have an autosomal dominant inheritance pattern and have shown incomplete penetrance. Incomplete penetrance means that there are people with these subtypes who may not have symptoms for AOS. AOS type 3 also has an autosomal dominant inheritance pattern but seems to have complete penetrance.

Dominant genetic disorders occur when only a single copy of a disease-causing gene variant is necessary to cause the disease. The gene variant can be inherited from either parent or can be the result of a new (de novo) changed gene in the affected individual that is not inherited. The risk of passing the gene variant from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.

AOS caused by variants in the EOGT gene (AOS4) or DOCK6 gene (AOS2) follow an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a disease-causing gene variant from each parent. If an individual receives one normal gene and one disease-causing gene variant, 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 gene variant and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.

Affected populations

AOS is a rare genetic disorder with an estimated incidence of approximately one in 225,000 live births. AOS affects males and females in equal numbers.

Disorders with Similar Symptoms

Symptoms of the following conditions can be like those of AOS. Comparisons may be useful for a differential diagnosis:

Scalp-ear-nipple syndrome is a rare condition which involves areas of hairless skin on the scalp that is present at birth. Ears are small and folded over and underdeveloped or no nipples are present. Other symptoms include brittle nails, dental issues, kidney problems and specific facial features such as a flat bridge of the nose and narrowed openings of the eyes.

Cutis marmorata telangiectatica congenita (CMTC) is a rare congenital condition associated with discolored patches of skin caused by widened surface blood vessels. Other symptoms can include skin abnormalities such as areas of absent skin; pink or dark red, irregularly shaped patches of skin; loss of muscle tissue on one side of the body; elevated fluid pressure within the eye; and undergrowth of one leg. CMTC occurs randomly for no apparent reason. It is thought that CMTC represents a form of genetic mosaicism, meaning that some cells have a gene variant and other cells do not.

Poland syndrome is a rare condition that is seen at birth. Associated features may be extremely variable from person to person. It is classically characterized by absence of chest wall muscles on one side of the body and abnormally short, webbed fingers of the hand on the same side. Other symptoms include the underdevelopment or absence of one breast/nipple; skeletal-related issues that can affect the ribs, shoulders and arms; and rarely, issues with the internal organs being located on the incorrect side of the chest.

Aplasia cutis congenita is a rare condition with a complicated pattern of inheritance. Babies are born with the absence of certain layers of skin, most often on the scalp, but also on the trunk and/or arms and legs. The affected area is typically covered with a thin, transparent membrane. The skull and/or underlying areas may be visible and incorrectly developed. Aplasia cutis congenita may be the primary disorder, or it may occur in association with other underlying disorders such as AOS.

There are other conditions (e.g., focal dermal hypoplasia, trisomy 13 syndrome, Johanson-Blizzard syndrome, etc.) that may have symptoms of scalp and skull issues that occur in association with changes of the hands and feet. These disorders usually have other physical features that may differentiate them from Adams-Oliver syndrome.

Diagnosis

Adams-Oliver syndrome (AOS) is diagnosed based on clinical and/or genetic criteria. Clinically, the diagnosis can be made when a person presents with at least two of the following major features: terminal transverse limb defects, aplasia cutis congenita (ACC), or a first-degree relative with confirmed AOS. Alternatively, a diagnosis can be made when one major feature is present along with one or more minor features, which include cutis marmorata, congenital heart defects and vascular abnormalities.

AOS may also be confirmed when an individual has one of the major features (ACC or limb defects) and a known pathogenic variant in one of the genes associated with AOS.

Standard Therapies

Treatment

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 people, 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.

Many hospitals recommend a conservative (non-surgical) approach for treating scalp ACC. This involves keeping the area clean, applying medical dressings and using antibiotics (creams or medicines) if there’s a risk of infection. Different types of dressings may be used. If the deeper protective layer of the brain (the dura) is exposed, the area must be kept moist, clean and covered at all times to prevent scab formation, which can delay healing or lead to complications.

In people who have larger wounds (more than 5 cm across) or if there is a missing piece of skull bone, doctors may recommend surgery. Surgical options include scalp flaps (moving nearby skin to cover the defect), skin grafts and bone grafts to rebuild the skull. These techniques have been successful and carry a low risk of complications. Other advanced surgical options such as using donor skin, engineered skin substitutes, or lab-grown skin grafts, have also been used with excellent results.

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.

Type of Doctor Department : A Clinical Geneticist and a Pediatrician