Introduction
Adams-Oliver syndrome is an uncommon disorder marked by various limb deformities and abnormal skin growth, especially on the scalp. Other names for Adams-Oliver syndrome include:
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Absence defect of limbs, scalp, and skull.
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AOS.
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Aplasia cutis congenita with terminal transverse limb defects.
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Congenital scalp defects with distal limb reduction anomalies.
What Are the Causes of Adams Oliver Syndrome?
Mutations can cause Adams-Oliver syndrome in the genes ARHGAP31, DLL4, DOCK6, EOGT, NOTCH1, or RBPJ. Additional genes that have not been discovered may also be implicated in this disorder, given that some affected people do not have mutations in any of these genes. An alteration in any known genes can affect the closely regulated process of embryonic development, resulting in the symptoms and signs of Adams-Oliver syndrome.
What Is the Pathophysiology of Adams Oliver Syndrome?
The pathophysiology of Adams-Oliver syndrome is
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Both the proteins made by the DOCK6 and ARHGAP31 genes are involved in controlling GTPases, which send signals vital to numerous stages of embryonic development. The proteins DOCK6 and ARHGAP31 seem crucial for GTPase regulation throughout the heart, skull, and limb development. GTPases are frequently referred to as molecular switches since they have an on or off switch. They are activated by the DOCK6 protein and turned off by the ARHGAP31 protein. Mutations in the DOCK6 gene result in a DOCK6 protein that is abnormally short and likely unable to activate GTPases, which lowers their activity. Additionally, GTPase activity is decreased by mutations in the ARHGAP31 gene, creating an unusually active ARHGAP31 protein that inhibits GTPases when it should not. The skin issues, bone abnormalities, and other characteristics of Adams-Oliver syndrome are caused by this reduction in GTPase activity.
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The NOTCH1 gene, DLL4 gene, and RBPJ gene all create proteins that are a component of the Notch pathway, a signaling pathway. Notch signaling regulates the growth of specific cell types, including those that produce the developing embryo's bones, heart, muscles, nerves, and blood arteries. The Notch pathway, which is crucial for the development of blood vessels, is stimulated by the Notch1 and DLL4 proteins working together like a lock and its key. Adams-Oliver syndrome is caused by mutations in the NOTCH1 and DLL4 genes, which are thought to impair Notch1 signaling and may contribute to blood vessel and heart abnormalities in specific affected individuals. According to researchers, the other characteristics of the illness may be brought on by improper blood vessel formation before birth.
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The RBP-J protein, made from the RBPJ gene, is stimulated by signaling through Notch1 and other Notch proteins to connect (bind) to particular sections of DNA and regulate the activity of genes involved in cellular development in various tissues throughout the body. Adams-Oliver syndrome is caused by mutations in the RBPJ gene that change the area of the RBP-J protein that usually binds DNA. The altered protein cannot attach to DNA, which prevents it from activating specific genes. Adams-Oliver syndrome is characterized by alterations in gene activity that contain the appropriate growth of the skin, bones, and other tissues.
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It is unclear how EOGT gene mutations cause Adams-Oliver syndrome. This gene produces a protein that adds a chemical called N-acetylglucosamine to other proteins, modifying those other proteins. The EOGT protein is thought to alter Notch proteins, stimulating the Notch signaling pathway. Uncertainty exists over how the alteration will affect Notch signaling. Adams-Oliver syndrome patients have at least three EOGT gene mutations, yet it is unclear how the genetic alterations affect the disorder's signs and symptoms.
What Are the Clinical Signs of Adams Oliver Syndrome?
Adams-Oliver syndrome's main characteristics include the following:
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Aplasia Cutis Congenita (ACC) - This defines small, scarred, hairless lesions on the scalp that are missing skin; these lesions can get infectious, and there may be an underlying bone abnormality.
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Terminal Transverse Limb Defects (TTLD) -This can involve anomalies of the nails, the fusion (syndactyly) or shortening of digits (brachydactyly), or the absence of digits (oligodactyly).
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Cutis Marmorata Telangiectasia Congenita - It is identified by a net-like pattern of red or purple on the skin and is caused by irregularities in the blood vessels.
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Renal Features - Small kidneys, hydronephrosis (one or both kidneys swell and stretch due to an accumulation of urine inside them), or renal cortical vascular anomalies.
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Eye Abnormalities - Microphthalmus (abnormally small eye), cataract, optic nerve hypoplasia, retinal detachment, or retinal hemorrhage leading to visual impairment.
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Cardiovascular Involvement - Congenital cardiac malformations, pulmonary hypertension (high blood pressure in the blood vessel supplying the lungs), heart abnormalities, dilated and tortuous scalp, and placental blood vessels.
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Neurologic Findings - Rare; some clinical findings reported are autism spectrum disorder, dyslexia (learning disorder), cognitive disability, seizures, and spastic diplegia (stiffness of muscles of lower extremities).
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Other Features - Developmental retardation, cleft lip or palate, supernumerary nipples, umbilical hernia, and cryptorchidism (a testicle that has not descended into the correct place in the pouch of skin hanging below the penis (scrotum) before birth).
What Is the Inheritance Pattern of Adams Oliver Syndrome?
There are numerous possible inheritance patterns for Adams-Oliver syndrome.
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Autosomal Dominant Pattern - The syndrome is inherited in an autosomal dominant manner when mutations bring it on in the genes for ARHGAP31, DLL4, NOTCH1, or RBPJ. According to the theory of autosomal dominant inheritance, one mutated gene copy in each cell is sufficient to induce the condition. Usually, the diseased parent passes on the changed gene to their offspring. Some NOTCH1 gene mutation-related cases result from new (de novo) mutations in the gene that happens during the production of reproductive cells (eggs or sperm) or in the early stages of embryonic development. People in these circumstances do not have a family history of the condition.
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Autosomal Recessive Pattern - Adams-Oliver syndrome is inherited in an autosomal recessive form when mutations bring it on in the DOCK6 or EOGT gene. Each cell's gene copies are mutated in diseases with this inheritance pattern. Each parent of a person with an autosomal recessive disorder carries one copy of the defective gene, although usually, neither parent exhibits the disease's signs and symptoms.
How Is Adams Oliver Syndrome Diagnosed?
One of the following can be used to confirm an AOS diagnosis in a genetic marker:
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Clinical results of scalp ACC and TTLD.
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A first-degree relative - having data compatible with AOS and ACC or TTLD.
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ACC or TTLD, two pathogenic variations in an autosomal recessive AOS-related gene, or one pathogenic variant in an autosomal dominant AOS-related gene (ARHGAP31, DLL4, NOTCH1, or RBPJ) (DOCK6 or EOGT).
How Is Adams Oliver Syndrome Treated?
Adams-Oliver syndrome has no known treatment; instead, efforts are made to reduce symptoms.
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Skin grafting, cranial surgery, and various procedures to treat skin lesions and deformities of the skull
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For limb abnormalities, physical therapy, surgery, and the usage of prosthetics are used.
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Lifestyle changes, such as wearing helmets while performing sports to protect the skull.
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Regular medical examinations.
Conclusion
In conclusion, Adams Oliver Syndrome (AOS) is a rare genetic disorder characterized by scalp defects and limb abnormalities. It is caused by mutations in certain genes involved in embryonic development. The syndrome presents with a wide range of symptoms and severity, including aplasia cutis congenita, vascular anomalies, and limb abnormalities. Diagnosis is typically made based on clinical examination and genetic testing. Treatment is focused on managing the specific symptoms and may involve surgical interventions for scalp defects or vascular anomalies. Although AOS is a complex condition, ongoing research and advancements in genetic testing have improved our understanding of the syndrome and may lead to more targeted therapies in the future.
