Adams–Oliver syndrome

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor-in-Chief: Edzel Lorraine Co, DMD, MD[2]

Synonyms and keywords: AOS, congenital scalp defects with distal limb anomalies

Overview

Adams-Oliver syndrome (AOS) is an autosomal dominant disorder which involves the mutation of six genes, namely the ARHGAP31, DLL4, DOCK6, EOGT, NOTCH1, and RBPJ genes. This disorder has an incidence of 1 in 225,000 births. Patients who have this condition typically present with some cardiovascular defects, terminal transverse limb defects (TTLD), neurologic findings, growth deficiency, accessory nipples, cryptorchidism, renal abnormalities, aplasia cutis congenita (ACC), and Poland sequence.

Historical Perspective

• Adams-Oliver syndrome was first described by American pediatric cardiologist Forrest H. Adams and Charles P. Oliver, a clinical geneticist, in 1945 after they had identified presence of terminal transverse defects of the limbs and aplasia cutis congenita of scalp in eight members of a three-generation family .
• This condition is associated with genetic mutations in DLL4, ARHGAP31, NOTCH1 and RBPJ leading to an autosomal dominant with variable penetrance expression, and EOGT and DOCK6 mutations causing autosomal recessive expression .
• Congenital vasculopathy is believed to be the underlying mechanism in the pathogenesisof AOS .

Classification

• Adams-Oliver syndrome may be classified into five groups according to American College of Medical Genetics (ACMG) guidelines:

• Pathogenic
• Likely pathogenic
• Uncertain significance
• Likely benign
• Benign .

• AOS can also be classified into six types according to location of mutation and mode of inheritance. These are:

Table 1.Classification of Adams-Oliver syndrome. .

Type	Inheritance	Location
Adams-Oliver syndrome 1	Autosomal dominant	3q13.32-q13.33
Adams-Oliver syndrome 2	Autosomal recessive	19p13.2
Adams-Oliver syndrome 3	Autosomal dominant	4p15.2
Adams-Oliver syndrome 4	Autosomal recessive	3p14.1
Adams-Oliver syndrome 5	Autosomal dominant	9q34.3
Adams-Oliver syndrome 1	Autosomal dominant	15q15.1

Pathophysiology

• The pathogenesis of Adams-Oliver syndrome still remains unidentified.
• However, several mechanisms of this disease have been proposed, which includes:
  • Compromise of the vasculature such as congenital, developmental defects, pericyte recruitment to vessel abnormalities, or blood supply interruption in the early embryonic stages
  • Genetic factors
  • Trauma
  • Teratogens (carbimazole, misoprostol, valproic acid, and methimazole .

Causes

• AOS is believed to be caused by genetic mutations with symptoms vary depending on the involved gene.

Differentiating Adams-Oliver syndrome from other Diseases

• Adams-Oliver syndrome must be differentiated from other diseases that cause syndromic aplasia cutis congenita, and terminal transverse limb defect, such as:

• Scalp-ear nipple syndrome (SEN)
• Focal dermal hypoplasia (Goltz syndrome)
• Dominant dystrophic epidermolysis bullosa (DDEB)
• Congenital dyserythropoeitic anemia type I

Epidemiology and Demographics

• This disorder has an incidence of 1 in 225,000 births.

Age

• AOS is already present at birth .

Gender

• AOS affects men and women equally ..

Race

• There is no racial predilection for AOS .

Risk Factors

• Risk factors associated in the development of AOS include having a family history of AOS and being born to parents with consanguineous marriage .

Natural History, Complications and Prognosis

• Early clinical features include congenital scalp defects and terminal transverse limb defect.
• If left untreated, patients with AOS may progress to develop some complications which include facial meningitis, hemorrhage, thrombosis, and cerebrospinal fluid (CSF) leak.
• If left untreated, it may lead to a long-term disability.
• Prognosis is generally excellent and can have a normal life span if no major organs are involved .

Diagnosis

Diagnostic Criteria

• The diagnosis of AOS is made when at least one of the following diagnostic criteria are met in a proband:

• Present of TTLD and ACC of the scalp
• TTLD or ACC and a first-degree relative manifesting with similar conditions suggestive of AOS
• TTLD or ACC and the presence of either one pathogenic variant in the autosomal dominant AOS-associated gene (DLL4, ARHGAP31, RBPJ, or NOTCH1), or two pathogenic variants in the autosomal recessive AOS-associated gene (EOGT or DOCK6)

History and Symptoms

• AOS is usually asymptomatic.

Physical Examination

• Patients with AOS may be remarkable for:

• Congenital scalp defects
• Increased head circumference
• Hyperpigmentation of the skin
• Telangiectatic lesions
• Facial asymmetry
• Congenital structural eye defects
• Cleft lip/ palate
• Deep philtrum
• Teeth crowding
• Deviated jaw
• Retrognathia
• Hypoplasia of the distal extremities
• Polydactyly
• Syndactyly
• Congenital hip dislocation
• Cardiac and vascular abnormalities
• Supernumerary nipples
• Hydronephrosis
• Cryptorchidism
• Intellectual disability
• Neurologic abnormalities

Laboratory Findings

• There are no specific laboratory findings associated with AOS.

Electrocardiogram (ECG)

• There are no ECG findings associated with AOS.

X-ray

• An x-ray may be helpful in the diagnosis of AOS. Findings on an X-ray suggestive of AOS include skull defects , and shortening of distal phalanges of fingers .

Echocardiography

• Echocardiography may be helpful in the diagnosis of AOS. Findings suggestive of AOS include ventricular septal defect (VSD), tetralogy of Fallot patent ductus arteriosus, and systolic pulmonary artery pressure .

Computed Tomography Scan (CT scan)

• A cranial CT scan may be helpful in the diagnosis of AOS. Findings on a CT scan suggestive of AOS include asymmetrical skull defects in the parietal bones with open fontanelles and ragged margins .

Magenetic Resonance Imaging (MRI)

• MRI of the brain may be helpful in the diagnosis of AOS. Findings on MRI suggestive of AOS include increased head circumference, and alterations in the cerebral ventricles and meninges .

Other Imaging Findings

• Abdominal ultrasound may be helpful in the diagnosis of AOS. Findings on an abdominal ultrasound suggestive of AOS include bowel malformations.

• Ocular examination may be helpful in the diagnosis of AOS. Findings suggestive of AOS include esotropia, macular involvement caused by bilateral falciform retinal folds, and bilateral retinal detachment .

Other Diagnostic Studies

• There are no other diagnostic studies associated with AOS.

Treatment

Medical Therapy

• Symptomatic and supportive treatment is the mainstay of therapy for AOS.
• Coordinated efforts among various specialists (cardiologist, ophthalmologist, pediatrician, orthopedic surgeon, plastic surgeon, physical therapist, and other medical allies) are needed .

Surgery

• Skin grafting, and skull surgery may be needed in patients with AOS who have skeletal problems.
• Cardiovascular surgery may be needed in patients with AOS who have cardiovascular anomalies.

Prevention

• Effective measures for the primary prevention of AOS include annual monitoring of symptoms in infants manifesting with the condition.
• Annual echocardiography should be done annually until three years old for signs of pulmonary hypertension.
• Genetic counseling is needed for individuals and families affected with AOS.