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]

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 44 per 10 million. 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 according to American College of Medical Genetics (ACMG) guidelines into five subtypes/ groups:

• 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

• The majority of patients with Adams-Oliver Syndrome remain asymptomatic for [duration/years].
• Early clinical features include [manifestation 1], [manifestation 2], and [manifestation 3].
• If left untreated, [#%] of patients with Adams-Oliver Syndrome may progress to develop [manifestation 1], [manifestation 2], and [manifestation 3].
• Common complications of [disease name] include [complication 1], [complication 2], and [complication 3].
• Prognosis is generally [excellent/good/poor], and the [1/5/10­year mortality/survival rate] of patients with [disease name] is approximately [#%].

Diagnosis

Diagnostic Criteria

• The diagnosis of Adams-Oliver Syndrome 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

• Adams-Oliver Syndrome 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

There are no ECG findings associated with AOS.

X-ray

There are no x-ray findings associated with [disease name].

OR

An x-ray may be helpful in the diagnosis of [disease name]. Findings on an x-ray suggestive of/diagnostic of Adams-Oliver Syndrome include [finding 1], [finding 2], and [finding 3].

OR

There are no x-ray findings associated with Adams-Oliver Syndrome. However, an x-ray may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3].

Echocardiography

Echocardiography/ultrasound may be helpful in the diagnosis of Adams-Oliver Syndrome. Findings on an echocardiography/ultrasound suggestive of/diagnostic of Adams-Oliver Syndrome include [[[ventricular septal defect]] (VSD), patent ductus arterioles, and systolic pulmonary artery pressure .

CT scan

There are no CT scan findings associated with AOS.

Magenetic Resonance Imaging (MRI)

MRI of the brain may be helpful in the diagnosis of Adams-Oliver Syndrome. Findings on MRI suggestive of/diagnostic of Adams-Oliver Syndrome include increased head circumference, and alterations in the cerebral ventricles and meninges .

Other Imaging Findings

There are no other imaging findings associated with AOS.

Other Diagnostic Studies

There are no other diagnostic studies associated with AOS.

Treatment

Medical Therapy

• There is no treatment for Adams-Oliver Syndrome; the mainstay of therapy is supportive care.

• The mainstay of therapy for Adams-Oliver Syndrome is [medical therapy 1] and [medical therapy 2].
• [Medical therapy 1] acts by [mechanism of action 1].
• Response to [medical therapy 1] can be monitored with [test/physical finding/imaging] every [frequency/duration].

Surgery

• Surgery is the mainstay of therapy for Adams-Oliver Syndrome.
• [Surgical procedure] in conjunction with [chemotherapy/radiation] is the most common approach to the treatment of [disease name].
• [Surgical procedure] can only be performed for patients with [disease stage] [disease name].

Prevention

• There are no primary preventive measures available for [disease name].

• Effective measures for the primary prevention of [disease name] include [measure1], [measure2], and [measure3].

• Once diagnosed and successfully treated, patients with [disease name] are followed-up every [duration]. Follow-up testing includes [test 1], [test 2], and [test 3].