Dermatology

Adams-Oliver syndrome

Adams-Oliver Syndrome (AOS) 757.39 (congenital skin anomaly)

Are You Confident of the Diagnosis?

Adams-Oliver syndrome (AOS) is a rare congenital disorder characterized by aplasia cutis congenita (ACC) of the vertex scalp, limb defects, and cutis marmorata telangiectatica congenita (CMTC) (Figure 1 , Figure 2 , Figure 3 , Figure 4 ). It was first described by Adams and Oliver in 1945.

Figure 1.

Newborn female with AOS and cutis marmorata. (Courtesy of Rhonda Schnur, MD)

Figure 2.

Same infant with AOS and cutis marmorata. (Courtesy of Rhonda Schnur, MD)

Figure 3.

Same patient at age 8 years showing healed ACC. (Courtesy of Rhonda Schnur, MD)

Figure 4.

Same patient at age 8 years showing brachydactyly and nail changes. Courtesy of Dr. Rhonda Schnur.

  • Characteristic findings on physical examination

Any child with ACC of the scalp should be examined for limb defects, which occur in 84% of patients with AOS. However, it is important to keep in mind that the limb defects can be subtle, including something as minor as an absent nail or broad fingertip. More pronounced limb defects include brachydactyly, syndactyly, loss of terminal phalanges, or complete absence of a finger, toe, hand, foot, arm, or leg. Interdigital webs have also been reported in some cases of AOS.

The limb defects are usually asymmetric with involvement of the lower limbs more commonly than the upper limbs. Brachydactyly (shortening of the fingers or toes) is the most common limb defect in AOS.

Not all patients with AOS have ACC of the scalp, but it is present approximately 75% of the time. The scalp defects can be mild or severe, in some cases even having underlying skull thinning or complete absence of the calvarium. An important finding is the presence of dilated, tortuous scalp veins. Ultrasound is helpful in evaluating the extent of skull involvement. In 64% of AOS patients with ACC, an underlying skull defect is found. Skull defects may also occur, less commonly, without overlying ACC.

The rate of CMTC is also significant, as it is found in nearly a fifth of all AOS patients. Among the organ systems affected, cardiac malformations are found in approximately 23% of patients as well.

  • Diagnostic confirmation

When both ACC and terminal transverse limb defects (TTLD) are present, a diagnosis of AOS can confidently be made. If either ACC or TTLD are present alone, diagnosis can still be made if a first-degree relative has a clinical picture consistent with AOS. Lastly, a formal diagnosis can be made if ACC or TTLD are present with an established genetic mutation known to cause AOS. Evaluation of the cardiovascular, central nervous, gastrointestinal, and genitourinary systems should then be performed.

Histopathology of an ACC lesion or healed scar will show loss of rete ridges, collagen deposition and loss of skin appendages.

Limb reductions have varied etiologies and are heterogeneous in their presentation. Molecular karyotyping is available to elucidate which genetic mutations are responsible for the malformations.

Who is at Risk for Developing Adams-Oliver syndrome?

AOS is thought to have an autosomal dominant mode of inheritance with variable expression, but sporadic and autosomal recessive cases have been described as well. The sporadic cases may appear sporadic due to incomplete penetrance.

Ultrasound detection of a limb defect around 16 weeks gestation has been proposed as a mechanism for prenatal diagnosis when a family history of AOS is present.

What is the Cause of the Adams-Oliver syndrome?

  • Pathophysiology

Many genes have been implicated in the development of AOS. A truncating mutation in the ARHGAP31 gene, which encodes a GTPase activating protein responsible for protein trafficking and cell growth, is thought to be behind the autosomal dominant form. Other genes implicated in this form are DLL4, NOTCH1, and RBPJ. Despite the inheritance pattern, intrafamilial variation in presentation is significant.

The autosomal recessive disease is caused by a mutation in DOCK6, a gene involved in actin cytoskeleton organization. Both mutations result in aberrant morphogenesis and cell spreading.

The genes resulting in AOS have varying individual risks. Of note, those with the ARHGAP31 are shown to have less neurologic involvement, while those with RBPJ have shown a high incidence of intellectual impairment. Mutations NOTCH1 and DLL4 are particularly associated with cardiovascular complications.

Other proposed mechanisms include vascular impairment in utero. Cranial vertex and limb abnormalities support the hypothesis of impaired circulation in watershed areas during development. Additional support for in utero vascular thrombotic accidents includes reports of AOS with dilated scalp veins, constriction rings, pulmonary hypertension, periventricular leukomalacia, and retinal folds.

Another proposed etiology of AOS includes abnormal pericyte recruitment, supported by a mouse model in which ALK1-deficient mice show poor migration, recruitment, and proliferation of pericytes. The pericyte is essential for the development of small vessels. Altered pericytes could lead to impaired blood to the skin, underlying skull, heart, and distal extremities.

Further theories have included impairment of intrauterine vascular development, adherence to fetal membranes, intrauterine trauma or compression, intrauterine herpetic infection, or drug exposure.

Systemic Implications and Complications

Other defects associated with AOS include CMTC (up to 25% of AOS patients), central nervous system (CNS) and cardiovascular abnormalities, accessory nipples, and cleft lip. Other reported anomalies include growth retardation, ACC of the knee, short palpebral fissures, dilated scalp veins, skin tags, hemangioma, undescended testes, wooly hair, microphthalmia, and hypoplastic optic nerve.

When present, CNS involvement may include spasticity, diffuse slow EEG activity, cerebral calcification, polymicrogyria, microcephaly, epilepsy, mental retardation, arrhinencephaly, hydrocephaly, and Dandy Walker malformation.

Congenital heart defects have been reported in approximately 20% of AOS patients. Findings may include membranous subaortic stenosis, aortic stenosis, hypoplastic aortic arch, parachute mitral valve, ventricular septal defect, atrial septal defect, tetralogy of Fallot, coarctation of the aorta, bicuspid aortic valve, pulmonic stenosis, double outlet right ventricle, and pulmonary hypertension.

Treatment Options

Treatment of AOS is mainly non-operative. ACC of the scalp should be allowed to heal in by secondary intention. As the child’s hair grows, the ACC scar can be concealed. In larger cases of ACC, surgery may be performed to remove the scar when the child is older. If an underlying skull defect, is present then a bone graft may be necessary. If the dura is exposed, it should be covered with full-thickness skin flaps or moist dressings to prevent eschar formation, as they carry high risk of infection and life-threatening hemorrhage. CMTC may fade within the first year of life as skin naturally develops and thickens. When limb abnormalities are mild, often no treatment is needed. When more severe, consultation with an orthopedic surgeon may be helpful. Occupational and/or physical therapy may assist with functionality of affected limbs. Obviously, if heart or CNS abnormalities are present then referral to the appropriate specialist is important.

Appropriate maintenance includes an echocardiogram every three years, an ocular exam by a pediatric ophthalmologist till the age of three, and ongoing neurologic assessment for psychomotor development.

Optimal Therapeutic Approach for Adams-Oliver syndrome

Therapeutic approach depends on severity. Mild scalp and limb defects require no intervention, whereas more severe defects may require surgery. Likewise, investigation for other AOS-associated anomalies should be pursued and treated when needed.

Patient Management

Once a diagnosis of AOS has been made, evaluation for cardiac and CNS abnormalities should be investigated. Mild cases of ACC and limb defects do not require ongoing treatment. If present, CNS or cardiac anomalies may necessitate ongoing care. Genetic counseling should be provided for families.

Unusual Clinical Scenarios to Consider in Patient Management

All infants born with ACC of the scalp should be evaluated for limb defects. As mentioned earlier, the limb defects may be mild with brachydactyly being the most common limb association. There are probably many infants with AOS who are simply diagnosed as having isolated scalp ACC.

A patient known to have the autosomal recessive form of the disease may have a poorer prognosis, as it is associated with structural brain malformations, ocular abnormalities, and intellectual disability.

What is the Evidence?

Seo, JK, Kang, JH, Lee, HJ, Lee, D, Sung, HS, Hwang, SW. "A case of Adams-Oliver syndrome". Ann Dermatol. vol. 22. 2010. pp. 96-8.

(This interesting case report reminds us that a diagnosis of AOS may be missed during infancy if clinicians do not recognize associated features. The authors report a case of a man in which a diagnosis of AOS was not made until age 21 years.)

Baskar, S, Kulkarni, ML, Kulkarni, AM, Vittalrao, S, Kulkarni, PM. "Adams-Oliver syndrome: Additions to the clinical features and possible role of BMP pathway". Am J Med Genet A. vol. 149A. 2009. pp. 1678-84.

(The authors present a case of AOS in which the only limb abnormalities include a delayed bone age and broad finger tip. They also explore different theories for the pathogenesis of AOS, including a possible bone morphogenetic protein pathway.)

Narang, T, Kanwar, AJ, Dogra, S. "Adams-Oliver syndrome: a sporadic occurrence with minimal disease expression". Pediatr Dermatol. vol. 25. 2008. pp. 115-6.

(The authors report an interesting case of AOS in which only a small erosion on the scalp had been present at birth, along with absence of two distal phalanges of the left hand.)

Anandan, V, Parveen, B, Prabhavathy, D, Priyavarthini, V. "Adams Oliver syndrome--a variant". Int J Dermatol. vol. 47. 2008. pp. 1260-2.

(The authors present a case of AOS with multiple skin anomalies, cardiac disease, and Dandy Walker malformation.)

Dadzie, OE, Tyszczuk, L, Holder, SE, Teixeira, F, Charakida, A, Scarisbrick, J. "Adams-Oliver syndrome with widespread CMTC and fatal pulmonary vascular disease". Pediatr Dermatol. vol. 24. 2007. pp. 651-3.

(The authors present a case of CMTC with AOS and provide a nice review of this association.)

Heras Mulero, C, Bartralot Soler, R, Rodríguez-Cano, L, Mollet Sánchez, J, Palacio Aller, L, Aparicio Español, G. "Aplasia cutis associated with coarctation of the aorta: could this be an incomplete form of Adams-Oliver syndrome". Br J Dermatol. vol. 157. 2007. pp. 836-7.

(The authors present a case of AOS and provide a nice discussion of different theories regarding the pathogenesis of AOS.)

Rajabian, MH, Aghaei, S. "Adams-Oliver syndrome and isolated aplasia cutis congenita in two siblings". Dermatol Online J. vol. 12. 2006. pp. 17.

(The authors present a case report of AOS involving siblings along with a nice discussion of AOS.)

Sankhyan, N, Kaushal, RK, Jaswal, RS. "Adams-Oliver syndrome: a case with complete expression". J Dermatol. vol. 33. 2006. pp. 435-6.

(The authors provide a good overview of AOS.)

Lin, AE, Westgate, MN, van der Velde, ME, Lacro, RV, Holmes, LB. "Adams-Oliver syndrome associated with cardiovascular malformations". Clin Dysmorphol. vol. 7. 1998. pp. 235-41.

(This manuscript reviews the cardiac abnormalities associated with AOS.)

Romaní, J, Puig, L, Aznar, G, Demestre, X, Altirriba, O, Alomar, A. "Adams-Oliver syndrome with unusual central nervous system alterations". Pediatr Dermatol. vol. 15. 1998 Jan-Feb. pp. 48-50.

(This report outlines the various CNS abnormalities seen in AOS.)

Cordisco, M, Bernhard, JD, Burkhart, CN, Morrell, D. "Adams-Oliver Syndrome". Visual Dx . N.p.. 1 Jan. 2016.

(The authors outline the genetic pathogenesis of AOS, as well as different treatment modalities.)

Shamseldin, HE, Anazi, S, Wakil, SM, Faqeih, E. "Novel Copy Number Variants and Major Limb Reduction Malformation: Report of Three Cases". Am. J. Med. Genet. American Journal of Medical Genetics Part A. vol. 170.5. pp. 1245-250.

(This article describes molecular karyotyping in pediatric malformation syndromes.)

Lehman, A, Wuyts, W, Patel, MS, Pagon, RA, Adam, MP, Ardinger, HH. "Adams-Oliver Syndrome". GeneReviews® [Internet]. University of Washington, Seattle. 2016 Apr 14. pp. 1993-2016.

(This chapter provides a thorough overview of AOS and genetic pathophysiology.)(Based on recent genetic analysis, Adams-Oliver syndrome appears to be a multigene and multipathway disorder. There are 6 variants of Adams Oliver syndrome as summarized in the OMIM (Online Mendelian Inheritance in Man) database (omim.org). The autosomal dominant forms include type 1 caused by mutations in ARHGAP31 gene on chromosome 3q13; type 3 caused by mutation in the RBPJ gene on chromosome 4p15; type 5 caused by mutation in the NOTCH1 gene on chromosome 9q34; and type 6 caused by mutation in the DLL4 gene on chromosome 5q32. The autosomal recessive variants include type 2 caused by mutation in the DOCK6 gene on chromosome 19p13.2, and type 4 caused by mutation in the EOGT gene on chromosome 3p14.)

Southgate, L, Machado, RD, Snape, KM. "Gain-of-function mutations of ARHGAP31, a Cdc42/Rac1 GTPase regulator, cause syndromic cutis aplasia and limb anomalies". Am. J. Hum. Genet. vol. 88. 2011. pp. 574-585.

(Adams-Oliver syndrome type 1 characteristics and gene identification.)

Sukalo, M, Tilsen, F, Kayserili, H. "DOCK6 Mutations Are Responsible for a Distinct Autosomal-Recessive Variant of Adams-Oliver Syndrome Associated with Brain and Eye Anomalies". Hum Mutat. vol. 36. 2015 Nov. pp. 1112.

(Adams-Oliver syndrome type 2 characteristics and gene identification.)

Hassed, SJ, Wiley, GB, Wang, S, Lee, JY. "RBPJ mutations identified in two families affected by Adams-Oliver syndrome". Am J Hum Genet. vol. 91. 2012. pp. 391-5.

(Adams-Oliver syndrome type 3 gene identification. RBPJ is a nuclear protein involved in Notch signaling.)

Shaheen, R, Aglan, M, Keppler-Noreuil, K, Faqeih, E. "Mutations in EOGT confirm the genetic heterogeneity of autosomal-recessive Adams Oliver syndrome". Am. J. Hum. Genet. vol. 92. 2013. pp. 598-604.

(Adams-Oliver syndrome type 4 characteristics and gene identification.)

Stittrich, AB, Lehman, A, Bodian, DL, Ashworth, J. "Mutations in NOTCH1 cause Adams-Oliver syndrome". Am J Hum Genet. vol. 95. 2014. pp. 275-84.

(Adams-Oliver syndrome type 5 characteristic and gene identification.)

Meester, JA, Southgate, L, Stittrich, AB. "Heterozygous Loss-of-Function Mutations in DLL4 Cause Adams-Oliver Syndrome". Am J Hum Genet. vol. 97. 2015 Sep 3. pp. 475-82.

(Adams-Oliver syndrome type 6 identification and characteristics. Of note, DLL4 is involved in NOTCH1 signaling.)
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