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Research

Reseach Overview

The clinical features of AOS are highly variable, and each AOS individual has different conditions to be addressed. Many AOS studies focus on two or three individual patients who share some common features and try to identify the pathology underlying a subset of AOS. There is no recognized pathophysiological mechanism for AOS, but vascular disruption has been proposed as a possible origin [1]. Because AOS is a polymalformation syndrome, different mechanisms may be identified in other subsets of AOS.
Recent studies have identified causative changes in genes and the related disruption of cytoskeleton in AOS patients [2,3].

Vasculopathy?

Different origins of vascular abnormalities, such as a problem of blood clotting and underdevelopment of arteries, have been thought to cause AOS.

The role of early embryonic vascular disruption is supported by the occurrence of different clinical features: cutis marmorata telangiectatica congenita (CMTC), pulmonary vascular abnormalities and hepatoportal vascular abnormalities [4].

A 2004 study has proposed that an abnormality of pericyte, which is defined as vascular wall cell, is the cause of vasculopathy in AOS [1]. Experimental evidence showed that pericytes had an important role in maintenance of the cardiovascular system. The autopsy of one patient showed that there were fewer than normal pericytes covering multiple vessels, leading to vessel dilation in lungs, skin, mesentery etc. The researchers proposed that a secondary phenomenon of increased rate of cell division in other vessels leads to stenosis and accounts for most pathology in AOS, including pulmonary hypertension. Sites most often affected in AOS were furthest away from the birth place of pericytes, so a defect in pericyte migration likely caused the problem [1].

Some Symptoms Related to Vasculopathy

Pulmonary hypertension (PH) was reported in two unrelated patients in a 2004 study and ultimately led to their death [1]. PH was not frequently observed in AOS, and all reported AOS patients with PH also had CMTC, which affected about 20% of AOS patients. Therefore, the researchers suggested that echocardiographic follow up should be performed for the CMTC subset AOS patients [1].

A 2005 study found pulmonary arteriovenous malformation (PAVM) in two AOS patient coming from the same family. This finding suggested that vascular defect underlies AOS and that screening for PAVMs should be done in AOS patients for early intervention for potential complications. However, further studies need to be done in order to establish a clear relationship between PAVM and AOS [5].

In a different study, neurological abnormalities were found together with other AOS features, including pulmonary hypertension. Researchers suspected that the neurological problem was caused by reduced blood flow, which was due to abnormality of blood vessels. Therefore, the researchers suggested pulmonary hypertension evaluation and central nervous system imaging in suspected patients, because such examinations could lead to early intervention for developmental delay [6].

An association of AOS and hepatoportal sclerosis was reported in three unrelated children by 2 different studies. Hepatoportal sclerosis in AOS patients was not always associated with obstruction of portal veins, and a vascular thrombotic mechanism is suggested to be responsible for both AOS and hepatoportal sclerosis. Portal hypertension could appear during the first years of life, so liver ultrasonography and careful clinical examination should be performed in AOS patients [7].

Disruption of Actin Cytoskeleton Organization and the Genes

Cytoskeleton is made up of different types of proteins and is the overall scaffold of the cells. It is responsible for cell division and movement and thus important for organ formation. Actin cytoskeleton is a subset of the overall cytoskeleton. A group of proteins, the Rho family of GTPases (including Cdc42 and Rac1), is a part of a control mechanism for actin cytoskeleton. The Rho family of GTPases are in turn regulated by other groups of proteins, including ARHGAP31 and DOCK6 [3].

A 2011 study identifies an ARHGAP31 mutation as the cause of autosomal dominant AOS [2]. The mutation makes ARHGAP31 proteins more active, disrupting the cytoskeletal structure through the inappropriate interaction with Cdc42/Rac1. Study of ARHGAP31 in mouse model, however, shows that this mutation cannot explain the occurrence of congenital cardiac abnormalities in some AOS individuals [2]. Future study may identify other mutations for AOS with different clinical features.

Researchers in a later study identify a DOCK6 gene mutation in one patient and confirm the finding in a second patient. Interestingly, DOCK6 protein also regulates Cdc42 and Rac1 [3].

These two studies suggest that inactivation of Cdc42 and Rac1 is a common pathway that lead to abnormal actin cytoskeleton organization. Further studies should be done to examine other regulators of proteins in the Rho family of GTPases [3]. Studies to identify gene mutations can help us better categorize AOS into different subsets and to understand the pathology, ultimately leading to more effective management of AOS.

Reference

1.         Patel MS, Taylor GP, Bharya S, Al‐Sanna’a N, Adatia I, Chitayat D, et al. Abnormal pericyte recruitment as a cause for pulmonary hypertension in Adams–Oliver syndrome. American Journal of Medical Genetics Part A. 2004 Sep 1;129A(3):294–9.
2.         Southgate L, Machado RD, Snape KM, Primeau M, Dafou D, Ruddy DM, et al. Gain-of-Function Mutations of ARHGAP31, a Cdc42/Rac1 GTPase Regulator, Cause Syndromic Cutis Aplasia and Limb Anomalies. Am J Hum Genet. 2011 May 13;88(5):574–85.
3.         Shaheen R, Faqeih E, Sunker A, Morsy H, Al-Sheddi T, Shamseldin HE, et al. Recessive Mutations in DOCK6, Encoding the Guanidine Nucleotide Exchange Factor DOCK6, Lead to Abnormal Actin Cytoskeleton Organization and Adams-Oliver Syndrome. Am J Hum Genet. 2011 Aug 12;89(2):328–33.
4.         Lascaratos G, Lam WW, Newman WD, MacRae M. Adams-Oliver syndrome associated with bilateral anterior polar cataracts and optic disk drusen. J AAPOS. 2011 Jun;15(3):299–301.
5.         Maniscalco M, Zedda A, Faraone S, Laurentiis G de, Verde R, Molese V, et al. Association of Adams–Oliver syndrome with pulmonary arterio‐venous malformation in the same family: A further support to the vascular hypothesis. American Journal of Medical Genetics Part A. 2005 Jul 30;136A(3):269–74.
6.         Piazza AJ, Blackston D, Sola A. A case of Adams–Oliver syndrome with associated brain and pulmonary involvement: Further evidence of vascular pathology? American Journal of Medical Genetics Part A. 2004 Oct 1;130A(2):172–5.
7.         Pouessel G, Dieux‐Coeslier A, Wacrenier A, Fabre M, Gottrand F. Association of Adams–Oliver syndrome and hepatoportal sclerosis: An additional case. American Journal of Medical Genetics Part A. 2006 Mar 10;140A(9):1028–9.