by Of the 1740 patients (Fig 2), significant medical records were independently available for 695 patients (data from interviews with families eliciting extensive comprehensive medical histories). patients are at risk for spontaneous hemorrhage, and likely increased risk secondary to the high frequency of self-injurious behavior. Although further studies are needed to better define the scope of the problem and to define SHC1 the mechanisms of thrombocytopenia in CdLS, we XL-228 would recommend screening for thrombocytopenia upon diagnosis and at five-year intervals thereafter. Keywords:cornelia de lange, thrombocytopenia, ITP, immune thrombocytopenia == Introduction == Cornelia de Lange Syndrome (CdLS, OMIM 122470, 300590 and 610759) or Brachmann-de Lange Syndrome (BdLS) is a rare multisystem genetic syndrome occurring in approximately 1:10,000 live births [Opitz, 1985;Kline et al., 2007]. It is inherited in a dominant manner and shows considerable phenotypic heterogeneity [Liu and Krantz 2008]. Thrombocytopenia was first reported in a case of CdLS by Froster in 1993 [Froster and Gortner, 1993] and subsequently only two other examples have been reported [Fryns and Vinken, 1994]. These reports describe three patients, including two severely affected individuals with limb anomalies, who were diagnosed at birth with thrombocytopenia. Two of the patients subsequently progressed to pancytopenia and death in the second and third decades of life [Fryns and Vinken 1994]. Despite these reports, thrombocytopenia continues to be an infrequently noted manifestation of this disorder. Even recent reviews of CdLS do not mention thrombocytopenia as a finding [Kline et al., 2007;Liu and Krantz 2008]. One current model for pathobiology of the CdLS phenotype is based on data demonstrating gene dysregulation as a result of dysfunction of the Cohesin complex [Dorsett, 2007;McNairn and Gerton, 2008;Wendt et al., 2008]. This gene dysregulation may play a central role in the development of thrombocytopenia. XL-228 Furthermore, several genetic disorders with immune dysregulation including the 22q deletion [Lawrence et al., 2003] and primary immunodeficiencies [Notarangelo, 2009] have been associated with Immune Thrombocytopenia (ITP), a common cause of thrombocytopenia in childhood. One alternative hypothesis is based on data that members of the Cohesin complex have been shown to play multiple roles in DNA damage repair [Kim et al., 2002;Yazdi et al., 2002;Watrin and Peters, 2009]. Several other disorders that have been linked to DNA damage repair can present with both skeletal limb anomalies and thrombocytopenia. Most notably, these include Fanconi anemia and some subtypes of VACTERL association [Shaw-Smith, 2006]. Interestingly, a number of additional diagnoses combine both of these findings including, thrombocytopenia with absent radii (TAR) [Hall et al., 1969], amegakaryocytic thrombocytopenia with radio-ulnar synostosis [Thompson et al., 2001] and several rarer reports combine limb anomalies and associated thrombocytopenias [von Bubnoff et al., 2004;Sahoo et al., 2005;Kranz et al., 2007]. Based on these observations, we also hypothesized that one of the common underlying mechanisms for these disorders of thrombocytopenia and limb anomalies, including CdLS, may also involve deficiencies in DNA damage repair. Although there is no published data demonstrating a direct role of sister chromatid cohesion in regulating immune function, there is an abundance of data both clinically and molecularly that connects immune dysfunction and defects in DNA damage repair (Figure 1). == Figure 1. Schematic representation of potential mechanisms for thrombocytopenia. == (A) Cohesin mediated direct effects on sister-chromatid adhesion result in dysregulation of endomitosis and dysfunctional megakaryopoiesis. This results XL-228 in not only decreased platelet production but also inability to respond appropriately to transient insults to platelet count resulting in an increased incidence of thrombocytopenia. (B) Cohesin effects on gene expression result in dysregulated B-cell.
