Disruption of sonic hedgehog signaling in Ellis-van Creveld dwarfism confers protection against bipolar affective disorder.

Ellis-van Creveld syndrome, an autosomal recessively inherited chondrodysplastic dwarfism, is frequent among Old Order Amish of Pennsylvania. Decades of longitudinal research on bipolar affective disorder (BPAD) revealed cosegregation of high numbers of EvC and Bipolar I (BPI) cases in several large Amish families descending from the same pioneer. Despite the high prevalence of both disorders in these families, no EvC individual has ever been reported with BPI. The proximity of the EVC gene to our previously reported chromosome 4p16 BPAD locus with protective alleles, coupled with detailed clinical observations that EvC and BPI do not occur in the same individuals, led us to hypothesize that the genetic defect causing EvC in the Amish confers protection from BPI. This hypothesis is supported by a significant negative association of these two disorders when contrasted with absence of disease (P=0.029, Fisher's exact test, two-sided, verified by permutation to estimate the null distribution of the test statistic). As homozygous Amish EVC mutations causing EvC dwarfism do so by disrupting sonic hedgehog (Shh) signaling, our data implicate Shh signaling in the underlying pathophysiology of BPAD. Understanding how disrupted Shh signaling protects against BPI could uncover variants in the Shh pathway that cause or increase risk for this and related mood disorders.

Ellis-van Creveld syndrome and congenital heart defects: presentation of an additional 32 cases.

Ellis-van Creveld (EVC) syndrome is a rare genetic abnormality that has been linked to a mutation in the EVC or EVC2 genes. Common atrium (CA) is an uncommon cardiac malformation, and yet it is commonly found in patients with EVC. We performed a retrospective review of the cases submitted to the Pediatric Cardiac Care Consortium (PCCC) between 1982 and 2007. A review of the English-language literature for previously published cases, as well as current genetic research findings, was also performed. Thirty-two pediatric patients with congenital heart disease (CHD) and EVC syndrome were identified in the PCCC database. Twenty-eight (88%) had an endocardial cushion defect, with 15 of these having primary failure of atrial septation resulting in CA. Persistent left superior vena cava (LSVC) and pulmonary venous connection abnormalities were common. The incidence of persistent LSVC and pulmonary venous abnormalities were greater than previously reported for patients with EVC. Our study reviews the reported literature and adds 32 additional cases from the PCCC database. Review of the cardiac phenotype in patients with EVC syndrome reveals a characteristic pattern of atrioventricular canal defects with systemic and pulmonary venous abnormalities. The frequent association of these abnormalities is strongly reminiscent of the cardiac phenotype found in patients with heterotaxy syndromes. Emerging molecular and developmental studies suggest that EVC and EVC2 proteins may be important for cilia function, which is implicated in the pathogenesis of heterotaxy syndromes. It is speculated that coordinate function between the EVC proteins is required for a cilia-dependent cardiac morphogenesis.

Congenital heart diseases associated with identified syndromes and other extra-cardiac congenital malformations in children in Lagos.

BACKGROUND: Congenital heart diseases are commonly associated with other extra cardiac congenital malformations. OBJECTIVE: To identify congenital heart diseases associated with identified syndromes and other extra cardiac congenital malformations in children in our hospital. METHODS: A prospective descriptive study done on children with congenital malformations referred to the Lagos University Teaching Hospital, Nigeria (LUTH) for echocardiographic evaluation. A thorough 2D assessment of the chambers, septa, heart vessels and concordance of the atrium and ventricle and the great vessels was made. Echo-cardiographic data obtained included M mode direct measurements of dimensions of left atrium, aortic root, right ventricular outflow tract, left ventricle in diastole/systole, wall thicknesses--right ventricular wall, interventricular septum, left ventricular posterior wall. Fractional shortening was derived from M mode data. Final diagnosis of the congenital heart disease was recorded. RESULTS: A total of 101 children with congenital malformations had echocardiography studies done as part of their clinical evaluation, 15 (14.9%) were neonates, 53 (52.5%) infants 25 (24.8%) were aged one to five years and 8 (7.9%) were above five years of age. Recognised syndromes were seen in 69 (68%) cases. Down syndrome with 54 children contributed 78.3% of those with known syndromes. Other identified syndromes and associations were Marfan's, Noonan's, Edwards, Prune Belly, Apert, Ellis-van Creveld syndrome and congenital rubella syndrome. Congenital heart diseases were detected in 73 (72.3%) patients while 28 (27.7%) had no heart defect. The commonest identified congenital heart disease was ventricular septal defect affecting 30 (29.7%) patients. CONCLUSION: Congenital heart diseases are common in children with congenital malformations. Down syndrome was the most common malformation and the congenital heart disease most associated with the congenital malformations was ventricular septal defect. This study emphasizes the need for cardiac assessment of children with congenital malformations.

Two cases of Ellis-van Creveld syndrome in a small island population.

Two individuals showing features typical of the autosomal recessive Ellis-van Creveld syndrome have been diagnosed in a population of 1340 individuals living on a small island off the west coast of Scotland. Clinical features and family relationships of the affected individuals are described.

Ellis-van Creveld syndrome in Kerala.

A case of the Ellis-van Creveld syndrome is described. Emphasis is laid on the probable relation to the frequency of consanguineous marriages among the Hindu community in Kerala.