Oral-facial-digital syndrome with Y-shaped fourth metacarpals and endocardial cushion defect

We report on a boy with pseudo-cleft of the upper lip, cleft palate, bifid uvula, lobulated tongue, hypoplasia of the epiglottis, both preaxial and central polydactyly of the hands (Y-shaped fourth metacarpals), bilateral preaxial polydactyly of the feet, postaxial polydactyly of the left foot, hearing impairment, and congenital heart disease with endocardial cushion defect. These clinical manifestations resembled oral-facial-digital syndrome type II (OFDS II, Mohr syndrome) or type VI (Váradi syndrome), associated with an atrioventricular canal. Clinical variability of OFDS II has been observed repeatedly. To the best of our knowledge, this is the first reported case of OFDS II with Y-shaped fourth metacarpals. In addition to Y-shaped fourth metacarpals, Mohr syndrome plus atrioventricular canal and hypoplasia of the epiglottis may represent an additional subgroup of OFDS. Am. J. Med. Genet. 86: 278–281, 1999. © 1999 Wiley-Liss, Inc.     

超声诊断胎儿先天性心内膜垫缺损

目的探讨产前超声诊断胎儿心内膜垫缺损的临床价值。方法对2004年10月～2008年10月77832例孕18w以上的胎儿心脏应用超声检查,以胎儿四腔心切面为常规,多切面扫查观察胎儿心脏大小、形态、房室结构、房室瓣开闭、左右心室流出道。结果发现心内膜垫缺损16例,伴发其他畸形4例,漏诊1例。结论产前超声是诊断胎儿先天性心内膜垫缺损的可靠方法及技术,可阻止严重先天性畸形——心内膜垫缺损的胎儿出生。     

Oral-facial-digital syndrome type IX in a patient with Dandy-Walker malformation.

We report a girl with oral, facial, and digital anomalies including multiple alveolar frenula, lobulated tongue with nodules, a posterior cleft palate, hypertelorism, a prominent forehead with a large anterior fontanelle, and postaxial polydactyly in both hands and the right foot, features compatible with the oral-facial-digital syndrome (OFDS). In addition, she had bilateral microphthalmia, optic disc coloboma, and retinal degeneration with partial detachment, thus establishing a diagnosis of OFDS type IX. Dandy-Walker malformation and retrobulbar cysts were observed on MRI. These additional malformations have not been reported in OFDS type IX. The frequent apnoeic spells which occurred immediately after birth were relieved after cystoperitoneal shunt implantation for hydrocephalus. Considering our case and previous reports of OFDS type IX, including two male sibs, a boy born to consanguineous parents, and three females, inheritance is probably autosomal recessive.     

Oral-facial-digital syndrome with fibular aplasia: a new variant

Figuera LE, Rivas F, Cantú JM. Oral-facial-digital syndrome with fibular aplasia: a new variant.
Clin Genet 1993: 44: 190–192. © Munksgaard, 1993
The oral-facial-digital (OFD) syndromes constitute a heterogeneous group of entities usually associated with certain features that permit a specific diagnosis. This report refers to a 10-month-old girl with cleft palate, mesomelic limb shortening, oligopolydactyly, and fibular aplasia. Since this combination has not been described previously, it is proposed as a distinct type of oral-facial-digital syndrome, and we suggest mutations of homeotic genes to explain some abnormalities present in the OFD syndromes.     

Oral-facial-digital syndrome with retinal abnormalities: Report of a new case

Smith-Magenis syndrome (SMS) is a multiple congenital anomalies/mental retardation syndrome associated with deletion of band p11.2 of chromosome 17. The deletion is typically detected by high-resolution cytogenetic analysis of chromosomes from peripheral lymphocytes. Fluorescence in situ hybridization (FISH) has been previously used to rule out apparent mosaicism for del(17)(p11.2p11.2) indicated by routine cytogenetics. We now report mosaicism for del(17)(p11.2p11.2) in a child with SMS. The mosaicism had gone undetected during previous routine cytogenetic analysis. FISH analysis of peripheral lymphocytes as well as immortalized lymphoblasts using markers from 17p11.2 revealed that approximately 60% of cells carried the deletion. To our knowledge, this is the first case of SMS associated with mosaicism for del(17)(p11.2p11.2). © 1996 Wiley-Liss, Inc.     

Rho kinases regulate endothelial invasion and migration during valvuloseptal endocardial cushion tissue formation.

Rho-associated kinase (ROCK) is a downstream effector of small Rho-GTPases, and phosphorylates several substrates to regulate cell functions, including actin cytoskeletal reorganization and cellular motility. Endothelial-mesenchymal transformation (EMT) is a critical event in the formation of valves and septa during cardiogenesis. It has been reported that ROCK plays an important role in the regulation of endocardial cell differentiation and migration during mouse cardiogenesis (Zhao and Rivkees [2004] Dev. Biol. 275:183-191). Immunohistochemistry showed that, during chick cardiogenesis, ROCK1 and -2 were expressed in the transforming and migrating endothelial/mesenchymal cells in the outflow tract (OT) and atrioventricular (AV) canal regions from which valvuloseptal endocardial cushion tissue would later develop. Treatment with Y27632, a specific ROCK inhibitor, of cultured AV explants or AV endothelial monolayers of stage 14-minus heart (preactivated stage for EMT) on three-dimensional collagen gel perturbed the seeding of mesenchymal cells into the gel lattice. In these experiments, Y27632 did not suppress the expression of an early transformation marker, smooth muscle alpha-actin. Moreover, Y27632 inhibited the mesenchymal invasion in stage 14-18 AV explants, in which endothelial cells had committed to undergo EMT. ML-9, a myosin light chain kinase inhibitor, also inhibited the mesenchymal invasion in cultured AV explants. These results suggest that ROCKs have a critical role in the mesenchymal cell invasion/migration that occurs at the late onset of EMT.     

Control of endocardial cushion and cardiac valve maturation by BMP signaling pathways

Congenital heart defects, the leading cause of deaths from birth defects, are estimated to occur in close to 1% of live newborns. Among these, abnormal septation of the heart and valve anomalies are the most frequent forms. Despite progress defining several genes involved in normal heart development, we still have a limited understanding of the signaling pathways involved in morphogenesis of the outflow tract (OFT) and, to date, very few genes have been identified that are responsible for defects in humans. Bone Morphogenetic Protein (BMP) signaling pathways are emerging as vital regulators of multiple aspects of cardiogenesis, including the septation of the OFT and valve maturation. Genetic and other in vivo evidence is now supporting the role for BMPs as inducers of endocardial cushion epithelial-to-mesenchymal transformation that was suggested by in vitro explant studies as well as by their patterns of expression in the developing heart. Here, we review briefly the in vitro data, and detail the novel mouse models where perturbed BMP signaling pathways result in impaired OFT septation and semilunar valvulogenesis. We propose that growth of the OFT valve cushions is regulated by the level of BMP signaling, under the control of other signaling pathways.     

Retinoic acid administration is associated with changes in the extracellular matrix and cardiac mesenchyme within the endocardial cushion

Retinoic acid has been associated with a number of cardiac defects, some of which seem to be related to changes in the endocardial cushions. Studies in mice and older chick embryos have suggested that these defects may be associated with a decrease in mesenchymal cell formation within the cushion. In a previous report we showed that retinoic acid lowered the number of mesenchymal cells in a culture bioassay of mesenchyme formation and that this response was due to retinoic acid modifying the production of particulate matrix from the myocardium. In this study, we have extended these observations to the embryo by implanting a retinoic acid coated bead into the embryo and examined the effect on cardiac mesenchyme formation and in the production of the particulate matrix. In all cases the addition of retinoic acid resulted in a decrease in the number of mesenchymal cells invading the endocardial cushions. In addition retinoic acid increased the production of hLAMP-1 and fibronectin but not transferrin, confirming our earlier report. Finally, we measured the volume of the cushion and calculated the cell density of both the inferior and superior cushions. The results suggest that the superior cushion is more sensitive to retinoic acid treatment than the inferior cushion. Collectively, these results support our earlier work that suggests that the mechanism of retinoic acid cardiac abnormalities involves a disruption in the production of particulate matrix from the myocardium and a subsequent decrease in cardiac mesenchyme cells that results in a malformed cardiac cushions.     

小鼠胚胎心流出道心内膜垫的形成与融合

目的观察不同发育时期小鼠胚胎心流出道心内膜垫的发育过程。方法对胚龄9-12d小鼠胚胎心脏连续切片进行HE染色和免疫组化染色。结果胚龄10d,流出道远端心胶质内开始观察到间充质细胞。胚龄11d,两侧流出道心内膜垫形成,心内膜垫内部分间充质细胞染色呈α-平滑肌肌动蛋白(α-SMA)阳性。胚龄12d,两侧流出道心内膜垫内部分间充质细胞聚集形成致密漩涡状结构,随着心内膜垫融合,两侧漩涡状结构融合。结论小鼠胚胎流出道心内膜垫形成于胚胎发育第11天,第12天融合,间充质细胞参与心内膜垫融合。     

Expression of bone morphogenetic protein-5 gene during chick heart development: possible roles in valvuloseptal endocardial cushion formation.

The bone morphogenetic protein (BMP) family, comprising multifunctional peptide growth factors, regulates many developmental processes in a variety of tissues. We examined the spatiotemporal expression of BMP5 by in situ hybridization in chick embryonic hearts from stages 5 to 33. The BMP5 gene was first expressed in the endoderm underlying the precardiac mesoderm at stages 5 to 8. Thereafter, BMP5 expression was restricted to the myocardium of the atrioventricular (AV) canal and outflow tract (OT) regions, where the valvuloseptal endocardial cushion tissue is induced. These results suggest that BMP5 may play important roles not only in myocardial differentiation, but also in the formation and maintenance of endocardial cushion tissue.     

Endocardial cushion defect in a patient with Crouzon syndrome carrying a mutation in the fibroblast growth factor receptor (FGFR)-2 gene

Crouzon syndrome is an autosomal dominant disorder caused by mutation in the fibroblast growth factor receptor (FGFR)-2 gene. Recent findings from animal studies imply a critical role for FGFs in the regulation of cardiac development including cardiac cushion proliferation and valvulogenesis. We report on a 36-year-old woman, who required surgical closure for an atrial septal defect, a clinical feature that has not been previously reported in other patients with Crouzon syndrome. The findings suggest that cardiac investigations are warranted in patients with a diagnosis of Crouzon syndrome.     

Endocardial cushion defect: further studies of "isolated" versus "syndromic" occurrence.

The isolated occurrence of endocardial cushion defect (ECD) has been suggested to differ from its occurrence within the context of a syndrome, with regard to the nature (complete or partial) of the defect and the associated cardiovascular malformations. Analysis of data derived from the Baltimore-Washington Infant Study of congenital cardiovascular malformations supports the observation that "syndromic" ECD tends to be of the complete atrioventricular canal type and is less frequently associated with left cardiac anomalies than the isolated form. However, each syndrome has a unique impact on the overall cardiovascular "phenotype", including the ECD. This is especially true for Down and Ivemark syndromes, which are most frequently associated with ECD, but also for other syndromes as well. It is also suggested that isolated ECD is specifically associated with gastrointestinal and urinary tract anomalies. However, in Down syndrome ECD appears to be a specific cardiovascular expression of the trisomic state that is unrelated to other noncardiac malformations. Additional information on the association of ECD with other less common genetic syndromes is needed in order to further investigate the possible genetic basis of this cardiac defect.     

Evidence for a fourth locus in Usher syndrome type I.

Usher syndrome type I (US1) is an autosomal recessive condition in which three different genes have been already localised (USH1A, USH1B, and USH1C on chromosomes 14q32, 11q13, and 11p15 respectively). The genetic heterogeneity of US1 has been confirmed in a previous study by linkage analysis of 20 French pedigrees. Here, we report the genetic exclusion of the three previously reported loci in two large multiplex families of Moroccan and Pakistani origin, suggesting the existence of at least a fourth locus in Usher syndrome type I.