Frizzled 2 and frizzled 7 function redundantly in convergent extension and closure of the ventricular septum and palate: evidence for a network of interacting genes.

Frizzled (Fz) 2 and Fz7, together with Fz1, form a distinct subfamily within the Frizzled family of Wnt receptors. Using targeted gene deletion, we show that: Fz7(-/-) mice exhibit tail truncation and kinking with 100% penetrance and ventricular septal defects (VSDs) with ~15% penetrance; Fz2(+/-);Fz7(-/-) mice exhibit VSDs with ~50% penetrance and cleft palate with less than 10% penetrance; and Fz2(-/-);Fz7(-/-) mice exhibit convergent extension defects and mid-gestational lethality with 100% penetrance. When Fz2 and/or Fz7 mutations are combined with mutations in Vangl2, Dvl3, Wnt3a, Wnt5a or Wnt11, an increased frequency of VSDs is observed with Dvl3, Wnt3a and Wnt11; an increased frequency of palate closure defects is observed with Vangl2; and early lethality and enhanced tail shortening are observed with Wnt5a. To assess the signaling pathways that underlie these and other Frizzled-mediated genetic interactions, we used transfected mammalian cells to analyze (1) canonical Wnt signaling induced by all pairwise combinations of the ten mouse Frizzleds and the 19 mouse Wnts and (2) localization of each Frizzled at cell-cell junctional complexes formed by mouse Celsr1, a likely indicator of competence for planar cell polarity signaling. These in vitro experiments indicate that Fz2 and Fz7 are competent to signal via the canonical pathway. Taken together, the data suggest that genetic interactions between Fz2, Fz7 and Vangl2, Dvl3 and Wnt genes reflect interactions among different signaling pathways in developmental processes that are highly sensitive to perturbations in Frizzled signaling.

Congenital heart defects in oculodentodigital dysplasia: Report of two cases.

Oculodentodigital dysplasia is caused by mutations in the GJA1 gene. Oculodentodigital dysplasia presents with a spectrum of clinical features including craniofacial, ocular, dental, and limb anomalies. Although recent findings implicate the major role of GJA1 during cardiac organogenesis, congenital heart defects are infrequently reported in oculodentodigital dysplasia. Here we report on two patients with GJA1 mutations presenting with cardiac malformations and type III syndactyly. Patient 1 presented with pulmonary atresia, an intact septum, right ventricular hypoplasia and tricuspid stenosis. The infant had a small nose, thin columella and bilateral 4-5 syndactyly of the fingers. A de novo c.226C>T (p.Arg76Cys) mutation was identified. Patient 2 presented at 6 months with a ventricular septal defect. The child had hypoplastic alae nasi with a thin columella and bilateral 4-5 syndactyly of the digits. A de novo missense mutation, c.145C>G (p.Gln49Glu) was found. Our two patients underscore the importance of cardiac evaluations as part of the initial workup for patients with findings of oculodentodigital dysplasia. Conversely, those patients with type III syndactyly and congenital heart defect should be screened for GJA1 mutations.

A 5.6-Mb deletion in 15q14 in a boy with speech and language disorder, cleft palate, epilepsy, a ventricular septal defect, mental retardation and developmental delay.

We report a male patient with speech and language disorder, cleft palate, epilepsy, a ventricular septal defect, mental retardation and developmental delay. Characteristic facial features include low-set ears, a beak-like nose, a prominent nasal bridge, a long philtrum, a narrow forehead, a long face, a pointed chin and dental position abnormalities. Array-comparative genomic hybridization (CGH) analysis demonstrated the presence of a 5.6-Mb deletion in 15q14 (chromosome 15: 3,18,33,000-3,74,77,000bp). The present case provides the evidence that 15q14 deletion outside the region encompassing the CHRNA7 gene can cause generalized epilepsy, and a locus in 15q14 is associated with speech and language disorder.

Congenital heart defects in patients with oculo-auriculo-vertebral spectrum (Goldenhar syndrome).

The oculo-auriculo-vertebral spectrum (OAVS) is a non-random association of microtia, hemifacial microsomia with mandibular hypoplasia, ocular epibulbar dermoid, and cervical vertebral malformations. Congenital heart defects (CHDs) have been reported in 5-58% of the patients. We analyze the frequency and anatomic features of CHD in a series of 87 patients with OAVS examined between January 1990 and February 2007 with normal chromosomes, ranging in age between 0.1 and 16.8 years. A twin pregnancy occurred in eight cases (dizygotic in six cases and monozygotic in two). CHDs were diagnosed in 28/87 (32%) patients, and classified into categories of postulated developmental mechanisms including 9 (32%) atrial and ventricular septal defects, 11 (39%) conotruncal defects, 4 (14%) targeted growth defects, two (7%) with situs and looping defects, one (4%) with a left-sided obstructive lesion and one (4%) with patent ductus arteriosus. As noted in other series, the most common individual CHDs were ventricular septal defect (six patients) and tetralogy of Fallot (TOF) (classic or with pulmonary atresia) (six patients). Comparing the frequencies of CHDs groups observed in the OAVS patients with the findings of the Emilia-Romagna Registry which ascertained CHDs prevalence in the general population, conotruncal defects, targeted growth defects, and heterotaxia were significantly associated with OAVS.

Asymmetric crying facies: a possible marker for congenital malformations.

Asymmetric crying facies (ACF) is caused by agenesis or hypoplasia of the depressor anguli oris muscle on one side of the mouth. Though it is an isolated finding in most cases, ACF can be associated with other congenital malformations especially of the cardiovascular system. We report a case of ACF that was subsequently diagnosed as Cayler syndrome based on associated tetralogy of Fallot (TOF) and deletion of chromosome 22q11.

Mutchinick syndrome in a Japanese girl.

We report on a 7-year-old Japanese girl with Mutchinick syndrome, a rare congenital malformation syndrome described in a pair of Argentinean sisters and a pair of German brothers; both originating from the same geographic region in the former East Prussia. The girl we describe had most of the clinical manifestations of the syndrome, including growth and developmental retardation, and craniofacial anomalies with microcephaly, hypertelorism, a broad straight nose, low-set malformed ears, and a wide, tented mouth. She also had the following hitherto undescribed manifestations: ventricular septal defect, palmoplantar hyperkeratosis, bilateral partial soft-tissue syndactyly of second and third toes, and megaloureters. The occurrence of the syndrome in a Japanese girl indicates that the syndrome is not restricted to the descendants of individuals from a confined region in northeastern Europe.

Growth retardation, distinct oriental-like facies, glaucoma, brachydactyly, ventricular septal defect and speech disorder. An unknown entity.

A caucasian boy with distinct oriental-like facies, short stature, brachydactyly, congenital ventricular septal defect, glaucoma, and speech disorder is reported. Routine laboratory tests, karyotype, and hormonal profile (IGF 1, growth hormone during provocative testing, thyroid hormones, prolactin, gonadotrophins) were normal. Radiologic skeletal survey did not disclose any abnormality. Both parents were apparently normal, but short in stature.

Autosomal dominant postaxial polydactyly, nail dystrophy, and dental abnormalities map to chromosome 4p16, in the region containing the Ellis-van Creveld syndrome locus.

We have studied a four-generation family with features of Weyers acrofacial dysostosis, in which the proband has a more severe phenotype, resembling Ellis-van Creveld syndrome. Weyers acrofacial dysostosis is an autosomal dominant condition with dental anomalies, nail dystrophy, postaxial polydactyly, and mild short stature. Ellis-van Creveld syndrome is a similar condition, with autosomal recessive inheritance and the additional features of disproportionate dwarfism, thoracic dysplasia, and congenital heart disease. Linkage and haplotype analysis determined that the disease locus in this pedigree resides on chromosome 4p16, distal to the genetic marker D4S3007 and within a 17-cM region flanking the genetic locus D4S2366. This region includes the Ellis-van Creveld syndrome locus, which previously was reported to map within a 3-cM region between genetic markers D4S2957 and D4S827. Either the genes for the condition in our family and for Ellis-van Creveld syndrome are near one another or these two conditions are allelic with mutations in the same gene. These data also raise the possibility that Weyers acrofacial dysostosis is the heterozygous expression of a mutation that, in homozygous form, causes the autosomal recessive disorder Ellis-van Creveld syndrome.