Abstract D-transposition of the great arteries (TGA) is one of the most common conotruncal heart defects at birth and is characterized by a discordant ventriculoarterial connection with a concordant atrioventricular connection. The morphological etiology of TGA is an inverted or arrested rotation of the heart outflow tract (OFT, conotruncus), by which the aorta is transposed in the right ventral direction to the pulmonary trunk. The rotational defect of the OFT is thought to be attributed to hypoplasia of the subpulmonic conus, which originates from the left anterior heart field (AHF) residing in the mesodermal core of the first and second pharyngeal arches. AHF, especially on the left, at the early looped heart stage (corresponding to Carnegie stage 10–11 in the human embryo) is one of the regions responsible for the impediment that causes TGA morphology. In human or experimentally produced right isomerism, malposition of the great arteries including D-TGA is frequently associated. Mutations in genes involving left–right (L–R) asymmetry, such as NODAL, ACTRIIB and downstream target FOXH1, have been found in patients with right isomerism as well as in isolated TGA. The downstream pathways of Nodal-Foxh1 play a critical role not only in L–R determination in the lateral plate mesoderm but also in myocardial specification and differentiation in the AHF, suggesting that TGA is a phenotype in heterotaxia as well as the primary developmental defect of the AHF.
Abstract This is the first population-based study in Thailand on the prevalence of congenital limb defects (CLD). Data were obtained from recently established birth defects registries in three southern Thailand provinces during 2009–2013. Entries in the birth defects registries included live births, stillbirths after 24 weeks gestational age, and terminations of pregnancy following a prenatal diagnosis of fetal anomaly. The total of 186 393 births recorded included 424 CLD cases, giving an average prevalence of 2.27 per 1000 births (95% CI, 2.05–2.49). The most common CLD was talipes equinovarus (44.1%), followed by polydactyly (13.9%) and syndactyly (9.4%). The prevalence significantly increased with maternal age from 1.81 in mothers aged <30 years to 2.75 in mothers 30 to < 35 years, and to 2.94 in mothers <35 years (P = 0.004). Overall 9.4% of the CLDs were syndromic CLD, again with significantly greater percentages in pregnant women aged <35 years than the non-syndromic CLD (32.5% vs 17.5% respectively, P = 0.03). In conclusion, the overall prevalence of CLD in the 3 southern Thailand provinces examined was 2.27 per 1000 births, and syndromic CLD was significantly higher in pregnant women aged ≥35 years than younger pregnant women.
Abstract Ellis-van Creveld syndrome (EvC) is a ciliopathy with cardiac anomalies, disproportionate short stature, polydactyly, dystrophic nails and oral defects. To obtain further insight into the genetics of EvC, we screened EVC/EVC2 mutations in eight Vietnamese EvC patients. All the patients had a congenital heart defect with atypical oral and/or skeletal abnormalities. One had compound heterozygous EVC2 mutations: a novel mutation c.769G < T-p.E177X in exon 6 inherited from father and another previously reported c.2476C < T-p.R826X mutation in exon 14 inherited from mother. The EVC2 mRNA expression level was significantly lower in the patient and her parents compared to controls. Another case had a novel heterozygous EVC mutation (c.1717C < G-p.S572X) in exon 12, inherited from his father. Of note, the mother without any EVC mutation on Sanger sequencing showed a lower expression level of EVC mRNA compared with controls. SNP array analysis revealed that the patient and mother had a heterozygous 16.4 kb deletion in EVC. This patient also had a heterozygous novel variant in exon 9 of EFCAB7 (c.1171 T <C-p.Y391H), inherited from his father. The atypical cardiac phenotype of this patient and the father suggested that EFCAB7 may modify the phenotype by interacting with EVC. In conclusion, we detected two novel nonsense mutations and a partial deletion of EVC/EVC2 in two Vietnamese families with EvC. Moreover, we found in one family a missense mutation of EFCAB7, a possible modifier gene in EvC and its related disorders.
Abstract Russell–Silver syndrome (RSS) is a congenital anomaly characterized by intrauterine and postnatal growth retardation, typical facial features, fifth-finger clinodactyly, and skeletal asymmetry. Although data on intrauterine and postnatal growth retardation have been reported, there are few reports concerning the typical maxillofacial morphology in individuals with RSS. The aim of this study was to describe the details of this systemic condition and to characterize maxillofacial morphology based on cephalograms in 11 Japanese patients (age range, 3.9–12.0 years) with RSS. All 11 individuals had intrauterine and postnatal growth retardation. In addition, most showed mandibular retrognathia and relative macrocephaly. Lateral cephalogram measurements showed that mandibular retrognathia resulted from short mandibular body length, whereas the depth of the cranial base was close to normal. Although asymmetry of hand, foot, and limb length were present in most individuals, obvious facial asymmetry was not common. Differences between left and right skeletal and dental age were not observed, indicating that children with RSS might show asymmetry because of quantitative differences in skeletal growth rather than delayed growth rate. Our findings not only provide important information about the maxillofacial characteristics of RSS, but also help to clarify the association between these characteristics and genetics, which will add to the body of information on clinical symptoms.
Abstract Polydactyly is one of the most common hereditary limb malformations, involving additional digits on the hands and/or feet, which is a very attractive model to appreciate clinical and genetic heterogeneity. A high level of heterogeneity in polydactyly has been identified in different regions. However, such data of the medical literatures for Asian populations are relatively limited. This study was intended to shed light on the phenotypic manifestations of polydactyly in the recruited Chinese population and to characterize the medical literature on this condition. A total of 459 well-characterized polydactyly cases from Shanghai Children's Medical Center were recruited. Their phenotypes, inheritance patterns, and clinical heterogeneity were obtained from clinical medical records. It was found that 4.8% of cases were familial and 95.2% were sporadic. The proportions of preaxial and postaxial polydactyly types were 74.7% and 25.3%, respectively. In preaxial polydactyly, type I formed the overwhelming majority (95.9%). Among the postaxial polydactyly cases, type A was most prevalent at 69.8% and type B was witnessed in 30.2% of cases. Familial and sporadic polydactyly patients mainly had unilateral presentations. A total of 583 limbs with additional digits were recorded in the 459 subjects. Upper limb involvement was more common than lower, and right hand involvement was more common than left for preaxial polydactyly, and lower limb involvement was more common than upper in postaxial polydactyly. This cohort added useful clinical/epidemiological information to the polydactyly literature in the Chinese population and highlighted its marked clinical heterogeneity.
Abstract The circle of Willis (CW) is a circulatory anastomosis that supplies blood to the brain and adjacent structures. We examined the timing of formation of CW in 20 Japanese human embryo samples by using 3-dimensional reconstruction of serial histological sections. The CW was closed in 1 (n = 6), 2 (n = 8), 2 (n = 3) and 2 (n = 3) samples at Carnegie stages 20, 21, 22, and 23, respectively. The CW was unclosed in 13 samples (unclosed at ACOM alone, 6 samples; ACOM and bilateral P1, 4; left PCOM and right P1, 1; right PCOM and right P1, 1; ACOM and left PCOM, 1). It was difficult to predict whether the circle would close during further development, as such variations frequently exist in adults.
Abstract Newborn cases of VACTERL association with lower urinary tract obstruction (LUTO) are rare and there have been no reports on those patients undergoing fetal therapy in English literature. We successfully performed vesico-amniotic shunting in a fetus having LUTO caused by abnormality of the external genitalia at 16 weeks’ gestation. Although fetal karyotype was normal 46XY, follow-up fetal ultrasound examinations revealed ventriculomegaly in the brain, a small stomach and a right multicystic dysplastic kidney. MRI at 31 weeks’ gestation suggested lobar type holoprosencephaly. Diagnosis of VACTERL association was confirmed postnatally. We consider that vesico-amniotic shunting is indicated for a fetus of VACTERL association with LUTO if the parents wish the procedure after genetic counseling and explanations about the fetal conditions.
Abstract An 18-year-old woman with mild Crouzon syndrome was referred with malocclusion and mandibular protrusion. Examination revealed Class III canine and molar relationships, hypoplastic maxilla, 1-mm overbite, and −2-mm overjet. Analysis showed 69° sella-nasion-A, 73.6° sella-nasion-B, and −4.6° A point-nasion-B point angles. Polysomnography revealed respiratory disturbance and 6.3% oxygen desaturation indices of 5.4/h and 9.0/h. We performed double-jaw surgery using high Le Fort I osteotomy and bilateral sagittal split ramus osteotomy for midfacial deformity correction. Twelve months post-surgery, her measures were 70.8°, 72°, −1.2°, 3.0/h, and 6.1/h, respectively. Esthetics were satisfactory. High Le Fort I osteotomy is effective for midfacial deformity correction in patients with Crouzon syndrome.