Molecular epidemiology of rubella virus in Asia: Utility for reduction in the burden of diseases due to congenital rubella syndrome

BACKGROUND: Rubella is a mild disease mainly of infants, involving a rash and a fever. However, when women who have no immunity to rubella are infected during the early stage of pregnancy, their babies are often born with congenital rubella syndrome (CRS), which is characterized by a few disorders including deafness, cataracts and heart malformations. To prevent CRS, several strains of live attenuated rubella vaccine have been developed and introduced into immunization programs in many countries. In most Asian countries except Japan, Singapore and Taiwan, rubella remains uncontrolled, and the burden of diseases from CRS is high. In order to develop a control program to reduce the number of CRS cases in Asian countries, it is necessary to conduct a survey of rubella and CRS cases, and to then determine the genotype of the circulating rubella virus in each country. METHODS: Cases of rubella and CRS, based on national reporting systems or active surveillance in the Asian countries, are summarized. Sequences of the E1 gene of the virus isolates from the Asian countries were compared by phylogenic analysis. RESULTS: Recent studies of the molecular epidemiology of rubella virus worldwide revealed that there are two genotypes, and that genotype I is circulating almost worldwide, while genotype II is an Asian prototype restricted to the Asian continent. Genotype I viruses fall into a number of groups, some of which are geographically localized. Antigenically these two genotypes are cross-reactive and immunization with either virus results in immunity to all rubella viruses. DISCUSSION: The hypotheses that rubella virus has evolved on the Asian continent is proposed. The World Health Organization (WHO) has recognized that a rubella immunization program can be combined with the measles immunization program. Inclusion of rubella in the expanded program of immunization (EPI) of measles would be ideal in Asian countries, as it would be efficient and cost effective to administer one injection containing a three-combined vaccine (MMR). It would also be desirable given that WHO require laboratory tests to confirm the presence of measles or rubella as part of it's measles control project, because rubella is often misdiagnosed as measles.     

Severe subaortic stenosis associated with congenital rubella syndrome: Palliation by percutaneous transcatheter device occlusion of a patent ductus arteriosus

Summary Congenital rubella syndrome has been associated with several forms of congenital heart disease including left-sided obstructive lesions. This report describes a patient with severe subaortic stenosis, patent ductus arteriosus, and mild pulmonary branch stenosis, a rare condition. Palliation was achieved with percutaneous transcatheter device occlusion of the patent ductus arteriosus.     

The cardio-facio-cutaneous syndrome: report of a patient and review of the literature

We report a 3-year-old girl with the cardiofacio-cutaneous (CFC) syndrome. She presented the typical combination of mild developmental delay, postnatal onset short stature with relative macrocephaly, a wide and prominent forehead with posteriorly rotated ears and down-slanting palpebral fissures, an atrial septal defect, and ectodermal abnormalities. All cases reported to date occurred sporadically. The actiology remains unknown; de novo mutations of an autosomal dominant gene seem the most likely explanation.     

多发性线粒体功能障碍综合征6 型1 例报告并文献复习

目的探讨PMPCB基因变异导致多发性线粒体功能障碍综合征6型(MMDS6)的临床表型和基因变异特点。方法回顾分析1例MMDS6患儿的临床资料,并结合文献进行复习。结果患儿,男,5月龄。表现为体质量不增、喂养困难、运动发育倒退、四肢肌张力低,伴高乳酸血症、心力衰竭。心脏彩超示肺动脉高压。全外显子和线粒体基因测序显示PMPCB基因c.524GA纯合核苷酸变异,父母均为杂合子,该纯合变异尚未见文献报道。结论 PMPCB基因c.524GA纯合核苷酸变异是MMDS6的致病变异。二代基因测序有助于基因型诊断。     

Epidemiologic survey of patients with congenital central hypoventilation syndrome in Japan

Background: Congenital central hypoventilation syndrome (CCHS) is a rare disease characterized by hypoventilation during sleep. This study discusses the first epidemiologic survey of patients with CCHS in Japan. Methods: The first survey was conducted between September and December 2006 and involved 507 registered institutes for pediatric training in Japan. The second survey was conducted between January and April 2007 and involved only those institutes that confirmed diagnosis of CCHS in the first survey or reported on CCHS at a conference during the preceding decade. Results: Thirty‐seven patients with CCHS were reported from 23 hospitals. Patient characteristics were as follows: 18 were male, 19 were female; and age range 4 months to 34 years. Diagnosis was based on clinical symptoms in 37/37 patients; blood gas analysis in 25/37; ventilatory response to inhaled CO₂ in 14/37; and genetic analysis (paired‐like homeobox gene 2B) in 11/37. Complications included Hirschsprung's disease in 13/37 and central nervous system disorders in 15/37. Prognoses were as follows: 3/37 died in hospital, 1/37 remained in hospital, 33/37 were on home mechanical ventilation (died 4/33, survived 29/33), and 0/37 were cured. Ventilation methods included tracheostomy (21/37), use of a nasal mask (9/37), use of a facemask (5/37), and diaphragmatic pacing (1/37). Conclusions: There is currently no consensus on the most appropriate methods for diagnosing and treating patients with CCHS in Japan. More CCHS‐related data need to be collected in the near future in order to enable appropriate diagnosis and management of patients with CCHS.     

Birth outcomes of cases with unclassified multiple congenital abnormalities and pregnancy complications in their mothers depending on the number of component defects. Population-based case-control study

Multiple congenital abnormalities (MCA) represent the most severe category of structural birth defects, (i.e. congenital abnormalities [CA]). Unfortunately, most MCA are not recognized and/or identified as MCA syndromes or MCA associations in the clinical practice. The term unclassified MCA (UMCA) is used for this category of MCA. We decided to evaluate the component CA of UMCA cases. The population-based large dataset of the Hungarian Case-Control Surveillance of Congenital Abnormalities (1980-1996) was evaluated. 'False' MCA, such as complex CA, polytopic field defects and sequences were excluded from the category of MCA. In addition, MCA syndromes caused by chromosomal aberrations and major mutant genes with preconceptional origin were excluded from the dataset of the Surveillance. MCA syndromes caused by teratogens and MCA associations with well-defined component CA were also excluded in the study. Thus, only UMCA cases (i) without the recognition of previously delineated MCA syndromes (ii) and/or without the identification of new MCA syndromes or (iii) caused by random combination of CA were included in the study. We compared data from 1349 cases with UMCA, 2405 matched population controls without any CA, and 21 494 malformed controls with isolated CA. There was a higher rate of stillbirth and a moderate male excess in UMCA cases, a somewhat shorter gestational age at delivery and an obvious reduction in birthweight. The intrauterine fetal growth retardation and rate of low-birthweight newborns showed an association with the number of component CA in UMCA cases. A similar association was not found with gestational age and the rate of preterm birth. UMCA represent one of the most severe categories of CA. The degree of intrauterine fetal growth retardation depends on number of component CA in UMCA cases.     

Increasing incidence of congenital heart disease in patients with Down syndrome

ABSTRACT Our impression that the incidence of congenital heart disease in patients with Down syndrome was increasing in our outpatient clinic was investigated. The change in the incidence of congenital heart disease was investigated during the period from January 1981 to December 1998 in 196 patients with Down syndrome diagnosed by chromosomal analysis. Of the 196 patients, 99 (50.5%) had congenital heart disease. The incidence increased during study period: 35.4% (1981–1983), 44.9% (1984–1986), 46.4% (1987–1989), 69.0% (1990–1992), 53.8% (1993–1995), and 81.3% (1996–1998). The number and the mean age of new outpatients were found to decrease. The incidence of Down syndrome patients whose disease was chromosomally proven by other institutions was increasing. The incidence of congenital heart disease in patients with Down syndrome is currently increasing in our outpatient clinic. However many factors might contribute to this phenomenon.     

FGFR2 mutation in a patient with Apert syndrome associated with humeroradial synostosis

Most cases of Apert syndrome are due to S252W or P253R mutations in the fibroblast growth factor receptor 2 (FGFR2) gene. Differences in the effects of S252W and P253R mutations on the clinical features of Apert syndrome have been studied, but little is known about the type of FGFR2 mutation in Apert syndrome with humeroradial synostosis. To study a correlation between the FGFR2 mutations and the clinical complications, we examined the FGFR2 gene in a patient with Apert syndrome associated with humeroradial synostosis, and found that the mutation was S252W. This report suggested that S252W mutation in FGFR2 may cause humeroradial synostosis in Apert syndrome.     

Delineation of a multiple congenital abnormality syndrome in the offspring of pregnant women affected with high fever-related disorders: a population-based study

Our previous study showed an association between high fever-related maternal diseases during the second and/or third gestational months and a higher risk of multiple congenital abnormalities (MCA) in the population-based large dataset of the Hungarian Case-Control Surveillance of Congenital Abnormalities. The objective of our analysis is to attempt the delineation of the spectrum of the characteristic component defects of an MCA syndrome associated with high fever-related maternal diseases. Of 1349 cases with MCA without recognized genetic and teratogenic syndromes in the total dataset, 181 had a possible association with influenza, common cold with secondary complications, tonsillitis and recurrent orofacial herpes with high fever in the second and/or third gestational months. At the evaluation of component defects in these 181 MCA cases, an association was found between the components of the so-called two schisis-type defects, such as neural-tube defects and orofacial cleft, in addition to microphthalmos, neurogenic limb contractures, and indeterminate sex (i.e. maldevelopment of male external genital organs, such as hypoplasia of the penis and pseudohermaphroditism). In addition, previous findings that showed an association between high fever and facial anomalies (micrognathia and midfacial hypoplasia), microcephaly and defects of external ears, were confirmed in our dataset. Thus, we delineated the maternal high fever-related MCA syndrome, including the above component defects and this MCA syndrome was identified in 38 MCA (21.0%) among 181 MCA babies born to mothers with high fever-related diseases. In the total dataset of 1349 MCA, 2.8% of cases can be associated with high fever.     

纵向可延长钛金属肋骨假体技术治疗先天性脊柱侧弯合并胸廓畸形

目的 报道我们采用纵向可延长钛金属肋骨假体(VEPTR)技术治疗先天性脊柱侧弯合并胸廓畸形的初步体会.方法 5例先天性脊柱侧弯合并胸廓畸形的患儿,男3例,女3例,平均年龄8.3岁(4.7～12.2岁);均自出生就发现脊柱畸形并呈进行性加重.除1例曾经接受过弧度段脊柱张力钢丝捆绑治疗外,其余病例均无过去手术史;所有病例体格矮小、躯体平衡失调并倒向凸侧;肺功能检测明显低下,其中最大肺活量(VCMAX)和最大自主通气量(MVV)分别只有同年龄、同身高正常预测值的24.8%～48.1%(平均32.8%)和20.8%～54.4%(平均34.5%);胸段脊柱混合型分节、分化不良,3例存在凹侧肋骨融合畸形;术前Cobb's角平均为77.6°(63°～106°);CT及CT三维重建测量,脊柱旋转(SR)平均为19.6°(11.4°～26.8°),胸廓旋转(TR)平均为61.4°(34.2°～477.2°),后半胸廓对称度(PHSR)平均为2.4(1.2～3.6);MRI脊髓扫描未发现异常.手术在神经监护仪下进行,所有病例均I期完成手术,4例进行了肋骨开放截骨,术中4例胸膜壁层破裂,所有病例胸膜脏层均保持完整.所有病例均各安置了肋骨-肋骨、肋骨-脊柱钛肋各一组.结果 所有病例均获得随访,平均随访时间14个月(12～18个月),所有病例均已完成了2次延长.术后所有病例躯体平衡获得明显改善,凹侧胸廓扩大,骨盆倾斜平衡恢复,脊柱高度增加,身高平均增长4.4 cm(3～7 cm).所有患儿肺功能检查均较术前有不同程度提高,VCMAX和MVV平均增加35 7%(10.4%～78.4%)和51.7%(8.2%～84.9%).呼吸系统易患感染、活动后气急等现象明显改善.脊柱畸形均有所矫正,Cobb's角测量平均57°(44°～69°),家长对患儿外观改变均表示满意.结论 VEPTR技术对于治疗先天性脊柱侧弯合并胸廓畸形所致的胸腔功能不全综合症显示了一定的效果,肺功能改善,脊柱畸形控制,脊柱生长继续,躯体平衡恢复.其中长期功效和并发症尚待观察.     

Recombinant human granulocyte-colony-stimulating factor in the treatment of patients with chronic benign granulocytopenia and congenital agranulocytosis (Kostmann''s syndrome)

Seven patients with chronic benign granulocytopenia and nine patients with congenital agranulocytosis, received consecutive seven-day courses of recombinant human granulocyte-colony stimulating factor at a starting dose of 50 micrograms/m2/day, subcutaneously. If there was no response the doses were increased to 300 micrograms/m2. All patients with chronic benign granulocytopenia responded rapidly at the minimum dose within 1-3 days after administration. By contrast, only three of the nine patients with congenital agranulocytosis responded within 1-7 days at this dose. Four patients with congenital agranulocytosis showed a response between days 7-19 at a dose of granulocyte-colony-stimulating factor 100-200 micrograms/m2 but in the remaining two cases no response was obtained. The administration of granulocyte-colony-stimulating factor was shown to be safe and effective also in reducing infectious episodes in these patients. Previously it was reported that granulocyte-colony-stimulating factor 10-30 micrograms/kg/day was effective for patients with congenital agranulocytosis. These results indicate that patients with congenital agranulocytosis may require much higher doses of recombinant human granulocyte-colony-stimulating factor than patients with chronic benign granulocytopenia and that the response to ordinary doses of recombinant human granulocyte-colony-stimulating factor may be useful in differentiating between chronic benign granulocytopenia and congenital agranulocytosis.     

Studies of malformation syndromes of man XXXIII: The FG syndrome. An X-linked recessive syndrome of multiple congenital anomalies and mental retardation

Three brothers and two of their male first cousins were affected with a previously apparently undefined multiple congenital anomaly, mental retardation syndrome which was designated the FG syndrome and which consists of variable growth problems with a disproportionately large head, characteristic appearance and minor anomalies, imperforate anus, mild to severe mental retardation and congenital hypotonia; pyloric stenosis, hypoplastic left heart, generalized dilatation of the urinary tract, cutaneous syndactyly of third and fourth fingers, and severe craniosynostosis were seen each in 1 patient. Partial agenesis of the corpus callosum seen in 1 patient is suspected in another on the basis of EEG abnormalities. 1 boy died neonatally with congenital heart disease, and 2 others of pneumonia at 20 and 23 months. The FG syndrome is an X-linked recessive condition; heterozygotes appear grossly normal.Paper No. 1705 from the University of Wisconsin Genetics Laboratory     

Auditory neural myelination is associated with early childhood language development in premature infants

Background

Auditory neural myelination (ANM) as evaluated by auditory brainstem evoked response (ABR) during the neonatal period has been used as a surrogate outcome for long-term neurodevelopment. The validity of ANM as a surrogate outcome for long-term neurodevelopment has not been well studied.

Aim

Evaluate the association of ABR I–V interpeak latency (IPL), an index of ANM, at 35 week postmenstrual age (PMA) with language outcome at 3 years of age.

Design

Prospective study.

Subjects

24–33 week gestational age (GA) infants were eligible if they did not meet exclusion criteria: craniofacial malformation, chromosomal disorders, deafness, auditory dys-synchrony, TORCH infection, or non-English speaking parents. Infants with malignancy, head injury, encephalopathy, meningitis, blindness, or who died or relocated were also excluded.

Outcome measures

ABRs were performed at 35 week PMA using 80 dB nHL and I–V IPL (ms) measured. Auditory Comprehension (AC) and Expressive Communication (EC) were evaluated by a speech-language pathologist at 3 years of age using Preschool Language Scale.

Results

Eighty infants were studied. The mean GA and birth weight of infants were 29.2 weeks and 1336 g, respectively. There was association of worse ear I–V IPL and better ear I–V IPL with AC (Coefficient − 5.4, 95% CI: − 9.8 to − 0.9 and Coefficient − 5.5, 95% CI: − 10  to−0.9, respectively) and EC (Coefficient − 5.6, 95% CI: − 9.5  to−1.8 and Coefficient − 6.7, 95% CI: − 10.6  to−2.7, respectively) after controlling for confounders.

Conclusion

The neonatal I–V IPL is a predictor of language development at 3 years of age in preterms.     

Continuation of metformin in the first trimester of women with polycystic ovarian syndrome is not associated with increased perinatal morbidity

This study aimed to assess the perinatal outcome, especially foetal growth, following the continuation of metformin during the first trimester of pregnancy. All women with polycystic ovary syndrome (PCOS) treated with metformin in the first trimester and who delivered a baby weighing 500 g or more between 2003 and 2005 were studied. Subjects were matched for age and parity with randomly selected controls. The perinatal outcomes studied were: growth parameters, gestational age, congenital defects, hypoglycaemia and neonatal unit admission. Sixty-six pregnancies were compared with 66 controls; all had singleton deliveries. There was no difference in mean birth weight between the metformin and the control groups (p = 0.84). The percentage of small (<10th centile) and large (>90th centile) for gestational age babies was lower in the metformin group. In the metformin group, there were no major congenital malformations and 24% of the babies were admitted to the neonatal intensive care unit (NICU) compared with 27% of the babies in the control group (non-significant). Neonatal hypoglycaemia was less common in the metformin group (18.5% vs. 24.5%) and fewer babies required intravenous glucose therapy (6.3% vs. 12%). We found no evidence that the continuation of metformin in the first trimester of pregnancy was associated withan adverse foetal outcome.