Infants of diabetic mothers are at increased risk for the oculo-auiculo-vertebral sequence: A case based and case-contro approach

Complutense University of Madrid, Madrid, Madrid, Spain
Journal of Pediatrics (Impact Factor: 3.79). 12/2002; 141(5):611-7. DOI: 10.1067/mpd.2002.128891
Source: PubMed


To determine if infants of diabetic mothers (IDM) are at increased risk for dysplastic ears and the oculoauriculo-vertebral spectrum (OAVS).
Cases of IDM with dysplastic external ears seen at Cedars-Sinai Medical Center were combined with case series in medical literature describing similar patients. Data from a large congenital birth defects registry in Spain were analyzed, and odds ratios (OR) for infants born to either a gestational or preconceptionally diabetic mother to have one of the studied malformations were calculated with 95% confidence intervals.
Among the 30 patients in the case series, 50.0% (15) had hemifacial microsomia; 46.7% (14) had hearing loss; 33.3% (10) had facial nerve palsy; 33.3% (10) had vertebral anomalies; 36.7% (11) had cardiovascular defects, of which 45% (5) were conotruncal defects; 26.7% (8) had renal anomalies; 13.3% (4) had limb defects (all radial ray hypoplasia); 10% (3) had DiGeorge sequence; 6.7% (2) had laterality defects; and 6.7% (2) had imperforate anus. Within the cases from the birth defects registry, the odds ratio for OAVS in infants of mothers with gestational diabetes mellitus was 2.28 (95% CI, 1.03-4.82, P =.03), and the OR for ear anomalies in these infants was 1.21 (95% CI, 0.94-1.56, P =.13). When infants of mothers with preconceptionally diagnosed type 1 or 2 diabetes were considered, the OR for OAVS was 1.50 (95% CI, 0.08-9.99, P =.49), and the OR for dysplastic ears was 0.94 (95% CI, 0.48-1.81, P =.85).
Our data indicate that OAVS occurs with a higher incidence in IDM than in the general population. Associated problems include hearing loss, athymia, and cardiac, renal, and limb malformations. Therefore, we recommend that an IDM with features consistent with OAVS undergo a workup including hearing evaluation, skeletal survey, echocardiogram, renal ultrasonogram, and immunodeficiency workup if clinically indicated. Furthermore, noting that most of these defects occur in structures of neural crest origin, we hypothesize that poorly controlled maternal diabetes interferes with cephalic neural crest cell migration.

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Available from: Raymond Y Wang, Sep 30, 2014
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    • "However , it seems doubtful that such under ascertainment would differ by maternal diabetes status because OAVS in association with maternal diabetes is not widely known. When Wang et al. (2002) examined microtia and other types of ear defects combined, ORs for gestational diabetes (OR, 1.2; 95% CI, 0.9–1.6) and pre-existing diabetes (OR, 0.9; 95% CI, 0.5–1.8) "
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    ABSTRACT: Background: Little is known about the etiology of nonsyndromic microtia. This study investigated the hypothesis that microtia is caused by vascular disruption. Methods: The study analyzed data from the population-based National Birth Defects Prevention Study (NBDPS) for deliveries between 1997 and 2005. Four hundred eleven nonsyndromic cases of microtia, with or without additional defects, were compared to 6560 nonmalformed infants with respect to maternal exposures to vasoactive medications and smoking during the periconceptional period and conditions that have previously been associated with vascular events (multiple gestation, maternal history of type 1, type 2, or gestational diabetes, and hypertension). Odds ratios (ORs) were estimated with multivariable models, controlling for the effects of race/ethnicity, education, periconceptional folic acid use, and study center. Results: Risk estimates for vasoactive medications and smoking were not meaningfully increased. Maternal type 1/2 diabetes was diagnosed before or during the index pregnancy in 4% and 1% of cases, respectively, compared to 1% and 0.05% of controls; the adjusted OR for these two groups combined was 7.2 (95% confidence interval [CI], 3.9-13.1). Gestational diabetes was observed for 9% of cases and 6% of controls; the OR was moderately elevated (OR, 1.4; 95% CI, 0.9-2.0). ORs were also increased for multiple gestations (OR, 2.5; 95% CI, 1.5-4.2) and pre-existing hypertension (OR, 1.6; 95% CI, 1.0-2.5). Conclusions: Because ORs were only elevated for diabetes and not for vasoactive exposures or other potential vascular events, findings suggest that some microtia occurrences may be part of the diabetic embryopathy rather than manifestations of vascular disruption. Birth Defects Research (Part A), 2013. © 2012 Wiley Periodicals, Inc.
    Preview · Article · Jan 2013 · Birth Defects Research Part A Clinical and Molecular Teratology
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    • "There is overlap between OAVS and other syndromes including Treacher Collins syndrome (associated with microtia, lower eyelid colobomas, and mandibular hypoplasia), Fanconi Anemia (radial ray abnormalities, short stature, elevated diepoxy butane induced chromosome breakage), and VACTERL syndrome. At the present time there is no common etiology for OAVS, although there is evidence supporting vascular disruption [78], maternal diabetes [79], and other teratogenetic agents including retinoic acid [80] and thalidomide [81]. Using high density oligonucletotide microarray CGH technology, 12 of 86 (14%) patients with hemifacial microsomia studied were identified as having a CNV, including 4 patients with deletions and/or 8 patients with duplications ranging between 2.3–2.8 "
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    ABSTRACT: Congenital and idiopathic scoliosis represent disabling conditions of the spine. While congenital scoliosis (CS) is caused by morphogenic abnormalities in vertebral development, the cause(s) for idiopathic scoliosis is (are) likely to be varied, representing alterations in skeletal growth, neuromuscular imbalances, disturbances involving communication between the brain and spine, and others. Both conditions are characterized by phenotypic and genetic heterogeneities, which contribute to the difficulties in understanding their genetic basis that investigators face. Despite the differences between these two conditions there is observational and experimental evidence supporting common genetic mechanisms. This paper focuses on the clinical features of both CS and IS and highlights genetic and environmental factors which contribute to their occurrence. It is anticipated that emerging genetic technologies and improvements in phenotypic stratification of both conditions will facilitate improved understanding of the genetic basis for these conditions and enable targeted prevention and treatment strategies.
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    • "Most cases are sporadic and the causes are largely unclear. Maternal use of medications (Jacobsson and Granstrom 1997; Johnston and Bronsky 1995) and maternal diabetes (Wang et al. 2002) contribute to infants with OAVS, which suggests that nongenetic factors play a role in the development of OAVS. Nevertheless, chromosomal aberrations (Engiz et al. 2007; Balci et al. 2006; Choong et al. 2003; Descartes 2006; Josifova et al. 2004; Ala-Mello et al. 2008; Xu et al. 2008; Rooryck et al. 2009) and the identification of several families with autosomal dominant (Tsai and Tsai 1993; Stoll et al. 1998; Tasse et al. 2007; Goodin et al. 2009; Vendramini-Pittoli and Kokitsu-Nakata 2009) or recessive inheritance (Kaye et al. 1992) indicate that OAVS has a hereditary basis. "
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    ABSTRACT: Oculo-auriculo-vertebral spectrum (OAVS) is a common developmental disorder involving first and second pharyngeal arches. Although some family cases and such patients showing chromosomal aberrations suggest that OAVS have a genetic basis, no consistent genetic defects have been recorded at present time. Thus, we conducted genetic studies of a three-generation family with five OAVS patients to identify a causative variant for OAVS. Cytogenetic studies revealed those family members had a normal karyotype and no causative mutations were founded in SALL1 and TCOF1, which known to be responsible for two other syndromes that have clinical overlapping with OAVS. Genotyping with commercially available BeadChips was performed on 13 individuals in the same family, showing no significant difference between the affected and normal members in terms of copy number variations (CNVs) in either number or size and no definitive causative CNV. A total of 8,224 informative autosomal SNPs that are evenly distributed throughout the genome were selected for both parametric and non-parametric linkage analysis. Significant negative LOD scores were obtained for the reported OAVS locus, providing further evidence for genetic heterogeneity of this complex disorder. The highest LOD score of 1.60 was noted on chromosome 15q26.2-q26.3 showing a potential linkage to this locus. The variable phenotypes of the affected members and the failure to identify a causative variant indicate that a complex etiology may be present even in a consanguineous family, which makes it more challenging to ascertain the cause of OAVS in further analysis.
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