Molecular studies in the GJB2 gene (Cx26) among a deaf population from Bogotá, Colombia: results of a screening program.

OBJECTIVE: We conducted a pilot screening program to define the prevalence of non-syndromic deafness and establish the frequency of mutations in the GJB2 gene (Cx26) in a population of children with congenital deafness in Bogotá, Colombia. METHOD: From a cohort of 731 children in 8 institutions for the deaf, we identified 322 (44%) with presumed non-syndromic deafness. These were invited to a more detailed evaluation, but 46 chose not to participate. The remaining 276 individuals received a complete ophthalmological evaluation that was normal in 205 (74.3%) and showed salt and pepper retinopathy in 55 (19.9%) and other ocular abnormalities in 16 (5.8%). A comprehensive medical history, and a detailed physical examination were performed in the 205 children with normal ocular exam. Of these, 93 were found to have acquired deafness and/or associated anomalies and 112 (15.3% of the initial 731 children), non-syndromic deafness. The GJB2 gene was sequenced in these 112 individuals. RESULTS: Based on family history, 59.8% (67/112) of these cases had autosomal recessive non-syndromic sensorineural hearing loss and the remaining 40.2% (45/112) were sporadic, without apparent known cause. We identified three mutations in the GJB2 gene: 35delG, S199F, and 167delT, all of which have been previously reported in the literature, the variant M34T, and the polymorphism V27I. S199F was the most frequent mutation (17.9%), followed by 35delG (17.0%) and 167delT (0.4%). The mutations in the GJB2 gene were present in 50.7% of the autosomal recessive group and in 33.3% of the sporadic cases. CONCLUSIONS: Our pilot study showed that 15.3% of institutionalized deaf children in Bogotá have non-syndromic deafness and among them, the frequency of the S199F mutation was higher than reported in previous studies, whereas the frequency of the 35delG is similar to Caucasian populations. The fact that the S199F mutation was the most frequent allele in our study confirms the fact that the prevalence of GJB2 mutations depends on the ethnic origin. We emphasize the need to follow a strict protocol to identify bona fide cases of non-syndromic deafness among individuals with congenital hearing loss in order to identify the molecular basis of this condition.

Pre-gestational maternal body mass index predicts an increased risk of congenital malformations in infants of mothers with gestational diabetes.

AIMS: The aim of the present study was to identify characteristics in women diagnosed with gestational diabetes mellitus (GDM) that could be predictive of congenital malformations in their infants. METHODS: Using data from the Spanish Collaborative Study of Congenital Malformations (ECEMC), a hospital-based case-control study and surveillance system, we assessed the relationship between a number of maternal variables, including pre-gestational body mass index (BMI), and specific congenital malformations in their infants. RESULTS: The overall risk for a selected group of congenital malformations in an infant of an obese mother with GDM compared with an obese mother with normal glucose tolerance (NGT) was 2.78 (1.38-5.55, P < 0.001). Within the group of mothers with GDM, obesity (BMI > or = 30 kg/m2) was associated with a significantly increased risk of cardiovascular defects compared with non-obese women [OR = 2.82 (1.31-7.04), P < 0.01]. In mothers with NGT, pre-gestational BMI was not associated with congenital malformations. CONCLUSION: Pre-gestational obesity is a predictive variable for congenital malformations in infants of mothers with GDM. The greater their BMI, the higher the risk for congenital malformations in their offspring. Given the blastogenic origin of the congenital defects identified, and the relationship between obesity and Type 2 diabetes, it is probable that this increased risk is as a result of previously unidentified pre-gestational diabetes mellitus (PGD). It is important that overweight and obese women planning a pregnancy be evaluated for the presence of diabetes.

Congenital anomaly rate in offspring of mothers with diabetes treated with insulin lispro during pregnancy.

AIM: To determine the rate of major congenital anomalies in offspring of a large group of women with diabetes mellitus treated with insulin lispro (Humalog). METHODS: This multinational, multicentre, retrospective study included mothers with diabetes mellitus (diagnosed prior to conception) who were treated with insulin lispro for at least 1 month before conception and during at least the first trimester of pregnancy. Anomalies were assessed by two independent dysmorphologists not affiliated with the sponsor. RESULTS: The charts of 496 women were reviewed for 533 pregnancies resulting in 542 offspring (500 live births, 31 spontaneous and seven elective abortions, and four stillbirths). Mothers' characteristics: mean (+/- SD) age was 29.9 (+/- 5.2) years, 85.6% were Caucasian and 97.2% had Type 1 diabetes mellitus. Insulin lispro continued to be the main mealtime insulin for more than 96% of the women during the second and third trimester. The dysmorphologists determined that 27 (5.4%) offspring had major congenital anomalies and 2 (0.4%) offspring had minor congenital anomalies. CONCLUSIONS: The rate of major congenital anomalies was 5.4% [95% CI (3.45%, 7.44%)] for offspring of mothers with diabetes mellitus treated with insulin lispro before and during pregnancy. The current published rates of major anomalies in infants born to mothers with diabetes treated with insulin are between 2.1 and 10.9%. This suggests that the anomaly rate with insulin lispro treatment does not differ from the published major congenital anomaly rates for other insulin treatments.

Exstrophy of the cloaca and exstrophy of the bladder: two different expressions of a primary developmental field defect.

Exstrophy of the bladder (EB) and exstrophy of the cloaca (EC) are generally recognizable as distinct clinical entities. In patients with EB, the posterior bladder wall is exposed through a midline defect of the abdomen. The umbilicus is inferiorly displaced and located close to the superior margin of the exstrophic bladder. Genital abnormalities are common in boys and girls who may present epispadias and a small, split phallus or a split clitoris, a bifid uterus, and a duplicate or exstrophic vagina. In contrast to classic EB, EC is commonly associated with omphalocele, spinal defects, and incompletely formed external genitalia and is always associated with imperforate anus. Some authors state that EC and EB constitute two distinct disorders, but others consider them part of a "continuum," representing different levels of severity within the same spectrum. The use of the acronym OEIS to refer to the combination of omphalocele, exstrophy, imperforate anus, and spinal defects, in our opinion, has not helped to clarify the clinical definition, pathogenesis, or cause of this multiple congenital anomaly (MCA) pattern, mostly because the term makes no distinction between EC or EB. Here we present the epidemiological analysis of a group of characteristics in infants with EC and infants with EB to determine if they constitute two different entities. We also analyze if the different combinations of omphalocele, imperforate anus, and spinal defects are more frequent in infants with EC than in infants with MCA patterns other than EC and EB. The prevalence in our data for EC was 1:200,233 live births and 1:35,597 for EB. The clinical analysis indicated that the study defects (omphalocele, spine defects, spina bifida, and imperforate anus) tend to occur together in the same child with a higher frequency if the child has the EC defect than in infants with MCA patterns that did not include EC or EB. Our findings of low birth weight, twinning, single umbilical artery, and preferentially associated malformations suggest that EC is the result of damage occurring very early in development and that EC and EB are two different expressions of a primary polytopic developmental field defect.

Pathogenetic classification of a series of 27,145 consecutive infants with congenital defects.

We studied a series of 27,145 consecutive infants with congenital defects and classified them into the currently recognized pathogenetic types of errors of morphogenesis, as defined by the International Working Group [Spranger et al., 1982: J Pediatrics 1:160-165]. Of all infants with congenital defects, 97.94% had malformations, 3.92% deformations, and 1.65% disruptions. Malformations associated with deformations were present in 3.12% of children with congenital anomalies, malformations with disruptions in 0.18%, deformations with disruptions in 0.07%, and malformations with deformations and disruptions in 0.14%. While deformations, including deformation sequences, were 2.38 times more common than disruptions and disruption sequences, isolated disruptions (1.27%) were more frequent than isolated deformations (0.59%). Knowledge of the frequencies of the different types of errors of morphogenesis (malformations, deformations, disruptions, developmental field defects, associations, complexes, unrecognized patterns of multiple congenital anomaly, and syndromes) may be of great value in the evaluation of patients with congenital anomalies.

Analysis of deformations in 26,810 consecutive infants with congenital defects.

Here we present the analysis of deformations observed in a series of 26,810 consecutive infants with congenital defects. We observed that 3.88% of these infants had deformations, for a prevalence figure of 0.07% live-born infants. From the present study we can conclude that there are three different types of deformation sequences: one with polyhydramnios, thin skin without dermal ridges, hypotonia, and multiple deformations (hypokinesia sequence), which is most often due to intrinsic problems; another with oligohydramnios, redundant thick skin, and multiple deformations, which can be produced by intrinsic or extrinsic factors; and the third, with normal amniotic fluid volume, which is due to compression of different causes. Deformations of extrinsic cause are more frequently isolated defects and have a better prognosis, while deformations of intrinsic origin are more frequently associated with other congenital anomalies and, generally, have a poor prognosis.

VACTERL as primary, polytopic developmental field defects.

Previously we proposed that the VACTERL association represents a dysmorphogenetic response of the primary developmental field, i.e., polytopic developmental field defects (DFD). As such, it should conform to the essential attributes of a DFD, namely, heterogeneity, homology, and phylogeneity. To study its heterogeneity, we analyzed the data of the Spanish Collaborative Study of Congenital Malformations (ECEMC). Our results confirm the observations indicating that the different patterns of defects that constitute this entity are not only clinically variable but also causally heterogeneous. This causal heterogeneity, which is of crucial importance in defining developmental fields, gives additional credence to the hypothesis that VACTERL constitutes a primary polytopic DFD.

Maternal and fetal factors related to abnormal amniotic fluid.

OBJECTIVE: The objective of this study was to identify maternal and infant characteristics related to alteration of amniotic fluid volume at birth. STUDY DESIGN: A series of 27,145 consecutive malformed newborn infants from the Spanish Collaborative Study of Congenital Malformations (ECEMC) was analyzed. From this total, 3.01% were found to have oligohydramnios and 3.69% were found to have polyhydramnios. RESULTS: As expected, renal/urinary tract and lung defects were associated with oligohydramnios, whereas esophageal and intestinal atresias, neural tube defects, and other central nervous system malformations were associated with polyhydramnios. In addition, other defects such as cardiovascular anomalies, hydrocephaly, and microcephaly were also related to abnormalities of amniotic fluid volume. After excluding the defects whose association to oligo- or polyhydramnios is well recognized, we compared the frequency of different variables among them and with infants with a normal volume of amniotic fluid. In comparison with infants with normal amniotic fluid volume, the groups with oligo- and polyhydramnios had lower birth weight, shorter gestational age and umbilical cord, higher parental ages, and a greater frequency of spontaneous abortions. The differences were more marked for weight in newborn infants with oligohydramnios, and for gestational age, umbilical cord length, number of previous pregnancies, and spontaneous abortions in polyhydramnios cases. Placental weight was lower in oligohydramnios cases than in infants with normal amniotic fluid, and higher in polyhydramnios cases. Parental consanguinity and twinning were more frequent in polyhydramnios. Maternal morbidity was higher in both groups with abnormal amniotic fluid volume, especially for acute diseases such as hypertension, diabetes mellitus, and gestational diabetes. Chromosomal aberrations were more frequent in the oligo- and polyhydramnios groups than in cases with a normal volume of amniotic fluid, which supports the suggestion of performing prenatal cytogenetic analysis in any pregnancy complicated by an abnormal volume of amniotic fluid. CONCLUSION: The fact that all of these results are similar in the control group of healthy infants suggests that at least some of the variables associated with abnormal amniotic volume could be considered as causal factors altering the production of fluid.

Epidemiological analysis of outcomes of pregnancy in gestational diabetic mothers.

The association between maternal diabetes mellitus and congenital defects has been well documented. However, few data exist on the potential teratogenic effect of gestational diabetes (GD). We analyzed 19,577 consecutive infants with malformations of unknown cause and compared the offspring of mothers with GD with those of nondiabetic mothers. The children with each of 20 types of selected anomalies among the two groups were used to calculate the odds ratio (OR). Because we used as a reference group for each congenital defect the rest of malformed infants, the value of the OR gives us the specificity between the association of GD and each congenital defect. Our analysis strongly supports the suggestion that GD is a significant risk for holoprosencephaly, upper/lower spine/rib, and renal and urinary system anomalies. GD is a heterogeneous disorder, which includes previously unrecognized and newly diagnosed nongestational diabetes mellitus (DM). Thus, it is possible that the teratogenic effect is related to latent DM. However, because it is not possible at this time to differentiate between these situations, pregnancies complicated by GD should be considered at risk for congenital anomalies. Prenatal ultrasound examination should be aimed particularly at the detection of abnormalities of the central nervous system, the renal and urinary system, and the spine/rib developmental field.

[Epidemiological aspects of children of women with bicornuate uterus]. / Aspectos epidemiológicos de los hijos de mujeres con útero bicorne.

BACKGROUND: Most published papers on women with a bicornuate uterus analyze their fertility problems, as well as certain pregnancy complications. We have not found any epidemiological study on the infants of mothers with this uterine malformation. Only in some papers a reference is made about the relationship of maternal bicornuate uterus with congenital deformations and disruptions in their infants. PATIENTS AND METHODS: Using data from the Spanish Collaborative Study of Congenital Malformations (ECEMC), which has a case-control methodology, some characteristics in a series of 26,945 malformed infants, such as birth weight, sex, gestational age, umbilical cord length, placental weight and maternal age, were analyzed by separating infants of mothers with normal uterus and those of mothers with a bicornuate uterus. RESULTS: Results showed that women with a bicornuate uterus have more daughters than sons and an increased risk for intrauterine growth retardation and prematurity with respect to infants of mothers with a normal uterus. On the other hand, the risk of having an infant with congenital defects is higher for women with a bicornuate uterus than for those with a normal uterus. CONCLUSIONS: Pregnancies of women with a bicornuate uterus have to be considered at risk since they have more risk for complications and for having an infant with congenital defects, premature birth and with intrauterine growth retardation.

Congenital anomalies in the offspring of mothers with a bicornuate uterus.

BACKGROUND: Most of the reports on mothers with bicornuate uterus analyze fertility, reproductive capacity, and pregnancy outcomes. Very few of them, however, mention the risk for congenital anomalies in their offspring. Further, to our knowledge, no epidemiologic studies estimating the risk for congenital defects and analyzing the type of anomalies observed in infants born to mothers with bicornuate uterus have been reported. METHODS: Using a case-control study series, we estimated the risk of congenital anomalies in the offspring of women with a bicornuate uterus. To identify the specific defects associated with the presence of a bicornuate uterus in the mother, we analyzed 26 945 consecutive malformed infants from the Spanish Collaborative Study of Congenital Malformations and assessed the frequency of congenital anomalies in the offspring of mothers with a bicornuate uterus and in those born to mothers with a normal uterus. We then calculated the relative frequency, which is the quotient of the frequency of the individual defects in each group. This figure expresses the times each congenital defect is more frequent in infants of mothers with a bicornuate uterus than in those born to mothers with a normal uterus. RESULTS: Offspring of mothers with a bicornuate uterus had a risk for congenital defects four times higher than infants born to women with a normal uterus. The risk was statistically significant for some specific defects such as nasal hypoplasia, omphalocele, limb deficiencies, teratomas, and acardia-anencephaly. CONCLUSIONS: Offspring of mothers with bicornuate uterus are not only at high risk for deformations and disruptions, but also for some type of malformations.

Errors of morphogenesis and developmental field theory.

Field theory provides a rational basis for birth defects terminology. During blastogenesis in higher metazoa, pattern formation in the primary field leads to the establishment of upstream expression domains of growth and transcription factors, which, in various permutations and at specific sites and times, lay down the pattern of progenitor fields. Further spatially coordinated, temporally synchronized, and epimorphically hierarchical morphogenetic events, mostly during organogenesis, lead to the attainment of final form in the secondary, epimorphic fields. Because of shared molecular determinants, spatial contiguity, and close timing of morphogenetic events during blastogenesis, most malformations arising during blastogenesis are polytopic, i.e., involving two or more progenitor fields, e.g., acrorenal, cardiomelic, gastromelic, or splenomelic anomalies. Defects of organogenesis tend to be monotopic malformations, e.g., cleft palate or postaxial polydactyly. We suggest that what were called "associations" (e.g., VATER, schisis) be designated primary polytopic developmental field defects, or simply polytopic field defects, and that the term "association" be reserved for the original definition of a statistical combination of anomalies (mostly of organogenesis) [Spranger et al. (1982): J Pediatr 100:160-165]. If genetically caused or predisposed, all structures involved in a polytopic or monotopic malformation are genetically abnormal, whereas the parts secondarily affected as a consequence of a malformation sequence (e.g., spina bifida) are genetically normal. Polytopic field anomalies, per se, must be distinguished from pleiotropy, although such anomalies may constitute a part of pleiotropy (e.g., in trisomy 18). Because they are downstream from pattern-forming events in the primary field, multiple anomalies of organogenesis more likely represent syndromal pleiotropy.

Primary developmental field. III: Clinical and epidemiological study of blastogenetic anomalies and their relationship to different MCA patterns.

Opitz [1993: BD:OAS XXIX (1):3-37] suggested that during blastogenesis the entire embryo constitutes a developmental field, i.e., the primary developmental field. Based on this principle, he postulated that a single "hit," that during late morphogenesis would cause a monotopic malformation, during blastogenesis would produce a polytopic malformation or an association. Lubinsky [1986: Am J Med Genet [Supp1]2:6-16] had stated previously that "since the embryo develops in an integrated manner, organized and differentiating spatially, temporally, and in an epimorphically hierarchical manner, disturbances result in nonrandom patterns of anomalies." He then concluded that "associations are derivatives of causally nonspecific disruptive events acting on developmental fields." These concepts, confirmed by our epidemiological observations [Martínez-Frías, 1994: Am J Med Genet 49:45-51], imply that some associations are, by definition, abnormalities of blastogenesis that is, that their component congenital anomalies are produced by events occurring during the first 4 weeks of development. We present an analysis of the characteristics of blastogenetic anom-alies and their relationship with midline abnormalities, as well as with the schisis and VACTERL associations.

Epidemiological analysis of the schisis association in the Spanish registry of congenital malformations.

Since its description by Czeizel [1981: Am J Med Genet 10:25-35], there has been general acceptance of the schisis association as a distinct entity although, to the best of our knowledge, no other epidemiological study has confirmed its existence. Here we present an epidemiologic study on schisis defects and their associations with each other in children with and without blastogenetic defects. This study demonstrates that most cases represent the dysmorphogenetic response of the primary developmental field.

Are blastogenetic anomalies sporadic?

Opitz [Birth Defects, 1993, 1:3-37] postulated that sporadic defects of blastogenesis generally are highly lethal and have a low recurrence risk. We have observed that mothers of infants with blastogenetic defects have more previous abortions than mothers of children with nonblastogenetic defects or than mothers of control infants. Thus the high lethality of blastogenetic abnormalities may be responsible for the spontaneous abortions, and there may be a potential for an increased recurrence risk in some cases. Our results also show that the increased rate of spontaneous abortions is not similar for all blastogenetic defects, since it is not elevated in mothers of infants with neural tube defects (NTD). Further, our analysis does not confirm the relationship between spontaneous abortions in the preceding pregnancy and the occurrence of NTD previously reported by other authors.

[Etiologic distribution of children with congenital defects]. / Distribución etiológica de los niños con defectos congénitos.

INTRODUCTION: Although it has been generally admitted that we know the cause of congenital malformations in about 40% of the cases, these data are based on very few studies. PATIENTS AND METHODS: Here we present the distribution of 22,784 malformed infants in our country by type of cause of their defects. RESULTS: Our results show a great impact of chromosomal alterations in causing congenital anomalies. On the other hand, performing the chromosomal study will enable the diagnosis of genetic entities, as well as environmental ones that are clinically similar to the clinical patterns produced by chromosomal abnormalities. CONCLUSIONS: We can recognize the cause of congenital defects in a proportion higher than the 40% which is generally accepted. Nowadays, there is no reason that justifies not performing a chromosomal study with high resolution band techniques in infants with congenital defects.

Neuroradiology and clinical aspects of Usher syndrome.

We describe the neurological evaluation and MRI analysis of 30 patients, belonging to 16 families with Usher syndrome (US) type I and type II (US1 and US2). In addition to the classic visual and audiological abnormalities seen in these patients, we observed abnormal gait in 88.9% of US1 and in 66.7% of US2 patients and abnormal coordination in 33.4% of US1, and in 58.3% of US2. Borderline mental retardation, depression or bipolar affective disorder were observed in 16.7% of US1 and 33.3% of US2 patients. MRI analysis showed cerebellar abnormalities in 50% of US1 and 75% of US2 patients, but no clear correlation was observed between structural abnormalities and clinical findings. A pattern for the MRI classification of US patients is suggested.

Kabuki make-up (Niikawa-Kuroki) syndrome in five Spanish children.

We describe 5 Spanish children with Kabuki make-up syndrome (KMS)-3 females and 2 males-identified in Badajoz, Spain, between 1988 and 1990. All had the characteristic clinical and radiological manifestations of the syndrome. Psychomotor/mental retardation, postnatal growth deficiency, distinctive facial appearance, sagittal vertebral clefts, and dermatoglyphic abnormalities were present in all 5. Congenital heart defects were present in 4 patients. In addition, one had myopia, astigmatism, and bilateral paralysis of the VI cranial nerve. Another had apparent fusion of the hamate and capitate. An additional patient, as well as his mother, had an apparently balanced 15/17 translocation [46,XY,t(15;17) (15q;21q)]. The fact that these patients were ascertained in a catchment area of approximately 250,000 inhabitants and in a relatively limited period of time suggests that the prevalence of the KMS may be higher than previously recognized.