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.

Cardiovascular manifestations in the Larsen syndrome.

The Larsen syndrome consists of a skeletal dysplasia with multiple joint dislocations and a characteristic facies. The basis of the abnormalities is felt to be a generalized mesenchymal disorder involving connective tissues. More than 80 cases have been reported in the literature with isolated reports of congenital cardiac septal defects and acquired abnormalities of the aorta and mitral valve. A case with marked aortic dilation and insufficiency as well as an aneurysm of the ductus arteriosus is presented. The aortic lesions are similar to those described in other connective tissue disorders, particularly the Marfan syndrome. Previous reports of ductal aneurysms have not revealed an association with connective tissue disorders, but have described a significant morbidity. In summary, patients with the Larsen syndrome are likely to have cardiac lesions similar to those classically associated with the Marfan syndrome; these patients deserve a careful investigation for cardiac anomalies. These aortic lesions may be as prognostically significant as cardiac lesions in the Marfan syndrome.

The Angelman ("happy puppet") syndrome.

We report studies of six patients with the Angelman "Happy Puppet" syndrome and compare the data with those from previous reports. The results confirm the classic findings of severe mental retardation, "puppet-like" gait, characteristic craniofacial abnormalities, and frequent episodes of laughter and suggest that this syndrome is more common than previously thought. Computerized axial tomographs of the brain demonstrating unilateral cerebellar atrophy in one patient constitute the first direct evidence of cerebellar abnormalities in this syndrome.

Apparent G syndrome presenting as neck and upper limb dystonia and severe gastroesophageal reflux.

We have studied a 3-month-old boy with severe gastroesophageal reflux, feeding difficulties, neck and upper limb dystonia, abnormal ears, normal genitalia, and anatomically apparently normal larynx and trachea. Initially diagnosed as suffering from Sandifer "syndrome," he was treated with a gastrostomy and Nissen fundoplication. However, his characteristic facial appearance subsequently led to the diagnosis of G syndrome.

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.

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.

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.

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.

Metaphyseal dysostosis and congenital nystagmus in a male infant with the fragile X syndrome.

A 14-month-old male with congenital nystagmus, sparse scalp hair, protuberant ears, developmental delay, and radiologic manifestations of mild metaphyseal dysostosis was coincidentally found to have the fra(X) chromosome in 67% of analyzed metaphases. This observation underscores the need for fra(X) analyses in children with developmental deficit of unknown cause.

Clinical/epidemiological analysis of malformations.

To investigate the heterogeneity of congenital malformations, we analyzed the distribution of 14 selected anomalies among 11,421 children with isolated defects and with different patterns of multiple congenital anomalies (MCA). Our study showed a marked variability in the distribution of each of these malformations. For example, although anophthalmia/microphthalmia, cleft palate, and limb deficiency were observed in all etiological categories of syndromes, no case with anencephaly was identified among the 1,244 children with different syndromes. Diaphragmatic hernia, esophageal atresia +/- tracheoesophageal fistula, and gastroschisis were not found in any monogenic syndrome in this sample. These observations may be of help to the clinician in the evaluation of individual children with MCA.

Bartsocas-Papas syndrome: three familial cases from Spain.

We report on 3 Spanish sibs with the Bartsocas-Papas syndrome. This appears to be the seventh reported family; all but one of them are of Mediterranean origin. We propose that a generalized vascular disruption is the most likely pathogenetic mechanism for the anomalies found in this syndrome.

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.

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.

Tracheoesophageal fistula, gastrointestinal abnormalities, hypospadias, and prenatal growth deficiency.

We studied 2 sibs, born to consanguineous parents, who presented with an MCA pattern which includes low birthweight, tracheoesophageal fistula, duodenal atresia, extrahepatic biliary atresia, hypoplastic pancreas, and hypospadias. This constellation of congenital anomalies appears to be a previously unreported autosomal recessive syndrome. A computerized search of the data files of the Spanish Collaborative Study of Congenital Malformations (ECEMC) identified 3 other unrelated infants with intestinal atresias, hypospadias, and low birth weight. These cases may represent a milder expression of the same syndrome.

Hypertrichosis, atrophic skin, ectropion, and macrostomia (Barber-Say syndrome): report of a new case.

We report on a child, born to a consanguineous parents, who presented with a multiple congenital anomalies (MCA) pattern consisting of severe hypertrichosis, macrostomia, ectropion, and atrophic skin. To our knowledge this is the third case with this combination of defects. The two previous cases were reported by Barber et al. [Syndrome Identification VIII(1):6-9, 1982], and David et al. [Am J Med Genet 41:192-195, 1991].

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.

Partial duplication 1q: report of four patients and review of the literature.

Here we report on 4 unrelated patients with reciprocal translocations which resulted in duplication of the distal portion of chromosome 1q. Although the patients had certain non-specific malformations in common, our investigation and a review of the literature do not suggest the existence of a distinct phenotype due to this chromosome abnormality. We think that the coexisting deletion present in each of these patients is responsible for most of the observed differences in clinical manifestations. The variable phenotype makes clinical recognition difficult and precludes making a long-term prognosis.

Brain magnetic resonance imaging findings in the Opitz G/BBB syndrome: extension of the spectrum of midline brain anomalies.

We report the brain magnetic resonance imaging findings in 4 patients with the Opitz BBB/G syndrome. The scans were assessed by subjective interpretation and computerized image analysis. Findings noted in 3 of the 4 patients include hypoplasia or agenesis of the corpus callosum (3 patients), cerebellar vermal hypoplasia (2 patients), cortical atrophy and ventriculomegaly (3 patients), macro cisterna magna (3 patients), and a wide cavum septum pellucidum (1 patient). One patient had a normal scan. The demonstration of a wide cavum septum pellucidum extends the spectrum of midline brain anomalies (ventral induction defects) reported in this condition. This study along with other recent reports suggests that midline brain anomalies may be frequent findings in Opitz syndrome.

The Johanson-Blizzard syndrome: case report and autopsy findings.

We report the case of a boy with the Johanson-Blizzard syndrome who died at the age of 8 years with complications of pancreatic exocrine insufficiency, and at autopsy was found to have a small thyroid filled with colloid, virtually complete replacement of the pancreas with adipose tissue, and a brain of normal size but with evidence of a cortical developmental defect consisting of abnormalities of gyral formation and of cortical neuronal organization. In addition the boy had postnatal growth failure, apparent severe mental retardation, congenital scalp defects and scalp hair patterning abnormalities, aplasia of the nasal alae, nasolacrimo-cutaneous fistulae, hypotonia, severe congenital sensorineural deafness, and small conical and widely spaced teeth. Evidence is accumulating that this syndrome is likely to be inherited as an autosomal recessive disorder. Our case represents the first report of autopsy findings in the syndrome.

Study of the etiology of deafness in an institutionalized population in Colombia.

To identify causative factors we screened 1,715 deaf individuals from 16 schools for the deaf in Colombia. We found evidence of environmental causation in 579 (33.8%) cases, genetic in 608 (35.4%), and in 528 (30.8%) we were unable to identify the etiology. The degree of hearing loss was severe to profound in 1,238 (72.2%), although in 987 (57.5%) of the deaf population studied the hearing impairment was not noticed until 2 to 5 years of age. The frequent association of deafness with other anomalies underscores the importance of a careful clinical and ophthalmologic evaluation in individuals with hearing loss. Our observations also emphasize the need for programs directed towards the prevention of hearing loss, including primary prevention as well as early diagnosis, investigation of possible genetic causes, and rehabilitation of deaf individuals.