Pierpaolo Mastroiacovo

Teratogenic effects of antiepileptic drugs : Use of an international database on malformations and drug exposure (MADRE)

Summary: Purpose: The study goal was to assess teratogenic effects of antiepileptic drugs (AEDs) through the use of a surveillance system (MADRE) of infants with malformations.

Genotype–phenotype correlations and clinical diagnostic criteria in Wolf-Hirschhorn syndrome

We report on a clinical-genetic study of 16 Wolf-Hirschhorn syndrome (WHS) patients. Hemizygosity of 4p16.3 was detected by conventional prometaphase chromosome analysis (11 patients) or by molecular probes on apparently normal chromosomes (4 patients). One patient had normal chromosomes without a detectable molecular deletion within the WHS critical region. In each deleted patient, the deletion was demonstrated to be terminal by fluorescence in situ hybridization (FISH). The proximal breakpoint of the rearrangement was established by prometaphase chromosome analysis in cases with a visible deletion. It was within the 4p16.1 band in six patients, apparently coincident with the distal half of this band in five patients. The extent of each of the four submicroscopic deletions was established by FISH analyses with a set of overlapping cosmid clones spanning the 4p16.3 region. We found ample variations in both the size of the deletions and the position of the respective breakpoints. The precise definition of the cytogenetic defect permitted an analysis of the genotype-phenotype correlations in WHS, leading to the proposal of a set of minimal diagnostic criteria, which in turn may facilitate the selection of critical patients in the search for the gene(s) responsible for this disorder. We observed that genotype-phenotype correlations in WHS mostly depend on the size of the deletion, a deletion of <3.5 Mb resulting in a mild phenotype, in which malformations are absent. The absence of a detectable molecular deletion is still consistent with a WHS diagnosis. Based on these observations a minimal WHS phenotype was inferred, the clinical manifestations of which are restricted to the typical facial appearance, mild mental and growth retardation, and congenital hypotonia.

Congenital malformations in twins: An international study

Data provided by nine registries based in European and Latin America countries were analyzed to assess whether there is an excess of malformations in twins compared to singletons. Specific congenital malformations were coded according to the ninth revision of the International Classification of Diseases (ICD). Malformation rates and rate ratios (RR) for twins compared to singletons were calculated for each registry, and the homogeneity of the RRs was tested using the test of Breslow and Day. If departure from homogeneity in the different registries was not significant, registry-adjusted RRs with 95% confidence intervals were calculated. Overall, among 260,865 twins, 5,572 malformations were reported. A total of 101 different types of malformations or groups of defects was identified, and a homogeneous estimate of the RRs among registries was found for 91.1% of the malformations. Thirty-nine of the 92 malformations with homogeneous estimates of RRs were more common in twins than in singletons. For the remaining nine malformations, heterogeneous estimates of RRs were obtained. This study confirms the majority of already known associations and further identifies previously unreported malformations associated with twins. In conclusion, there is an excess of malformations in twins compared with singletons, and all anatomical sites are involved. The number of specific malformations associated with twins is higher than that previously reported in smaller studies.

Epidemiology and genetics of microtia-anotia: a registry based study on over one million births.

The epidemiology and genetics of microtia-anotia (M-A) were studied using data collected from the Italian Multicentre Birth Defects Registry (IPIMC) from 1983 to 1992. Among 1,173, 794 births, we identified 172 with M-A, a rate of 1.46/10,000; 38 infants (22.1%) had anotia. Of the 172 infants, 114 (66.2%) had an isolated defect, 48 (27.9%) were multiformed infants (MMI) with M-A, and 10 (5.8%) had a well defined syndrome. The frequency of bilateral defects among non-syndromic cases was 12% compared to 50% of syndromic cases (p = 0.007). Among the MMI only holoprosencephaly was preferentially associated with M-A (four cases observed upsilon 0.7 expected, p = 0.005). No significant variations were identified in the prevalence of non-syndromic cases by geographical area (range 0.62-2.37/10,000 births) or by five month time periods (range 0.21-2.58/10,000 births), nor was there evidence of time trends. When M-A cases were compared to controls, we found that mothers with parity 1 had a higher risk of giving birth to an MMI with M-A, and that mothers with chronic maternal insulin dependent diabetes were at significantly higher risk for having a child with M-A. MMI with M-A had higher rates of prematurity, low birth weight, reduced intrauterine growth, and neonatal mortality than infants with isolated M-A and controls. Babies with isolated M-A had, on average, a lower birth weight than controls; the difference was higher for females. The analysis of pedigrees and familial cases suggests an autosomal dominant trait with variable expression and incomplete penetrance in a proportion of cases, or a multifactorial aetiology. Three cases had consanguineous parents, but the absence of M-A among previous sibs does not support autosomal recessive inheritance.

Limb defects associated with major congenital anomalies: clinical and epidemiological study from the International Clearinghouse for Birth Defects Monitoring Systems.

Although limb defects associated with other congenital anomalies are rarely studied, they may provide insights into limb development that may be useful for etiologic studies and public health monitoring. We pooled data from 11 birth defect registries that are part of the International Clearinghouse for Birth Defects Monitoring Systems. We identified 666 infants, born from 1983 through 1993, who had a non-syndromal limb defect plus at least one other major malformation (rate 12.9/100,000 population). We used observed/expected ratios and log-linear models to detect association patterns. We found that specific limb defects occurred with relatively distinct sets of malformations. Preaxial limb defects occurred more frequently with microtia, esophageal atresia, anorectal atresia, heart defects, unilateral kidney dysgenesis, and some axial skeleton defects; postaxial defects with hypospadias; transverse defects with craniofacial defects, micrognathia, ring constrictions, and muscular defects; intercalary defects with omphalocele; split hand/foot with encephalocele; and amelia with anorectal atresia, omphalocele, severe genitalia defects, unilateral kidney dysgenesis, gastroschisis, and ring constriction. Log-linear modeling identified higher order associations among some of these same malformations.

Does googling for preconception care result in information consistent with international guidelines: a comparison of information found by Italian women of childbearing age and health professionals

BackgroundPreconception counseling is effective in reducing the risk of adverse pregnancy outcomes. The Internet is commonly used by women and health professionals to search for health information. We compared the consistency of preconception information found on the Internet with the recommendations published by American Journal of Obstetrics and Gynecology (AJOG) simulating a web search by women of childbearing age and health professionals.MethodsWe reviewed websites resulting from a Google search performed using search strings selected by Italian women of childbearing age and health professionals. We investigated if retrieved information was consistent with AJOG recommendations for preconception care. Logistic regression was used to compare presence of consistent recommendations between women and health professionals.ResultsThe highest frequency of correct recommendations was found for folic acid supplementation (39.4% of websites). Consistency of preconception information did not significantly differ between search strategies except for folic acid supplementation. “Communities and blogs” website category provided less frequently correct recommendations compared with “Medical/Public Agency category (i.e. folic acid supplementation (aOR 0.254; CI 0.098-0.664; pu2009=u2009<0.01). Commercial links, found in 60% of websites, were associated with presence of correct recommendations excepting few items (i.e. physical exercise (aOR 1.127; CI 0.331-3.840; pu2009=u20090.848).ConclusionsPreconception information found is poor and inaccurate regardless of the search is performed by women or health professionals. It is unlikely that information found on the web have any positive impact among women and health professionals in our setting. Strategies to improve preconception information on the web and education of health professionals for web searching of health information should be considered.

Severe form of Freeman-Sheldon syndrome associated with brain anomalies and hearing loss

We describe a child with whistling face and multiple contractures, including ulnar deviation of fingers, compatible with a diagnosis of Freeman-Sheldon syndrome (FSS). This patient also presented severe hypertonicity, multiple episodes of pneumonia, difficulty in swallowing, and poor weight gain, which are characteristic of the most severe cases of FSS. A brain CT scan showed cerebellar and brainstem atrophy. Auditory brainstem responses were absent. The child died at 5 months of respiratory failure. This case suggests the possibility that, especially in the most severe forms, brain abnormalities may be responsible for some of the clinical manifestations of this syndrome, i.e., respiratory problems, difficulty in swallowing and severe hypertonicity. We assume that there is more than one pathogenetic mechanism (muscular, skeletal, and neurological) underlying FSS, which, together with the genetic heterogeneity and the wide range of clinical symptoms leads us to suggest that it is more appropriate to speak of a Freeman-Sheldon spectrum rather than syndrome and that thorough investigation for CNS and auditory abnormalities should be part of the initial work-up of these patients.

Birth weight discordancy in twins: New definition and standard

OBJECTIVEnThe aim of this study was to improve the definition of birth weight discordancy based on its distribution in the population after a correction in the unlike sex pairs.nnnSTUDY DESIGNnThe analysis was conducted on 849 Italian twin pairs. Males birth weight in the unlike sex pairs was corrected by the physiological birth weight difference estimated on 21.595 Italian twins data. Birth weight discordancy was computed as a percentage of the larger twins birth weight and it was compared by sex pairs and by gestational ages (Kruskal-Wallis test). Kolmogorov-Smirnov test was used to fit a normal distribution to the square-root transformed birth weight discordancy.nnnRESULTSnThe estimated physiological birth weight difference between males and females was 4.39%, without any difference among gestational ages. The 90th centile of birth weight discordancy was 23.9% and the 95th centile was 29.2%.nnnCONCLUSIONSnNinetieth and 95th centiles of the fitted distribution are proposed as cut-off values for the definition of mild and severe birth weight discordancy.

Opitz C trigonocephaly syndrome and midline brain anomalies

We describe a child with trigonocephaly, strabismus, upslanting palpebral fissures, nasal bridge hypoplasia, hypertrophic alveolar ridges and large gingivo-labial frenula, short neck, hip dysplasia, equinovarus deformities, cryptorchidism, atrial septal defect ostium secundum, and severe mental retardation, findings consistent with C syndrome. The patient also had a Dandy-Walker malformation, complete callosal agenesis, and occipital meningocele. These structural defects are independent of the premature closure of the metopic suture, and confirm that midline brain anomalies are part of C syndrome. The hypothesis that the basic developmental defect in this syndrome primarily affects the midline field is supported by the concomitance of other anomalies, such as conotruncal heart defects, omphalocele, and genital anomalies.

Cerebro-facio-articular syndrome of Van Maldergem: confirmation of a new MR/MCA syndrome

Van Maldergem et al. (1992) described a new syndrome in an 11‐year‐old girl, characterized by: mental retardation, hypotonia, dysmorphic facies with telecanthus, epicanthus, broad flattened nose, large inverted W‐shaped mouth, malformed ears, finger camptodactyly, and joint hyperlaxity. In this report we present a 5‐year‐old girl with very similar clinical findings. We confirm the existence of this condition as an independent clinical entity, and we propose that, based on the major clinical manifestations, it should be defined as “cerebro‐facio‐articular” syndrome.