Eduardo E. Castilla

Epidemiology of congenital pigmented naevi: I. Incidence rates and relative frequencies

Pigmented naevi (PN) were clinically diagnosed in 1083 newborn infants from a series of 531,831 consecutive livebirths examined in fifty‐nine hospitals in South America. Isolated PN (IPN) were seen in 989 (0.2%) non‐malformed infants, while PN associated with other congenital anomalies (APN) were observed in ninety‐four (1.0%) malformed babies. Incidence rates calculated from the fifty‐nine hospitals were very variable due to under‐reporting, which might have been as high as 80%. The PN were classified by their location, number, size, texture, and colour. Observed locations were compared with random expected distributions based on the surface proportions of the newborn. IPN were preferentially found on the chest and abdomen, with a low concentration on the head and upper limbs. No examples were observed on soles or palms. IPN were single in 90% of cases. Size was small (1–9 mm) in 29%, medium (10–;40 mm) in 63%, and large (over 40 mm) in 8% of cases. Abnormal texture, (rugose, raised, and/or hairy) was found in 7–11% of IPN. Colour was brown in 68%, black in 21%, and of other colours in 11%. The large IPN tended to be multiple in number and abnormal in texture. Small IPN tended to be black. IPN on the chest and abdomen were more frequently small, non‐black, and of normal texture; those found on the back tended to be black and abnormal in texture; black IPN were also frequent on the upper limbs; large IPN frequently affected the lower limbs. The APN did not differ from the IPN in their number, size, texture, or colour. APN were less common than expected on the back and upper limbs. An association was observed between the PN and the following four congenital anomalies: ear deformities, preauricular appendages, angiomas, and other skin anomalies. The differences in distribution of PN in the newborn infant and that in the adult that have been previously published suggest that most of the PN found in the adult are not congenital.

Epidemiology of congenital pigmented naevi: II. Risk factors.

Genetic and environmental risk factors were investigated in a sample of 989 non‐malformed newborn infants with skin pigmented naevi (PN), and in 989 non‐malformed non‐PN, control babies. The samples were obtained from a population of 531,831 livebirths, from fifty‐nine South‐American maternity hospitals. No significant differences were observed between the PN and control groups for the following risk factors: sex, twinning, parental consanguinity, socioeconomic level, parental ages, birth order, fetal presentation, type of delivery, postnatal mortality, and first trimester of pregnancy histories for maternal chronic illnesses or immunizations, radiation exposure, drug intake, and vaginal bleeding. PN infants were associated with high frequencies of Black racial ancestry, positive prenatal history for maternal acute illnesses, and high mean values for length of gestation and birth weight. The observed association of PN with maternal acute illnesses could be a spurious one, due to partial dependence upon Black racial ancestry, and to maternal memory bias. The analysis of the intrauterine growth curves showed that PN infants have a low prematurity rate, and a high mean birth weight within the postmature group, lacking the normal post‐term weight loss pattern shown by the control newborn group. This observation suggests that congenital PN appear in the latest stages of intrauterine development. No evidence was obtained to allow us to consider congenital PN as true developmental anomalies.

Frequency of holoprosencephaly in the International Clearinghouse Birth Defects Surveillance Systems: Searching for population variations

BACKGROUND Holoprosencephaly (HPE) is a developmental field defect of the brain that results in incomplete separation of the cerebral hemispheres that includes less severe phenotypes, such as arhinencephaly and single median maxillary central incisor. Information on the epidemiology of HPE is limited, both because few population-based studies have been reported, and because small studies must observe a greater number of years in order to accumulate sufficient numbers of births for a reliable estimate. METHODS We collected data from 2000 through 2004 from 24 of the 46 Birth Defects Registry Members of the International Clearinghouse for Birth Defects Surveillance and Research. This study is based on more than 7 million births in various areas from North and South America, Europe, and Australia. RESULTS A total of 963 HPE cases were registered, yielding an overall prevalence of 1.31 per 10,000 births. Because the estimate was heterogeneous, possible causes of variations among populations were analyzed: random variation, under-reporting and over-reporting bias, variation in proportion of termination of pregnancies among all registered cases and real differences among populations. CONCLUSIONS The data do not suggest large differences in total prevalence of HPE among the studied populations that would be useful to generate etiological hypotheses.

Risk Assessment in Reproductive Toxicology as Practiced in South America

Comprehensive assessments of safety and efficacy of medicinal products and risk assessment of pesticides, food additives, industrial chemicals, and others, have rarely been, if ever, undertaken in South America. Moreover, when risk estimates are used for risk management in South America, those estimates are drawn, in most instances, from studies conducted in industrialized countries which do not necessarily take relevant characteristics of the particular exposure scenarios into account.

Molecular analysis of holoprosencephaly in South America

Holoprosencephaly (HPE) is a spectrum of brain and facial malformations primarily reflecting genetic factors, such as chromosomal abnormalities and gene mutations. Here, we present a clinical and molecular analysis of 195 probands with HPE or microforms; approximately 72% of the patients were derived from the Latin American Collaborative Study of Congenital Malformations (ECLAMC), and 82% of the patients were newborns. Alobar HPE was the predominant brain defect in almost all facial defect categories, except for patients without oral cleft and median or lateral oral clefts. Ethmocephaly, cebocephaly, and premaxillary agenesis were primarily observed among female patients. Premaxillary agenesis occurred in six of the nine diabetic mothers. Recurrence of HPE or microform was approximately 19%. The frequency of microdeletions, detected using Multiplex Ligation-dependant Probe Amplification (MLPA) was 17% in patients with a normal karyotype. Cytogenetics or QF-PCR analyses revealed chromosomal anomalies in 27% of the probands. Mutational analyses in genes SHH, ZIC2, SIX3 and TGIF were performed in 119 patients, revealing eight mutations in SHH, two mutations in SIX3 and two mutations in ZIC2. Thus, a detailed clinical description of new HPE cases with identified genetic anomalies might establish genotypic and phenotypic correlations and contribute to the development of additional strategies for the analysis of new cases.

Renal defects and limb deficiencies in 197 infants

Dieker and Opitz in 1969 described the simultaneous occurrence of limb deficiencies (LDs) and renal anomalies (RAs) in three patients. Curran and Curran introduced in 1972 the term “acrorenal syndrome.” Since then, the term “acrorenal syndrome” is used occasionally, but a well‐circumscribed definition has never been established. On the other hand, the concept of an acrorenal polytopic developmental field defect was postulated by Opitz and others to explain the association between RAs and LDs. We undertook this study to investigate whether this acrorenal “syndrome” could be identified in a large group of cases with congenital RAs and a limb deficiency. Eleven birth defect registries that are part of the International Clearinghouse for Birth Defects Monitoring (i.e., registries of ICBDMS in Finland, France [Paris and Strasbourg], Israel, Italy [IPIMC and Emilia Romagna], Mexico, Northern Netherlands, South America, Spain, and the United States [Atlanta]) provided data on 815 infants who had a LD and at least one other major congenital anomaly. These 815 cases were ascertained among 5,163,958 births. We selected the 197 cases who had both a limb deficiency and a renal or urinary tract anomaly. In about 50% of these cases a diagnosis or a recognized phenotype was reported, with chromosomal aberrations and VACTERL being most frequent. In the group with no diagnosis or recognized phenotype (95 cases), we looked for (a) clustering of specific types of LDs and RAs, and (b) for clustering of associated anomalies, in order to find evidence for and be able to define better the term “acrorenal syndrome.” Our data suggest that an association exists between LDs and RAs, possibly explained by the concept of the acrorenal polytopic developmental field defect. However, our dataset does not yield evidence for the existence of one distinct “syndrome,” defined as a pattern of causally related multiple anomalies. Therefore, use of the term “acrorenal syndrome” should be avoided.