Purpose: To provide insight into the possible etiology and prevalence of heterotaxy, we studied conditions associated with heterotaxy in a consecutive hospital population of newborns. Methods: From 1972 to March, 1999 (except February 16, 1972 to December 31, 1978, 5 8 cases of heterotaxy were ascertained from a cohort of 201,084 births in the ongoing Active Malformation Surveillance Program at the Brigham and Women's Hospital.This registry includes livebirths, stillbirths, and elective abortions. Prevalence among nontransfers (i.e., patients whose mothers had planned delivery at this hospital) was calculated as approximately 1 per 10,000 total births (20 of 201,084). Results: We analyzed a total of 5 8 patients consisting of 20 (34%) nontransfers and 3 8 (66%) transfers. Patients were categorized by spleen status as having asplenia (7 nontransfers, 25 total), polysplenia (8,20), right spleen (4, l l ) , normal left (0, I ) , and unknown (1, 0). Among the 20 nontransfer and 5 9 total heterotaxy patients, the following associated medical conditions were present: chromosome abnormality ( 1 nontransfer, 2 total), suspected Mendelian or chromosome microdeletion disorder (1 nontransfer, 6 total), and maternal insulindependent diabetes mellitus ( 1 nontransfer, 2 total). There were 6 twins ( 1 member each from 6 twin pairs including 1 dizygous, 4 monozygous, 1 conjoined; 2 were nontransfers). An associated condition occurred in 5 (25%) nontransfer and 1 6 (28%) total patients, or among 1 0 of 53 singleton births (19%). Conclusions: Although most cases of heterotaxy in this series were sporadic events, an associated condition was present in about one-fourth of the cases. Not all of these conditions would be considered causative etiologies. Based on this small series alone, maternal insulin-dependent diabetes cannot be viewed as a risk factor for heterotaxy. However, the specific association of diabetes with polysplenia with/without left atrial isomerism is noteworthy, and adds weight to animal and epidemiologic case-control data. Genetics in Medicine, 2000:2(3):157-172.Key Words: Asplenia, cardiovascular malformations, congenital heart defects, defects of right, left determination, genetic epidemiology, heterotaxy, isomerism, laterality defects, maternal diabetes, polysplenia, prevalence, situs ambiguous, situs inversus Errors in the development o f the normal right-left axis in humans can produce a variety o f laterality defects. The classification o f these complexes is most meaningful when information about the heart, lungs, cilia, spleen, and abdominal organs is combined. Classical heterotaxy refers t o abnormal abdominal and thoracic visceral situs, which may include the presence o f symmetry (i.e., right or left isomerism), ambiguous or inFront the 'Departrrrmt ofNpwborn klnircrnc, tlr~. Brtglrottr olld l\'otrrcn', Hosprml; tlrc-'Gcnetrcs and Terntolory Urrir, IJ~diatric Servrce, and 'Dn,rsrotr ufPediatrr<-Gtrdrolug) verted situs, abnormalities o f the spleen and complex cardiovascular malformations (CVM...

ABSTRACT. Objective. The prevalence rate of all types of limb reduction defects in general and those that potentially are caused by vascular disruption in particular is needed to provide a baseline for the evaluation of infants who are exposed in utero to teratogens that cause vascular disruption. The objective of this study was to determine this prevalence rate.Methods. All infants with any limb deficiency among 161 252 liveborn and stillborn infants and elective terminations were identified in a hospital-based Active Malformations Surveillance Program in Boston in the years 1972 to 1974 and 1979 to 1994. An extensive search was made to identify infants who were missed by the Surveillance Program; an additional 8 infants (7.3% of total) were identified. The limb reduction defects were classified in 3 ways: 1) by the anatomic location of the defect, that is longitudinal, terminal, intercalary, etc; 2) for infants with absence/hypoplasia of fingers or toes, a tabulation of which digit or digits were affected; and 3) by apparent cause.Results. The prevalence rate for all types of limb deficiency was 0.69/1000. The apparent causes included single mutant genes, familial occurrence, and known syndromes (24%); chromosome abnormalities (6%); teratogens (4%); vascular disruption (35%); and unknown cause (32%).Conclusions. A hospital-based surveillance program can be used to establish the prevalence of limb reduction defects, if ascertainment is extended to include elective terminations for fetal abnormalities. An apparent cause can be established for most limb defects when the clinical findings are used rather than reliance only on the International Classification of Diseases, Ninth Revision, codes of the discharge diagnoses. The prevalence rate of limb reduction defects as a result of presumed vascular disruption was 0.22/1000. Pediatrics 2001;108(4). URL: http://www.pediatrics.org/cgi/content/full/108/4/e64; limb deficiency, vascular disruption.

Limb deficiencies, the congenital absence or hypoplasia of a long bone and/or digits, vary greatly in their anatomy and etiology. Previous attempts to classify the range of possible phenotypes have not included all types of deficiencies. We present a new classification system, which includes all potential phenotypes. Infants with limb deficiencies were identified in the hospitalbased Active Malformations Surveillance Program at Brigham and Women's Hospital in Boston, MA from the years 1972 to 1974 and 1979 to 2000. Affected infants were classified based on the anatomy and apparent cause of their deficiencies. The prevalence rate of all types of limb deficiency was 0.79/1,000. Upper limb deficiencies were significantly more common than lower limb deficiencies. There was no significant difference in frequencies between deficiencies on the left and right sides of the body. Longitudinal defects were more common than terminal transverse defects; intercalary defects were uncommon. Longitudinal defects were most likely to occur on the preaxial side of the limb. Almost half of affected infants had affected digits, with normal long bones. The most common apparent cause of limb deficiencies was vascular disruption defects (0.22/1,000), such as amniotic band-related limb deficiency. This new classification system includes deficiency of each long bone, as well as absence of any finger or toe. This system will make it possible to establish the prevalence of each specific phenotype. The large number of distinct apparent causes illustrates the marked etiologic heterogeneity of limb deficiencies.