Limb/pelvis hypoplasia/aplasia with skull defect (Schinzel phocomelia): distinctive features and prenatal detection.

Schinzel phocomelia syndrome is characterized by limb/pelvis hypoplasia/aplasia: specifically, intercalary limb deficiencies and absent or hypoplastic pelvic bones. The phenotype is similar to that described in a related multiple malformation syndrome known as Al-Awadi/Raas-Rothschild syndrome. The additional important feature of large parietooccipital skull defects without meningocele, encephalocele, or other brain malformation has thus far been reported only in children with Schinzel phocomelia syndrome. We recently evaluated a boy affected with Schinzel phocomelia born to nonconsanguineous healthy parents of Mexican origin. A third-trimester fetal ultrasound scan showed severe limb deficiencies and an absent pelvis. The infant died shortly after birth. Dysmorphology examination, radiographs, and autopsy revealed quadrilateral intercalary limb deficiencies with preaxial toe polydactyly; an absent pelvis and a 7 x 3-cm skull defect; and extraskeletal anomalies including microtia, telecanthus, micropenis with cryptorchidism, renal cysts, stenosis of the colon, and a cleft alveolar ridge. A normal 46,XY karyotype was demonstrated, and autosomal recessive inheritance was presumed on the basis of previously reported families. This case report emphasizes the importance of recognizing severe pelvic and skull deficiencies (either post- or prenatally) in differentiating infants with Schinzel phocomelia from other multiple malformation syndromes that feature intercalary limb defects, including thalidomide embryopathy and Roberts-SC phocomelia.

A case-control study of maternal alcohol consumption and intrauterine growth retardation.

PURPOSE: Heavy maternal drinking during pregnancy causes fetal alcohol syndrome, but whether more moderate alcohol consumption is associated with such adverse pregnancy outcomes as intrauterine growth retardation (IUGR) remains controversial. METHODS: Using data from a case-control study, we examined the association between maternal alcohol consumption and risk for IUGR among 701 case and 336 control infants born during 1993-1995 in Monroe County, New York. RESULTS: Our results provide no evidence of an independent association between moderate maternal alcohol consumption (<14 drinks per week) and risk for IUGR. The risk for IUGR among heavy drinkers (> or =14 drinks per week) around the time of conception was OR = 1.4 (95% CI 0.7-2.6) for IUGR < or = 5th percentile and OR = 1.4 (95% CI 0.7-2.8) for IUGR 5th-10th percentile. For heavy drinkers during the first trimester, the OR was 1.3 (95% CI 0.4-4.5) for IUGR < or = 5th percentile and OR = 1.3 (95% CI 0.4-4.8) for IUGR 5th-10th percentile. CONCLUSIONS: Since IUGR is a heterogeneous outcome with a possible multifactorial origin, further studies are needed to examine the combined effects of alcohol and other environmental and genetic factors on IUGR risk for subgroups of IUGR.

On the symmetry of limb deficiencies among children with multiple congenital anomalies.

In humans, unpaired organs are placed in a highly ordered pattern along the left-right axis. As indicated by animal studies, a cascade of signaling molecules establish left-right asymmetry in the developing embryo. Some of the same genes are involved also in limb patterning. To provide a better insight into the connection between these processes in humans, we analysed the symmetry of limb deficiencies among infants with multiple congenital anomalies. The study was based on data collected by the International Clearinghouse for Birth Defects Monitoring Systems (ICBDMS). Registries of the ICBDMS provided information on infants who, in addition to a limb deficiency, also had at least one major congenital anomaly in other organ systems. We reviewed 815 such cases of which 149 cases (18.3 %) were syndromic and 666 (81.7 %) were nonsyndromic. The comparisons were made within the associated limb deficiencies, considering the information on symmetry, using a comparison group with malformations associated not involved in the index association. Among the non-syndromic cases, the left-right distribution of limb deficiencies did not differ appreciably between limb deficiency subtypes (e.g., preaxial, transverse, longitudinal). The left-right distribution of limb anomalies did not differ among most types of non-limb anomalies, though a predominance of left-sided limb deficiencies was observed in the presence of severe genital defects - odds ratio [OR], 2.6; 95 % CI, 1.1-6.4). Limb deficiencies (LDs) were more often unilateral than bilateral when accompanied by gastroschisis (OR, 0.1) or axial skeletal defects (OR, 0.5). On the contrary, LDs were more often bilateral than unilateral when associated with cleft lip with or without cleft palate (OR, 3.9) or micrognathia (OR, 2.6). Specifically, we found an association between bilateral preaxial deficiencies and cleft lip, bilateral amelia with gastroschisis and urinary tract anomalies, and bilateral transverse deficiencies and gastroschisis and axial skeleton defects. Of 149 syndromic cases, 62 (41.6 %) were diagnosed as trisomy 18. Out of the 30 cases of trisomy 18 with known laterality, 20 cases were bilateral. In the remainder the right and left sides were equally affected. Also, in most cases (74.4 %) only the upper limbs were involved. In conclusion the left-right distribution of limb deficiencies among some non-limb anomalies may suggest a relationship between the development of the limb and the left-right axis of the embryo.

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.

Sickle hemoglobin (HbS) allele and sickle cell disease: a HuGE review.

Sickle cell disease is caused by a variant of the beta-globin gene called sickle hemoglobin (Hb S). Inherited autosomal recessively, either two copies of Hb S or one copy of Hb S plus another beta-globin variant (such as Hb C) are required for disease expression. Hb S carriers are protected from malaria infection, and this protection probably led to the high frequency of Hb S in individuals of African and Mediterranean ancestry. Despite this advantage, individuals with sickle cell disease exhibit significant morbidity and mortality. Symptoms include chronic anemia, acute chest syndrome, stroke, splenic and renal dysfunction, pain crises, and susceptibility to bacterial infections. Pediatric mortality is primarily due to bacterial infection and stroke. In adults, specific causes of mortality are more varied, but individuals with more symptomatic disease may exhibit early mortality. Disease expression is variable and is modified by several factors, the most influential being genotype. Other factors include beta-globin cluster haplotypes, alpha-globin gene number, and fetal hemoglobin expression. In recent years, newborn screening, better medical care, parent education, and penicillin prophylaxis have successfully reduced morbidity and mortality due to Hb S.

Preventing morbidity and mortality from sickle cell disease. A public health perspective.

CONTEXT: Sickle cell disease is a group of conditions characterized by production of abnormal hemoglobin, with clinical manifestations that vary by genotype and age. OBJECTIVE: To discuss current public health issues associated with sickle cell disease, and approaches to preventing complications from these conditions in the United States. DESIGN: Literature review. RESULTS: Most clinical interventions for people with sickle cell disease discussed in the medical literature can be classified as tertiary prevention: for example, therapy to ameliorate anemia, reduce the frequency of pain crises, or prevent stroke recurrences. A form of secondary prevention, newborn screening, has emerged as an important public health approach to identifying affected children before they develop complications. Newborn screening is the starting point for simple public health strategies such as parental education, immunization, and penicillin prophylaxis. Identification of affected families by newborn or community screening programs has also been an entry point for genetic counseling, although utilization of prenatal testing has varied by factors such as geographic location. Public health agencies have had significant involvement with funding, policy making, and formulation of laboratory and clinical guidelines for sickle cell disease. Since the introduction of penicillin prophylaxis policies, newborn screening, new immunizations, and comprehensive medical care centers, the survival of young children with sickle cell disease has improved. CONCLUSIONS: Although the efforts of preventive medicine providers in public health programs are not solely responsible for the improved survival of children with sickle cell disease, such programs remain an important component in preventing sickle cell complications.

Goldenhar syndrome among infants born in military hospitals to Gulf War veterans.

Reports in the popular press described the occurrence of Goldenhar syndrome among children of Persian Gulf War veterans (GWVs). The objective of this investigation was to compare the birth prevalence of Goldenhar syndrome among infants born in military hospitals to GWVs and to military personnel who were not deployed to the Gulf War (NDVs). Computerized hospital discharge data were reviewed for infants conceived after the war and born prior to the 1st of October, 1993, in medical treatment facilities (MTFs) operated by the U.S. Department of Defense. Medical records were evaluated for infants diagnosed at birth with at least one abnormality that might be related to Goldenhar syndrome. Two pediatricians, blinded to the parental Gulf War status of each infant, reviewed records. An estimated 75,414 infants were conceived after the Gulf War and born in MTFs during the study period (34,069 GWV infants and 41,345 NDV infants). Seven infants fulfilled the case criteria (five GWV infants and two NDV infants). All infants had fathers who served in the military at the time of their conception and birth. The birth prevalence was 14.7 per 100,000 live births among GWV infants (95% confidence interval [CI]: 5.4-36.4) and 4.8 per 100,000 live births (95% CI: 0.8-19.5) among NDV infants (relative risk: 3.03; 95% CI: 0.63-20.57; P values: [2-tailed] = 0.26, [1-tailed] = 0.16). The few affected cases and the broad confidence intervals surrounding the relative risk require that these results be interpreted with caution and do not exclude chance as an explanation for these findings.

Contribution of birth defects and genetic diseases to pediatric hospitalizations. A population-based study.

OBJECTIVE: To estimate the contribution of birth defects and genetic diseases to pediatric hospitalizations by use of population-based data. DESIGN: Hospital discharges were categorized according to the diagnostic codes of The International Classification of Diseases, Ninth Revision, Clinical Modification. Hospitalizations that were related to birth defects and genetic diseases were compared with hospitalizations for other reasons, with respect to age, race/ethnicity, sex, length of stay, charges, source of payment, and mortality rate. Hospitalization rates and per capita charges were computed with the use of population estimates from 1990 census data. MATERIALS: The 1991 population-based hospital discharge data from California and South Carolina. RESULTS: Nearly 12% of pediatric hospitalizations in the 2 states combined were related to birth defects and genetic diseases. These children were, on average, about 3 years younger, stayed 3 days longer in a hospital, incurred 184% higher charges, and had a 4 1/2 times greater in-hospital mortality rate than children who were hospitalized for other reasons. The rate of hospitalizations that were related to birth defects and genetic diseases was 4 per 1000 children in both states, but these rates varied by age and race. CONCLUSION: These population-based data are the first contemporary findings to show the substantial morbidity rate and hospitalization charges associated with birth defects and genetic diseases in the pediatric population. IMPLICATIONS: This information is important for planning effective health care strategies, especially as the causes, treatments, and prevention of these disorders are being further elucidated by findings from human genome research and epidemiologic studies.

Does periconceptional multivitamin use reduce the risk for limb deficiency in offspring?

There is accumulating evidence that periconceptional multivitamin use may prevent the occurrence of some birth defects other than neural tube defects. Using data from the population-based Atlanta Birth Defects Case-Control Study, we investigated the possible association between periconceptional multivitamin use and the occurrence of limb deficiency. We examined the periconceptional use of multivitamins among mothers of 117 babies with nonsyndromic limb deficiency who were liveborn or stillborn to residents of metropolitan Atlanta from 1968 to 1980 and among mothers of 3,029 control babies born without birth defects who were randomly selected through birth certificates. We found that children whose mothers were periconceptional multivitamin users had a lower risk of having a limb deficiency [odds ratio (OR) = 0.47; 95% confidence interval (CI) = 0.23-0.97]. This protective effect, however, was mostly seen for transverse limb deficiency (OR = 0.30; 95% CI = 0.07-1.32) and not for longitudinal deficiency (including preaxial and postaxial deficiencies; OR = 1.03; 95% CI = 0.17-4.30). Adjustment for potential confounding factors did not change these findings. We found a trend of decreasing risk for all transverse limb deficiencies with earlier vitamin use. These data indicate that mothers' periconceptional multivitamin use may reduce the risk for some types of limb deficiency among their offspring. In addition, because we did not find the protective effect for all types of limb deficiency, the data may also indicate causal heterogeneity of limb deficiencies.

Epidemiology of biliary atresia: a population-based study.

OBJECTIVE: Biliary atresia is the leading cause of extrahepatic obstructive jaundice in the newborn and is the single most frequent indication for liver transplantation in children. The cause of biliary atresia is unknown, although several mechanisms have been postulated to explain the inflammatory process that obliterates the bile ducts. Most interest has been directed toward viral infections. Information about the epidemiologic characteristics of biliary atresia in well-defined populations is lacking but is essential for developing and addressing hypotheses of causation for the disease. METHODS: Infants with biliary atresia were identified in metropolitan Atlanta from 1968 through 1993 by a population-based birth defects surveillance system that ascertains infants with serious birth defects in the first year of life using active case ascertainment. Birth prevalence rates were analyzed for spatial and temporal clustering and effects attributable to county of residence, sex, race, maternal age, parity, and birth weight. Logistic regression was used to study the independent effects of the risk factors and to look for interactions. RESULTS: Fifty-seven infants with biliary atresia were identified, for a rate of 0.73 per 10,000 live births. There was significant seasonal clustering of the disease, with rates three times higher from December through March compared with rates from April through July. Rates were significantly higher among nonwhite infants compared with white infants (0.96 vs 0.44 per 10,000 live births) and infants born at term with low birth weights (<2500 g) compared with infants born at term with normal birth weights (> or = 2500 g) (2.62 vs 0.75 per 10,000 live births). CONCLUSIONS: Our study is the first in the United States to describe the epidemiologic characteristics of biliary atresia using a population-based approach. The demonstration of significant seasonal clustering provides support for theories that biliary atresia may be caused by environmental exposure (consistent with a viral cause) during the perinatal period.

The return of thalidomide: are birth defects surveillance systems ready?

In the 1960s, thalidomide caused limb deficiencies in thousands of infants worldwide. The limb deficiencies were frequently of the intercalary type. As a result, numerous countries started birth defect surveillance programs. In 1967, the Centers for Disease Control (CDC) started the Metropolitan Atlanta Congenital Defects Program (MACDP), a population-based surveillance system, to provide early warning against new teratogens. Recent studies have shown that thalidomide may be beneficial for a range of conditions, including cancer and AIDS, and it may once again become widely available. Here, we examine the ability of MACDP to detect an increase in the birth prevalence of limb deficiency as an early warning of fetal exposure to thalidomide. We calculated base rates for all limb deficiencies, for bilateral nonsyndromic intercalary or preaxial deficiencies, and for all nonsyndromic intercalary limb deficiencies among Atlanta infants born from 1968 through 1993. We used relative risk estimates from previous studies and a range of pregnancy exposure rates for thalidomide. We tested the statistical power of MACDP to detect subtle changes in the birth prevalence of these defects using Poisson and cumulative sum (CUSUM) techniques. The base rates for all limb deficiencies, for bilateral intercalary or preaxial deficiencies, and for all intercalary limb deficiencies, were 0.53, 0.035, and 0.022/1,000, and the estimated relative risks were 175, 4,570, and 8,180, respectively. We varied the assumed rate of exposure to thalidomide from 1/10,000 to 5/100. With a 1/1,000 exposure rate, both Poisson and CUSUM techniques will detect a rate change in intercalary limb deficiency in about 6 months of monitoring, and a rate change in bilateral intercalary or preaxial deficiencies in about 12 months of monitoring. When monitoring all limb deficiencies, a pregnancy exposure rate of 3.5% or less would go unnoticed by the Poisson method and would take more than 50 years for the CUSUM method to signal an alarm with a 1/1,000 exposure rate. However, for rates of exposure less than 1/1,000, a progressively longer period of time or larger sample are needed to detect a rate change by both methods. Our findings highlight the importance of enlarging the monitored population and correct case classification in birth defects surveillance.

Cystic fibrosis deaths in the United States from 1979 through 1991. An analysis using multiple-cause mortality data.

OBJECTIVE: To analyze mortality trends among people who died with a diagnosis of cystic fibrosis from January 1, 1979, through December 31, 1991. METHODS: We reviewed death certificate reports in the Multiple-Cause Mortality Files compiled by the National Center for Health Statistics. RESULTS: Of the 26,866,600 decedents in the study period, 6500 had a diagnosis of cystic fibrosis listed on their death certificates; of these, 6014 (92.5%) had cystic fibrosis listed as the underlying cause of death. The age-adjusted mortality rate decreased 21%, from 2.4 per 1 million in 1979 to 1.9 per 1 million in 1991, with similar decrements among males and females. The median age of death increased from 15 years in 1979 to 23 years in 1991. During the study period, whites were 6 times more likely to die with a diagnosis of cystic fibrosis than were blacks, and 8 times more likely than were people of other races. Comorbid conditions mentioned on death certificates included obstructive lung disease in 744 (11.5%), pneumonia in 1192 (18.3%), and right heart failure in 986 (15.2%). CONCLUSIONS: From 1979 through 1991, the age-adjusted mortality rate for cystic fibrosis decreased and the median age of death among decedents with a diagnosis of cystic fibrosis increased. These results probably are due to improved treatment of the disease in children, although we cannot exclude other explanations for these findings, such as changes in death certification and coding or better diagnosis of the disease.

Chorionic villus sampling and transverse digital deficiencies: evidence for anatomic and gestational-age specificity of the digital deficiencies in two studies.

Several but not all studies indicate that chorionic villus sampling (CVS) is associated with an increased risk for transverse limb deficiencies, including digital deficiencies. It has been suggested that variations in results regarding the transverse digital deficiencies (TDDs) may be due to the use of different classification criteria. We present the combined analysis of two case-control studies, the U.S. Multistate CVS (US) study and the Italian Multicentric Birth Defects (IP-IMC) study, using two different definitions of TDDs. We compared the frequency of CVS exposure in control infants with that among those infants with any number of affected digits (any TDD), and those with all five digits of at least one limb affected (extensive TDDs). The estimated relative risk (RR) for any TDD following CVS was 10.6 (IPIMC) and 6.6 (US). For the extensive TDDs, the RR was 30.5 (IPIMC) and 10.7 (US). In both studies, extensive TDDs were less than 25% of all TDDs. Compared to all TDDs, extensive TDDs were more likely to occur after CVS performed earlier in the first trimester (before 10-11 weeks' gestation). These findings suggest a relationship between the timing of CVS and the severity of TDDs; indicate that using a restrictive definition of TDDs (all five digits affected) may limit the ability to evaluate the association between CVS and TDDs in populations in whom CVS is usually performed at or after 10 weeks' gestation; and highlight the necessity to consider gestational age in any evaluation of the relative risk for limb deficiencies associated with CVS.

Increased risk for transverse digital deficiency after chorionic villus sampling: results of the United States Multistate Case-Control Study, 1988-1992.

Although numerous infants have been reported with transverse limb deficiencies after their mothers had undergone chorionic villus sampling (CVS), it has been unclear whether the procedure caused these defects. We report the results of the first multistate case-control study to assess and quantify the risk for specific limb deficiencies associated with CVS. Case subjects were 131 infants with nonsyndromic limb deficiency ascertained from 7 population-based birth defect surveillance programs, and born from 1988-1992 to mothers 34 years of age or older. Control subjects were 131 infants with other birth defects. We ascertained exposure to CVS from medical records and maternal and physician questionnaires. We assessed rates and timing of exposure to CVS, and estimated relative and absolute risks for anatomic subtypes of limb deficiency. The odds ratio for all types of limb deficiency after CVS from 8-12 weeks' gestation was 1.7 (95% confidence interval, 0.4-6.3). For specific anatomic subtypes, the strongest association was for transverse digital deficiency (odds ratio = 6.4; 95% confidence interval, 1.1-38.6). The risk for transverse digital deficiency increased with earlier gestational exposure (P < 0.01 for trend). We estimated that the absolute risk for transverse digital deficiency in infants after CVS was 1 per 2,900 births (0.03%). Exposure to CVS was associated with a sixfold increase in risk for transverse digital deficiency. The causality of this association is supported by its strength, specificity, biologic plausibility, and consistency with the results of previous studies. Although some centers already inform patients about risk for limb deficiency, this study quantifies the magnitude of risk associated with CVS from 8-12 weeks' gestation.

Harlequin Ichthyosis among the Navajo: Counseling issues.

Harlequin Ichthyosis is a rare, fatal congenital disorder of keratinization characterized by thickened, scale-like plaques of skin with a diamond configuration. Autosomal recessive inheritance has been established, and prenatal diagnosis for this disorder remains controversial. Five infants with this disorder were born among approximately 25,000 Navajo women who delivered in Gallup, New Mexico from 1970 to 1989. The incidence of 1 in 5000 among the Navajo in Gallup is high compared to previous reports in other populations. Two families with affected infants were seen in a genetics outreach clinic. Two important counseling issues were raised: (1) reluctance to discuss the possibility of recurrence for fear of affecting the outcome, and (2) feelings of guilt caused by cultural beliefs which attributed the birth defect to paternal behavior during pregnancy. Such issues are encountered in many traditional cultures, and they can be addressed by tailoring the timing and content of counseling.