Hypothesis: Symbrachydactyly.

The term symbrachydactyly has been used for the phenotype of two or three short fingers or toes, hypoplasia of the middle and distal phalanges and variable syndactyly of the affected digits. Some clinicians have extended this diagnosis to include other phenotypes, specifically cleft hand, terminal transverse limb defects, hypoplasia of the thumb and fifth finger with nubbins for fingers 2, 3, and 4 and the hand deformity of the Poland anomaly. A malformations surveillance program can identify enough affected infants to characterize a phenotype. In the Active Malformations Surveillance Program in Boston (1972-2012) among 289,365 births, all infants and fetuses with structural abnormalities were identified from reading the examination findings by the pediatricians and pathologists and the results of diagnostic tests. Liveborn and stillborn infants were included, as well as fetuses from elective terminations because of anomalies identified in prenatal testing. We present the findings in 14 infants, all liveborn, who had symbrachydactyly of one or both hands (n = 12) or feet (n = 2). We suggest restricting the term symbrachydactyly to this single phenotype to improve counseling and to focus future research on identifying the cause(s).

Hypothesis: Central digit hypoplasia.

Limb deficiencies are a common birth defect. A malformations surveillance program among many newborns, stillborn fetuses, and malformed fetuses in elective terminations can identify a sufficient number of infants with the same set of abnormalities to characterize a specific limb deficiency phenotype. The active malformations surveillance program was carried out among 289,365 births at Brigham and Women's Hospital in Boston over a 41-year period (1972-2012). The research assistants identified the affected infants and fetuses from reading the findings recorded in each newborn's medical record by the examining pediatricians and consultants and by the pathologists in autopsies. One hundred ninety-four newborn infants and fetuses were found to have a limb deficiency either as an isolated abnormality or as one of multiple malformations. We identified three phenotypes of limb deficiency. We present here the seventeen infants and fetuses with "central digit hypoplasia," a term we suggest for this phenotype: hypoplasia of the thumb and fifth finger with nubbins of soft tissue in place of fingers 2, 3, and 4 at the level of the metacarpal-phalangeal joint. Central digit hypoplasia is to be distinguished primarily from the terminal transverse limb defect that ends at the wrist. In symbrachydactyly, the middle and distal phalanges of the fingers and toes are hypoplastic. In addition, central digit hypoplasia should be distinguished from the amniotic band syndrome, the most common and incorrect diagnosis suggested by the pediatricians and the consultants in this survey. The affected infant and her/his parents benefit from more accurate and specific counseling.

Terminal transverse limb defects with "nubbins".

BACKGROUND: A terminal transverse limb defect with absence of the forearm and hand or just the hand is an uncommon limb deformity in an otherwise healthy newborn. Most of the affected infants also have tiny digit-like nubbins on the stump of the affected limb, a finding that could represent an attempt at regeneration following vascular obstruction in early limb development. METHODS: One hundred ninety-four newborn infants with a limb deficiency were identified among 289,365 births in an active malformations surveillance program at Brigham and Women's Hospital in Boston, MA from 1972 to 2012. Twenty-eight infants with terminal transverse limb defects were identified. RESULTS: Twenty-four had tiny digit-like nubbins (0.5 cm in length) on the stump at one of three levels: the proximal portion of the forearm, the wrist or the forefoot. The examination of the placentas of eight affected infants showed no evidence of amnion rupture. Three of these 28 infants had associate chromosome abnormalities: trisomy 21, chromosome 11q deletion and the deletion of 22q11.2. CONCLUSION: Terminal transverse limb defects reflect failure of early limb development. Awareness of this phenotype at birth, or when identified by ultrasound screening, can provide more accurate counseling than occurs with the more common misdiagnosis of "amniotic band syndrome."

Limited surface examination to evaluate potential teratogens in a resource-limited setting.

BACKGROUND: To determine the frequency of malformations that would be identified in the limited surface examination of a newborn by the delivering nurse midwife in a resource-limited setting. METHODS: The limited surface examination will identify visible external anomalies, but not abnormalities inside the mouth, most heart defects, undescended testes, inguinal hernias, hip dysplasia, peripheral vascular anomalies, and some internal anomalies. The findings in a malformations surveillance program, involving 289,365 births in Boston, have been used to establish the prevalence rate of malformations that would be identified and not identified. In African countries, the number of anomalies to be identified should also be reduced by excluding polydactyly, postaxial, type B, a common minor finding, from the list of potential malformations. RESULTS: Of note, 2.05% (n = 5,941) of the 289,365 births surveyed had one or more malformations. The abnormalities that would have been missed, using surface exam alone, accounted for 0.5% of all of malformations identified and reduced the overall prevalence rate of malformations to 1.5%. In addition, excluding all infants with isolated postaxial polydactyly, type B reduced the expected prevalence rate of malformations to 1.3% in unexposed newborn infants. CONCLUSION: A limited surface examination can detect the majority of malformations among newborn infants.

Polydactyly, postaxial, type B.

BACKGROUND: Postaxial polydactyly, type B is the most common type of polydactyly. The vestigial sixth finger is attached by a narrow neurovascular pedicle to the lateral aspect of the hand or foot at the level of the metacarpal-phalangeal joint or the metatarsal-phalangeal joint. The occurrence of this type of polydactyly varies among racial groups, by sex and sidedness. Postaxial polydactyly, type A is a fully developed extra digit on the lateral aspect of the hand or foot with a bifid fifth or sixth metacarpal/metatarsal and is much less common. METHODS: In a malformations surveillance program, the frequency in racial groups, sex ratio and the frequency of other anomalies can be established. RESULTS: Five hundred forty-five affected infants were identified from 1972 to 2012 in the surveillance of 289,365 liveborn and stillborn infants and elective terminations because of fetal anomalies detected prenatally. Postaxial polydactyly, type B was an isolated anomaly in 95% of the affected newborns. There were more affected males than females. Black infants were affected more often than White infants: 0.91/100 vs. 0.035/100 infants. The dangling extra digit was much more common in the hands than in the feet. CONCLUSIONS: Postaxial polydactyly, type B is almost always an isolated, mild malformation with no medical significance. Postaxial polydactyly, types B and A occurred in several infants, suggesting that either the underlying mutation(s) can cause both types of postaxial polydactyly or that some affected infants have more than one mutation. Autosomal dominant inheritance with variable expressivity is postulated.

Malformations among infants of mothers with insulin-dependent diabetes: Is there a recognizable pattern of abnormalities?

BACKGROUND: Infants of diabetic mothers have been shown in several studies to have an increased frequency of malformations. In previous studies, an increased frequency of several specific malformations has been noted, including anencephaly, bilateral renal agenesis, and double outlet right ventricle. Surveillance, used to identify all malformed infants in a consecutive sample of births, can identify a distinctive pattern of malformations among the affected infants. METHODS: The infants of insulin-dependent, pregestational diabetic mothers were identified in the daily review of the medical records of each newborn infant with a malformation and her/his mother's medical record. Infants of mothers with gestational diabetes were excluded. The frequency of each malformation was compared to that among the malformed infants of nondiabetic mothers. RESULTS: One hundred and eighty-three malformed infants of diabetic mothers were identified among the 289,365 births. The most notable malformations were: neural tube defects (anencephaly, 9%), heart defects (transposition of great arteries, 4%), bilateral renal agenesis or dysgenesis (6%), and vertebral anomalies (hemivertebrae, 4%). CONCLUSIONS: There was a recognizable pattern of malformations and characteristics of infants of diabetic mothers, although there was variation in the pattern among affected infants. Some of the malformations in the diabetic embryopathy can be identified in prenatal screening by ultrasound. More important, their occurrence can be reduced significantly by the mother achieving much better control of her diabetes mellitus prior to conception.

Malformations attributed to the process of vascular disruption.

BACKGROUND: Several malformations have been attributed to the process of vascular disruption. The central hypothesis for this etiology is that blood flow to a structure has been altered after that structure had formed normally. The decreased blood flow leads to hypoxia, endothelial cell damage, hemorrhage, tissue loss, and repair. After recovery, some structures are normal and others show either tissue loss or structural abnormalities, such as syndactyly and constriction rings. METHODS: The phenotypic features of the 7,020 infants with one or more malformations, who were born to women who had always planned to deliver at Brigham and Women's Hospital (BWH) between, 1972 and 2012, that is, maternal nontransfers, were reviewed. The phenotypes associated with vascular disruption, such as the amniotic band syndrome and terminal transverse limb defects (TTLD), were identified. RESULTS: One hundred and five fetuses and infants had malformations attributed to the process of vascular disruption. Some specific causes of the amniotic band limb deformity were identified. TTLD with associated small digit-like nubbins occurred at three levels: proximal forearm, wrist, and metacarpal-phalangeal joint. Other causes included severe hemoglobinopathies and exposures to misoprostol and to prenatal procedures. CONCLUSIONS: Malformations attributed to the process of vascular disruption were a distinctive entity, among the recognized etiologies. The timing of the causative event in the first trimester was established for infants with exposures to either the prostaglandin misoprostol or the prenatal diagnosis procedure chorionic villus sampling. One challenge is to identify the developmental steps in vascular disruption when no causative exposure can be identified.

Malformations among 289,365 Births Attributed to Mutations with Autosomal Dominant and Recessive and X-Linked Inheritance.

BACKGROUND: The number of malformations attributed to mutations with autosomal or X-linked patterns of inheritance has increased steadily since the cataloging began in the 1960s. These diagnoses have been based primarily on the pattern of phenotypic features among close relatives. A malformations surveillance program conducted in consecutive pregnancies can identify both known and "new" hereditary disorders. METHODS: The Active Malformations Surveillance Program was carried out among 289,365 births over 41 years (1972-2012) at Brigham and Women's Hospital in Boston. The findings recorded by examining pediatricians and all consultants were reviewed by study clinicians to establish the most likely diagnoses. The findings in laboratory testing in the newborn period were reviewed, as well. RESULTS: One hundred ninety-six (0.06%) infants among 289,365 births had a malformation or malformation syndrome that was attributed to Mendelian inheritance. A total of 133 (68%) of the hereditary malformations were attributed to autosomal dominant inheritance, with 94 (71%) attributed to apparent spontaneous mutations. Forty-six (23%) were attributed to mutations with autosomal recessive inheritance, 17 associated with consanguinity. Seventeen (9%) were attributed to X-linked inheritance. Fifteen novel familial phenotypes were identified. The family histories showed that most (53 to 71%) of the affected infants were born, as a surprise, to healthy, unaffected parents. CONCLUSION: It is important for clinicians to discuss with surprised healthy parents how they can have an infant with an hereditary condition. Future studies, using DNA samples from consecutive populations of infants with malformations and whole genome sequencing, will identify many more mutations in loci associated with mendelizing phenotypes. Birth Defects Research 110:92-97, 2018.© 2018 Wiley Periodicals, Inc.

The Active Malformations Surveillance Program, Boston in 1972-2012: Methodology and demographic characteristics.

BACKGROUND: Malformations surveillance programs have been carried out in consecutive populations of newborn infants at single hospitals, as well as in several hospitals in defined populations. A surveillance program begins with the review of the findings recorded by the examining pediatrician in each infant's medical record. The results of diagnostic tests, consultations, and imaging studies are obtained, also, from that infant's medical record. Some malformations surveillance programs identify additional malformations over several months, as the infants have hospitalizations and additional diagnostic testing. METHODS: 289,365 infants (liveborn, stillborn, and fetuses in pregnancies terminated because of anomalies) were surveyed from 1972 to 2012 at an urban maternity center in Boston to identify each infant with one or more malformations. Each mother was interviewed to obtain demographic characteristics, results of prenatal testing, family history, and information about exposures in pregnancies. Specific diagnoses were established by the study geneticists. RESULTS: 7,020 (2.4%) of the 289,365 infants surveyed had one or more malformations. The etiologies identified included chromosome abnormalities, phenotypes attributed to dominant or recessive autosomal or X-linked mutations, vascular disruption, environmental factors, and complications of twinning. CONCLUSION: The surveillance of a large consecutive population of newborn infants, stillbirths, and aborted fetuses can identify with high reliability all infants with one or more malformations. This process of ascertainment of affected newborns can be used to improve genetic counseling, identify "new" phenotypes, and serve as a system for testing new technologies to establish more causes of congenital malformations.

Stillborn Infants: Associated Malformations.

BACKGROUND: Stillbirth, defined as death of a fetus in utero after 20 weeks of gestation, occurs in 1 to 2% of pregnancies in the United States. Many of these stillborn infants have associated malformations, including chromosome abnormalities, neural tube defects, and malformation syndromes. Other causes are abnormalities of the placenta and maternal conditions, such as pre-eclampsia and obesity. A consecutive sample of malformed stillborn infants can establish the relative frequency and severity of the associated malformations. METHODS: Stillbirths were identified in the Active Malformations Surveillance Program at Brigham and Women's Hospital (1972-2012). The findings at autopsy, including the findings in the placenta and the results of diagnostic studies, were compiled. RESULTS: One hundred twenty-seven stillborn infants with malformations were identified at autopsy among 289,365 pregnancies, including trisomies 21, 18, and 13; 45,X; triploidy; anencephaly; lower urinary tract obstruction; holoprosencephaly and severe heart defects, such as hypoplastic left heart syndrome and tetralogy of Fallot with pulmonary atresia. The severity of the abnormalities in stillborn infants was more severe than the spectrum of abnormalities identified in live-born infants. CONCLUSION: An autopsy of the stillborn fetus, including chromosome microarray and an examination of the placenta, can identify the underlying causes of the stillbirth. This review of stillborn fetuses with malformations showed that several different lethal malformations and heart defects are more common than among live-born infants. These postmortem examinations can improve the counseling of the parents about risks in future pregnancies. Birth Defects Research 110:114-121, 2018.© 2018 Wiley Periodicals, Inc.

Exposure to Sodium Valproate during Pregnancy: Facial Features and Signs of Autism.

BACKGROUND: Valproic acid (VPA) is the most teratogenic anticonvulsant drug in clinical use today. Children exposed prenatally to VPA have previously been shown to have dysmorphic craniofacial features, identified subjectively but not by anthropometric methods. Exposure to VPA has also been associated with an increased frequency of autism spectrum disorder (ASD). An increased cephalic index (the ratio of the cranial lateral width to the cranial anterior-posterior length) has been observed in children with ASD. METHODS: Forty-seven children exposed to VPA during the first trimester of pregnancy were evaluated for dysmorphic facial features, identified subjectively and by measurements. Each VPA-exposed child was evaluated for ASD using the Social Communication Questionnaire, Autism Diagnostic Interview-Revised, and Autism Diagnostic Observation Schedule. The same physical examination was carried out on an unexposed comparison group of 126 children. The unexposed children also had testing for cognitive performance by the Wechsler Intelligence Scale for Children. RESULTS: Several dysmorphic craniofacial features, including telecanthus, wide philtrum, and increased length of the upper lip were identified subjectively. Anthropometric measurements confirmed the increased intercanthal distance and documented additional findings, including an increased cephalic index and decreased head circumference/height index. There were no differences between the craniofacial features of VPA-exposed children with and without ASD. CONCLUSION: An increased frequency of dysmorphic craniofacial features was identified in children exposed to VPA during the first trimester of pregnancy. The most consistent finding was a larger cephalic index, which indicates a disproportion of increased width of the skull relative to the shortened anterior-posterior length. Birth Defects Research 109:1134-1143, 2017. © 2017 Wiley Periodicals, Inc.

Vascular limb defects and maternal age.

BACKGROUND: The prenatal diagnosis procedure chorionic villus sampling is associated with increased risk of vascular disruption limb defects. Some studies have suggested that these defects are more common among infants born to women 35 years and older while other studies have shown a correlation with younger mothers. METHODS: All infants with vascular disruption defects were identified in the Active Malformations Surveillance Program at Brigham and Women's Hospital in the years 1972-1974, 1979-2011. We compared the rate of occurrence of infants with vascular limb defects among women in theses age groups: ≤19, 20 to 34, and ≥35 years to the rate of occurrence of infants with preaxial polydactyly, adjusting for race. Infants with an identifiable cause of their defects were excluded. RESULTS: 106 infants with vascular disruption defects and 67 with preaxial polydactyly were identified. Seventeen percent of the infants with vascular disruption defects and 25% of the infants with preaxial polydactyly were born to women 35 and older (p = 0.23). In contrast, 16% of the infants with vascular disruption defects were born to young mothers (≤19 years) compared with 6.0% of the mothers of infants with preaxial polydactyly (adjusted odds ratio vs. 35+ years = 5.3, 95% confidence interval 1.4-21, p = 0.017). CONCLUSION: Women 35 years old or older did not have increased risk for having a child with vascular disruption defects, but these defects were more common among infants of young (≤19) mothers, compared with the preaxial polydactyly group.