Anorectal anomalies associated with or as part of other anomalies

Anorectal anomalies occurring with other anomalies or as part of syndromes were analyzed to determine how their epidemiological characteristics differed from those of isolated anal anomalies. Almost 15% of cases were chromosomal, monogenic or teratogenic syndromes, whereas the rest were of unknown cause including sequences (9.3%), VACTERL associations (15.4%) and multiple congenital anomalies (MCA) (60.2%). Almost half of babies with MCA had one or two VACTERL anomalies with distribution frequencies that did not differ significantly from those in babies with the full VACTERL association. There were considerable differences in the frequency of the VACTERL association among babies with different types of anorectal anomaly. Babies with anal anomalies occurring with sequences, VACTERL or MCA showed the same sex differences as babies with isolated anal anomalies, namely male predominance in anal atresia without fistula or cloaca, no sex difference in anal atresia with fistula, and female predominance in ectopic anus and congenital anal fistula. These anomalies, however, were associated with significantly lower mean gestational lengths and birth weights, and higher frequencies of fetal death and pregnancy termination than babies with isolated anal anomalies. Twins were more frequent in sequences, VACTERL and MCA than in isolated anomalies, monogenic syndromes or chromosome anomalies. Five cases were conjoined twins, representing 15% of all cases of twin pregnancies with an anal anomaly. Indeterminate sex was more frequent in babies with anal atresias without fistula than in those with fistula. Anal anomalies are defects of blastogenesis attributable to disorders in expression of pattern determining genes. The differential sex involvement in different types of anal anomaly may be manifestations of expression of the HY/SRY genes during blastogenesis or of X-linkage.     

Likelihood of meeting defined VATER/VACTERL phenotype in infants with esophageal atresia with or without tracheoesophageal fistula

Esophageal atresia (EA) with or without tracheoesophageal fistula (TEF) is a foregut defect that is a major component of the VATER/VACTERL association. The specific diagnostic criteria for the VATER/VACTERL association phenotype have changed over time. The current definition is presence of at least three of the following: V ertebral defects, A nal atresia, C ardiac defects, TE fistula, or R enal and L imb anomalies in the absence of a specific genetic diagnosis. Using the Texas Birth Defect Registry, 1,175 cases of EA+/?TEF (174 EA; 1,001 EA + TEF) were evaluated against strict definitions of VATER/VACTERL. Nine (5.2%) cases of EA alone and 164 (16.3%) cases of EA + TEF met criteria for a diagnosis of VATER; and 20 (11.5%) and 223 (22.2%), respectively, met criteria for VACTERL. Trisomy 21, Trisomy 18, 22q11 deletion, and CHARGE were the most common syndromic diagnoses. About 88.5% (154) cases of EA and 77.8% (778) cases of EA + TEF were likely not to meet the criteria for VACTERL. EA+/?TEF is more likely to be an isolated defect or part of a multiple malformation syndrome in a pattern other than VACTERL, than be part of the defined association. This study reinforces the need to consider broader evaluation for alternate diagnoses in the presence of these defects.     

Tracheal agenesis and associated malformations: a comparison with tracheoesophageal fistula and the VACTERL association

Tracheal agenesis is a rare malformation of the lower respiratory tract. Investigation of a patient with multiple congenital anomalies and tracheal agenesis prompted a review of the literature which uncovered 42 previously published cases, most of whom had other defects. The presence in our patient of a tracheal abnormality in association with radial hypoplasia, single umbilical artery, tetralogy of Fallot, and left hydroureter initially suggested presence of the VACTERL association. However, numerical classification of malformation patterns in the reported patients with tracheal agenesis and in a series of patients with tracheoesophageal fistula and other components of the VACTERL association suggests that tracheal agenesis does not occur in the VACTERL association and may be part of another pattern of malformations which includes laryngeal atresia, complex congenital heart anomalies, radial ray defects, and duodenal atresia.     

Should chromosome breakage studies be performed in patients with VACTERL association?

The VACTERL association is characterized as a non-random pattern of defects including at least three of the following cardinal features: vertebral anomalies, anal atresia, cardiovascular malformations, tracheoesophageal fistula, renal and limb anomalies, and is postulated to be a very heterogeneous disorder. These defects can also be seen as part of the Fanconi anemia (FA) spectrum. Although VACTERL with hydrocephaly has clearly been associated with FA, the indication for chromosome breakage studies is not clear in VACTERL without hydrocephaly. We report on three unrelated patients with the VACTERL phenotype and the confirmed diagnosis of FA. Together with the data of 13 similar cases extracted from a European genotype-phenotype correlation study for FA and those from the four reported cases of the literature, we show that (i) in a series of individuals proven to have FA, 5% (13/245) also have the VACTERL phenotype, (ii) all have radial ray anomalies and 12 of these 13 subjects show at least 1 other feature of FA (café au lait spots, growth retardation, microcephaly, dysmorphism), and (iii) the VACTERL phenotype appears to be over represented in the FA complementation groups D1, E, and F. Since the diagnosis of FA is important for genetic counseling and early therapeutic intervention in patients, we conclude that chromosomal breakage studies should be performed, not only in cases of VACTERL with hydrocephaly, but also in cases VACTERL with radial-ray anomalies and especially if the individual has additional FA associated manifestations such as skin pigmentation abnormalities, growth retardation, microcephaly, or microphthalmia.     

Ear anomalies and hearing loss in patients with VACTERL association and the effect of maternal diabetes

VACTERL association is typically defined as the presence of three components among these birth defects: vertebral anomalies, anal atresia, cardiac anomalies, esophageal atresia/tracheoesophageal fistula (EA/TEF), renal anomalies, and limb defects. There is increasing recognition that VACTERL and other recurrent constellations of embryonic development often overlap clinically and might share pathogenesis. We conducted a comprehensive chart review of a large patient population with VACTERL association from two tertiary care centers in California. We included patients with incomplete VACTERL expression, which we denoted as “partial VACTERL” (pVACTERL). We assessed the occurrence of craniofacial (CF) findings in these two groups and the combined cohort. We collected data on potential risk factors and demographic information such as sex, Hispanic ancestry, pregnancy complications, and maternal age. The study included 409 participants, of whom 263 had VACTERL and 146 pVACTERL. CF abnormalities were found in 17.3% of VACTERL patients and 9.4% of pVACTERL patients. In the VACTERL group, ear anomalies were found in 10.2%, microtia in 5.9%, hearing loss (HL) in 13.90%, and orofacial clefts in 3.1%. In the pVACTERL group, ear anomalies were found in 7.2%, microtia in 5.0%, HL in 9.3%, and orofacial cleft in 2.2%. Maternal diabetes significantly increased the risk for HL in VACTERL (odds ratio [OR]: 3.71, 95% confidence interval [CI]: 1.5–7.3) and pVACTERL patients (OR: 6.7, 95% CI: 1.70–23.4). Poorly controlled maternal diabetes significantly increased the risk for all the outcomes in VACTERL patients including CF anomalies (OR: 4.2, 95% CI: 1.9–9.6), ear anomalies (OR: 4.7, 95% CI: 1.8–11.8), microtia (OR: 5.4, 95% CI: 1.7–16.6), and HL (OR: 8.1, 95% CI: 3.4–19.4). Twin status was significantly associated with the occurrence of microtia (p = 0.038) in VACTERL patients. Occurrence of CF features, particularly ear anomalies, microtia, and HL, might be considered as part of phenotypic diversity of VACTERL association. Diabetes and twinning might appear to play a role in increasing the risk for this phenotype in VACTERL association.     

Patterns of acrorenal malformation associations

Limb and urinary tract defects have frequently been reported to occur together as components of a single acrorenal field defect or in many multiple malformation syndromes. However, the concordance of such anomalies has rarely been studied on a population basis or the relationships between specific limb and renal defects defined. This paper documents the patterns of acrorenal associations seen in over 1,500,000 infants born in Hungary in 1975–1984. In all, 1 in 1,800 infants had a limb deficiency and 9% of these (75 cases) had a urinary tract anomaly. Urinary tract anomalies were most commonly seen with radial ray defects, micromelia and amelia. The commonest recognized patterns were VACTERL association and the cloacal exstrophy and caudal regression sequences. Chromosomal and single gene defects also occurred. Numerical taxonomic techniques delineated six main clusters of patients. Important groupings included micromelia with renal agenesis, split hand/foot with hydronephrosis, and radial ray anomalies with VACTERL defects. The radial ray groups differed in the nature of the VACTERL anomalies seen and with respect to laterality, symmetry, and non-VACTERL anomalies. There was a strong association of bilateral limb defects with bilateral renal anomalies and unilateral with unilateral. Ipsilateral defects tended to occur in typical VACTERL cases, while contralateral defects tended to occur with additional non VACTERL midline anomalies. Although renal and limb anomalies are associated, in almost all cases malformations in other systems are also present. The precise nature of the malformation patterns seen appear to reflect differences in the nature and magnitude of the underlying dysmorphogenetic processes as well as the timing of their effects. © Wiley-Liss, Inc.     

Patterns of acrorenal malformation associations.

Limb and urinary tract defects have frequently been reported to occur together as components of a single acrorenal field defect or in many multiple malformation syndromes. However, the concordance of such anomalies has rarely been studied on a population basis or the relationships between specific limb and renal defects defined. This paper documents the patterns of acrorenal associations seen in over 1,500,000 infants born in Hungary in 1975-1984. In all, 1 in 1,800 infants had a limb deficiency and 9% of these (75 cases) had a urinary tract anomaly. Urinary tract anomalies were most commonly seen with radial ray defects, micromelia and amelia. The commonest recognized patterns were VACTERL association and the cloacal exstrophy and caudal regression sequences. Chromosomal and single gene defects also occurred. Numerical taxonomic techniques delineated six main clusters of patients. Important groupings included micromelia with renal agenesis, split hand/foot with hydronephrosis, and radial ray anomalies with VACTERL defects. The radial ray groups differed in the nature of the VACTERL anomalies seen and with respect to laterality, symmetry, and non-VACTERL anomalies. There was a strong association of bilateral limb defects with bilateral renal anomalies and unilateral with unilateral. Ipsilateral defects tended to occur in typical VACTERL cases, while contralateral defects tended to occur with additional non VACTERL midline anomalies. Although renal and limb anomalies are associated, in almost all cases malformations in other systems are also present. The precise nature of the malformation patterns seen appear to reflect differences in the nature and magnitude of the underlying dysmorphogenetic processes as well as the timing of their effects.     

The syndromology of anorectal malformation (atresia,stenosis, ectopia)

The syndromes, associations, and developmental field defects that include anorectal dysgenesis (atresia, stenosis, ectopia) as a principal or facultative sign are discussed. Most of these disorders are identifiable by their genetic or teratogenic etiology, their distinctive phenotype, or both. Their precise diagnosis is crucial for estimation of recurrence risk and other aspects of reproductive counseling, and it is essential for classificatory progress. The “VACTERL association” should not be used to label a patient with anorectal malformation and other anomalies except by exclusion; this rule is particularly relevant when the patient lacks tracheoesophageal malformation. The degree (or variety) of anorectal malformation that occurs in a given pattern of multiple congenital anomalies may be inconstant. Furthermore, anorectal malformation may be a solitary expression of a familial syndrome.     

The syndromology of anorectal malformation (atresia, stenosis, ectopia).

The syndromes, associations, and developmental field defects that include anorectal dysgenesis (atresia, stenosis, ectopia) as a principal or facultative sign are discussed. Most of these disorders are identifiable by their genetic or teratogenic etiology, their distinctive phenotype, or both. Their precise diagnosis is crucial for estimation of recurrence risk and other aspects of reproductive counseling, and it is essential for classificatory progress. The "VACTERL association" should not be used to label a patient with anorectal malformation and other anomalies except by exclusion; this rule is particularly relevant when the patient lacks tracheoesophageal malformation. The degree (or variety) of anorectal malformation that occurs in a given pattern of multiple congenital anomalies may be inconstant. Furthermore, anorectal malformation may be a solitary expression of a familial syndrome.     

Retrospective evaluation of clinical and molecular data of 148 cases of esophageal atresia

Developmental abnormalities provide a unique opportunity to seek for the molecular mechanisms underlying human organogenesis. Esophageal development remains incompletely understood and elucidating causes for esophageal atresia (EA) in humans would contribute to achieve a better comprehension. Prenatal detection, syndromic classification, molecular diagnosis, and prognostic factors in EA are challenging. Some syndromes have been described to frequently include EA, such as CHARGE, EFTUD2-mandibulofacial dysostosis, Feingold syndrome, trisomy 18, and Fanconi anemia. However, no molecular diagnosis is made in most cases, including frequent associations, such as Vertebral-Anal-Cardiac-Tracheo-Esophageal-Renal-Limb defects (VACTERL). This study evaluates the clinical and genetic test results of 139 neonates and 9 fetuses followed-up at the Necker-Enfants Malades Hospital over a 10-years period. Overall, 52 cases were isolated EA (35%), and 96 were associated with other anomalies (65%). The latter group is divided into three subgroups: EA with a known genomic cause (9/148, 6%); EA with Vertebral-Anal-Cardiac-Tracheo-Esophageal-Renal-Limb defects (VACTERL) or VACTERL/Oculo-Auriculo-Vertebral Dysplasia (VACTERL/OAV) (22/148, 14%); EA with associated malformations including congenital heart defects, duodenal atresia, and diaphragmatic hernia without known associations or syndromes yet described (65/148, 44%). Altogether, the molecular diagnostic rate remains very low and may underlie frequent non-Mendelian genetic models.     

Anal atresia, vertebral, genital, and urinary tract anomalies: a primary polytopic developmental field defect identified through an epidemiological analysis of associations

Anal atresia (AA) is observed per se or as part of different Mendelian or chromosomal syndromes, and as part of the VACTERL primary developmental field, CHARGE association, cloacal extrophy, in a mitochondrial cytopathy, and other multiple congenital anomaly patterns. There are only a few studies on the defects associated with AA, and in all of them it was observed that genitourinary defects are most frequent in infants with AA. Here we present the analysis of 28,410 malformed infants to study the frequency of 11 selected congenital defects in infants with AA in relation to their frequency in infants with multiple congenital anomaly patterns without AA. We conclude that the association of AA + spine defects + renal/urinary tract defects + genital defects constitutes a group of defects that tends to be present together in the same child because they are pathogenetically related, and since they are of blastogenetic origin they constitute a primary polytopic developmental field defect.     

Aberrant bronchi and cardiovascular anomalies

In an investigation of malformation associations in consecutive perinatal autopsies, 4 infants were identified as having a displaced or supernumerary bronchus. Each had a different type of bronchial abnormality and 3 had congenital heart defects and other malformations. Review of the literature found 38 other cases of aberrant bronchi with additional defects, especially cardiovascular or costovertebral anomalies. Structural cardiac defects were more common in patients with super-numerary tracheal bronchi (67%) than in those with displaced tracheal bronchi (27%) or bronchoesophageal connections (23%). There was also a strong negative association (P = 0.01) of cardiovascular and costovertebral defects unless multiple anomalies were present. The combinations of anomalies seen appear to reflect relatively specific developmental field defects affected both by the spatial relationships of organs near the developing foregut and by temporal sequence. Recognition of these patterns has clinical and embryological importance. Aberrant bronchi should be considered when children with cardiac defects or multiple anomalies such as the VACTERL association have unexplained respiratory symptoms and surgeons planning to treat such bronchial abnormalities should be aware of the high frequency of abnormal vessels in these cases.     

Oesophageal atresia, related malformations, and medical problems: a family study.

Oesophageal atresia (OA) and tracheo-oesophageal fistula (TOF) are life-threatening malformations of generally undefined cause. Previous reports of familial cases suggest a genetic contribution. The pattern of inheritance appears non-Mendelian, i.e., multifactorial. Individuals with OA/TOF often have other malformations and medical problems. The aim of this study was to determine the association in OA/TOF cases and healthy control subjects of associated malformations, midline defects, and medical conditions. We also investigate the relationships of these conditions in the relatives of the cases and controls. The results show that infants with OA/TOF frequently have VACTERL anomalies (vertebral, 17%; anal, 12%; cardiac, 20%; renal, 16%; limb, 10%) and other midline defects (cleft lip and palate, 2%; sacral dysgenesis, 2%; urogenital anomalies, 5%). The following medical problems were also reported: oesophageal dysmotility, 21%; gastro-oesophageal reflux, 22%; chest infections, 6%; and autonomic dysfunction, 0.5%. The first-degree relatives of children with OA are much more likely to have one of the aforementioned malformations or medical conditions when compared with the control group: one or more VACTERL anomalies (P < 0.01), gastro-oesophageal reflux (P < 0.05), recurrent respiratory infections (P < 0.05), and autonomic dysfunction (P < 0.001). The more distant relatives also show an increased incidence of such problems although in this case the data must be viewed with caution. The results confirm that the associated malformations and related medical problems occur significantly more frequently in the relatives of individuals with OA/TOF. These families may prove valuable for linkage analysis in an attempt to determine the genetics of OA/TOF.     

Tibial developmental field defect is the most common lower limb malformation pattern in VACTERL association

VACTERL association is one of the most common recognizable patterns of human malformation and has been recently defined as a multiple polytopic developmental field defect. Limb anomalies are a key component of this condition and characteristically reflect perturbation of radial ray development. However, the pattern of appendicular malformations in VACTERL association is wider and includes a broad spectrum of additional and apparently nonspecific anomalies. We report on the sporadic case of a 4-10/12-year-old boy presenting with multiple costovertebral defects, dextrocardia, bilateral radial ray hypo/aplasia, unilateral kidney agenesis and anal atresia. Homolaterally to the more severe radial ray defect and kidney aplasia, he also has a complex lower limb malformation, consisting of distal tibial aplasia, clubfoot, hallucal deficiency and preaxial polydactyly. Literature review identifies 24 additional patients with VACTERL manifestations and lower limb malformations (excluding cases with isolated secondary deformations). Tibial hypo/aplasia with or without additional tibial field defects, reported in about 2/3 (68%) of the patients, represents the most common finding, while involvement of the fibular ray is rare (20%) and very often accompanies tibial anomalies. The relatively high frequency of tibial ray anomalies in VACTERL patients could easily be explained by the principle of homology of the developmental field theory. Careful search of lower limb anomalies of the "tibial type" is, therefore, indicated in all patients with multiple polytopic developmental field defects.     

Congenital abnormalities associated with limb deficiency defects: A population study based on cases from the Hungarian congenital malformation registry (1975–1984)

Limb deficiency defects (LD) occurring among 1,575,904 births in Hungary during 1975–1984 were reviewed. The overall birth prevalence of LD was 1 in 1,816. This paper discusses the nature and distribution of the limb and other defects in the 275 (32%) children who had structural malformations in other systems. Two main forms of classification were used: morphologic and causal. Additional malformations were most commonly seen in infants with amelia, rudimentary limb (RL), radial/tibial (RT), intercalary or central axis (CA) LD and rarely in those with terminal transverse (TT) or ulnar/fibular (UF) defects. Upper limbs (81%) were involved significantly more often than lower limbs (42%) and there were more right-sided defects (83% vs. 71%) due to an excess of right arm involvement especially with radial ray and split hand anomalies. Single limb involvement was relatively common withy amelia (88%), UF (82%), RT (50%), and TT defects. With other LD, multimelic involvement was more characteristic. This was usually symmetric with Ca anomalies and digital deficiencies (DD). From a causal perspective, 17% of cases had genetic disordes, 52% had recognized associations, anomalies, sequences, environmental causes or patterns of unknown origin, and 31% had unknown patterns of malformations. The commonest entities were amnion disruption sequence (16% of cases) and VACTERL association (8%). Both of these disorders showed unusual temporal distribution. As anticipated, patterns of malformations differed with the type of LD. Amelia and digital amputations were often seen with body wall defects, atypical anencephaly or encephalocele, and cleft lip reflecting amnion disruption. Rudimentary limb was seen with anencephaly, omphalocele, renal agenesis, aberrant genitalia, and imperforate anus, reflecting defects of blastogenesis including the cloacal exstrophy and caudal regression sequences and Schisis association. Radial/tibial defects were associated with different patterns depending on whether the limp defects were unilateral or bilateral. Unilateral defects occurred with anomalies suggesting VACTERL association or the facio-auriculo-vertebral anomaly, while bilateral defects occured more often in genetic or potentially genetic disorders including VACTERL with hydrocephalus. Central axis defects showed three main patterns of association: one reflecting the ectrodacyly-ectodermal dysplasia-clefting syndrome; one with tongue anomalies representing a variant of oro-mandibular-limb (Hanhart) anomaly, and the last with hydronephrosis indicating a group of “acrorenal” syndromes. Strong associations with other anomalies were not seen in the grups with TT, UF, or intercalary defects. © 1994 Wiley-Liss, Inc.     

Analysis of FOXF1 and the FOX gene cluster in patients with VACTERL association

VACTERL association, a relatively common condition with an incidence of approximately 1 in 20,000 -35,000 births, is a non-random association of birth defects that includes vertebral defects (V), anal atresia (A), cardiac defects (C), tracheo-esophageal fistula (TE), renal anomalies (R) and limb malformations (L). Although the?etiology is unknown in the majority of patients, there is evidence that it is causally heterogeneous. Several studies have shown evidence for inheritance in VACTERL, implying a role for genetic loci. Recently, patients with component features of VACTERL and a lethal developmental pulmonary disorder, alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV), were found to harbor deletions or mutations affecting FOXF1 and the FOX gene cluster on chromosome 16q24. We investigated this gene through direct sequencing and high-density SNP microarray in 12 patients with VACTERL association but without ACD/MPV. Our mutational analysis of FOXF1 showed normal sequences and no genomic imbalances affecting the FOX?gene cluster on chromosome 16q24 in the studied patients. Possible explanations for these results include the etiologic and clinical heterogeneity of VACTERL association, the possibility that mutations affecting this gene may occur only in more severely affected individuals, and insufficient study sample size.     

Anencephaly and limb deficiencies.

Limb deficiencies (LDs) are rarely reported in anencephalic infants. A review of 662 patients in the literature on non-neural defects in anencephaly only showed five patients with LDs. We report on eight patients with various LDs from the records of 141 necropsies of the anencephalic infants found among 495,830 births. Compared with another group of anencephalic infants reported in the literature, the patients in this group of anencephalic infants with LDs were predominantly male, their mean gestational age was younger by approximately 5 weeks, their mean birth-weight was approximately 1,400 g less, and they presented with a higher incidence of polyhydramnios during gestational development. The association of this pair of anomalies, which was 100 times more frequent than expected, seems not due to chance. Since all eight patients had other multiple congenital anomalies (MCA), in addition to anencephaly and LDs, the postmortem study should be mandatory in anencephalic infants with LDs. The most common associated anomalies were cardiovascular and renal defects. Oral clefts, diaphragmatic hernia, esophageal atresia, and imperforate anus were also observed in these infants. The recognition of LDs in anencephalic infants indicates severe and extensive disturbance of the early embryogenesis (blastogenesis), which affects the midline of the embryo.     

Tracheal agenesis revisited: analysis of associated anomalies

We describe five new cases of tracheal agenesis and report on epidemiological and numerical analyses of nearly 100 such cases with multiple congenital anomalies. Malformations seen with tracheal agenesis form patterns which overlap with, but are distinct from, VACTERL association. They have a high frequency of other lower respiratory tract anomalies; e.g., laryngeal atresia and lung lobation defects, and complex heart anomalies, but fewer anal and vertebral malformations. Cluster analysis of the malformations in 86 patients identified four consistent groups. Anomalies in the first group were primarily restricted to the trachea, larynx, and cardiovascular system. In the second group, the patients had more severe cardiac defects, and lung lobation anomalies, while in the third they had a caudal component in addition to thoracic abnormalities, with anal and renal anomalies being common. Each of these groups showed a male excess and may represent increasingly severe perturbations in development fields encompassing the developing respiratory tract. Although the nature of the causative insult is unknown and probably heterogenous, one underlying pathogenetic mechanism may be abnormal epithelial-mesenchymal interactions. Patients in the fourth group also had multisystem involvement with a high incidence of aberrant vessels, complex cardiac malformations, lung lobation defects, and anomalies of other foregut derivatives. The sex ratio in this group was normal and such cases could represent a disturbance in the primary development field during blastogenesis with secondary vascular disruptions. Complete tracheal agenesis is a lethal anomaly. However, segmental forms may be correctable and, in this group of infants, the nature of associated anomalies may well determine long-term prognosis.     

Anencephaly and limb deficiencies

Limb deficiencies (LDs) are rarely reported in anencephalic infants. A review of 662 patients in the literature on non-neural defects in an-encephaly only showed five patients with LDs. We report on eight patients with various LDs from the records of 141 necropsies of the anencephalic infants found among 495,830 births. Compared with another group of anencephalic infants reported in the literature, the patients in this group of anencephalic infants with LDs were predominantly male, their mean gestational age was younger by approximately 5 weeks, their mean birth-weight was approximately 1,400 g less, and they presented with a higher incidence of polyhydramnios during gestational development. The association of this pair of anomalies, which was 100 times more frequent than expected, seems not due to chance. Since all eight patients had other multiple congenital anomalies (MCA), in addition to anencephaly and LDs, the postmortem study should be mandatory in anencephalic infants with LDs. The most common associated anomalies were cardiovascular and renal defects. Oral clefts, diaphragmatic hernia, esophageal atresia, and imperforate anus were also observed in these infants. The recognition of LDs in anen-cephalic infants indicates severe and extensive disturbance of the early embryogenesis (blastogenesis), which affects the midline of the embryo. © 1992 Wiley-Liss, Inc.