Pentalogy of Cantrell and ectopia cordis, a familial developmental field complex.

The association of sternal fusion defects with various cardiac, diaphragmatic, and anterior body wall defects represents a developmental field complex that includes the Pentalogy of Cantrell and ectopia cordis. No familial cases have been reported previously. We present 3 consecutively born brothers with extensive diaphragmatic defects, 2 who had the Pentalogy of Cantrell. One of the 2 also had ectopia cordis.     

Co-occurrence of severe Goltz-Gorlin syndrome and pentalogy of Cantrell - Case report and review of the literature

Goltz-Gorlin syndrome is a highly variable disorder affecting many body parts of meso-ectodermal origin. Mutations in X-linked PORCN have been identified in almost all patients with a classical Goltz-Gorlin phenotype. The pentalogy of Cantrell is an infrequently described congenital disorder characterized by the combination of five anomalies: a midline supra-umbilical abdominal wall defect; absent or cleft lower part of the sternum; deficiency of the diaphragmatic pericardium; deficiency of the anterior diaphragm; and congenital heart anomalies. Etiology and pathogenesis are unknown. We report on an infant with findings fitting both Goltz-Gorlin syndrome (sparse hair; anophthalmia; clefting; bifid nose; irregular vermillion of both lips; asymmetrical limb malformations; caudal appendage; linear aplastic skin defects; unilateral hearing loss) and the pentalogy of Cantrell (absent lower sternum; anterior diaphragmatic hernia; ectopia cordis; omphalocele). The clinical diagnosis Goltz-Gorlin syndrome was confirmed molecularly by a point mutation in PORCN (c.727C>T). The presence of molecularly confirmed Goltz-Gorlin syndrome and pentalogy of Cantrell in a single patient has been reported twice before. The present patient confirms that the pentalogy of Cantrell can be caused in some patients by a PORCN mutation. It remains at present uncertain whether this can be explained by the type or localization of the mutation within PORCN, or whether the co-occurrence of the two entities is additionally determined by mutations or polymorphisms in other genes, environmental factors, and/or epigenetic influences.     

Two rare cases of the Pentalogy of Cantrell or its variants

The Pentalogy of Cantrell (PC) is a rare association of defects involving the lower sternum, abdominal wall, diaphragm, pericardium and heart. We report two rare cases of the PC (variant form), showing fatal progression. Case 1 only survived two hours because of severe cardio-respiratory failure. Physical examination showed midline abdominal and thoracic defects, ectopic heart, pericardial defect, diaphragmatic defect, bilateral undescended testis, scoliosis, and adherence between left upper limb and trunk. In addition, the autopsy revealed diaphragmatic agenesia, intraabdominal testis, bilateral lung hypoplasia and lymphocytic meningitis. Case 2 only survived 15 minutes. In addition to the physical findings, including lower sternal defect, ectopic heart, epigastric omphalocele and scoliosis, the autopsy showed left diaphragmatic agenesia, pericardial agenesia, bilateral lung hypoplasia, deformed rib cage, anterior thoracic myeloschisis, adreno-hepatic fusion, left renal agenesia, meckel diverticulum and multiple accessory spleens. When comparing with other cases of PC, the concurrence of bilateral intraabdominal testis and lymphocytic meningitis in case 1, and adreno-hepatic fusion, anterior myeloschisis, meckel diverticulum, multiple accessory spleens, and renal agenesia in case 2 have not been described previously.     

Pentalogy of Cantrell and associated midline anomalies: A possible ventral midline developmental field

Five cases of the Pentalogy of Cantrell (PC), ascertained through the Baltimore–Washington population-based study of infants with congenital cardiovascular malformations, represent a regional prevalence of 5.5/1 million liveborn infants for this disorder. Three of these patients had cleft lip with or without palate. Review of the reported literature of the Pentalogy of Cantrell and various combinations of the anomalies within the spectrum of this pentad suggests that the PC defines a specific midline ventral developmental field. Cleft lip with or without cleft palate and encephalocele tend to specifically associate with ventral midline anomalies within the spectrum of PC. These associations might either illustrate the previously observed tendency of specific occurrence of certain combinations of midline defects or represent defined subunits of the midline developmental field.     

Pentalogy of Cantrell and associated midline anomalies: a possible ventral midline developmental field.

Five cases of the Pentalogy of Cantrell (PC), ascertained through the Baltimore-Washington population-based study of infants with congenital cardiovascular malformations, represent a regional prevalence of 5.5/1 million liveborn infants for this disorder. Three of these patients had cleft lip with or without palate. Review of the reported literature of the Pentalogy of Cantrell and various combinations of the anomalies within the spectrum of this pentad suggests that the PC defines a specific midline ventral developmental field. Cleft lip with or without cleft palate and encephalocele tend to specifically associate with ventral midline anomalies within the spectrum of PC. These associations might either illustrate the previously observed tendency of specific occurrence of certain combinations of midline defects or represent defined subunits of the midline developmental field.     

Trisomy 18 with Cantrell pentalogy in a stillborn infant

A 34-week stillborn infant had omphalocele, agenesis of the sternum and anterior rib cage, membranous diaphragms with eventration of the viscera, ectopia cordis with absence of the pericardium, and congenital heart defect. These findings are consistent with a diagnosis of Cantrell pentalogy. The presence of bilateral clubfeet, spina bifida, hydrocephalus, abnormal ears, and horseshoe kidneys suggested a chromosome abnormality. Chromosome analysis showed trisomy 18. Individuals with manifestations of Cantrell pentalogy deserve cytogenetic evaluation.     

Trisomy 18 associated with ectopia cordis and occipital meningocele

A premature infant presented with ectopia cordis, occipital meningocele, and manifestations of trisomy 18; cytogenetic analysis confirmed a 47,XX,+18 chromosome constitution. While most cases of ectopia cordis appear as isolated, sporadic defects, careful evaluation is warranted to detect evidence of an associated chromosome abnormality.     

Ectopia cordis and cleft sternum: evidence for mechanical teratogenesis following rupture of the chorion or yolk sac

We present case material and a literature survey to document the association between ectopia cordis and band disruption anomalies. The occurrence of thoracic ectopia cordis with a cephalic-pointing cardiac apex suggests an arrest of cardiac descent at 3 weeks of development, consistent with our finding of ectopia cordis in a 28-day human embryo. Mechanical compression secondary to rupture of the chorion and/or yolk sac at 3 weeks of gestation would interfere with normal cardiac descent and compress the chest, yielding thoracic and pulmonary hypoplasia. Congenital heart defects associated with ectopia cordis may represent deformations secondary to mechanical distortion of the developing heart following early rupture of the chorion and/or yolk sac. As is illustrated by our clinical specimens, tethering of the heart to periumbilical structures by bands could yield thoracoabdominal ectopia cordis. The milder anomaly of cleft sternum, which is also associated with band disruptions, may occur later in development following rupture of the chorion, yolk sac, or amnion.     

Omphalocele and gastroschisis and associated malformations

The etiology of gastroschisis and omphalocele is unclear and their pathogenesis is controversial. Because previous reports have inconsistently noted the type and frequency of malformations associated with omphalocele and gastroschisis, we assessed these associated malformations ascertained between 1979 and 2003 in 334,262 consecutive births. Of the 86 patients with omphalocele, 64 (74.4%) had associated malformations. These included patients with chromosomal abnormalities (25, 29.0%); non-chromosomal syndromes including Beckwith-Wiedemann syndrome, Goltz syndrome, Marshall-Smith syndrome, Meckel-Gruber syndrome, Oto-palato-digital type II syndrome, CHARGE syndrome, and fetal valproate syndrome; malformation sequences, including ectopia cordis, body stalk anomaly, exstrophy of bladder, exstrophy of cloaca, and OEIS (Omphalocele, Exstrophy of bladder, Imperforate anus, Spinal defect); malformation complexes including Pentalogy of Cantrell, and non-syndromic multiple congenital anomalies (MCA) (26, 30.2%). Malformations of the musculoskeletal system (31, 23.5%), urogenital system (27, 20.4%), cardiovascular system (20, 15.1%), and central nervous system (12, 9.1%) were the most common other congenital malformations in patients with omphalocele and non-syndromic MCA. Of the 60 patients with gastroschisis, 10 (16.6%) had associated malformations. In contrast to omphalocele, gastroschisis was rarely associated with a complex pattern of malformation, that is, one each (1.7%) with a chromosomal abnormality (trisomy 21), sequence (amyoplasia congenita), unspecified dwarfism, and 7 (11.7%) with MCA. We observed a striking difference in the prevalence of total malformations (74.4% vs. 16.6%, P < 0.001) and specific patterns of malformations associated with omphalocele and gastroschisis which emphasizes the need to evaluate all patients with omphalocele and gastroschisis for possible associated malformations. Malformation surveillance programs should be aware that the malformations associated with omphalocele can be often classified into a recognizable malformation syndrome or pattern (44.2%).     

Transmission of electric and magnetic foetal cardiac signals in a case of ectopia cordis: the dominant role of the vernix. caseosa

Foetal electrocardiograms (fECGs) and foetal magnetocardiograms (fMCGs) were recorded in the 26th, 29th and 31st weeks of gestation from a foetus with ectopia cordis-a rare condition in which the heart lies outside the chest wall. This provided an opportunity to study foetal cardiograms uninfluenced by the insulating effects of the foetal skin and vernix caseosa. The fECG of the ectopia cordis foetus was striking. Unlike recordings from age-matched normal foetuses, recordings from this subject had very high signal-to-noise ratio and showed no anomalous signal transmission properties. In contrast, fMCGs recorded from the ectopia cordis foetus and normal foetuses were largely similar. Both showed high signal-to-noise ratio and signal transmission properties consistent with volume conduction. The findings corroborate the hypothesis that high foetal skin resistance due primarily to the vernix caseosa is responsible for the low amplitude and anomalous transmission properties of the normal fECG, and demonstrate that the fMCG is relatively insensitive to conductivity inhomogeneities.     

Successful Vaginal Delivery of a Pregnant Woman with Cantrell's Pentalogy

Cantrell''s Pentalogy is a rare condition that consists of defects involving the abdominal wall, lower sternum, anterior diaphragm, pericardium, and heart. In the literature to date, pregnant women with Cantrell''s Pentalogy have not been discussed. We performed successful vaginal delivery of a 23-yr-old nulliparous, primigravid woman who had been diagnosed with this condition. Diagnosis was based on cardiac catheterization, angiography, and echocardiogram, and abdominopelvic CT. Vaginal delivery may be an option for women with Cantrell''s Pentalogy and may be attempted with caution.     

Limb-body wall complex: 4 new cases illustrating the importance of examining placenta and umbilical cord

Limb-body wall complex (LBWC) is a rare, sporadic, congenital defect defined as a combination of at least two of three characteristics: 1. limb defects, 2. anterior body wall defects, and 3. exencephaly or encephalocoele with/without facial clefts. Three pathogenic mechanisms have been proposed: early amnion rupture, vascular disruption and embryonic dysgenesis. In this study we carried out the pathological evaluation of four fetuses with LBWC and their placentas. None of the cases had craniofacial defects. Three fetuses showed an abdominal wall defect with eventration of abdominal organs, cloacal exstrophy, absent external genitalia, abnormal internal genitalia, scoliosis and lower limb defects. One fetus showed failure of closure of both thoracic and abdominal walls with ectopia cordis, evisceration of left lung and abdominal organs, severe reduction defect of left arm, but normal colon, anus, bladder, genitalia and lower limbs. All cases had a short, malformed umbilical cord, incompletely covered by amnion. The umbilical vessels were embedded in an amniotic sheet which connected the skin margin of the anterior body wall defect to the placenta. These anomalies suggest an abnormal body stalk development as a pathogenic mechanism for LBWC. Prenatally, the abnormal fetoplacental attachment can be detected ultrasonographically by the end of the first gestational trimester. Postnatally, the examination of placenta, umbilical cord and membranes is crucial in confirming the diagnosis of LBWC.     

The embryology of body wall closure: relevance to gastroschisis and other ventral body wall defects

During the 3rd and 4th weeks post-fertilization (5 and 6 weeks from the last normal menstrual period [LNMP]), the human embryo is transformed from a flat disc-shaped organism into the classic shape of an embryo in the "fetal" position. This change is effected by simultaneously rolling the top layer of the disc, the ectoderm, into the neural tube and the bottom layers of the disc, the endoderm and mesoderm, into the gut tube and body wall, respectively. In this manner, the flat disc is transformed into two tubes, one dorsal to the other, surrounded by supporting structures in the body wall. If closure of the neural tube fails, then neural tube defects (NTDs), such as anencephaly and spina bifida, occur; if closure of the ventral body wall fails, then ventral body wall defects, such as ectopia cordis, gastroschisis, and bladder and cloacal exstrophy, occur. Interestingly, no known closure defects have been described for the gut tube. Note, however, that all of the closure defects that do occur have their origins early in gestation during the third and fourth weeks of development.     

New multiple congenital anomalies syndrome in a stillborn infant of consanguinous parents and a prediabetic pregnancy

We report on a term stillborn female infant with multiple congenital anomalies (MCA) which have not previously been reported as occurring together. The malformations include a first and second branchial arch sequence, ectopia cordis with congenital heart defect, caudal "regression" sequence with absent sacrum and hypoplastic right femur, ectrodactyly, left radial abnormality, islet cell hyperplasia, and skin lesions. The pregnancy was complicated by abdominal cramping with exercise, heavy vaginal bleeding, maternal obesity, and a normal screening glucose tolerance test at 6 months gestation. The infant was born to 20-year-old G3P1SAB2 Mexican-American parents who are first cousins. There was strong maternal family history of adult-onset diabetes. The malformations have some findings in common with those seen in infants of diabetic mothers. Structural defects similar to, but not inclusive of, those in our infant have been reported in 2 sibs born to a prediabetic mother with a first cousin marriage as well as in focal dermal hypoplasia. Parental consanguinity is suggestive of an autosomal recessive disorder. Alternatively, it may represent a combined multifactorial effect making the conceptus more sensitive to metabolic teratogens and thus placing it at increased risk for disruption of normal development.     

Atrioventricular and ventriculo-atrial branches of the human coronary arteries supplying the walls of heterolateral cardiac chambers

In 20% of 40 human hearts, AV and VA branches of the coronary arteries supplied the wall of cardiac chambers on the opposite side of the heart. VA branches were more frequent than AV branches and both were observed at the level of the crux cordis (in the diaphragmatic aspect of the heart).     

Diaphragmatic defects and limb deficiencies - taking sides

Diaphragmatic defects and limb deficiencies usually occur as independent anomalies, as a polytopic field defect (in which ipsilateral anomalies might be expected) or as wider pattern of defects, potentially involving disturbance of laterality or the midline (in which bilateral or contralateral defects would occur). Data on cases from previous studies and/or the literature were used to determine whether there is an association between the sides involved in the defects. The 88 adequately described cases identified included 20 with de Lange syndrome, seven with Poland anomaly, four with trisomy 18, 52 with other patterns of multiple malformations and five with diaphragmatic and limb defects alone. Evaluation of the position of the limb (left, right, bilateral) and the diaphragmatic defects (left, right, bilateral) did not show significant association in patterns of sidedness (P = 0.48). In 56% of cases, the limb deficiencies were bilateral. Among the 32 unilateral cases, 19 (59%) were ipsilateral (15 left; 4 right) and 13(41%) were contralateral (P = 0.38). Eleven of the 13 contralateral cases had left sided diaphragmatic defects and right sided limb deficiency; four had de Lange syndrome and nine had other patterns of multiple anomalies. Only cases with Poland anomaly or otherwise isolated defects showed a trend towards ipsilateral defects. Most cases with multiple congenital anomalies, had limbs defects on both the right and left (57%) or both sides of the diaphragm were affected (an additional 10%), indicating a widespread dysmorphogenetic process rather than a more restricted field defect. In other cases, defects were bilateral or, if unilateral, reflected the propensities for diaphragmatic defects to more often involve the left side, and limb defects, the right.     

Defects of blastogenesis

Ever more frequent and closer involvement by clinical geneticists and counselors in the prenatal assessment of development mandates a better understanding of all stages of human ontogeny, but especially those of earliest development during which most of the lethal and all of the gross, multiple and complex defects of morphogenesis arise. Because of the phenomenon of universality, i.e., identical molecular inductive mechanisms involved in the process of embryonic pattern formation in all vertebrates, experimental animals indeed are a most valuable approach to an understanding of the causal and formal aspects of development and are beginning to forge essential, strong bonds between molecular biologists and clinicians in a mutually supportive discipline of developmental biology. However, to grieving parents of a stillborn fetus with, say, Pentalogy of Cantrell, sirenomelia or otocephaly, mouse data offer little comfort or reassurance about recurrence; thus, it is imperative to make ever more effective a science of human teratology (sensu lato) with participating reproductive geneticists, obstetricians, neonatologists, ultrasonographers, pediatric/fetal pathologists, cytogeneticists and pediatric geneticists to generate the diagnostic, pathogenetic and causal data necessary to counsel and to comfort the parents. Few molecular data exist on causes of blastogenetic defects in humans; however, the phenomenon of parsimony, whereby the same "morphogenetic" molecule, say, sonic hedgehog (SHH), is "deployed" simultaneously or sequentially during the morphogenesis (and even the histogenesis) of several/many embryonic primordia, makes it likely that a genetic/epigenetic disturbance of such an inductive system will have multiple effects on blastogenetic, organogenetic and perhaps also histogenetic events in the embryo. If causally defined, such a pattern of anomalies constitutes pleiotropy, and the embryo/fetus can be said to have a syndrome. If cause is unknown, the presumption of pleiotropy is less certain, and the fetus/infant may be said to have an "association" with low empiric recurrence risk.     

Struma cordis. Ectopic thyroid goiter in the right ventricle

Intracardiac thyroid goiter (struma cordis) is an exceptionally rare finding. To our knowledge, only two cases have been reported in the literature to date. A middle-aged woman was the subject of our case, in which an intracardiac tumor was clinically diagnosed and surgically resected. The mass, adhesive to the ventricular septum and obstructing the right ventricular outlow tract, histologically was formed by thyroid tissue, separated from the myocardium by fibrous tissue. The woman died of renal failure two weeks after the operation, and at autopsy the thyroid gland showed strumous changes. The similarity to previously reported cases suggests a dysembryologic origin of this ectopia.     

Maternal isodisomy for 14q21-q24 in a man with diabetes mellitus

The association of craniosynostosis with ectopia lentis is extremely rare. This was recently reported in monozygotic twin sisters, supporting a genetic etiology for this syndromic association. We report on female first cousins once removed who were born with unilateral coronal synostosis. One cousin also had peripheral pulmonic branch stenosis at birth and was later found to have ectopia lentis and severe myopia. The other cousin had an atrial septal defect, mitral valve prolapse, and only mild myopia. Their intelligence is normal. The inheritance is likely autosomal dominant with variable expression and incomplete penetrance and further defines this syndrome to include congenital heart defects. These findings will have important implications for genetic counseling.     

Craniosynostosis,ectopia lentis,and congenital heart defects: Further delineation of an autosomal dominant syndrome with incomplete penetrance

The association of craniosynostosis with ectopia lentis is extremely rare. This was recently reported in monozygotic twin sisters, supporting a genetic etiology for this syndromic association. We report on female first cousins once removed who were born with unilateral coronal synostosis. One cousin also had peripheral pulmonic branch stenosis at birth and was later found to have ectopia lentis and severe myopia. The other cousin had an atrial septal defect, mitral valve prolapse, and only mild myopia. Their intelligence is normal. The inheritance is likely autosomal dominant with variable expression and incomplete penetrance and further defines this syndrome to include congenital heart defects. These findings will have important implications for genetic counseling. © 2001 Wiley‐Liss, Inc.