Severe Intrauterine Amputations in One Dichorionic Twin With Pentalogy of Cantrell: Further Evidence and Consideration for Mechanical Teratogenesis

Introduction

Pentalogy of Cantrell (PC, Cantrell-Haller-Ravitch syndrome) is a rare congenital syndrome that affects 1 in 65,000 live births and is characterized by a midline supraumbilical abdominal wall defect, lower sternum defect, anterior diaphragmatic and pericardial defect, and congenital cardiac anomalies. ¹ Besides the well-known clinical variability in the severity and presentation of PC, its etiology is still unknown; yet, major gene mutation, familial recurrence, chromosomal aneuploidy, developmental field defect, amniotic band disruption, and a vascular origin offers insight into possible etiologic influences.^1–9 In this context, evidence for mechanical teratogenesis in PC is limited. ³ Here, we describe in one dichorionic twin with complete PC, additional severe intrauterine amputations (mainly head and neck) not previously reported and resultant from mechanical teratogenesis. This morphologic constellation prompts us to emphasize the consideration of this etiological influence and provides further evidence for mechanical teratogenesis in PC.

Case Report

The affected fetus, who was the first of twins, was born at the 20th week of gestation to a 35-year-old G3 P3 Mexican woman and her 37-year-old husband. Both were healthy and denied exposure to teratogens, consanguinity, and family history of multiple congenital anomalies or genetic disease. The pregnancy had been uneventful until the second trimester when fetal growth retardation and multiple malformations were detected ultrasonographically in one fetus but not in the other who appeared normal. Seven days after the mother’s admission, preterm labor occurred and intrauterine death of both male fetuses was confirmed. After expulsion, the abnormal fetus was found to exhibit severe growth retardation (weight 195 g and length 14.5 cm; both were below the third centile), complete absence of craniofacial and neck structures (intrauterine amputations) with posthemorrhagic necrosis-scarred skin over the cranial and dorsal regions, posthemorrhagic tissue with disruption of the lower sternum (cleft lower sternum) and a skin tag with rings of constriction, complete absence of parietal pericardium and presence of thoracoabdominal ectopia cordis and hypoplastic left ventricle (intrauterine amputations), posthemorrhagic tissue with disruption of the anterior midline thoracoabdominal wall and diaphragmatic defect, posthemorrhagic necrosis with fusion and disruption of second to fifth fingers and absence of the first finger of the left hand and right upper extremity (intrauterine amputations), and a skin tag with rings of constriction (Figure 1). There were no genital or lower extremity anomalies. The patient’s male twin sib had normal phenotypic appearance. The diagnosis of PC was confirmed on the postmortem examination and autopsy confirmed clinical findings; the anatomy and histology of other viscerae, bones, placenta (diamnionic-dichorionic), and umbilical vessels were unremarkable. Cytogenetic examination (G-banding) was 46,XY and radiographic evaluation showed no gross pathology.

OPEN IN VIEWER

Figure 1.

General clinical and autopsy findings. A and B, Anterior and posterior view of the affected fetus showing extreme intrauterine amputations of craniofacial, neck, thoracoabdominal ectopia cordis, and right upper extremity structures. Note posthemorrhagic tissue with disruption of the lower sternum and the anterior midline thoracoabdominal wall, as well as several rings/bands of constriction and posthemorrhagic necrosis. C and D, Anterior and posterior view of the male twin sib with normal phenotypic appearance.

Discussion

As originally described in 1958 by Cantrell, Haller, and Ravitch, ¹ the pattern of anomalies in the affected fetus fulfills all 5 criteria and, additionally, includes severe intrauterine amputations. Although incomplete expression of the syndrome is well recognized, the full pentalogy is a rare occurrence; even more so in dichorionic twins. The fact that the affected fetus displayed a typical but enhanced phenotype expands the clinical spectrum and provides new insight into the severity and presentation of PC. In a case series and literature review of 5 patients with the association of ectopia cordis, cleft sternum, and band disruption anomalies, ³ none of them showed the additional anomalies seen in the affected fetus described here. Thus, our observation represents the first PC patient in a set of dichorionic twins with this pattern of anomalies and highlights a new degree of clinical variability in PC due to mechanical teratogenesis.

To date, several etiological influences have been postulated in PC. PORCN mutations (locus Xp11.23) have been confirmed in patients with Goltz-Gorlin syndrome and PC phenotype, whereas a maternally inherited microduplication of chromosome 15q21.3 involving the ALDH1A2 gene has been associated with PC in a single patient.^8,9 Also, familial recurrence of PC in male siblings suggests X-linked inheritance. ⁵ Midline anomalies within the spectrum of PC are included among the defects of the midline developmental field.^2,4,10 Based on clinical features and G-banded karyotype, we excluded the aforementioned influences; however, the combination of cytogenetic and molecular techniques may identify mutations and polymorphisms in genes within critical signaling pathways in the patterning and organogenesis such as Wnt ¹¹ and ultimately allow for an accurate characterization of the PC phenotype and PC-related features such as limb-body wall defect. ¹² Nonetheless, deformations due to mechanical teratogenesis and vascular anomalies are significant etiological factors in PC.^3,6,7 Postmortem examination in the affected fetus confirmed these arrays of anomalies due to mechanical stimulations that caused the teratogenesis; specifically, focal areas of defective tissue by means of constriction rings, vascular compromise, posthemorrhagic necrosis, band disruption, and amputations defects. According to Kaplan et al., ³ ectopia cordis and thoracic hypoplasia result from mechanical compression whereas band disruption involves local tethering, ischemia, and necrosis. Moreover, cleft sternum might also result from early, but less severe compression. These predictions agree with our findings; however, these were in the main, more severe, and extreme in addition to prevent midline fusion of the developing thoracoabdominal wall.

The overall pattern of anomalies that results from the affected fetus provides further evidence for mechanical teratogenesis and conforms to animal and human hypothesis that early rupture of the amnion is associated with either band-mediated disruptions or compression-mediated deformations; notwithstanding, there are no specific correlation or pattern of anomalies following chorion/yolk sac/amnion rupture (Kaplan et al. ³ and references therein). The latter contention is consistent with both failure of migration of the mesodermal folds to midline and septum transversum as early as the 14th to 18th day of fetal development. In addition, disruption of the primordial mesenchymal structures may result in the PC phenotype. ¹

In conclusion, the extreme intrauterine amputations here described provide new insight into the severity and presentation of PC due to mechanical teratogenesis, which is a significant etiological consideration in clinical evaluation and implies that the syndrome involves a complex defective fetal development.