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Table of Contents
CASE REPORT
Year : 2021  |  Volume : 70  |  Issue : 3  |  Page : 176-182

Anophthalmic cyclopia with proboscis, acardia, amelia, sirenomelia – Case report


1 Research Scholar, Department of Anatomy, Bharath Institute of Higher Education and Research, Chennai, Tamil Nadu; Department of Anatomy, Amala Institute of Medical Sciences, Thrissur, Kerala, India
2 Department of Anatomy, Vinayaka Mission's Kirupananda Variyar Medical College, Salem, Tamil Nadu, India
3 Department of Anatomy, Sri Lakshmi Narayana Institute of Medical Sciences, Bharath Institute of Higher Education and Research, Puducherry, India
4 Department of Anatomy, Sree Balaji Medical College and Hospital, Bharath Institute of Higher Education and Research, Chennai, Tamil Nadu, India

Date of Submission31-Jan-2020
Date of Acceptance15-Feb-2021
Date of Web Publication23-Sep-2021

Correspondence Address:
Dr. Jinu Merlin Koshy
Department of Anatomy, Sree Balaji Medical College and Hospital, 7, Works Road, Chrompet, Chennai - 600 044, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JASI.JASI_19_20

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  Abstract 


True or primary anophthalmic cyclopia is an extremely rare and severe malformation of eye. It is the apparent absence of eyeball in a median orbit and it results from failure of the optic vesicle (optic primordial) to form from the cerebral or prosencephalic vesicles. Proboscis is a skin-covered median tubular appendage above the anophthalmic median orbit. It results from the defective development of the olfactory placodes. Sirenomelia, or mermaid syndrome, is a rare abnormality characterized by complete or incomplete fusion of lower limbs. Acardiacus is a fatal complication of monozygotic twin pregnancy. The acardiacus maintains its circulation through the heart of its normal twin reversed arterial perfusion mate. This manuscript reports on a severely malformed monozygotic stillborn twin with anophthalmic cyclopia, proboscis, acardia, absence of upper limb, sirenomelia, and aprosencephaly; agenesis of diaphragm, respiratory system, genitourinary system, lymphatic system, endocrine system, and external genitalia; and intestinal atresia, liver atresia, vascular atresia, hypoplastic skeletal system, and muscular system. In general, in all these fetal abnormalities, there are various degrees of malformation causing group of groups of anomalies. Probable cause of these anomalies is discussed.

Keywords: Monochorionic-monoamniotic twin, twin reversed arterial perfusion, twin–twin transfusion syndrome


How to cite this article:
Markose B, Shastri D, Rajesh B, Koshy JM. Anophthalmic cyclopia with proboscis, acardia, amelia, sirenomelia – Case report. J Anat Soc India 2021;70:176-82

How to cite this URL:
Markose B, Shastri D, Rajesh B, Koshy JM. Anophthalmic cyclopia with proboscis, acardia, amelia, sirenomelia – Case report. J Anat Soc India [serial online] 2021 [cited 2021 Dec 3];70:176-82. Available from: https://www.jasi.org.in/text.asp?2021/70/3/176/326426




  Introduction Top


True or primary anophthalmic cyclopia with proboscis, sirenomelia, acardia, and associated malformations, is extremely rare and severe malformation occurring in early stages of development.[1] The monozygotic twins occur in approximately 1 in 200 births, which represent the most common aberration of morphogenesis noted in the human.[2] The prevalence of anophthalmic cyclopia is approximately 30 per 100,000, and sirenomelia is found in approximately 1 out of every 100,000 live births, 100 times more likely to occur in identical twins than single birth or fraternal twin.[3] There are approximately 300 cases of sirenomelia reported in the literature, 15% of which are associated with twinning, more often monozygotic.[4] “Monochorionic-monoamniotic (MoMo)” twins are very rare with an occurrence of 1 in 35,000 to 1 in 60,000 pregnancies corresponding to about 1% of twin pregnancy. Acardiac twinning is thought to affect 1 in 100 monozygotic twin gestation and 1 in 35,000 pregnancies overall. In monozygotic twinning, if the division occurs unequally, one component may become dependent on its co-twin's cardiovascular system and can develop into an acardiac fetus.[5] The anomalous monster twin was a heterogeneous mass of tissue with a well-developed skull, ribs, sternum, dural folds, and spinal cord. All the remaining tissues were either absent or poorly developed. An acardiacus refers to a hemodynamically disadvantaged nonviable twin which occurs in association with a twin reversed arterial perfusion (TRAP) sequence which corresponds to twin–twin transfusion syndrome (TTTS).[6] In TTTS, arterial-arterial and venous-venous anastomoses in the placenta permit twin–twin transfusion and reversal of blood flow in the umbilical vessels and aorta of the recipient twin. The anomalous twin had a cephalic attachment of the umbilical cord so that the head has got maximum tissue differentiation compared to other regions. The present article describes the details of the anomalous with the help of dissection and X-rays.


  Case Report Top


A 28-year-old female, with consanguineous marriage, G1P1, with an unremarkable family history was admitted to a peripheral hospital, at 35 weeks of gestation with labor pain. Antenatal ultrasound revealed a monozygotic twin pregnancy. Antenatal diagnosis by ultrasound examination was confirmed the monozygotic twin (MoMo twin) gestation and detected most of the associated malformations in the anomalous twin; the co-twin was a normal fetus. Other than ultrasound scan during the second trimester, the parents never did any investigations because of economic and social status. The selective termination of the anomalous twin was not done because the patient's family did not allow to do any intrauterine interventions. Because of the economic and social status, the family never did any investigations during the pregnancy. Only when she was suffering from labor pain, they came to the hospital. She had undergone a lower-segment cesarean section, because of delay in normal progress of the labor. The first of the twin was an apparently healthy male neonate, with 3.2 kg birth weight. On examination, the co-twin was found to be a monstrous stillborn fetus having a dysmorphic face, with a median single eye, absence of nose, micrognathia, and a proboscis, all of which made anophthalmic cyclopia, and associated malformations the possible initial diagnosis. Anomalous twin had a crown–rump length of 19.5 cm, weighs 1000 g, and shows the following anomalies which are described in [Table 1]. Two umbilical cords were noticed. The umbilical cord of the normal twin was long with a pair of umbilical arteries and one umbilical vein. The anomalous twin had a short umbilical cord of 7.5 cm long with a single small umbilical artery and a big umbilical vein. The umbilical cord was attached to the head–trunk junction of the fetus. There was no obvious neck, but there was a transverse linear constriction on ventral region. The anomalous twin was very soft, edematous with sloughed-off skin. All the clinical features were confirmed by the radiological pictures and the dissection photographs of the body. Chromosomal analysis was not carried out as consent was not given by the parents.
Table 1: Dissection findings of the variant twin

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  Discussion Top


We have reported on a 36-week gestation stillborn fetus with anophthalmic cyclopia with associated malformation. To our knowledge, this is a bizarre form of anomalies and the fetus can be the victim of monozygotic twinning. In this case, no apparent comparable cases could be extracted from the literature for comparison. Cyclopia represents a severe deficit in early midline facial development, the eyes become fused, and the olfactory placodes consolidate into a single tube-like proboscis above the eye. Anophthalmic cyclopia occurs due to failure in the development of optic primordia. There is failure in the cleavage of the prosencephalon resulting in the absence of the forebrain (aprosencephaly). The absence of an organ may be due to its disappearance in the subsequent development owing either to an inherent genetic deficiency in the tissue or due to interference with its blood supply by a different developmental abnormality. The inductive stimulus is not adequate in strength or if the substrate tissue does not give the normal response, the resulting organ will be smaller than normal (hypoplasia) and incompletely differentiated. Cyclopia refers to a single median orbit that contains ocular structures that are of three types, namely (1) anophthalmic (no ocular structures and has four subdivisions – [a] primary, [b] secondary, [c] clinical [degenerative], and [d] inherited isolated anophthalmia),[7] (2) monophthalmic, and (3) synophthalmic, and are shown in [Table 2]. Anophthalmia is always associated with multisystem malformation syndromes such as Waardenburg recessive anophthalmic syndromes or Lenz microphthalmic syndromes.[8],[9] We classified our case into true or primary anophthalmic cyclopia. A proboscis is usually present above the orbit. Both lateral and medial nasal swellings are diminished and the remaining tissue continues to proliferate to form the tubular proboscis. Gene controlling the ocular development is SOX2 and the mutation to SOX2 genes or environmental factors have been associated with anophthalmic cyclopia.[10] Agent like magnesium salts, alcohol, lithium chloride, retinol, and radiation, induces cyclopia in animals.[11] Experimental cyclopia has been produced in the saltwater minnow (Fundulus heteroclitus) by the addition of magnesium salts to the seawater containing the fertilized egg.[12] Our patient had no history of taking calculates or any other drugs during her pregnancy. During embryogenesis, the prechordal mesoderm not only forms the median facial bones but also induces rostral neuroectodermal differentiation and morphogenesis.[13] At the 22nd day of gestation (beginning of eye development), PAX-6 gene, a master gene for eye development, is expressed in the single eye field at the anterior neural ridge of the neural plate before neurulation begins. The single eye field is separated into two optic primordial vesicles by sonic hedgehog (SHH) signal expressed in the prechordal plate. Prechordal mesoderm ensures that the median neural plate cells regulate the retinal precursor gene expression so that these cells proliferate to form the ventral diencephalon. An absence in this signaling will lead to the improper differentiation of these cells, so that the median neural plate cells instead of developing into retinal precursors and merge with the single form fused retinal field. In addition, the prechordal plate stimulates the prosencephalon to divide and migrate to form the forebrain. Hence, a deficiency in prechordal plate material will decrease the induction of forebrain growth and development. SHH signaling inhibition in vivo results in craniofacial neural crest cell death.[14] Proboscis in cyclopia represents the anterosuperior part of the normal nasal cavity developed in the absence of median components. Holoprosencephalic facial anomalies were due to faulty embryogenesis of the prechordal cephalic mesenchyme, leading to failure of telencephalic cleavage and of neural crest-mediated development of the calvaria and facial prominences.[15],[16],[17],[18] Malformations are a result from the disappearance or abnormal development of various parts of the pharyngeal arch. They are probably due to insufficient migration of arch I neural crest cells and are associated with anomalies of the mandibular swelling and ear. Auricular atresia occurs along a spectrum from an isolated malformed auricle to, at the most extreme form, an absent external auditory canal with severe inner, middle, and external ear defects. Arhinencephaly and agenesis of the corpus callosum are considered as heterogeneous entities, often totally distinct and independent from the malformative process of the holoprosencephaly; it appears that in arhinencephaly, the deficiencies in the frontonasal mesenchyme secondary to deficient neural crest formation result in a range of malformations varying from fairly typical clefts of the lip to almost complete absence of all frontonasal derivatives.[19],[20],[21] TRAP sequence refers to a rare, unique complication of mono-chorionic twin pregnancy in which a twin with an absent or a nonfunctioning heart (acardiac twin) is perfused by its co-twin (pump twin) through placental arterial anastomoses. The acardiac twin usually has a poorly developed heart, upper body, and head. Complications are more with monochorionic twin gestations due to placental sharing.[22] The TRAP sequence, also known as acardiac twinning, is a malformation that occurs only in monochorionic pregnancies, with a frequency of about 1 per 35,000 deliveries.[23],[24],[25] Acardiac twin can be classified by the degree of gross morphologic malformation present into four morphological types and is shown in [Table 3].[26],[27],[28] Two theories exist as to the etiology of this condition:
Table 2: Morphological classification of cyclopia

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Table 3: Morphological classification of Acardiacus Twin

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Figure 1: Morphological features of the fetus. (a) Anterior view of gross appearance of variant twin showing all external deformities such as no neck, no upper limb, cyclopia with proboscis, and sirenomelia. (b) Anterior view of face – arrowheads pointing to bilateral absence of orbits, proboscis. (c) Anterior view of face – arrowheads pointing single median eye, proboscis. (d) Anterolateral view – arrowheads pointing to umbilical cord, sirenomelia

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Figure 2: Dissection findings of the fetus. (a) Exposed single cavity in the trunk without diaphragm – arrowheads pointing to showing a network of primitive blood vessels and coils of intestine. (b) Cavity of the trunk – arrowheads showing intestinal loop (forceps tip pointing), umbilical cord with umbilical vessels. (c) Exposed cranial cavity (3/4th) empty – arrowheads pointing to cerebellum, brainstem, and optic canal (forceps tip pointing). (d) Exposed vertebral canal – arrowheads pointing to spinal cord and nerves

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Figure 3: Radiological features of the fetus – total radiograph showing cranium, well-developed vertebral column with scoliosis, ribs, and the remaining bones are hypoplastic

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One theory holds that the TRAP anomaly is caused by an abnormal twinning event.[26] Deep placental anastomoses in early embryogenesis cause malformation of the acardiac twin. The early pressure flow in one twin exceeds that of the other, leading to the reversal of flow in the umbilical artery of the co-twin.[28],[29]

The alternative hypothesis is that acardia is a primary defect in embryogenesis in one twin leading to failure of cardiac development. The normal twin then perfuses the acardiac twin through artery-artery anastomoses. The anastomoses are not responsible for the cardiac anomaly but are established as a result of it.[28],[29]

The acardiac twin, otherwise destined to end in an early spontaneous abortion, continues to grow because of monochorionic vascular anastomoses to a normal co-twin.[26] The case reported belongs to acardius acormus partly because of cephalic attachment of umbilical cord and partly belongs to acardius amorphous due to nonseparation of the head and trunk. The fetal head is the only part which has 50% of development compared to other regions that may be due to abnormal insertion of the umbilical cord directly to the fetal head. The umbilical cord contains two blood vessels instead of normal three. About 1% of singleton and about 5% of multiple pregnancies have an umbilical cord which contains two blood vessels instead of normal three. In all these cases, one artery is missing. This type of vascular anomaly is considered as a remnant of the vitelline artery complex and appears as a unique anomaly almost always associated with sirenomelia.[30] Sirenomelia results from injury to the caudal mesoderm between 28 and 32 days of fetal development.[31] Studies suggested that the developmental arrest of the primitive streak initiates the formation of a second primitive streak, giving rise to a second normal embryo. This may account for the high incidence of sirenomelia in twins. There was a canal communicating the anterior cranial fossa to median anophthalmic orbit, indicating the presence of optic canal, but the corresponding parts of the eyes were not developed due to non development of diencephalon. It is very rare. When the head is fully developed in size, the brain is not developed proportionately, but paradoxically, when the lower limbs are not properly developed, the nerves to the lower limbs are well seen in proportionate thickness. It is strange that the spinal nerves (C5-T1) forming the brachial plexus were emerging out of the vertebral column, but it did not form brachial plexus due to the absence of upper limbs. The cytogenetic studies proved that cyclopia is relatively common in trisomy 13 patients and has been reported in triploidy, trisomy 18 combined dup 1q32 →qter and del 7q34 →qter, dup 3p21 →3pter, del 18 P and ring 18, and monosomy G.[1],[25] Twinning may predispose the midline to further problems and could account for the anomalies. Twinning may be the cause of the association of multiple midline defects and sirenomelia.[32] The twins are in a sense, the ultimate midline anomaly: complete duplication![33] Anomalies observed in sirenomelia are described as the most severe form of caudal regression syndrome.[34] Fusion of the lower extremities, presence of single umbilical, and persistent vitelline artery are the major features of sirenomelia.[35] Studies proved the high incidence of acardiacus in monozygotic twinning. Early malformation in monozygotic twins is due to reversed or disrupted vascular shunts between monozygotic twins, vascular disruption or hypoperfusion, and defective inherent genes. Based on the theory of defective blastogenesis, an impaired blastogenesis, in which the lower body organs have inappropriate angiogenesis, leads to insufficient growth and incomplete development of the caudal region.[36] Although genetic defects in humans are still unknown in the mermaid syndrome, two defects in the Cyp26a1 and BMP7 genes in mice result in the birth of a mermaid neonate. The Cyp26a1 gene is responsible for coding the enzyme that breaks down retinoic acid (the metabolite of Vitamin A). Retinoic acid temporarily increases the vasculature in the caudal region of the embryo. Disruption of the Cyp26a1 gene and incomplete development of the caudal region of the embryo result in a mermaid syndrome in mice. Bone morphogenetic protein-7 is an important protein that plays an important role in angiogenesis in vitro. Stimulating endothelial cells of the caudal region, vascular and tissue production leads to normal growth of the lower limbs in the fetus.[37],[38],[39] Anomalies that are commonly seen with the mermaid syndrome include cleft palate pulmonary hypoplasia, cardiac defect omphalocele, pentalogy of Cantrell, and meningomyelocele.[39] The buds of the upper limbs can be identified 26 days after fertilization and reach a length of 20–22 mm around the 53rd day of pregnancy.[40] The stimulus for bud formation is provided through secretion of a protein named SHH by the notochord.[41] The great majority of congenital deformities arise between the 4th and 8th weeks of pregnancy. Agenesis of the upper limb and disruption or malformation of the primitive streak's caudal vasculature could lead to malformation of structures derived from its mesoderm.[42] Mesodermal derivatives such as muscles and bones are fairly developed and differentiated. However, most of the endodermal derivatives were missing except a coil of the intestine. Although the surface ectoderm is moderately developed, the cranial end of neuroectoderm fails to develop and differentiate. The findings suggest that hypoxia-ischemia due to TRAP may play an important role in the pathogenesis of all these malformations. Any mutation occurring in regulating genes or signaling molecules results in either agenesis or hypoplasia of the tissue. The etiology of this rare syndrome, a combination of anophthalmic cyclopia, with associated malformation-acardiac twin, sirenomelia, is unknown. Most cases are sporadic.[43] Possible risk factors include: maternal diabetes, infections during pregnancy {TORCH -Toxoplasmosis, Other Agents, Rubella, Cytomegalovirus, and Herpes Simplex}, drugs during pregnancy (alcohol, aspirin, lithium, anticonvulsants, hormones, retinoic acid, anticancer agents, and fertility drugs), physical agents like ultraviolet light, and chromosomal3 (mostly trisomy 13) and genetic causes like familial occurrences in twins and in consanguineous marriages have been documented[10],[11],[12],[13],[14],[15],[16],[43],[44] The reported case comes under consanguineous marriages. We must deduce this rare, dramatic, bizarre malformation to be a random occurrence.


  Conclusion Top


It is a rare case of monozygotic twin fetus with multiple anomalies. In all the cases so far known in the past (after 1535), wherever there is a reduction in size of the brain, there is an invariable reduction in size of the skull as seen in anencephaly or microcephaly. Here, in this case, the skull is of normal size for a full-term fetus and the major parts of the brain are missing. It is important to recognize these syndromes clinically and to determine their relationship to various chromosomal abnormalities. The recognition of carrier states with the help of advanced imaging techniques and in utero cytogenetic studies of amniotic cells may spare the unfortunate parents of such monstrosities from similar traumatic experiences. One more aspect of unrevealed secrets of nature is unfolded in this work.

Consent

Informed consent was obtained from parents for the publication of this case report and any accompanying images. Ethical clearance was obtained from the institutional ethical committee. The fetus was donated to the department and was preserved in the Department of Anatomy, VMKV Medical College, Salem, Tamil Nadu, India.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that her name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

Acknowledgment

The authors are thankful to Late Dr. Muthukrishnan, Professor of Anatomy, VMKV Medical College, Salem, for the most valuable guidance throughout this work and helped us to achieve the best paper presentation award in Tamil Nadu State Anatomy conference. We sincerely acknowledge Dr. T. A. Ajith, Professor of Biochemistry, AIMS, Thrissur, for his expert and sincere help in the preparation of this work. We are grateful to Dr. Sugathan for his great help in the proofreading. We are grateful to Mrs. Leena and Mrs. Rengini K. V. for their help in typing the manuscript. We are thankful to the staff of the Department of Anatomy, AIMS, Thrissur, and VMKV Medical College, Salem.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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