|Year : 2018 | Volume
| Issue : 3 | Page : 177-180
Cyclopia-otocephaly-agnathia-synotia-astomia complex: A case report
Kanwar Singh, Shruti Sharma, Khushboo Agarwal, Abhimanyu Kalra
Department of Paediatrics, J. L. N. Medical College, Ajmer, Rajasthan, India
|Date of Web Publication||2-Aug-2018|
Dr. Kanwar Singh
A.211, Budhvihar, Near Power House, Alwar, Rajasthan
Source of Support: None, Conflict of Interest: None
Agnathia is an extremely rare condition. Disorder has also been termed agnathia-holoprosencephaly spectrum, agnathiaotocephaly complex, agnathia-astomia-synotia, or cyclopia-otocephaly association. The spectrum of agnathia ranges from isolated agnathia or virtual absence of the mandible to otocephaly. Agnathia-otocephaly can occur alone or in association with other abnormalities, Holoprosencephaly being the most common. A severe form of holoprosencephaly resulting in children being born with Cyclopia. It results from failure of the cerebral hemisphere to separate during fetal development. It is incompatible with life. Majority result in miscarriages or stillbirths. In this report we present a male preterm baby with cyclopia, otocephaly, agnathia, astomia and synotia (Kanwar Syndrome). As it is a lethal syndrome, knowledge of every variant of this is important for prenatal diagnosis and prognostication. To the best of our knowledge, this unique combination is the first case reported by us in the world.
Keywords: Agnathia, astomia, asynotia, cyclops, holoprosencephaly, synotia, otocephaly
|How to cite this article:|
Singh K, Sharma S, Agarwal K, Kalra A. Cyclopia-otocephaly-agnathia-synotia-astomia complex: A case report. J Clin Neonatol 2018;7:177-80
Agnathia is an extremely rare condition. The disorder has also been termed agnathia-holoprosencephaly spectrum, agnathia-otocephaly complex (AOC), agnathia-astomia-synotia, or cyclopia-otocephaly association.
The spectrum of agnathia ranges from isolated agnathia or virtual absence of the mandible to otocephaly, which refers to a broader malformation of mandibular hypoplasia or agnathia, downward displacement of ears, and/or synotia (approximation of the ears in the midline), with or without aglossia (no tongue), and microstomia (small mouth). Otocephaly term is commonly used for all ear abnormalities with midline displacement. Agnathia-otocephaly is a lethal malformation complex characterized by the absence of the mandible, microstomia, aglossia, and midline positioned ears. Agnathia-otocephaly can occur alone or in association with other abnormalities, holoprosencephaly being the most common.
Agnathia is typically sporadic. Few cases reported showed a possibility of genetically heterogeneous inheritance with cases of possible autosomal recessive and autosomal inheritance. Few cases have shown mutation in two genes, paired-related homeobox 1 (recessive or dominant) and orthodenticle homeobox 2 (dominant). Drugs such as salicylates, amidopyrine, and theophylline are considered to have an association.
Holoprosencephaly refers to a group of disorders arising from the failure of normal forebrain development during embryonic life. Three levels of increasing severity are described: alobar holoprosencephaly (cyclopia being the most severe form), with a single brain ventricle and no interhemispheric fissure; semilobar holoprosencephaly with a partial separation; and lobar holoprosencephaly, where the right and left ventricles are separated, but with some continuity across the frontal cortex.
Cyclopia (alobar holoprosencephaly) is a rare and lethal complex human malformation, resulting from incomplete cleavage of prosencephalon into right and left hemispheres occurring between the 18th and the 28th day of gestation. Holoprosencephaly occurs in 1/16,000 live births and 1/250 during embryogenesis. Approximately 1.05 in 100,000 births are identified as infants with cyclopia, including stillbirths.,,
Cyclopia refers to a single midline orbit that contains ocular structures that could be monophthalmic, synophthalmic, or anophthalmic. Cyclopia typically presents with a median single eye or a partially divided eye in a single orbit, absent nose, and a proboscis above the eye. Extracranial malformations described in stillbirths with cyclopia include polydactyl, renal dysplasia, and an omphalocele.
The etiology of this rare syndrome, which is incompatible with life, is still largely unknown. Most cases are sporadic. Heterogeneous risk factors have been implicated. Possible risk factors include maternal diabetes (the only formally recognized environmental factor with a 1% risk and a 200-fold increase in fetal holoprosencephaly), infections during pregnancy (Toxoplasma, others, rubella, cytomegalovirus, and herpes [TORCHs]),,,,, drugs during pregnancy, (alcohol, aspirin, lithium, anticonvulsants, hormones, retinoic acid, anticancer agents, and fertility drugs), physical agents such as ultraviolet light, previous pregnancy loss and first trimester bleeding, and chromosomal (mostly trisomy 13). Familial occurrences in twins and in consanguineous marriages have been documented and would be consistent with a single gene abnormality. In normal differentiation of the cephalic midline structures, there is increase expression of Pax2 gene and inhibition of Pax6 gene from the notochord. However, inappropriate expression of these genes may result in cyclopia. Mutation of sonic hedgehog gene has also been implicated in the formation of cyclopia. Other genes that play a role in the formation of these defects include ZIC2, TG-interacting factor, and SIX3. In recent years, several isolated case report of cyclops or holoprosencephaly in humans and animals have been associated with abnormal chromosomes.
One highly teratogenic alkaloid toxin that can cause cyclopia is cyclopamine or 2-deoxyjervine, found in the plant Veratrum californicum (also known as corn lily or vetch weed). The mistake of ingesting V. californicum while pregnant is often due to the fact that hellebore, a plant with which it is easily confused, is recommended as a natural treatment for vomiting, cramps, and poor circulation, three conditions that are quite common in pregnant women.
A male child was delivered to a 20-year-old third gravida Muslim mother by normal vaginal delivery with premature labor pains at gestational age of 27 weeks in Janana hospital Ajmer, Rajasthan, India, on September 16, 2017. The baby had a birth weight of 1000 g and was pronounced dead at birth. The baby was born out of nonconsanguineous marriage. Mother has a history of two spontaneous abortions in the past at 6—8 weeks of gestation. She was nondiabetic and normotensive. Hepatitis B Antiegn, venereal disease research laboratory test (VDRL), and TORCH were negative, and HIV test was nonreactive, and blood group was B positive. No drug intake or radiation exposure history was found. She, however, had anemia (Hb 10 g%) and was on tablet iron and folic acid starting the second trimester of pregnancy. Mother was immunized against tetanus. There was no known past family history of holoprosecephaly in our case.
The baby had one single midline orbit and eye (cyclopia), absent mouth (astomia), a proboscis in midline above the orbit, absent mandible (agnathia), and ears fused in the midline below the orbit (synotia). On physical examination, baby had no other gross abnormalities or abdominal organomegaly. Umbilical cord had two arteries and one vein. No abnormalities were found in the placenta [Figure 1] and [Figure 2].
|Figure 1: Picture showing closeup of the facial features of the cyclopia, proboscis, astomia, and synotia|
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|Figure 2: Picture showing the features of cyclopia, agnathia, astomia, and synotia|
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Ultrasonography done on May 16, 2017 showed gestational age of 9—10 weeks with adequate liquor. Fetal heart sounds were present at that time.
Agnathia is an extremely rare condition. Agnathia ranges from isolated agnathia or virtual absence of the mandible to otocephaly. AOC (also known as agnathia-microstomia-synotia syndrome) which is a rare lethal malformation characterized by the association of agnathia (agenesis of mandible) or mandibular hypoplasia, melotia (anteromedial malposition of ears), microstomia (small mouth), and aglossia or microglossia (absent or rudimentary tongue). This rare anomaly of the ventral portion of the first brachial arch is a consequence of the failure of migration of neural crest cells from hindbrain.
During the 4th week of gestation, the neural tube forms the three primary brain vesicles (prosencephalon, mesencephalon, and rhombencephalon) and by the 5th gestational week, the prosencephalon further divides into the telencephalon and diencephalon. The two cerebral hemispheres and the lateral ventricles arise from the telencephalon, whereas the thalami, hypothalamus, and the basal ganglia arise from the diencephalon.
Holoprosencephaly refers to a group of disorders arising from the failure of normal forebrain development during embryonic life.
Cyclopia is a rare and lethal condition. Most infants with cyclopia at birth were reported to have the typical facial features including midline single orbit, proboscis above the orbit, and a single mouth.
In 2006, India reported a baby girl with cyclopia. Her only eye was in the center of her forehead. She had a small mouth and absent nose and fully developed ears.
Furthermore, reported was a live female infant (1.5 kg) delivered a cyclopes baby by cesarean section on August 23, 2006, in Benin city, Nigeria, with single midline orbit, single mouth, no proboscis, single umbilical artery, and fully developed ears.
Another case was reported at Prince Hashem Military Hospital — Zarqa city/Jordan in 2015, where a live full-term baby with birth weight of 2900 g, with features of cyclopia, single orbit in midline, single mouth, huge omphalocele, bladder extrophy, polydactyly and ambiguous genitalia, and fully developed ears was born.
Sharma et al. reported a case from Chandigarh, India, of female fetus with otocephaly, absent right ear and low-lying left pinna with small tags, aglossia, microstomia, and hypoplastic mandible.
Another case of a female infant with cyclopia-astomia-agnathia-holoprosencephaly association was reported by Sezgin et al.
In 1987, Carles et al. described a new rare case of cyclopia with otocephaly and additional brain malformations. An inductive defect of prechordal mesoderm affecting neural crest cells is considered the cause of this malformation. The baby had a single eye, midline fused ears (synotia), astomia, and absent proboscis.
A case with AOC, AOC (agnathia-microstomia-synotia) syndrome was reported by Wai and Chandran. They reported a baby with agnathia, melotia (anteromedial malposition of ears), microstomia, aglossia, or microglossia (absent or rudimentary tongue).
In all the above reported cases, baby were found to have a single eye and small mouth in the midline, no nose and fully developed ears. The originality of our case is that baby having single midline eye (cyclopia), absent mouth (astomia), absent mandible (aganthia), midline displaced ears (otocephaly), midline fused ears (synotia) with midline proboscis above the orbit to be reported yet.
In this report we present a male preterm baby with cyclopia, otocephaly, agnathia, astomia and synotia. As it has been reported by us, we have named it, “KANWAR Syndrome”. It is a lethal syndrome and the presentation of cyclopia-agnathia-astomia complex is not fully exposed, so knowledge of every variant of this is important for prenatal diagnosis and prognostication of the pregnancy. To the best of our knowledge, complex of cyclopia with otocephaly-agnathia-astomia-synotia is the first case reported by us in the world.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]