Cyclopia

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 by Donny W. Suh, MD,FAAP on September 9, 2019.


A rare manifestation of the most severe degree of alobar holoprosencephaly, cyclopia results when the eye fields fail to separate, and develops as a single socket in the middle of the face with varying degrees of fusion of the globes. Since it is associated with very high neonatal mortality rates, miscarriages, and stillbirths; it is not encountered in clinical practice.

Disease Entity

Cyclopia. ICD-10 Reportable Congenital Malformations Coding : Q87.0

Disease

Cyclopia is a manifestation of the most severe form of a congenital anomaly called holoprosenchephaly (HPE). Cyclopia is a rare variety of synophthalmia, in which varying degrees of fusion of both eyes can be seen in a single, central orbit located in the middle of the face.

Incidence

Synophthalmia, as a spectrum, occurs in 1/100,000 live births, out of which there is a female predominance of 61%[1]. The preponderance of female babies born with cyclopia might be explained by the increased number of male stillbirths.

Risk Factors

The etiology is still largely unknown, but, possible heterogeneous risk factors have been identified[2], some with stronger evidence than others.

Fetal factors:

  • chromosomal anomalies - most commonly associated with Patau syndrome (trisomy 13)
  • female sex
  • multiple pregnancies, especially twinning[3]
  • syndromic associations of alobar holoprosencephaly (eg. : Smith - Lemli - Opitz syndrome)

Maternal factors:

  • previous unexplained miscarriages
  • gestational diabetes
  • TORCH complex / trans-placental infections
  • insulin (during the gestational period)
  • alcohol consumption
  • smoking (nicotine exposure)
  • retinoic acid exposure during pregnancy
  • anticonvulsant usage during pregnancy
  • lithium
  • birth control pills (to a smaller extent)
  • cyclopamine - a highly alkaloid toxin, Veratrum californicum, found in corn lily or false hellebore is implicated in causing cyclopia (when ingested believing the plant to be hellebore, which can cure the morning sickness symptoms associated with the first few months of pregnancy)

Pathophysiology

To understand how an anomaly like cyclopia occurs, we first need to have an understanding of the normal development of the neural tube, forebrain, and subsequently, the eye fields.

Once the notochord has been formed in the mesoderm by the invagination of primitive streak cells, it induces the neural ectoderm lying above to form the neural plate. The process of neurulation, or the conversion of the neural plate into the neural tube, is central to the development of the central and peripheral nervous system. This happens when the neural plate folds over itself to form a tube; and now lies beneath the ectoderm, and above the notochord. The cells in the area of fusion of the two ends of the neural plate, called the neural crest cells, come to lie directly above the neural tube, to later differentiate into most of the structures of the peripheral nervous system.

At this stage of development, the hollow neural tube extends along the length of the embryo, and is the precursor of the brain and spinal cord. The part of the neural tube destined to be the future brain becomes three distinct dilated demarcations, called primary vesicles. They are given names corresponding to which part of the neural tube they occupy; from cranial to caudal - prosencephalon, mesencephalon, and rhombencephalon. These areas correspond, in order, to the forebrain, midbrain, and the hindbrain; and the rest of the neural tube later becomes the spinal cord.

The anterior-most part of the developing neural tube undergoes folding, so that the prosencephalon comes to lie ventral to the rhombencephalon, with the mesencephalon connecting the two. The primary vesicles differentiate further, the cranial-most part of the prosencephalon now divides into two lateral vesicles, called the telencephalon, (corresponding to the cerebrum); and the remaining part of the prosencephalon is now called the diencephalon, corresponding to the thalamus, epithalamus, and hypothalamus. The newly formed diencephalon and telencephalon are the secondary vesicles, and of particular interest to us is the diencephalon, which is the area where the optic vesicles develop.

Around day 22, when the developing embryo is about 2mm in length, and is at the eight-somite stage; two small grooves develop on the sides of the developing forebrain. With the closure of the neural tube, these become out-pouchings from the area of the primary brain vesicle, and are henceforth called optic vesicles. They grow laterally, and as they come closer to the layer of surface ectoderm, the optic vesicle stimulates the overlying ectoderm to differentiate into a specialised mass of cells called the lens placode (corresponding to the future lens) by secreting the growth factor BMP4. The ability of the surface ectoderm to respond to this stimulus lies in the expression of the PAX6 gene by the ectoderm.[4]  

The Sonic Hedgehog Factor

 The development of the eyes is based on a delicate interplay between the various genes and transcription factors involved in the process, and the most important one among them might be the expression of sonic hedgehog factor.

Even before neurulation occurs, there already exists the designation of a single eye field in the neural plate. This area, after development of the neural tube, divides into two, only under the influence of sonic hedgehog, which sets off the process that stimulates the growth of two separate eyes and orbital cavities.[5] The postulated theory is that the secretion of sonic hedgehog from the prechordal plate causes down-regulation of the PAX6 gene, and activation of the PAX2 gene, which then divides the single eye field into two.

Holoprosencephaly and Shh

Defects in the sonic hedgehog protein or its signalling pathway are implicated in holoprosencephaly, since the shh is necessary for the brain to develop into distinct left and right lobes; a process that normally occurs between the eighteenth and twenty eighth day of gestation. Only subject to this can the visual cortex begin to develop.

At this point, an embryo with a single forebrain region (a condition called alobar holoprosencephaly) will be likely to develop a single eye; and embryos with separate cerebral hemispheres will develop two eyes. Failure of the events that Shh sets into place would mean that there is no expression of PAX2, and no down-regulation of PAX6, which is necessary for the formation of a distinct visual field corresponding to each hemisphere.

Genes implicated in synophthalmia

The development of the forebrain and the eye fields is an intricate interplay between a plethora of genes and transcription factors, and the fraction of it that has been studied and understood has been summarised below.[6]

GENES IMPLICATED IN SYNOPHTHALMIA

SHH[7], SIX3[8], TGIF1[9][10], ZIC2[11], PTCH1[12], FOXH1[13], NODAL[14], CDON[15], FGF8[16], GLI2[17], FOXG1[18]

Associated features

The child presents with microcephaly, since the lobes of the brain and the ventricles are hypoplastic. Perhaps the most striking feature of all, with the exception of a single central eye, is the absence of a nose, or the presence of a proboscis above the eye. The eye is located in a single central orbit; it could be one single eye (true cyclopia), or partially fused eyes within the single orbit (synophthalmia). The mouth is usually not well formed, it could just be a mound of soft tissue with a cleavage where the mouth would be, with associated micrognathia. 

Since cyclopia, (or in a broader sense, alobar holoprosencephaly) is not compatible with life, there are only a few anatomical features, evident on dissection, recorded in literature:[19]

  • Complete or near-complete interhemispheric non-separation.
  • Absence of falx cerebri
  • Absent corpus callosum
  • Single midline ventricle
  • Absent olfactory bulbs
  • Fused deep grey nuclei
  • Extra cranial manifestations : polydactyly, omphalocoele, renal dysplasia[20]

There appears to be a tendency for holoprosencephaly to run in families, but this is only true of the milder varieties of presentation. There is a wide range of presentations that come with varying degrees of holoprosencephaly, and cyclopia is the extreme end of the spectrum. It is incompatible with life, and it is mostly seen in spontaneous miscarriages and stillbirths. More often than not, death of the fetus usually occurs in utero, or, in rare cases that a child is born with cylopia, a mere few hours after birth.   

Screening

Prenatal ultrasound remains the best modality to diagnose holoprosencephaly, and awareness of the range of features in cyclopia (and, varying degrees of holoprosencephaly) can improve the chances of detection and increase accuracy of an early diagnosis. Some features that may point to alobar holoprosencephaly are:

  • monoventricle
  • absence of third ventricle
  • absence of interhemispheric fissure
  • absence of corpus callosum / hypoplastic corpus callosum
  • fusion of thalami
  • changes in vasculature of middle and anterior cerebral arteries
  • severe facial deformations

[21]

Timely USG detection of features of alobar holoprosencephaly in the NT scan (done at 11 to 136 weeks of gestation), can enable early diagnosis and, if required, termination of pregnancy within the recommended safe limit of gestational age (in accordance with the country's legislation).

Prognosis

The prognosis for cyclopia, which is the extreme presentation of alobar holoprosencephaly, is grave. It is not a condition compatible with life, and death occurs; if not in utero, within a few hours after birth.

The maximum recorded lifespan of a child born with cyclopia is one day.  

A picture of a cyclopic infant circa 1800, taken from Armand Marie Leroi's book, Mutants - On genetic Variety and the Human Body.
[22]

Cyclopia through the ages

The few recorded cases of cyclopia that have occured in humans remain in a very small proportion as compared to the recorded incidence in other species.

  • In Indonesia, on September 13th, 2018, a baby with cyclopia was born without a nose and one eye. The baby weighed 2.4 kg and the heart rate was recorded as hundred beats per minute. The child reportedly died seven hours after birth.
  • A paper published in September 2014 talked about a child born with microcephaly, cyclopia, cleft palate and no nose. The Apgar score was 7/8/8, and the child died 10 hours after birth.[23]
  • In 2006, a baby with cyclopia was born in India. She had marked absence of a nose, and the post-mortem report showed presence of only a single hemisphere. The child passed away one day after her birth.
  • In his book, Mutants, On Genetic Variety and the Human Body; Armand Marie Leroi reveals the photograph of a stillborn with cyclopia from 1893.
  • Going further back into historical archives, a record of a baby with cyclopia born in 1793 was found in Sweden; the child reportedly died after two hours of birth.
  • It is not a far leap to assume that the cyclopes of the ancient Greek Mythology were, in fact, inspired from a baby born with cyclopia at a time when congenital abnormalities were feared and thought to be bad omens.

Additional Resources

Mutants - On Genetic Variety and the Human body by Armand Marie Leroi.

Grey's Anatomy - Embryology

References

  1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4484722/
  2. https://onlinelibrary.wiley.com/doi/abs/10.1002/ajmg.c.30233  
  3. https://www.ncbi.nlm.nih.gov/pubmed/29761639   
  4. http://education.med.nyu.edu/courses/macrostructure/lectures/lec_images/eye.html  
  5. https://ghr.nlm.nih.gov/gene/SHH  
  6. https://rarediseases.org/rare-diseases/holoprosencephaly/  
  7. https://www.researchgate.net/profile/Tim_Wiltshire/publication/12930306_Mutations_in_the_homeodomain_of_the_human_SIX3_gene_cause_holoprosencephaly/links/542011f30cf203f155c2a15b/Mutations-in-the-homeodomain-of-the-human-SIX3-gene-cause-holoprosencephaly.pdf   
  8. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4101187/
  9. https://www.ncbi.nlm.nih.gov/pubmed/23397132
  10. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3285584/
  11. https://www.ncbi.nlm.nih.gov/pubmed/13678579
  12. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4817771/
  13. https://www.ncbi.nlm.nih.gov/pubmed/18331719
  14. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4624997/
  15. https://www.sciencedirect.com/science/article/pii/S0002929711002655
  16. https://www.ncbi.nlm.nih.gov/pubmed/10842056
  17. https://onlinelibrary.wiley.com/doi/pdf/10.1002/dvdy.20658  
  18. https://www.scholars.northwestern.edu/en/publications/six3-dosage-mediates-the-pathogenesis-of-holoprosencephaly  
  19. http://medind.nic.in/ibv/t11/i6/ibvt11i6p457.pdf  
  20. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4324465/  
  21. https://radiopaedia.org/articles/alobar-holoprosencephaly
  22. 'Mutants - On Genetic Variety and the Human Body' by Armand Marie Leroi
  23. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4054394/