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    This article is worth 1 CME unit.

    Cebocephaly, Cyclopia – Holoprosencephaly
    And Other Causes For Hypotelorism

    Author: Craig V. Towers M.D.

    Objectives: Upon the completion of this CME article, the reader will be able to

    1. Describe the various categories of disorders that may produce or be associated with hypotelorism.
    2. Discuss the embryologic development of the brain and the differences between the three types of holoprosencephaly.
    3. Describe the various forms that are possible for the holoprosencephalic malformation sequence and their differences.
    4. State the prognosis for holoprosencephaly (based on the type) and the risk of recurrence (based on the etiology).

    Introduction

    Hypotelorism, by definition, is a decrease in the interorbital distance and is an uncommon disorder. It most often is associated with central nervous system abnormalities, especially holoprosencephaly malformation sequence. There are normograms for the interorbital distance and if interested, the reader is referred to most major textbooks that discuss obstetrical ultrasound. Other causes for hypotelorism, if not due to a central nervous system anomaly, include the following:

    • Chromosomal abnormalities (especially, trisomy 13, trisomy 18, and chromosomal deletions)
    • Various Syndromes – the most common is Meckel-Gruber Syndrome, which is an autosomal recessive disorder characterized by polydactyly, microcephaly, polycystic kidneys, and a posterior encephalocele. Others include Oculodentodigital Syndrome, which is an autosomal dominant disorder with small eyes, finger and toe anomalies, and hypoplastic tooth enamel; Coffin-Siris Syndrome, which is autosomal recessive with hypoplastic nails and facial abnormalities; and Williams Syndrome, which is sporadic in inheritance and involves multiple cardiac defects with finger and toe and facial anomalies.
    • Microcephaly – though the distance between the orbits is below normal, with microcephaly, the entire head is small.
    • Fetal effects of maternal phenylketonuria or PKU
    • Trigonocephaly – is a skull defect of the frontal bone (forehead) at the site of the metopic suture (the suture between the two halves of the frontal bones). The defect results in a sharp angulation forward making the forehead narrow and the eyes closer together (from a top view, the forehead has somewhat of a triangular shape).

    Case Report:

    The patient was a 27-year-old female gravida 2 para 1 who was seen in consultation at 29 weeks gestation because of preterm labor. She denied any prior complications in the pregnancy and had excellent dates based on a prior 8-week ultrasound evaluation. There was no family history of any genetic abnormalities. On admission to labor and delivery, she complained of painful contractions that were occurring every 2 to 3 minutes, and on examination, she was found to be 2 centimeters dilated. Her obstetrician immediately started her on tocolytic treatment (medications to stop contractions) and quickly increased this to a maximum dosage. Over the next couple of hours her contractions spaced out and she had no further change in her cervical dilation.

    Because of the unexplained preterm labor, a comprehensive ultrasound was performed that identified a fetus in transverse lie with the fetal head on the mother’s left side. The amniotic fluid volume appeared somewhat increased and the amniotic fluid index measured 26 cm consistent with mild polyhydramnios. The placenta was anterior and fundal in location. The fetal measurements were symmetrical at 26 weeks size. In scanning the fetal head, the structure of the brain was abnormal revealing a monoventricular cavity for the lateral ventricles and the thalami were fused in the midline (figures 1 and 2). In addition the falx cerebra was not present. Also from these views, it appeared that the ears were low set. In scanning the fetal face, the lips appeared to be intact, however the nose only had one nostril (figure 3).

    The diagnosis was alobar holoprosencephaly with facial anomalies consistent with cebocephaly (figure 4). Many of these disorders are associated with trisomy 13 or trisomy 18; however, the patient was presently at 29 weeks gestation by excellent dates based on the prior 8-week ultrasound evaluation. Because of the extremely poor prognosis for this finding, the tocolytic therapy was discontinued. The patient again went back into labor and ultimately converted to a breech presentation and delivered vaginally. The infant was taken to the neonatal intensive care unit, but expired on the second day of life. Chromosomal studies were performed and the child was found to have trisomy 13.

    Discussion:

    Cebocephaly is part of a group of defects called the holoprosencephalic malformation sequence. The development of the forebrain is closely associated with the development of the midline facial structures including the upper lip, the tissue between the orbits (including the nose) and the forehead. Holoprosencephaly (discussed below) can be an isolated finding or can be seen with different facial anomalies, which are as follows:

    1. Cyclopia – is probably the most disturbing because there is only one eye (that develops because of fusion of the orbits) and there is no true nose. Instead there is a proboscis that is often located above the single orbit (figures 5 and 6). In addition, there is hypoplasia or absence of many of the facial bones, low set ears, and an absent philtrum (the philtrum is the shallow groove in the tissue of the upper lip seen in the midline below the nose) (see figure 7). The incidence of cyclopia is reported as 1 in 40,000 births.
    2. Ethmocephaly – also has an absent nose, but there are two orbits in close approximation (hypotelorism). Instead of a nose there is a proboscis that is usually located between the orbits and is generally in the same plane as the orbits. In addition, the ears are usually low set and there is an absent philtrum.
    3. Cebocephaly – has a rudimentary nose but only a single nostril. There are two orbits that are again in close approximation consistent with hypotelorism. The ears are usually low set and the philtrum is again absent. The incidence of cebocephaly is 1 in 16,000 births.
    4. Median Cleft Lip – this is a cleft lip that is directly in the midline and involves the area of the philtrum (the philtrum is absent). It is different than the common cleft lip, which is found lateral to the philtrum. Median cleft lip may have hypotelorism and can also have a cleft palate; however, both of these can also be absent.

    Holoprosencephaly is a central nervous system disorder that develops because of failure of the prosencephalon to properly cleave in the early stages of development. The prosencephalon is the most rostral (superior) part of the developing brain. As review, the embryologic development of the brain is divided into 3 major parts, which are the forebrain (prosencephalon), the midbrain (mesencephalon), and the hindbrain (rhombencephalon). The prosencephalon is further divided into the telencephalon and the diencephalon. The telencephalon includes the cerebral hemispheres, the interhemispheric fissure, the falx cerebri, and the lateral ventricles. The diencephalon primarily includes the thalami and the third ventricle. Because holoprosencephaly involves abnormalities of the entire prosencephalon, a major portion of the brain can be affected. For purposes of completion, the rhombencephalon (hindbrain) is further divided into the metencephalon (which develops into the pons and the cerebellum) and the myelencephalon (which develops into the medulla).

    Holoprosencephaly can come in three forms (which are alobar, semilobar, and lobar). The most severe form and the most common is alobar holoprosencephaly. In this form, the lateral ventricles are fused creating one large monoventricle. The falx cerebri are absent, and the thalami are fused in the midline. In addition, alobar holoprosencephaly can have three configurations, which are the "ball", "cup", and "pancake". These configurations are based on the amount of cerebral tissue that remains. The most common form is the ball form where a small amount of cerebral cortex still covers the monoventricle (as seen in figure 8, as well as, figures 1 and 2). In essence, on sagittal view, the remaining cerebral cortex circles the monoventricle (like a ball). In the cup configuration, the cortex does not completely circle the monoventricle (in the sagittal view). The remaining cortex has a "cup" shape. In the pancake configuration, the small amount of remaining cortex, on sagittal view, is flattened down and is located by the base of the skull.

    In semilobar holoprosencephaly, there is some separation of the cerebral hemispheres in the occipital area with a rudimentary falx, but no separation (or falx) occurs in the frontal region. There is a monoventricle and the thalami are fused in the midline. The majority of semilobar and alobar holoprosencephaly cases are detected in the second trimester or early third trimester. However, with the advances in sonography and the use of transvaginal scanning, a few of these anomalies have been detected in the first trimester.

    Lobar holoprosencephaly is the least severe, and has a separation of the cerebral hemispheres both anteriorly and posteriorly (with a falx that is seen both anteriorly and posteriorly). However, the lateral ventricles are still usually fused somewhat in the frontal horn region and the septum cavum pellucidum is absent. Lobar holoprosencephaly is the most difficult to diagnose antenatally and is most often detected after birth. The septum cavum pellucidum is absent in all forms of holoprosencephaly. Therefore, the presence of this structure will exclude the diagnosis; however, other brain anomalies can have an absent septum cavum pellucidum. Thus, if the septum cavum pellucidum is absent, holoprosencephaly is only part of the differential.

    As discussed in the beginning of this article, hypotelorism is a decrease in the interorbital distance. This is an uncommon antenatal ultrasound finding, but if seen in association with another defect, is usually abnormal. The most common abnormalities that will produce hypotelorism are the holoprosencephalic malformation sequence and hypotelorism associated with a chromosomal anomaly. The fetal effects of maternal PKU, trigonocephaly, and the various syndromes listed at the start of this article are exceedingly rare. The interorbital measurement (when calculated based on the true gestational age) is decreased in cases with microcephaly; however, by definition the entire head is small in microcephaly (and the orbits are usually normally spaced for the small head size).

    Prognosis and Follow-up:

    The prognosis for alobar holoprosencephaly is invariably poor. If not delivered as a stillbirth, these children usually die within the first year of life (and in most cases, within a few days to weeks of delivery – but not in all cases). For semilobar holoprosencephaly, the prognosis is also usually poor and again most pregnancies usually end as a stillbirth or the child dies shortly after delivery. Some cases have been reported to live into childhood; however, they will have profound mental retardation. Children with lobar holoprosencephaly often survive childhood but still have some level of mental retardation. However, many cases have been described as mild and the individuals have learned to live freely (without help) in society

    Though holoprosencephalic malformation sequence can occur on its own, it is also often associated with chromosomal abnormalities (especially trisomy 13 or trisomy 18). Therefore, if detected antenatally in a pregnancy, genetic amniocentesis should be offered. When alobar or semilobar holoprosencephaly is found with trisomy 13 or 18, the diagnosis is uniformly lethal. Therefore, some couples may choose to end a pregnancy. If this combination diagnosis is found after 23 to 24 weeks gestation, some centers will still allow termination (often after the case is reviewed by the institution’s ethics committee) because it is not compatible with life.

    In obstetrics, pregnancies may unfortunately develop complications of preterm premature rupture of the membrane or preterm labor. Currently there are protocols for treating these complications that will hopefully improve the chances for the preterm fetus. For preterm labor, one therapy is the use of tocolytic agents (drugs that try to stop uterine contractions). These drugs are very safe when used according to a protocol, but there is still some risk to the mother that is not negligible. Likewise, there are protocols for prolonging a pregnancy after the membranes rupture early; however, these also carry a small risk for the mother. If preterm labor or preterm premature rupture of the membranes occurs after 23 to 24 weeks gestation in a case of alobar or semilobar holoprosencephaly, the use of these protocols is not recommended. This is because the potential risk to the mother with these protocols is greater that the potential benefit for the fetus (because these disorders are nearly always associated with a very poor fetal / neonatal outcome).

    If the diagnosis is made antenatally but genetic testing is not performed or if the diagnosis is made after delivery, it is still highly recommended that a genetic karyotype be performed. The reason for this recommendation is to help in defining the recurrence risk. If the holoprosencephalic malformation sequence is related to a chromosomal anomaly, the recurrence risk will depend on the abnormality. If it is trisomy 13 or 18 (or some other trisomy), the risk of recurrence is 1% or less (unless one of the parents has a balanced translocation). If it is an isolated finding, the etiology is considered multifactorial with a recurrence risk of about 4% to 6%. For the case described in this article, the neonate was found to have an isolated trisomy 13 (not related to a parental chromosome translocation). Therefore, this couple’s risk for recurrence in a future pregnancy is 1% or less.

    Figures

    1. Holoprosencephaly with a monoventricle. Note that the thalami are fused in the midline and the ear is low set.
    2. Holoprosencephaly with a monoventricle. Note that the thalami are fused in the midline and the ear is low set.
    3. Facial view revealing normal appearing lips but only a single nostril.
    4. View of the infant following delivery revealing the single nostril, the low set ears, and the close proximity of the eyes (hypotelorism).
    5. Profile view of the fetal face revealing a proboscis located above the single orbit in a case of cyclopia.
    6. Another facial view showing intact lips with a single orbit and a proboscis in a case of cyclopia.
    7. View of the infant following delivery that depicts the single orbit and the proboscis situated above.
    8. The "ball" configuration of holoprosencephaly revealing a rim of cortex that is located around the monoventricle (and fused thalami).

    References or Suggested Reading

    1. Lai TH, Chang CH, Yu CH, et al. Prenatal diagnosis of alobar holoprosencephaly by two-dimensional and three-dimensional ultrasound. Prenat Diagn 2000;20:400-3.
    2. Wong HS, Lam YH, Tang MH, et al. First-trimester ultrasound diagnosis of holoprosencephaly: three case reports. Ultrasound Obstet Gynecol 1999;13:356-9.
    3. Golden JA. Towards a greater understanding of the pathogenesis of holoprosencephaly. Brain Dev 1999;21:513-21.
    4. Romero R, Pilu G, Jeanty P, Ghidini A, Hobbins JC. Prenatal Diagnosis of Congenital Anomalies. Appleton & Lange 1988 pp. 59-65 and 96-7.
    5. Smith DW. Recognizable Patterns of Human Malformation, Third Edition. W. B. Saunders Company 1982 pp. 140-1, 182-3, 200-1, 436-7.
    6. Muenke M, Beachy PA. Genetics of ventral forebrain development and holoprosencephaly. Curr Opin Genet Dev 2000;10:262-9.
    7. Kinsman SL, Plawner LL, Hahn JS. Holoprosencephaly: recent advances and new insights. Curr Opin Neurol 2000;13:127-32.
    8. Wallis D, Muenke M. Mutations in holoprosencephaly. Hum Mutat 2000;16:99-108.
    9. Callen PW. Ultrasonography in Obstetrics and Gynecology. W. B. Saunders Company 1988 pp. 103-8.
    10. Chen CP, Chern SR, Lee CC, et al. Prenatal diagnosis of de novo isochromosome 13q associated with microcephaly, alobar holoprosencephaly and cebocephaly in a fetus. Prenat Diagn 1998;18:393-8.
    11. Kesby G. Repeated adverse fetal outcome in pregnancy complicated by uncontrolled maternal phenylketonuria. J Paediatr Child Health 1999;35:499-502.
    12. Moriyama E, Beck H, Iseda K, et al. Surgical correction of trigonocephaly: theoretical basis and operative procedures. Neurol Med Chir 1998;38:110-5.
    13. Schneider EN, Bogdanow A, Goodrich JT, et al. Pronto-ocular syndrome: newly recognized trigonocephaly syndrome. AM J Med Genet 2000;93:89-93.

    About the Author

    Dr. Towers is currently on a sabbatical writing a series of books that deal with the safety of over-the-counter drugs, herbal medications, and natural remedies used during pregnancy. The first is in print entitled "I’m Pregnant & I Have a Cold – Are Over-the-Counter Drugs Safe to Use?" published by RBC Press, Inc.

    Before his sabbatical, Dr. Towers was an Associate Professor in the Department of Obstetrics and Gynecology at the University of California, Irvine. He also was the Director of Perinatal Medicine at Long Beach Memorial Women’s Hospital in Long Beach California. He has practiced clinically in the states of Kansas, California, and Wisconsin. Dr. Towers has multiple publications in peer review medical journals and he has given lectures on a wide variety of obstetrical topics nationwide.

    Examination:

    1. Hypotelorism, is a decrease in the interorbital distance and is most often associated with
    1. central nervous system abnormalities
    2. renal abnormalities
    3. cardiac abnormalities
    4. limb anomalies
    5. unilateral cleft lip
    1. Causes for hypotelorism include all of the following except
    1. Trigonocephaly
    2. Trisomy 18
    3. Fetal Effects of maternal phenylketonuria
    4. Macrocephaly
    5. Meckel-Gruber Syndrome
    1. Trigonocephaly is a skull defect that involves the
    1. parietal bone
    2. occipital bone
    3. frontal bone
    4. maxillary bones
    5. temporal bones
    1. In the case report described in this article, the diagnosis was consistent with
    1. cebocephaly
    2. cyclopia
    3. Meckel-Gruber Syndrome
    4. ethmocephaly
    5. Coffin-Siris Syndrome
    1. The development of the forebrain is closely associated with the development of all of the following facial structures except
    1. the upper lip
    2. the tissue between the orbits
    3. the mandible
    4. the forehead
    5. the nose
    1. Cyclopia has all of the following characteristics except
    1. a single orbit
    2. a nose with a single nostril
    3. holoprosencephaly
    4. absent philtrum
    5. low set ears
    1. Holoprosencephaly associated with facial anomalies described as an absent nose, two orbits, a proboscis that is located between the orbits, and an absent philtrum is describing
    1. Meckel-Gruber Syndrome
    2. Cyclopia
    3. Coffin-Siris Syndrome
    4. Cebocephaly
    5. Ethmocephaly
    1. All of the following disorders listed below have an absent philtrum except
    1. Cebocephaly
    2. Cyclopia
    3. Median Cleft Lip
    4. Ethmocephaly
    5. Common Cleft lip
    1. Holoprosencephaly is a central nervous system disorder that develops because of failure of the _________ to properly cleave in the early stages of development.
    1. mesencephalon
    2. diencephalon
    3. rhombencephalon
    4. prosencephalon
    5. myelencephalon
    1. The portion of the embryologic brain that includes the thalami and the third ventricle is the
    1. mesencephalon
    2. diencephalon
    3. metencephalon
    4. telencephalon
    5. myelencephalon
    1. The most common form of holoprosencephaly is the
    1. lobar form
    2. Coffin-Siris form
    3. alobar form
    4. semilobar form
    5. Meckel-Gruber form
    1. The ball configuration of holoprosencephaly describes
    1. the small amount of remaining cerebral cortex that is located by the base of the skull (in a clump or ball shape).
    2. the thalami that are fused in the midline (to look like a ball).
    3. small amount of remaining cerebral cortex that does not completely circle the monoventricle (which looks like a ball in a glove)
    4. the monoventricle (which looks like a ball)
    5. small amount of remaining cerebral cortex that completely circles the monoventricle (like a ball)
    1. The type of holoprosencephaly that has a monoventricle, fused thalami, and some separation of the cerebral hemispheres in the occipital area with a rudimentary falx, but no separation in the frontal region is describing the
    1. lobar form
    2. Coffin-Siris form
    3. alobar form
    4. semilobar form
    5. Meckel-Gruber form
    1. The type of holoprosencephaly that is the most difficult to diagnose antenatally is the 
    1. alobar form
    2. Coffin-Siris form
    3. Meckel-Gruber form
    4. semilobar form
    5. lobar form
    1. All forms of holoprosencephaly have an absent
    1. falx
    2. third ventricle
    3. aqueduct of Sylvius
    4. septum cavum pellucidum
    5. forth ventricle
    1. Regarding the prognosis for alobar holoprosencephaly,
    1. if not delivered as a stillbirth, these children usually die within the first year of life.
    2. most cases survive into childhood but with profound mental retardation.
    3. most cases survive into childhood but with mild mental retardation.
    4. most cases survive into childhood and with therapy can learn to live freely (without help) in society.
    5. it is uniformly lethal, with death occurring in only hours after birth.
    1. Though holoprosencephalic malformation sequence can occur on its own, it is also often associated with chromosomal abnormalities especially
    1. trisomy 3 and 8
    2. trisomy 14 and 15
    3. trisomy 13 and 18
    4. monosomy 14 and 15
    5. monosomy 3 and 18
    1. If preterm labor or preterm premature rupture of the membranes occurs after 23 to 24 weeks gestation in a case of alobar or semilobar holoprosencephaly, the use of treatment protocols to prolong the pregnancy are not recommended because
    1. the disorders make the therapy ineffective.
    2. the potential risk to the mother with these protocols is greater that the potential benefit for the fetus.
    3. the necessary medications may cause more damage to the already anomalous fetus.
    4. it is important to deliver as soon as possible so that therapy can be instituted to improve the newborn’s outcome.
    5. the protocols will improve the chances for a better outcome and longer survival of the baby, which would not be desired by the couple.
    1. If a diagnosis of holoprosencephalic malformation sequence is made antenatally but genetic testing is not performed or if the diagnosis is made after delivery, it is still highly recommended that a genetic karyotype be performed because
    1. it helps determine if the cause was due to maternal phenylketonuria.
    2. it helps in defining the recurrence risk.
    3. it helps determine if the cause was due to Meckel-Gruber Syndrome.
    4. it helps determine if the cause was due to Coffin-Siris Syndrome.
    5. it helps determine if the cause was due to some drug or environmental agent that the mother took or was exposed to during the pregnancy.
    1. If the holoprosencephalic malformation sequence is an isolated finding, the etiology is considered multifactorial with a recurrence risk of about
    1. 4% to 6%
    2. 1%
    3. 10%
    4. less than 1%
    5. 25%

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