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Numerical structuralabnormalities csbrp
This document discusses genetic disorders caused by abnormalities in human chromosomes. It begins by describing karyotyping and the banding patterns used to identify chromosomes. It then describes several types of numerical chromosome abnormalities including aneuploidy, where there is an extra or missing chromosome, and polyploidy, where there are extra sets of chromosomes. Structural abnormalities are also outlined, such as deletions, duplications, inversions, translocations, and ring chromosomes. Specific genetic disorders are then examined in more detail, including Down syndrome caused by trisomy 21, Edward's syndrome from trisomy 18, and Patau's syndrome involving trisomy 13. Sex chromosome disorders like Klinefelter syndrome (XXY
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Numerical structuralabnormalities csbrp
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- 2. Karyotype Each armis divided into 2 or more regions Each region is divided into bands and sub bands They are numbered from centromere outwards ex. Xp 21.2
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- 6. Numerical Abnormalities • Diploid(2n) • Polyploid (2n+….) • Euploid (exact multiples of n) • Autopolyploidy • Allopolyploidy • Aneuploid • Hyperaneuploidy • Hypoaneuploidy
- 7. Numerical Abnormalities • Diploid •Polyploid • Euploid (exact multiples of n) • Autopolyploidy • Allopolyploidy • Aneuploid • Hyperaneuploidy • Hypoaneuploidy
- 8. Numerical Abnormalities • Diploid •Polyploid • Euploid (exact multiples of n) • Autopolyploidy • Allopolyploidy • Aneuploid • Hyperaneuploidy • Hypoaneuploidy
- 9. Numerical Abnormalities • Diploid(2n) • Polyploid (2n+….) • Euploid (exact multiples of n) • Autopolyploidy • Allopolyploidy • Aneuploid (addition of 1 or 2 chr) • Hyperaneuploidy (2n+1, 2n+2) • Hypoaneuploidy (2n-1, 2n-2)
- 10. Mechanism of Aneuploidy Non disjunction – Failure of chromosome to separate normally during cell division result in monosomy or trisomy Anaphase lag - One chromosome fail to reach the pole of dividing cell at the same time and is left out of nucleus of daughter cell Mosaicism – Individual has 2 or more types of cell lines derived from same zygote ex. cancers
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- 15. Structural abnormalities Translocation– Transfer of a segment of one chromosome to another non- homologous chromosome 1. Balanced translocation – When two fragments of chromosomes exchange materials without any loss of genetic materials. ex. Philadelphia chromosome – t(9:22) (q34:q11) 2. Robertsonian translocation
- 16. Structural abnormalities - Translocation Balancedtranslocation
- 17. Structural abnormalities 2. Robertsoniantranslocation – When two acrocentric chromosome lose their short arm and fuse at the centromere so that eventually the cell is left with 45 chromosomes.
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- 19. Structural abnormalities Translocation: Ex:Acute Myelogenous Leukemia Philadelphia chromosome t(9,22)
- 20. Structural abnormalities Deletion Loss of part of the DNA from a chromosome. Deletion may be from terminal portion/ Middle portion
- 21. Deletion – Terminal deletionof short arm
- 22. Deletion – Terminal deletionof long arm
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- 24. Can you giveone best example for deletion resulting in disease? Alfa-Thalassemia
- 25. Structural abnormalities Ring chromosome:When both ends of a chromosomes are lost and the damaged ends join together, they form Ring chromosomes
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- 27. Diseases in whichring chromosomes are seen include: Some tumors of adipose tissue Fanconi’s anemia
- 28. Structural abnormalities Duplications: Ex:Fragile X syndrome The most common form of mental retardation The X chromosome have over 700 repeats due to duplications (Normal upto 29) Affects 1:1500 males, 1:2500 females
- 29. Structural abnormalities Duplications: Ex:Fragile X syndrome
- 30. Structural abnormalities Isochromosomeformation result when the centromere divides in a tranverse plane rather than in a normal long axis of the chromosome Ex. One with 2 short arms & one with 2 long arms
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- 32. Structural abnormalities Inversion:Rearrangement that involves two breaks within a single chromosome with reincorporation of inverted segment Paracentric Pericentric
- 33. Inversion – (long arm) ParacentricPericentric
- 34. Mutation Permanent changein the DNA Mutation in germ cell – Inherited diseases Mutation in somatic cells – Cancer, congenital malformation
- 35. Mutation Genomic Mutation– Monosomy/ trisomy Chromosomal Mutation – rearrangement of genetic material with visible structural changes in chr. Gene Mutation – Submicroscopic 1. Point mutation 2. Frame shift mutation
- 36. Mutation Point mutation– single nucleotide base is substituted by different base. e.g. sickle cell disease – glutamic acid replaced by valine at 6th position from the aminoterminal of beta globin chain of Hemoglobin
- 37. Mutation Frame shiftmutation One or two base pairs may be inserted/ deleted from the DNA, leading to alterations in the reading frame of the DNA strand
- 38. Frameshift Mutation (1-2 bp(s)deletion) (1-2 bp(s) insertion)
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- 43. Down’s Syndrome Trisomy21, 47 XY + 21 Most common chromosomal disorder 1 in 700 live births Due to non disjunction Or Robertsonian translocation Parents – Normal karyotype Risk factor Mother over 35 years
- 44. The fertilization ofa genetically abnormal egg carrying an extra chromosome 21 (orange) by a normal sperm (green) produces an embryo with Down syndrome (purple).
- 45. Trisomy 21 --Down’s syndome
- 46. Click to seeanimation on Non-Disjun
- 47. Down’s Syndrome ClinicalFeatures Major cause of mental retardation IQ 25-50 Very gentle, shy & friendly Diagnosed at birth by “mongol” look – Flat facial profile, oblique palpebral fissure, epicanthic folds 40 % of patients – CHD ASD, Ostium primum, A-V valve malformation, VSD
- 49. Down’s syndromeDown’s syndrome NormalMongols Down’s baby With Mongoloid look
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- 51. Down’s syndromeDown’s syndrome Normalhand Simian crease
- 52. Down’s syndromeDown’s syndrome SimiancreaseSimian crease
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- 57. Down’s Syndrome AcuteLeukemia – 10 to 20 fold ^ risk Alzheimer’s disease < 40 years of age Abnormal immune response – Infection Simian crease, Hypotonia, Umbilical hernia
- 58. Down’s Syndrome AcuteLeukemia – 10 to 20 fold increased risk Transient MyeloproliferativeTransient Myeloproliferative SyndromeSyndrome
- 59. Other Trisomies Trisomy18 – Edward’s syndrome Trisomy 13 – PATAU syndrome High mortality
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- 61. Edward’s syndrome 1:10,000live births Almost every organ system is affected do not live more than a few months
- 62. Trisomy 18 ---Edward’s syndrome
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- 64. Trisomy 18 Edward’s syndrome Over lappingfingers & toes and rocker bottom feet
- 65. Trisomy 18 Edward’s syndrome 1.Over lappingfingers & toes 2.Rocker bottom feet 3.Syndactyly
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- 68. Patau’s syndrome 1:5000live births Cleft palate Serious eye, brain, CVS defects Children rarely live more than a few months
- 69. Trisomy 13 ---Patau syndrome
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- 73. Trisomy 13 -Patau syndrome
- 76. When to suspect Trisomy? • Congenital heart & renaldiseases • Mental retardation • Rocker bottom feet • Extra digits and cleft lip / palate
- 77. CYTOGENETIC DISORDERSCYTOGENETIC DISORDERS INVOLVINGINVOLVING SEXCHROMOSOMESSEX CHROMOSOMES
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- 80. Klinefelter’sKlinefelter’s SyndromeSyndrome 47, XXY Male hypogonadism 1 in 850 live male births Rarely diagnosed before puberty Increased length between sole and pubic bone Small testis, small external genitalia Lack of secondary male features
- 81. Klinefelter’s Syndrome Gynaecomastia ↑ FSH , Testosterone↓ ↓ Spermatogenesis – Male Infertility Testis – Atrophic tubules, Prominent Leydig cells
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- 91. KlinefelterKlinefelter ’s’s SyndromeSyndrome Chromosomes In sperms: X (green) Y(red) & 18 (orange) Human Reproduction Vol15. no2. pp 440-444, 2000
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- 94. Turner’s Syndrome 45,X0 (57%) 45, X0 / 46, XX – Mosaic Type Most common sex chromosomal abnormality in female Female hypogonadism Infancy Edema of hand & foot Swelling of nape of neck CHD – Coarctation of aorta, bicuspid aortic valve
- 95. Turner’s Syndrome 1:5000live births The only viable monosomy in humans Genetically female They do not mature sexually during puberty and are sterile Short stature and normal intelligence 98% of these fetuses die before birth
- 97. Turner’s Syndrome Puberty Failure of secondary sexual character – Breast, external genitalia Short stature Amenorrhea – single most important cause Hypothyroidism, glucose intolerance, obesity, insulin resistance Atrophic ovaries
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- 105. Sex chromosomal disorder Lyon hypothesis: Random inactivation of one of X ch. in females. Inactive X ch.- Barr body / Drumstick appendages Minimum of 30% cells should show sex chromatin
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- 107. Nucleus of afemale amniotic fluid cell Top: Both X- chromosome territories are detected by FISH. Bottom: Same nucleus stained with Dapi. The Barr body is indicated by the arrow, it identifies the inactive X (Xi).
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Editor's Notes
- #4 Figure 5-21 Details of banding pattern of the X chromosome (also called &quot;idiogram&quot;). Note the nomenclature of arms, regions, bands, and sub-bands. On the right side, the approximate locations of some genes that cause disease are indicated.
- #7 Autoploidy = have similar sets of chromosomes derived from the same species. Eg: Autotriploidy (3n) will have three sets of chromosomes (AAA) of same genome as in watermelon, banana. Autotetraploidy (4n) will have four sets of chromosome (AAAA) of same genome as in corn, rye plant, apple, marigold Allopolyploidy = These have multiples of haploid (n) sets of chromosomes derived from different related species Such plants are geenrally derived by hybridization. Eg: Allotetraploidy (4n) will have AABB (where A and B are haploid sets from two different species) as in new world cotton plant Allohexaploidy (6n) will have AA BB DD as in wheat. Here genomes of three species are involved.
- #8 Autoploidy = have similar sets of chromosomes derived from the same species. Eg: Autotriploidy (3n) will have three sets of chromosomes (AAA) of same genome as in watermelon, banana. Autotetraploidy (4n) will have four sets of chromosome (AAAA) of same genome as in corn, rye plant, apple, marigold Allopolyploidy = These have multiples of haploid (n) sets of chromosomes derived from different related species Such plants are geenrally derived by hybridization. Eg: Allotetraploidy (4n) will have AABB (where A and B are haploid sets from two different species) as in new world cotton plant Allohexaploidy (6n) will have AA BB DD as in wheat. Here genomes of three species are involved.
- #9 Autoploidy = have similar sets of chromosomes derived from the same species. Eg: Autotriploidy (3n) will have three sets of chromosomes (AAA) of same genome as in watermelon, banana. Autotetraploidy (4n) will have four sets of chromosome (AAAA) of same genome as in corn, rye plant, apple, marigold Allopolyploidy = These have multiples of haploid (n) sets of chromosomes derived from different related species Such plants are geenrally derived by hybridization. Eg: Allotetraploidy (4n) will have AABB (where A and B are haploid sets from two different species) as in new world cotton plant Allohexaploidy (6n) will have AA BB DD as in wheat. Here genomes of three species are involved.
- #10 Monosomies are not compatible with life. Only exception in the case of humans are Turner’s syndrome (45, X0)
- #13 Origins of monosomy and trisomy. (a) During mitotic metaphase or meiotic metaphase II, one pair of sister chromatids does not align at the equatorial plane. Consequently, both sister chromatids move to the same cell. One daughter cell will show trisomy and another daughter cell will have monosomy. (b) During meiotic metaphase I, two homologous pairs of sister chromatids do not align at the equatorial plane and subsequently move to the same cell (a phenomenon called nondisjunction). The resulting daughter cells also have either monosomy or trisomy.
- #15 Inversion, Deletion and Ring Structure Two breaks in a single chromosome can cause inversion, deletion or ring structure as shown in the figure. Chromosomal abnormality resulting from two breaks in a single chromosome. Inversion: The segment between two breakpoints is inverted before resealing the breaks. Deletion: The breaks reseal without including the segment between breakpoints. Examples: cri-du-chat syndrome and William&apos;s syndrome. Ring chromosome: Two ends of the segment between breakpoints are joined to form a circular structure.
- #16 Translocation – Transfer of a segment of one chromosome to another non-homologous chromosome Balanced translocation – When two fragments of chromosomes exchange materials without any loss of genetic materials. ex. Philadelphia chromosome – t(9:22) (q34:q11)
- #18 Robertsonian translocation is caused by breaks at the centromeres of two nonhomologous acrocentric chromosomes (chromosomes with centromeres near their ends, e.g., chromosome 13, 14, 21, and 22). After the breaks, the long arms of two chromosomes join together to form a single chromosome. The short arms may join to form another chromosome, but it is usually lost within a few cell divisions. Therefore, the karyotype of a person with Robertsonian translocation usually exhibits only 45 chromosomes.
- #20 Translocation: a fragment of a chromosome is moved (&quot;trans-located&quot;) from one chromosome to another - joins a non-homologous chromosome. The balance of genes is still normal (nothing has been gained or lost) but can alter phenotype as it places genes in a new environment. Can also cause difficulties in egg or sperm development and normal development of a zygote. Acute Myelogenous Leukemia is caused by this translocation.
- #29 Fragile X: the most common form of mental retardation. The X chromosome of some people is unusually fragile at one tip - seen &quot;hanging by a thread&quot; under a microscope. Most people have 29 &quot;repeats&quot; at this end of their X-chromosome, those with Fragile X have over 700 repeats due to duplications. Affects 1:1500 males, 1:2500 females.
- #30 Fragile X: the most common form of mental retardation. The X chromosome of some people is unusually fragile at one tip - seen &quot;hanging by a thread&quot; under a microscope. Most people have 29 &quot;repeats&quot; at this end of their X-chromosome, those with Fragile X have over 700 repeats due to duplications. Affects 1:1500 males, 1:2500 females.
- #44 Mechanism: Due to non disjunction during meiosis in one of the parents In addition to the trisomy 21 mentioned above, the Down&apos;s syndrome may also be caused by Robertsonian translocation, in which the long arm of chromosome 21 is attached to another chromosome, usually chromosome 14 or itself.
- #51 Palpebral slant The direction of the slant of a line drawn from the outer corner of the eye to the inner corner is known as the palpebral slant. The most commonly recognized syndrome associated with an abnormal palpebral slant is Down&apos;s syndrome.
- #55 An abnormal crease is seen on the hand of this baby with trisomy 21 (Down syndrome). A single transverse crease extends transversely across the palm. There is also just a single flexion crease on the fifth finger, a feature seen in about 20% of babies with Down syndrome. Note: There is an increased risk of Trisomy 21 in individuals with only 11 ribs. If you measure out the long bones of the limbs, the humeri and femurs come out to be relatively shorter than the middle segments in Down syndrome, and the middle phalanges of the fifth fingers will be hypoplastic or unmineralized in Down Syndrome. If you have any of these other findings, IUGR, or other anomalies, you should get a karyotype. Galen Schauer &lt;Galen.Schauer@kp.org&gt; Kaiser Permanente, Oakland CA.
- #56 Characteristic Palmar Features in Down&apos;s Syndrome Cheiromorphognomy: - short, broad palms with short fingers - short Air fingers (55% cases) (normally only found in 5% hands) - clinodactyly of Air finger (55% of cases) (normally only found in 6% of hands) - single interphalangeal crease on Air finger (26%) (virtually never seen normally) - hyperflexive lower thumb joint (77%) (normally only found in 28% of hands) - Simian lines commonly present (53%) (normally only found in 1-2% of hands)
- #59 Transient Myeoloproliferative Syndrome: Seen in Down’s patients which resembles acute leukemia, but reverses to normalcy on it’s own. With such recurrent events the patient’s may land in acute leukemia – AML.
- #63 This karyotype demonstrates trisomy 18 (47, XY, +18) also known as Edward&apos;s syndrome. It is uncommon for fetuses with this condition to survive, so the incidence is only 1 in 8000 live births. It is rare for babies to survive for very long if liveborn because of the multitude of anomalies that are usually present.
- #65 Over lapping fingers and toes and rocker bottom feet.
- #67 The characteristic overlapping fingers (clenched fist) of a fetus with trisomy 18 is shown here. This appearance is highly suggestive of trisomy 18. Note that digits 2 and 5 overlap 3 and 4.
- #70 The karyotype here demonstrates trisomy 13 (47, XX, +13) also known as Patau&apos;s syndrome. It is rare for fetuses with this condition to go to term, so it occurs in only 1 in 6000 live births. It is rare for babies to survive for very long if liveborn because of the multitude of anomalies that are usually present.
- #72 This is a prominent bilateral cleft lip associated with trisomy 13. Post-axial polydactyly, particularly of all extremities, strongly suggests trisomy 13 (Patau syndrome). Note the extra digit on the hand shown here. An extra finger (polydactyly) is present on this hand of an infant with trisomy 13 (Patau syndrome).
- #73 This baby with trisomy 13 has cyclopia (single eye) with a proboscis. Along with midline defects such as cleft lip and/or palate, cyclopia, and proboscis, a baby with trisomy 13 may have holoprosencephaly, a condition in which the brain does not form two complete cerebral hemispheres. Seen here is the &quot;alobar&quot; form of holoprosencephaly in which there is only a single ventricle. [
- #74 Trisomy 13. Neutrophil - Blood film: Composite of neutrophils in a patient with this cytogenetic abnormality. Note elongated nuclei with atypical constrictions and multiple dumbbell projections from nuclei.
- #75 Aberrant Nuclear Projections of Neutrophils in Trisomy 13 Mohamed E. Salama , MD, Veena Shah , MD, Robert Roger Lebel , MD, FACMG, and Daniel L. VanDyke , PhD, FACMGFrom the Departments of Pathology and Medical Genetics, Henry Ford Hospital, Detroit, Mich Accepted: October 1, 2003 ---------------------------------------- A 26-year-old gravida 2, para 1 woman was referred to the Medical Genetics Clinic for consultation at 25 weeks of gestation for a questionable “double bubble” (gastric and duodenal distension proximal to a presumed atretic site) that was observed on ultrasound examination. A repeat ultrasound examination revealed a fetus growing appropriately for gestational age but with an echogenic bowel. The double bubble was not seen, but a fluid-filled structure was identified, probably representing a distended gallbladder. The family history revealed no birth defects or mental retardation. This woman&apos;s first child was alive with no abnormalities. The mother declined amniocentesis. Because of the echogenic fetal bowel, maternal blood was drawn to evaluate titers for toxoplasmosis, other infections, rubella, cytomegalovirus infection, and herpes simplex infection and to search for cystic fibrosis mutations. Because of partial French-Canadian ancestry, she was also tested for Tay-Sachs carrier status. Results of all those tests were normal or negative. A 2750-g girl was born at 35 weeks&apos; gestation by normal vaginal route. Apgar scores were 4 at 1 minute, 6 at 5 minutes (after intubation), and 8 at 10 minutes. Postaxial polydactyly of all 4 extremities was noted, and echocardiography for respiratory distress and hypotension revealed tetralogy of Fallot. At this point, it was thought that the child might have either Edwards syndrome or Patausyndrome. The cardiac malformation greatly compromised her condition, resulting in refractory hypotension and hypoxemia, and the family decided to withdraw ventilator support. A few hours after her death, the Genetics Laboratory reported preliminary fluorescent in situ hybridization findings consistent with trisomy 13 (Patau syndrome) (Figure, A: fluorescent in situ hybiridization image of a cell showing +13; the green signal is the 13 probe and the orange signal is the 21 probe). The final karyotype report confirmed the trisomy 13 (Figure, B). Review of a peripheral smear revealed 2 or more small threadlike projections from the nuclei in more than 80% of the neutrophils (Figure, C). Trisomy 13 usually occurs by nondisjunction during gametogenesis. The prognosis is poor. Fetal death is frequent, and 90% of these babies that are born alive die within 1 year. Most have severe brain anomalies (especially holoprosencephaly). Heart defects, polydactyly and other limb anomalies, facial clefting, abdominal wall defects, and kidney malformations are also common. Any affected child may have some but not all of these problems. If the child survives the early weeks, growth is slow, and healing of wounds and recovery from illness are compromised. The few who live longer do not usually walk or speak meaningfully. Thus, they are significantly more severely handicapped than most children with Down syndrome.1 Huehns et al2 reported numerous pedunculated nuclear projections attached to the surface of nuclei in neutrophils of persons with trisomy 13. Electron microscopic examination revealed the presence of chromatin in these projections. Huehns et al2 concluded that this feature is specific to trisomy 13. Walzer et al3 proposed that a finding of 2 or more projections in 15% of the leukocytes is highly suggestive of D1 trisomy. In normal females, 2% to 10% of mature neutrophils exhibit a single drumstick (nuclear projection) (Figure, D), representing the inactivated X chromosome. A pathologist&apos;s identification of structural anomalies of the neutrophils on a blood smear can provide rapid (less than 1 hour) support to the clinical suspicion of trisomy 13. This information may assist clinicians and families facing complex decisions about life support or transport after the delivery of an infant with multiple anomalies. Even in the most advanced centers, a fluorescent in-situ hybridization report usually requires 24 hours to obtain. ReferencesBaty, B. J. , B. L. Brent , and J. C. Carey . Natural history of trisomy 18 and trisomy 13: I. Growth, physical assessment, medical histories, survival, and recurrence risk. Am J Med Genet 1994. 49:175–188.Huehns, E. R. , M. Lutzner , and F. Hecht . Nuclear abnormalities of the neutrophils in D1 (13–15) trisomy syndrome. Lancet 1964. 13:589–590.Walzer, S. , P. S. Gerald , G. Breau , D. O&apos;Neill , and L. K. Diamond . Hematologic changes in the trisomy syndrome. Pediatrics1966. 38:419–429. Article Citation: Mohamed E. Salama, Veena Shah, Robert Roger Lebel, and Daniel L. VanDyke (2004) Aberrant Nuclear Projections of Neutrophils in Trisomy 13. Archives of Pathology & Laboratory Medicine: February 2004, Vol. 128, No. 2, pp. 243-244.
- #76 Pathologic Quiz Case: A 32-Year-Old Woman With an Abnormal Female Fetus at 19 Weeks of Gestation Bo Jin , MD, Mousa A. Al-Abbadi , MD, and Karoline S. Puder , MDFrom the Departments of Pathology (Drs Jin and Al-Abbadi) and Obstetrics and Gynecology (Dr Puder), Sinai-Grace Hospital, Detroit, Mich Accepted: July 27, 2004 ------------ A 32-year-old white woman, gravida 1, para 0, was at 19 weeks of gestation. She was referred to our prenatal diagnostic center because of inability to identify fetal facial structures. No history of substance abuse, medication intake, or exposure to any toxic materials or radiation was noted. Her social, family, and past medical history was unremarkable. Ultrasound examination (Figure, A) revealed the presence of the following abnormalities: alobar holoprosencephaly (HPE), single orbit with 2 small eyes, proboscis superior to orbit, ventricular septal defect, overriding aorta, pulmonary artery atresia, and bilateral large echogenic kidneys. Amniocentesis with cytogenetic analysis revealed fetal karyotype of 47,XX,+13. The patient underwent induction, and a nonviable female fetus was delivered vaginally. The mother gave permission only for external examination of the fetus. The external examination of the fetus showed the facial anomalies with a single orbit containing 2 fused eyeballs, absence of nose, and a blind-ended proboscis superior to the orbit (Figure, B and C). What is your diagnosis? Pathologic Diagnosis: CyclopiaCyclopia is a congenital facial abnormality with medial monophthalmia and proboscis (tubular appendage) superior to the orbit. Historically, the term cyclops is Greek/ Latin in origin and was used to describe 1-eyed giants or monsters. The orbit may contain 1 eye (monophthalmia) or 2 fused eyeballs (synophthalmia).1 Occasionally the eyeball is completely absent (anophthalmia). These facial anomalies are usually associated with holoprosencephalic disorders of the brain. Holoprosencephaly is a malformation characterized by impaired midline cleavage of the embryonic forebrain. The HPE occurs when the prosencephalon fails to cleave sagittally into the cerebral hemispheres, transversely into the telencephalon and diencephalon, and horizontally into the olfactory and optic bulbs. Holoprosencephaly can be classified as alobar, semilobar, or lobar depending on the severity of the malformation.1 A variety of facial deformities are associated with HPE, including less severe facial dysmorphism, median cleft lip, cebocephaly, ethmocephaly, and cyclopia.1 The incidence of cyclopia is approximately 1.05 in 100 000 births including stillbirths.2 It is more common in female fetuses and is incompatible with life.3 Prenatal diagnosis can be achieved by ultrasound examination, which is usually followed by amniocentesis for fetal karyotype determination. Chromosomal aberrations have been found in some cases of cyclopia. The common ones are trisomy 13 (Patau syndrome), as in our case, trisomy 18, and triploidy.4,5 Other chromosomal abnormalities have also been identified, including terminal deletion 7q, partial trisomy 3p(3p23-pter), monosomy 7q(7q36-pter), and deletion 11q.6–8 Many studies have also shown that malfunction of the “Sonic Hedgehog” (SHH) protein is associated with HPE, including cyclopia. This signal protein is encoded by a gene located at 7q36 and is expressed in the medial neural plate and ventral neural tube. This SHH protein–signaling pathway involves attachment of cholesterol and mediation by another group of genes called GLI genes.9Matsumoto et al10 and Roessler et al11 have demonstrated that a mutation of the GLI2 gene, found on 2q14, is linked to the occurrence of HPE. In addition, some animal studies suggested that disruption of cholesterol transport may play a role in the development of HPE through interference with protein signaling of the SHH gene family.12 However, whether this cholesterol transport hypothesis applies to humans is still uncertain and is a potential venue for further research. However, in some cases of cyclopia, an associated chromosomal abnormality cannot be found. Multiple conditions and agents have been incriminated as possible etiologic factors, such as maternal rubella viral infection, drug ingestion, radiation, and other factors associated with altered gene stability. Rare cases have been reported with normal chromosomal analysis in mothers using contraceptive pills or aspirin in the first trimester.13,14 Therefore, and because chromosomal anomalies are pleiotropic, a chromosomal abnormality should be suspected when HPE is found in association with other scalp defects, postaxial polydactyly, renal cystic disease, and malrotation. On the other hand, if the anomaly is seen only in the central nervous system, a nonchromosomal etiology is favored. In summary, cyclopia is a congenital facial dysmorphism usually associated with HPE. The possible underlying causes are heterogeneous. Prenatal diagnosis by ultrasound and cytogenetic studies are achievable at early stages of pregnancy. ReferencesGorlin, R. J. , M. M. Cohen , and L. S. Levin . Syndromes of the Head and Neck. 3rd ed. New York: Oxford University Press; 1990.Kullen, B. , E. E. Castilla , and P. A. L. Lancaster . The cyclops and the mermaid: an epidemiologic study of two types of rare malformation. J Med Genet 1992. 29:30–35.Cohen, M. M. Perspective on holoprosencephaly, part I: epidemiology, genetics, and syndromology. Teratology 1989. 40:211–236.Hodes, M. E. , J. Cole , C. G. Palmer , and T. Reed . Trisomy 18 (29 cases), trisomy 13 (19 cases): a summary. Birth Defects 1978. 14:377–382.Hsu, T. E. , S. Y. Chang , and C. Y. Ou . et al. First trimester diagnosis of holoproscencephaly and cyclopia with triploidy by transvaginal three dimensional ultrasonography. Eur J Obstet Gynecol Reprod Biol 2001. 19:235–237.Chen, C. P. , F. F. Liu , S. W. Jan , C. L. Lin , and C. C. Lan . Prenatal diagnosis of terminal deletion 7q and partial trisomy 3p in fetus with holoprosencephaly. Clin Genet 1996. 50:321–326.Chen, C. P. , K. Devriendt , C. C. Lee , W. L. Chen , W. Wang , and T. Y. Wang . Prenatal diagnosis of partial trisomy 3p(3p23 → pter) and monosomy 7q(7q36 → qter) in a fetus with microcephaly alobar holoprosencephaly and cyclopia. Prenat Diagn 1999. 19:986–989.Helmuth, R. A. , D. D. Weaver , and E. R. Wills . Holoprosencephaly, ear abnormalities, congenital heart defect, and microphallus in a patient with 11q-mosaicism. Am J Med Genet 1989. 32:178–181.Mizuguchi, M. Molecular pathology of human cerebral malformation. Congenital Anomalies 2003. 43:22–28.Matsumoto, N. , M. Fujimoto , R. Kato , and N. Niikawa . Assignment of the human GLI2 gene to 2q14 by fluorescence in situ hybridization. Genomics 1996. 36:220–221.Roessler, E. , Y. Z. Du , and J. L. Mullor . et al. Loss-of-function mutation in the human Gli2 gene are associated with pituitary anomalies and holoprosencephaly-like features. Proc Natl Acad Sci U S A. 2003. 100:13424–13429.Strauss, E. One-eyed animals implicate cholesterol in development. Science 1998. 280:1528–1529.Sezgin, I. , S. Sungu , E. Bekar , M. Cetin , and H. Ceran . Cyclopia-astomia-agnathia-holoprosencephaly association: a case report. Clin Dysmorphol 2002. 11:225–236.Batts, J. A. Jr , H. H. Punnet , M. Valdes-Dapena , J. W. Coles , and W. R. Green . A case of cyclopia. Am J Obstet Gynecol 1972. 112:657–661.Article Citation: Bo Jin, Mousa A. Al-Abbadi, and Karoline S. Puder (2005) Pathologic Quiz Case: A 32-Year-Old Woman With an Abnormal Female Fetus at 19 Weeks of Gestation. Archives of Pathology & Laboratory Medicine: January 2005, Vol. 129, No. 1, pp. e19-e20.
- #77 Trisomy 13. Neutrophil - Blood film: Composite of neutrophils in a patient with this cytogenetic abnormality. Note elongated nuclei with atypical constrictions and multiple dumbbell projections from nuclei.
- #80 This is Klinefelter&apos;s syndrome with a 47, XXY karyotype. A non-dysjunctional event in meiosis (maternal or paternal) left two X chromosomes in an ovum or a sperm. This is relatively common (about 1 in 500 males). Affected males are usually normal, though they may be tall and have small testes. Infertility results from absent sperm. About half have gynecomastia. About 10% of cases are mosaics and are less affected.
- #86 Klinefelter syndrome (47,XXY) 16-year-old boy; presenting symptom delayed puberty, female fat distribution (more fat around hips), horizontal border of pubic hair, slight gynecomastia, no beard growth, absent body hair; voice broken. Testicular volume 4 ml.Laboratory values: testosterone 6.5 nmol/l; FSH 17.8 U/l; LH 14.9 U/lTreatment: testosterone substitution, e.g. with testosterone enanthate 250 mg every 3 weeks i.m.
- #87 Klinefelter Syndrome (47,XXY). 21-year-old male, noticed at medical examination for military service because of testicular volume of 2 ml. The sparse virile hair (horizontal upper border of pubic hair, absent hair on trunk and legs, practically no beard growth), gynecomastia (with lipomastia) and female fat distribution stand out. The lower body segment is distinctly longer than the upper body segment. Normal male voice.Laboratory values: testosterone 10.5 nmol/l (low), LH 14.2 U/l, FSH 25.1 U/l (clearly elevated).Treatment: testosterone substitution with Testoviron® Depot 250 mg every 3 weeks i.m.
- #88 Comments: This testicular biopsy is from an adult male with history of normal semen volume and severe oligospermia. He had small firm testes and body habitus suggestive of Klinefelter’s syndrome. The biopsy shows small hyalinized seminiferous tubules and pseudo-adenomatous clusters of leydig cells.
- #89 Comments: Couple of hyalinized seminiferous tubules surrounded by leydig cells containing abundant microvacuolated cytoplasm. Even though leydig cells may appear morphologically normal in Klinefelter?s syndrome, they are often functionally deficient and androgen levels are often reduced accompanied by elevated FSH and LH levels.
- #90 This photomicrograph from an undescended testis shows intratubular germ cell neoplasia with testicular microliths. Isolated testicular microliths may be seen in cryptorchid testes, prepubertal Klinefelter’s syndrome, male pseudohermophrodites, and rarely in normal testes.
- #91 This photomicrograph from an undescended testis shows intratubular germ cell neoplasia with testicular microliths. Isolated testicular microliths may be seen in cryptorchid testes, prepubertal Klinefelter’s syndrome, male pseudohermophrodites, and rarely in normal testes.
- #92 [altered colours] Cover design: The front cover of Human Reproduction: shows the results of fluorescence in-situ hybridization analyses of a Klinefelter syndrome patientÕs spermatozoa and spare preimplantation embryos using DNA probes specific for chromosomes X (green) Y (red) and 18 (orange). An abnormal sperm nucleus XY18 is shown (top left) along with abnormal nuclei from one chaotic embryo: XXYY1818 (top right), X1818 (bottom left), Y18 (bottom right). The frequency of sex chromosome hyperploidy in the spermatozoa of the Klinefelter patient was higher than normal. Only 3 out of the 10 spare embryos were normal for the chromosomes tested. Human Reproduction Vol15. no2. pp 440-444, 2000.
- #94 This is monosomy X (Turner&apos;s syndrome, with karyotype 45, X). It is uncommon for fetuses with monosomy X to survive. However, women with Turner&apos;s syndrome can live relatively normal lives, though they are unable to bear children.
- #99 One very characteristic feature of a fetus with monosomy X is the &quot;cystic hygroma&quot; of the neck. This is not a true neoplasm, but represents failure of lymphatics to form and drain properly. It is this structure that eventually forms the &quot;web neck&quot; feature of women with Turner&apos;s syndrome. Note the grey coloration from prolonged intrauterine demise.
- #100 One very characteristic feature of a fetus with monosomy X is the &quot;cystic hygroma&quot; of the neck. This is not a true neoplasm, but represents failure of lymphatics to form and drain properly. It is this structure that eventually forms the &quot;web neck&quot; feature of women with Turner&apos;s syndrome. Note the grey coloration from prolonged intrauterine demise.
- #101 One very characteristic feature of a fetus with monosomy X is the &quot;cystic hygroma&quot; of the neck. This is not a true neoplasm, but represents failure of lymphatics to form and drain properly. It is this structure that eventually forms the &quot;web neck&quot; feature of women with Turner&apos;s syndrome. Note the grey coloration from prolonged intrauterine demise.
- #102 One very characteristic feature of a fetus with monosomy X is the &quot;cystic hygroma&quot; of the neck. This is not a true neoplasm, but represents failure of lymphatics to form and drain properly. It is this structure that eventually forms the &quot;web neck&quot; feature of women with Turner&apos;s syndrome. Note the grey coloration from prolonged intrauterine demise.
- #103 One very characteristic feature of a fetus with monosomy X is the &quot;cystic hygroma&quot; of the neck. This is not a true neoplasm, but represents failure of lymphatics to form and drain properly. It is this structure that eventually forms the &quot;web neck&quot; feature of women with Turner&apos;s syndrome. Note the grey coloration from prolonged intrauterine demise.
- #105 The &quot;streak ovaries&quot; of Turner&apos;s syndrome are shown here. Bilaterally below the fallopian tubes at the top of the photograph are long thin bands of tan ovarian tissue in this 55-year-old woman. No ova were ever present.
- #108 Nucleus of a female amniotic fluid cell. Top: Both X-chromosome territories are detected by FISH. Shown is a single optical section made with a confocal microscope. Bottom: Same nucleus stained with Dapi and recorded with a CCD camera. The Barr body is indicated by the arrow, it identifies the inactive X (Xi). Preparation of specimen as described in: R Eils, S Dietzel, E Bertin, E Schrock, MR Speicher, T Ried, M Robert-Nicoud, C Cremer and T Cremer (1996): Three-dimensional reconstruction of painted human interphase chromosomes: active and inactive X chromosome territories have similar volumes but differ in shape and surface structure. Journal of Cell Biology, Vol 135, 1427-1440. PMID:8978813