Chapter 52
Chromosomes: Structure, Function, and Clinical Syndromes
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Sanger's demonstration in 1953 that proteins are unique linear arrays of amino acids and the suggestion by Watson and Crick in that same year that DNA, the genetic material, is similarly a linear array of bases gradually led to the realization that genes are expressed by the linear translation of the base sequence of nucleic acids into the amino acid sequence of proteins. The genetic code is simply the sequence relationship between bases in genes and the amino acids they encode. The entire genetic blueprint of humans is composed of linear double-helix deoxyribonucleic acid (DNA) and is present in the 46 chromosomes of every human nucleated cell. Each species has a characteristic number of chromosomes. The functional unit of the genetic blueprint is the gene, a segment of DNA required to code for one polypeptide. The human genome was previously believed to contain approximately 100,000 distinct genes, however, the Human Genome Project reported that value as being closer to 30,000.1

The disorders discussed in this chapter are the result of loss, duplication, or rearrangement of whole groups of adjacent genes. As a result, patients show generalized and widespread systemic abnormalities, depending on the number and relative importance of the genes lost or duplicated. The chromosomal disorders may involve the entire genome resulting in triploidy or polyploidy or the disorders may be numerical resulting in monosomies and trisomies. Even with the latest banding techniques, the smallest detectable deletion or duplication of a single chromosome contains many genes.

The common dominant, recessive, or X-linked genetic disorders are the result of single-gene defects. Although generalized abnormalities are frequently present, they are caused by the effect of that single-gene product on many different aspects of development. Detection requires molecular techniques because the single-gene defects are not visible by cytogenetic techniques. Chromosomal disorders may be inherited in a dominant manner, but their generalized abnormalities are the result of multiple-gene imbalances and their generalized defects are often so severe that affected individuals often do not reproduce.

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The 46 chromosomes exist in 23 homologous pairs in the normal individual; one chromosome of each pair is from the mother, the other is from the father and one of each pair is transmitted to each child. Twenty-two pairs of chromosomes are alike in males and females and are, hence, called the autosomes; the two sex chromosomes, the remaining pair, differ in males and females. The members of the homologous pair carry the same genetic information; they have the same gene loci in the same sequence, although at any one locus they may have either the same or different alleles. Each of the human genes is, therefore, paired, and the total expression of any particular gene is the sum of the products coded for by both the maternal and paternal copies, or alleles, of that gene. Chromosomal abnormalities will, as a rule, involve only one of the two chromosomes in any pair. When a chromosome or part of chromosome is missing, the impaired alleles on the other chromosomes are expressed without modification. In the case of genes that code for enzymatic proteins, total activity will be reduced by 50% if the enzyme activity is gene dose dependent. On the other hand, when an entire chromosome or a position of one is duplicated, the genes in that segment have three alleles, and the gene product is present in 150% of normal amounts.

The abnormal dose effect of multiple genes in chromosomal disorders may have widespread effects on the developing organism. In Drosophila, mutations or deletions involving as many as 41 loci on all four chromosomes produced a similar phenotype consisting of slow development, small body size, large rough eyes, thin wings, and low fertility. These 41 loci represent sites of synthesis of transfer DNA, deficiency of which results in a generalized decreased rate of protein synthesis.2 Many of the human chromosomal abnormalities share common features: mental retardation, low fertility, growth retardation, and coarse and abnormal facial features, among others. In humans, as in Drosophila, the recurrent and overlapping phenotypes seen with many of the chromosomal abnormalities can be explained on the basis of a generalized decreased rate of protein synthesis.

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Table 1, which summarizes the ocular features of some of the partial trisomies and partial deletion chromosomal syndromes, demonstrates the considerable phenotypic overlap among the various chromosomal disorders. It is believed that abnormal rates of cell division at critical times in embryogenesis, likely the result of abnormal gene dose effect, result in the generalized growth retardation and the congenital anomalies noted at birth.2 For example, closure of the fetal choroidal fissure takes place between the fifth and seventh week of gestation. If an embryo has an abnormal karyotype that causes retardation of localized cell division, the result may be that closure of the fetal choroidal fissure will not occur. Uveal coloboma is a feature of chromosomal disorders involving many different chromosomes.


Table 1. Ocular Signs in Partial Trisomy and Partial Deletion Chromosomal Syndromes

Ocular Signs by RegionOcular Signs by RegionOcular Signs by Region
OrbitAntimongoloid lid slantMotility
4p-Trisomy 818q-
Trisomy 811q-Trisomy 8
10q-14q +9p-
10q+18p -11p+
13 ring10q+20p +
13q-18p-Anterior Segment
18p-Epicanthal foldsCorneal leukoma
Hypotelorism4p-Trisomy 8
14q+5p-Ectopia pupillae
Flat supraorbital ridges6q-Uveal Tract
Microphthalmia18p-Trisomy 8
Trisomy 818q-10p+
10 p+Telecanthus13q-
13q-9p+Optic Nerve
14q+20p+Optic atrophy
16q +Blepharophimosis18q-
Lids and Brows4p+Optic pit
Mongoloid lid slant10q+9p-
10p+Tear deficiencyPigmentary degeneration


Many of the ocular abnormalities noted in the chromosomal disorders are not chromosome specific; rather, they are secondary phenotypes. Orbital hypotelorism is found in many chromosomal disorders. In trisomy 21, the abnormally narrow space between the orbits is a result of primary hypoplasia of the central facial structures, whereas in the 13q+ and the 18p- syndromes the hypotelorism is associated with some degree of holoprosencephaly and trigonocephaly. In both situations, however, the end result is a phenotypic anomaly that results secondarily from a more basic defect in development as well. The ocular pathology in embryos with chromosomal abnormalities demonstrated that not only does retardation of development occur but also that various forms of dysgenesis of ocular structures occur. Specific findings included microphthalmia, cataract, subluxation of the lens, staphyloma of the optic nerve, retinal dysplasia, and cyclopia.3

Microphthalmia is an ocular abnormality seen in several chromosomal syndromes. The microphthalmia in trisomy 13 is probably related to the presence of holoprosencephaly. However, because microphthalmia is seen in other syndromes in which holoprosencephaly is not present, the defect must be nonspecific or related to some other specific gene locus. It is known, for example, that mutations on all four chromosomes of Drosophilia may produce small eyes or anophthalmia. In the mouse, genes on three separate chromosomes may result in the same ocular anomalies. Deletion or duplication of different portions of the human karyotype can result in microphthalmia. Hypertelorism, antimongoloid lid slant, epicanthal folds, highly arched eyebrows, strabismus, and colobomas are abnormalities that are frequently found among the chromosomal disorders (see Table 1).

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Before 1956 there were believed to be 48 human chromosomes; however, in that year Tjio and Levan4 showed that 46 was the correct number. In 1979, Hsu published a book reviewing the history of human cytogenetics in which he divided the subject into four eras: the dark ages before 1952, the hypotonic period from 1952 to 1958, the trisomy period between 1959 and 1969, and the current chromosome banding era that started in 1970.

In the dark ages, Painter, in 1923, was studying slides of paraffin-sectioned testes and suggested 48 as the number of chromosomes in humans. Because his paper was cited repeatedly that number was eventually repeated as fact. During this era, the squash technique for separating human metaphase chromosomes was developed, and the chemical prefixation technique and the use of colchicine to block cell division metaphase were also introduced. In 1952, Hsu introduced the hypotonic technique, which leads to control of swelling of the cells and separation of individual chromosomes. It was this technique that allowed Tjio and Levan to determine the correct number of human chromosomes. The techniques introduced during the hypotonic era were applied to the analysis of chromosomes from individuals who were mentally retarded or who had other congenital anomalies. In 1959, Lejeune and associates described the first known human trisomy, Down syndrome. In that same year, Ford and associates reported that patients with Turner's syndrome had only one of the two X chromosomes, for a total of 45 chromosomes instead of 46. Rapidly thereafter, additional chromosomal defects were defined, and the cataloguing of human trisomies compatible with life was exhausted. Attention was then turned to structural aberrations and their phenotypic consequences.

Most human chromosomes could not be identified individually before 1970. In that year, Caspersson and associates5 applied fluorescence microscopy to human chromosomes. It was found that chromosomes, when stained with quinacrine, exhibited fluorescent cross bands of different widths. Subsequently, nonfluorescent banding was achieved through a number of different techniques, including various ways of partially denaturing chromosomal DNA. With several of these partial denaturation techniques, subsequent Giemsa staining resulted in reproducible banding patterns that were unique for each chromosome. The technique of banding prophase chromosomes made it possible to define chromosomal segments and break points even more accurately. Through banding techniques, small deletions or duplications of segments of DNA within the chromosome can be precisely identified. This advance made possible the description of a whole new class of chromosomal diseases, the partial trisomy and partial deletion syndromes.

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The incidence of chromosomal abnormalities among newborn infants has been studied extensively. Pooled data shows that karyotypic abnormalities are found in approximately 5.7/1000 newborns and congenital ocular malformations occur in approximately 6.0/10,000.6–10
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The abbreviations and terminology commonly used in describing chromosomal rearrangement are as follows. The letter p is used to represent the short arm of a chromosome and the letter q the long arm. The letters are used after the number of the chromosome under discussion. A plus sign (+) after the letter indicates duplication or partial trisomy for the portion of the arm indicated. A minus sign (-) indicates a partial deletion for a portion of that arm. For example, the 5q+ syndrome is the name used to refer to the clinical entity resulting from any partial duplication of the long arm of chromosome 5. More precise localization along a chromosome arm is provided by a numbering system based on prominent bands beginning at the centromere. Each arm of a chromosome is divided into three to five regions, and these are again subdivided into three or more subunits. Using this system, a single band can be named.


Trisomy or monosomy for autosomes other than 13, 18, 21, and 22 are almost invariably lethal and are frequently seen in spontaneous abortions.

Trisomy 13 (Patau Syndrome)

Trisomy 13 occurs among newborns at a frequency of 1 in 20,000.11 High maternal age is a factor predisposing to trisomy 13, as it is for other trisomies. About 45% of affected infants die before the age of 1 month with only 5% reaching the age of 3 years, and there are only 5 reports of patients surviving beyond the first decade.12 Wide phenotypic variability in trisomy 13 is the rule and may be secondary to the variable allelic content of the three homologous chromosomes. Partial trisomy for different parts of chromosome 13 has been described. Patients with these partial trisomies have only some of the features of trisomy 13. A clinical chromosomal map has been constructed by matching common clinical features with common regions of chromosome involvement. Clinical features of trisomy 13 include severe mental retardation resulting from holoprosencephaly, cleft lip and palate, and polydactyly (Fig. 1). These patients are often deaf and may have capillary hemangiomas and scalp defects (Fig. 2). The heel is often prominent and the bottom of the foot has the shape of the runners on a rocking chair.13 The ocular features in trisomy 13 range from anophthalmia to microphthalmia. A fleshy pterygium-like corneal opacification may be seen (Fig. 3), and iris and choroidal colobomas are common (Fig. 4). Hypertelorism occurs in almost all cases.14

Fig. 1. Postaxial polydactyly in a patient with trisomy 13. A skin tag is present on the right hand. (Courtesy of Irene Maumenee, MD)

Fig. 2. Scalp defects in a patient with trisomy 13. (Courtesy of Irene Maumenee, MD)

Fig. 3. Central corneal opacity in a patient with trisomy 13.

Fig. 4. Inferior nasal coloboma and a corresponding sector cataract in a patient with trisomy 13, who is probably mosaic. The lens opacity had been stable for 2½ years.

Trisomy 18 (Edward's Syndrome)

Trisomy 18 occurs among newborns at a frequency of 1 in 6000.15 High maternal age is a factor predisposing to trisomy 18, and about 90% of affected infants die before the age of 6 months with only about 5% reaching the age of 1 year. A nearly diagnostic feature for this syndrome is the positioning of the thumb and fingers in a tightly clenched fist. The thumb is flexed inside the fist with the index finger overriding the third digit. Infants with trisomy 18 have a characteristic constellation of clinical features that includes mental retardation, hypertonicity, cardiac defects, low-set malformed ears, and flexion deformities.16 Ocular malformations are commonly found in trisomy 18 patients with hypertelorism described in 87% of patients, and prominent epicanthal folds, microphthalmia/anophthalmia, and ptosis seen in about one third of cases. Other less commonly described findings include globe abnormalities such as corneal opacity, anterior segment abnormalities, cataract, and optic nerve pits and colobomas.17

Trisomy 21 (Down Syndrome)

Down syndrome, the most frequent form of mental retardation caused by a microscopically demonstrable chromosomal aberration, is characterized by well-defined and distinctive phenotypic features and natural history; Down syndrome occurs in 1/800 newborns.18 Trisomy 21 is the most common of all the trisomy syndromes and is the result of aneuploidy involving the smallest human chromosome; 75% of these embryos are aborted spontaneously. Incidence increases with maternal age; the risk of having a liveborn with Down syndrome at maternal age 30 is 1 in 1000 and at maternal age 40 is 9 in 1000.19

The characteristic face of a child with trisomy 21 exhibits epicanthus, oblique palpebral fissures, a protruding tongue, a flat nasal bridge, and low malformed ears. Individuals with Down syndrome have specific major congenital malformations (found in 30% to 40% of patients) such as those involving the heart, particularly the atrioventricular canal, and the gastrointestinal tract. Patients with Down syndrome also have between 10 to 20 times greater risk of leukemia than the chromosomal normal population. In particular, there is an increase of 200 to 400 times the incidence of acute megakaryocytic leukemia. The affected child is mentally retarded and has shortened anteroposterior (AP) skull diameter; short stature; a typical dermatoglyphic pattern that consists of a simian line, distal palmar axial triradius, and a high frequency of ulnar loops; and a life expectancy that is reduced to 71% at 30 years. In the most common form of trisomy 21, there are three free copies of chromosome 21; in about 5% of patients one copy is translocated to another acrocentric chromosome, most often chromosome 14 or 21.20

Eye findings can be extensive and include Brushfield spots, which are circumferentially distributed white spots on the iris. Brushfield spots are a hallmark of Down syndrome and are found in one third of patients. Similar lesions may be present in the chromosomally normal individuals in whom they are referred to as Wofflin nodules. Lens changes are present in the Down syndrome population with approximately 300-fold greater incidence than the general population (11%). Epicanthal folds with short or sparse eyelashes are present in more than 50% of patients. Other eye abnormalities include strabismus (57%), esotropia (90%) greater than exotropia (5%), and frequently associated A or V patterns. Extremes in refractive errors are prevalent in the form of myopia (23%), hyperopia (21%), and astigmatism (22%). Nystagmus has a reported incidence of 29% without specified type. Keratoconus develops in some 15% of Down syndrome patients, and nasolacrimal duct obstruction is present in 15% of patients.21

Trisomy 22

Trisomy 22 is a rare disorder with only 20 reported cases. It is lethal in the immediate postpartum period. Mean maternal age at the time of birth is 30.5 years.22 All of the patients have obvious mental and physical retardation. The most common congenital abnormalities include microcephaly, preauricular skin tags, congenital heart disease, micrognathia, a long philtrum, malformed ears, and a long nose. At least 50% of the patients had cleft palate, malposed thumb and long slender fingers, congenitally dislocated hips, and hypotonia. As many as 30% have hypoplastic or lowset nipples. Cryptorchism was noted in all males. The most common ocular malformations are chorioretinal colobomas and microphthalmia. Other less common features include strabismus and antimongoloid lid slant.23


Partial trisomies and monosomies can be viable depending on the size and location of the aberration. These can arise de novo or as a result of unbalanced segregation from a parent carrying a balanced rearrangement. These phenotypes are more variable than those of complete trisomies because the amount of unbalanced genetic material is variable. Nevertheless, several phenotypes emerge as characteristics of extra or missing chromosomal segments in particular regions. Before beginning the discussion of the partial trisomy and partial deletion syndromes, it should be stressed that the exact phenotype associated with a chromosomal deletion or duplication will depend on how much of the chromosome is affected and on which genes are deleted or duplicated. The clinical phenotypes discussed here are useful diagnostically, however, because patients with a deletion or duplication of one arm of a particular chromosome are likely to share certain clinical abnormalities. It is quite possible that two patients, both with a partial duplication or deletion of one arm of a chromosome, share no common clinical features if the affected chromosomal segments do not overlap.

Partial trisomies and partial deletion syndromes with consistent ocular findings are outlined in the following discussion. Partial trisomies or partial deletion syndromes without significant ocular findings or those with isolated reports of eye findings are not included.

3q Plus Syndrome (Cornelia de Lange Phenotype)

Trisomy of a segment of the distal end of chromosome 3 is uncommon. The exact site of duplication lies within the region 3q23 to 3q27 in one of the number 3 chromosomes resulting in a partial trisomy for the distal segment. In most cases, the partial trisomy is the result of a balanced translocation in one parent. Because of these findings, careful banding study should be carried out in all patients with the Cornelia de Lange phenotype. These patients share many of the clinical features described for Cornelia de Lange's syndrome: “carp” mouth, failure to thrive, profound mental retardation, a long philtrum, microcephaly, and congenital heart disease.24 Ocular features include most commonly long eyelashes, hypertelorism, and prominent epicanthal folds.25

4p Plus Syndrome

The clinical features of the 4p+ syndrome are sufficiently consistent to permit clinical diagnosis at birth. In the young child, the face is round, there is a short nose with aplasia the nasal root, and the glabella protrudes over a hypoplastic nasal root. The upper lip is elongated and projects slightly; the chin is pointed and recessed. The ears are low set and usually abnormal. Skeletal deformities of the extremities may be present. Other findings include microcephaly and kyphoscoliosis. Height is usually considerably below normal, and obesity is common. Retardation is severe and may be complicated by seizures.26 Ocular features include iris and choroidal colobomas.27

4p Minus Syndrome

The 4 p- syndrome has an incidence of 1/50,000 live births.31 Children are feeble and hypotonic at birth. Major systemic manifestations include developmental delay (100%), growth retardation (90%), cleft lip and palate, congenital heart disease, and seizures. Simian creases, cryptorchism, and hypospadias are less common.28 Ocular abnormalities play a major role in the phenotypic findings and include strabismus (50%), iris coloboma (30%), and epicanthal folds in addition to hypertelorism, which is a marked feature in patients with the 4p- syndrome (70%).29,30

4q Plus Syndrome

Microcephaly is a consistent feature in the 4q+ syndrome, and the nasal crest continues with a prominent receding forehead. The upper lip is short, and when the mouth is closed both lips protrude in a very distinct manner. Duplication or absence of digits is common. Growth retardation is common. Mental retardation is severe and is frequently complicated by seizures. The ocular features include narrow palpebral fissures, ptosis, epicanthus, and corneal leukomas.31

5p Plus Syndrome

5p+ syndrome is an extremely rare syndrome, which is lethal before 6 months of age. Major manifestations include macrocephaly, low-set posteriorly rotated ears, cleft palate, and short philtrum. Ocular manifestations include primarily hypertelorism and telecanthus.32

5p Minus Syndrome (Cri du Chat Syndrome)

The mewing cat cry of babies with 5p- syndrome, from which the French name for this disorder is derived, becomes less pronounced with increasing age. Patients are unusually chafe as infants, and virtually all affected babies are of low birth weight, exhibit slow growth, and have microcephaly. IQ is severely affected and is usually in the 20 to 30 range. Hypertelorism and a large prominent glabella are present in more than 90% of patients. An antimongoloid lid fissure is present in more than 80% of patients, and epicanthal folds, as well as strabismus, are also common. Aside from the catlike cry and retarded growth, the ocular features are the most consistent findings.33

6p Minus Syndrome

Major malformations in the 6p- syndrome include craniosynostosis (70%) and congenital heart disease (90%), which are hallmarks of the disease. Eye abnormalities occur in about 65% of patients, and microphthalmia, anterior segment dysgenesis, iris colobomas, and prominent epicanthal folds have been reported.34

6q Minus Syndrome

Systemic manifestations of the 6q- syndrome include developmental delay, umbilical hernia, palmar creases, microcephaly, short stature, congenital heart disease, and ectopic kidneys. Prominent ophthalmic findings include downslanting small palpebral fissure (82%) and prominent epicanthal folds (58%).35

7q Plus Syndrome

There are two clinically distinct phenotypes involving duplications of different portions of the long arm of chromosome 7. The first syndrome is caused by deletion of the terminal portion of the long arm and is characterized by low birth weight, growth and mental retardation, cleft palate, micrognathia, a small nose, small palpebral fissures, and hypertelorism. The other 7q+ phenotype is caused by a more proximal duplication in the long arm. The clinical picture for this includes retarded development, hypertelorism, strabismus, and low-set ears. In both, hypertelorism is a prominent ocular feature.27

Trisomy 8 (Warkany Syndrome)

Trisomy 8 is associated with total duplication of one of the medium-sized autosomes. Most of the cases described have been mosaics; that is, they have both normal and abnormal chromosomal cell lines. Most patients are retarded with an IQ that ranges from 10 to 80. Skeletal abnormalities are frequently present including accessory ribs, vertebral defects, absent patella, and a distinctive toe posture with digits two and three having an equal length. Dermatoglyphics show deep furrows in the palms and soles.36 Hypertelorism was noted in 12.5% of patients, and a pronounced antimongoloid lid slant has been observed (33%) (Fig. 5). Less frequent findings related to the eye include ptosis, strabismus, corneal opacity, microphthalmia, coloboma, and heterochromia.36

Fig. 5. Prominent antimongoloid lid slant in a patient with trisomy 8. (Courtesy of Irene Maumenee, MD)

9p Minus Syndrome

In the reported cases of 9p- syndrome, the patients' features are similar enough to allow clinical description. Trigonocephaly, microcephaly, a long upper lip, down-turned corners of the mouth, and a significant protrusion of antihelices are systemic features37 (Fig. 6). The ocular findings include glaucoma, enlarged and highly arched eyebrows, prominent eyes, epicanthal folds, and a mongoloid lid slant.38,39

Fig. 6. This child with the 9p- syndrome has pronounced trigonocephaly, microcephaly, and epicanthal folds. The comers of the mouth are downturned, and mental retardation is significant. (Courtesy of George Donnell, MD, and Omar Alfi, MD, Childrens Hospital of Los Angeles, CA)

9q Plus Syndrome

In the reported cases of 9q+ syndrome, only global delay is a consistent feature. Strabismus, epicanthus, and deep-set eyes are reported ocular findings.40

10p Plus Syndrome

The most common systemic findings associated with this syndrome include hypotonia, frontal bossing, abnormal nares, and clubfoot, all of which occur in greater than 60% of cases.41 Ocular findings are uncommon with this syndrome and include microphthalmia and coloboma.42

10q Plus Syndrome

10q+ syndrome is characterized by a high prominent forehead, an oval face, growth retardation, microcephaly, a small nose with a depressed nasal bridge and anteverted nostrils, a carp-shaped mouth with a prominent upper lip, close-set ears, a short neck, and undescended testicles. Skeletal defects involving the digits of the hands and feet, as well as cardiac defects, are occasionally present. Antimongoloid lid slant, hypertelorism, arched and widespread eyebrows, blepharophimosis, and microphthalmia and ptosis have also been described.43

10q Minus Syndrome

In 10q- syndrome, developmental delay is the rule with associated midfacial hypoplasia, prominent receding forehead, and hypotonia. Various dermatologic lesions are associated with this syndrome, although lesions frequently do not present until puberty. As with many partial deletion syndromes, hypertelorism and midfacial hypoplasia are prevalent ocular findings.44

11p Plus Syndrome

The developmental abnormalities in the few cases of the 11p+ syndrome that have been described are due primarily to disturbance of craniofacial development. Systemic findings include a high, prominent forehead with frontal upsweep of hair, wide glabella, a broad flat nasal bridge, and cleft lip or palate. Psychomotor retardation and hypotonia are the rule for this disorder. Ocular findings include supraorbital ridges antimongoloid palpebral fissures, as well as strabismus and nystagmus.45

11p Minus Syndrome

Wilms' tumor, aniridia, genitourinary abnormalities, and mental retardation (WAGR) syndrome is associated with a deletion in the short arm of chromosome 11 involving PAX6 at 11p11.3.46 Systemic manifestations of WAGR syndrome include hypotonia, midline brain abnormalities, and hearing deficits. The heterogeneity in the aniridia deletion syndrome is secondary to small variations in the amount of genetic material deleted in patients. Both males and females are affected with the 11p- syndrome, and nearly all cases have been sporadic. Gonadoblastoma with aniridia has been reported in children with the 11p- syndrome. The fact that dominantly inherited aniridia generally is not associated with Wilms' tumor or other abnormalities is not surprising, because linkage studies have shown that the locus for the mild familial form of aniridia is on chromosome 1.47 Wilms' tumor is usually associated with the sporadic form of aniridia. Aniridia is the most consistent eye finding, although others including cataracts, foveal hypoplasia, nystagmus, and glaucoma are also prevalent.48

11q Minus Syndrome (Jacobsen Syndrome)

This uncommon disorder has an incidence of less than 1 in 100,000 births.49 Developmental delay and trigonocephaly are the most common systemic abnormalities occurring in greater than 95% of patients afflicted with the syndrome.50 Micrognathia, carp-shaped mouth, cardiac abnormalities, and skeletal abnormalities are also common. Commonly reported ocular findings include hypertelorism, ptosis, and prominent epicanthal folds.51,52

13q Plus Syndromes

When the entire chromosome is duplicated, the well-described trisomy 13 syndrome occurs. There are at least two groups of patients with different clinical pictures who show partial duplication of chromosome 13.53 In the first group, the trisomy consists of duplication of the proximal one third to one half of the long arm of chromosome 13. The clinical features are nonspecific and include psychomotor retardation, microcephaly, low-set ears, microsomia, micrognathia, and clinodactyly with little ocular involvement. When the distal one third to two thirds of the long arm is present in triplicate, many of the features of complete trisomy 13 are present. In this group, unlike in the complete trisomy syndrome, deafness, eye malformations, cleft palate, harelip, and heart defects are not observed.

13q Minus Syndrome

Chromosome 13 is of particular interest to ophthalmologists because when a portion of the long arm is deleted, retinoblastoma may occur. A review of patients with partial deletion of chromosome 13 showed that the presence of hypoplastic thumbs indicates involvement of the distal segment of the long arm of chromosome 13. Other clinical features of the distal segment deletion included mental retardation, microcephaly, and hypertelorism in approximately 85% of cases.54 Additional findings included a protruding maxilla, epicanthal folds, renal abnormalities, heart disease, metacarpal fusion, aplastic thumbs, microphthalmia, coloboma, and large low-set ears. A number of the patients with 13q minus syndrome had retinoblastoma subsequently found to be associated with a deletion that included a band in the proximal portion of the long arm.55 Although most of the children whose retinoblastoma is associated with the deletion of the long arm of chromosome 13 have other congenital abnormalities, some appear to be normal except for a mild developmental delay. The severity of the associated abnormalities depends on the amount of chromosomal material lost (Fig. 7). Among patients with retinoblastoma, approximately 3% have a chromosome 13 deletion. Because both unilateral and bilateral retinoblastoma have been observed in patients with deletion of chromosome 13, it may be virtually impossible to determine clinically whether a chromosomal deletion might be present. For these reasons, when observing a new patient with retinoblastoma, ophthalmologists should search diligently for evidence of other developmental abnormalities. Even in the absence of any systemic developmental defects, however, one cannot be certain that the chromosome deletion does not exist.56,57

Fig. 7. Unilateral congenital ptosis and antimongoloid lid fissures (outer canthus lower than inner canthus) in a child with the 18p- syndrome. (Courtesy of Irene Maumenee, MD)

14q Plus (Proximal and Distal) Syndrome

The 14q plus (distal) syndrome is one of two partial trisomy syndromes involving the long arm of chromosome 14. Mental retardation is severe. Other abnormalities include microcephaly, a high forehead, low-set ears, a highly arched or cleft palate, a protruding upper lip, camptodactyly, micrognathia, congenital heart disease, and 12th rib hypoplasia.58 Ocular features include epicanthal folds and antimongoloid slant. Prominent features of the 14q plus (proximal) syndrome include motor and mental retardation, seizures, hypotonia, low anterior hairline, low-set ears, a prominent philtrum, long tapered fingers, kyphosis, and a short neck. Ocular features include antimongoloid lid slant, small palpebral fissures, microphthalmia, strabismus, and ptosis.58

15q Minus Syndrome

The Prader-Willi syndrome and Angelman syndrome are associated with deletions of the long arm of chromosome 15. Systemic findings in Prader-Willi syndrome include hypotonia, developmental delay, and small extremities, as well as hypogonadism and cryptorchidism. Angelman syndrome has the systemic findings of Prader-Willi syndrome with more significant developmental delay including seizures.59 Ocular findings are not a large part of these syndromes.

16p Minus Syndrome

This rare deletion syndrome is most commonly associated with developmental delay and alpha thalassemia. Other systemic findings include capillary hemangiomas and midfacial hypoplasia. As with many other deletion syndromes, hypertelorism and prominent epicanthal folds are common eye findings.60

17p Minus Syndrome (Smith-Magenis Syndrome)

The most characteristic physical findings of Smith-Magenis syndrome include short stature, midfacial hypoplasia, and brachydactyly, as well as developmental delay and profound mental retardation.61 Ocular findings are inconsistent and include most commonly prominent epicanthal folds, with scattered reports of Brushfield type spots and high myopia.62

18p Minus Syndrome

Clinical features of the 18p- syndrome include mental retardation, growth delay, and abnormal ears (see Fig. 7). Myopia, antimongoloid lid fissures, cataract, and uveal colobomas are reported to be present27 (Fig. 8).

Fig. 8. Typical iris coloboma in a patient with the 18p- syndrome (same patient shown in Figure 7). (Courtesy of Irene Maumenee, MD)

18q Minus Syndrome (DeGrouchy Syndrome)

DeGrouchy syndrome is perhaps the most common of all the partial trisomy and partial deletion syndromes. More than 100 cases have been studied and reported. Systemic features include low birth weight, profound mental retardation, developmental delay, short stature, microcephaly, midface dysplasia, carp-shaped mouth, widely spaced nipples, long tapering fingertips, and irregular external ears.63 Conspicuous skin dimples are present over the sides of the patella and the back of the hands. Ocular abnormalities include nystagmus (30%) and bilateral optic atrophy (29%), as well as strabismus, glaucoma, pigmentary retinal degeneration, and ocular colobomas.27,64

20p Plus Syndrome

Patients with partial trisomy of the short arm of chromosome 20 are almost always thought to be normal at birth. The development of prominent cheeks and a short chin characterizes the facies. Telecanthus is present in 50% of cases, and there is a mongoloid like lid slant in 75% of cases.45

20p Minus Syndrome

Prominent physical findings in this condition include triangular chin with prominent forehead and long straight nose. Systemic associations are cholestasis, hemivertebrae, and pulmonary tree stenosis. Ocular features such as hypertelorism and deep-set eyes, as well as anterior segment digenesis including posterior embryotoxon and iris adhesions, are common.45 Alagille syndrome is believed to be a variant of 20p minus syndrome involving a single gene site, 20p11.23–12.65

22q minus Syndrome (DiGeorge Syndrome)

DiGeorge syndrome occurs in 1/4000 live births. The hallmark systemic findings include conotruncal heart anomalies, hypoplastic thymus, and variable developmental delays. Ophthalmic findings have been well studied and include posterior embryotoxon (69%), tortuous retinal vessels (58%), and upper lid hooding (41%) among others.66

The Cat-Eye Syndrome (Supernumerary Chromosome 22q)

The cat-eye syndrome is associated with a supernumerary marker derived from chromosome 22q. However, in many of the reported cases, the marker is present in only a portion of the patient's cells. Because mosaicism is sometimes transmitted through generations, Mendelian factors may be important in its causation.67 Although variability of clinical features is enormous, the usual triad necessary for the diagnosis of the cat-eye syndrome is made up of uveal coloboma, an imperforate anus, and renal malformations. The disorder was named the cat-eye syndrome because of the characteristic vertical iris colobomas that are frequently present. Additional systemic findings are preauricular skin pits, fistulas, or tags and congenital heart disease.68 Although the disorder has been described with a normal karyotype, the usual finding is the presence of a small, extra submetacentric chromosome. Variable features of the syndrome may be present in other family members. The exact nature of the extra fragment in all cases is not agreed on, and it is clear that the extra fragment is mitotically unstable and may retard cell division during the critical period of embryogenesis when the fetal fissure would normally be closing.

Several reports suggest that the coloboma, which is a consistent feature of trisomy 13, might be contributed to the cat-eye syndrome by the portion of chromosome 13 that is near the centromere. That portion of the cat-eye syndrome that is similar to trisomy 22 might be contributed by the portion of chromosome 22 near the centromere. A balanced translocation carrier state may explain those families in which generations seem to be skipped.69

The minimal criteria for making the diagnosis of cat-eye syndrome are as follows: (1) combination of two major features, coloboma and anal atresia, with or without associated abnormalities; (2) combination of one major feature, coloboma or anal atresia, with at least one of the most frequently associated minor anomalies, such as preauricular skin tags or renal anomalies; (3) the presence of one major feature plus several less frequently found abnormalities, such as antimongoloid lid slants, congenital heart disease, and skeletal anomalies; and (4) a combination of five or more minor specific features. There is some overlap in clinical features between trisomy 22 and the cat-eye syndrome.70

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Decoding the DNA that constitutes the human genome has been widely anticipated for the contribution that it will make toward understanding human evolution, the causation of disease, and the relationship between the environment and heredity in defining the human condition. Now that the Human Genome Project is essentially completed with the reporting of the 3.2 billion base pair sequences of the human genome, the true challenge becomes the interpretation and use of this vast amount of genetic data. As recently as 15 years ago, the genes for three major genetic disorder: retinoblastoma, chronic granulomatous disease, and Duchenne muscular dystrophy were reported. This initiated a new phase in the application of the molecular genetics to the dissection of human inherited diseases. In all three cases, researchers tracked the genes in question by cytogenetic clues, rather than by insights into function of the protein or positional cloning. With the completion of the Human Genome Project, genetics is now embarking on a new chapter, one that will have profound changes in the way information for positional cloning is gathered, analyzed and used.

Ophthalmologic disorders have played prominent roles in the mapping story. Zonular pulverulent cataracts were shown to be linked to the first human gene mapped, the Duffy blood group. Because of that linkage, the gene for this type of cataract was able to be mapped to chromosome 1. Evidence that the locus for dominant retinoblastoma was on chromosome 13, closely linked to the locus for esterase D in chromosomal region 13q14, was also reported. Mapping of ocular disorders and the delineation of closely linked enzyme or DNA polymorphisms could provide a most productive pathway to improved genetic counseling and prenatal diagnosis in ocular disorders. Many dominant eye diseases may potentially be mapped. It is possible that a detailed map of the chromosomes could be a valuable resource for gene repair and replacement in ocular conditions.

As welcome as these advances are, there is a major leap between identifying genes for rare disorders and contributing to and treating the medical condition. It has been predicted that complete sequencing in the human genome would open up new strategies for human biologic research and would have a major impact on medicine, public health, and society. Effects of that biomedical research are already being sought, and the assembly of the human genome sequence is the first step on a long journey towards understanding the rule of the genome project in ophthalmology.

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