Hospital for Sick Children's, The: Atlas of Pediatric Ophthalmology & Strabismus, 1st Edition

Ocular Manifestations of Systemic Disease

13

Chromosomes

Nasrin Najm-Tehrani

Alex V. Levin

The genetic information in each cell is in the form of DNA, the majority of which is in the nucleus as chromosomes. A much smaller proportion of DNA is located in the mitochondria in the cytoplasm of the cell. Mitochondrial disorders are covered elsewhere in this book (Chapter 21: Neurologic). Humans have 23 pairs of nuclear chromosomes, including the X and Y chromosomes that determine gender. Reported aberrations in the human genome are extremely numerous. This chapter deals with some of the more common and recognizable abnormalities, which include:

  1. Trisomy: A duplication (i.e., three copies rather than two) of part or all of a chromosome
  2. Monosomy: A deletion (i.e., one copy rather than two) of part or all of a chromosome
  3. Translocation: A rearrangement of chromosomal material such that part of one chromosome is found attached to another chromosome. If the translocation is balanced, then there may be no resulting clinical abnormalities. However, translocations may result in damage or deletion of genes, particularly at the points where one chromosome is broken or where a part of another chromosome is attached.
  4. Other rearrangements: A wide variety of rearrangements of a chromosome (e.g., inversions, rings) can result in gene disruption and disease.

To test the integrity of nuclear chromosomes, a karyotype is performed. At a specific stage of cellular replication, chromosomes are harvested from lymphocytes (the test can also be performed on tissues such as skin fibroblasts) and stained to create banding patterns. These bands do not correspond to specific genes. Rather, each band contains many of the approximately 35,000 human genes. Therefore, a cytogenetically visible chromosomal aberration almost always means that more than one gene has been disrupted. As a result, the patient will usually have more than one abnormality, one of which often is developmental delay. A normal karyotype does not rule out disease, as there can still be a submicroscopic aberration (e.g., microdeletion) or a molecular change within a single gene.

This chapter focuses on the systemic manifestations of chromosomal aberrations, as many of the individual ocular manifestations (e.g., coloboma, cataract) are otherwise generic and featured elsewhere in this atlas.

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Figure 13.1 Deletion 4p (Wolf-Hirschhorn Syndrome)

The classical findings in partial deletion of the short arm of chromosome 4 are microcephaly, developmental delay, growth retardation, cleft lip/palate, congenital heart disease, seizures, genital abnormalities, and a characteristic head shape with a prominent glabella and long nasal root (beaked nose) that have led to comparison to a Greek helmet in profile. Most children die before reaching 2 years old. The critical deleted region appears to be 4p16.3. Oculofacial manifestations include hypertelorism, arched eyebrows with medial thinning, epicanthus, colobomatous microphthalmia, ptosis, and strabismus. Anterior segment abnormalities include Axenfeld-Rieger spectrum, corneal opacities such as the Peter anomaly, and cataracts.

 

Figure 13.2 Deletion 5p (Cri du Chat Syndrome)

Partial deletion of the short arm of chromosome 5 presents in the neonate with low birth weight, hypotonia, and slow growth rate. The striking catlike cry of the infant is due to structural anomalies in the larynx. Typical facies show microcephaly, micrognathia, and low-set ears. Cardiac abnormalities may be present. Ophthalmic involvement includes epicanthus, ptosis, myopia, decreased tear production, strabismus, cataracts, glaucoma, retinal vessel tortuosity, foveal hypoplasia, optic atrophy, and colobomatous microphthalmia

 

Figure 13.3 Deletion 11q (Jacobsen Syndrome)

The critical deleted region for the development of Jacobsen syndrome is 11q23.3-24.1. Ocular abnormalities most commonly associated include telecanthus and/or hypertelorism, ptosis, epicanthal folds, and strabismus. Less common ocular abnormalities are coloboma with or without microphthalmia, nuclear cataract, abnormal eyelashes/eyebrows, iris discoloration, microcornea, nasolacrimal duct obstruction, amblyopia, and exotropia with anomalous extraocular muscles. Patients often have growth and mental retardation, craniosynostosis, abnormal facies, thrombocytopenia/pancytopenia, and, less commonly, congenital heart malformations and hand/foot anomalies.

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Figure 13.4 Trisomy 13 (Patau Syndrome)

Trisomy 13 is characterized by microphthalmia, scalp defects, cleft lip/palate, polydactyly, congenital heart defects, and severe developmental delay. It is associated with a markedly shortened life span, although approximately 10% of children can survive into later childhood. Eye abnormalities include hypertelorism, epicanthal folds, colobomatous microphthalmia, cataracts, corneal opacities, glaucoma, persistent hyperplastic primary vitreous (Chapter 7: Fig. 7.14), intraocular cartilage, and retinal dysplasia with possible retinal nonattachment (Chapter 8: Fig. 8.24).

 

Figure 13.5 Deletion 15q (Prader-Willi and Angelman Syndromes)

Although each syndrome is potentially caused by a mutation in a different gene, the manifestations are more often caused by deletion of a region involving both genes. However, this region is imprinted such that the gene associated with Prader-Willi is only expressed from the paternal copy of the region and the gene associated with Angelman is only expressed on the maternal allele. Prader-Willi, pictured here, is characterized by hypotonia, hypogonadism, small hands and feet, and obesity. It is caused by the deletion of the paternally derived copy of 15q11.3. Angelman syndrome, characterized by seizures often associated with laughter, absent speech, severe developmental delay, and puppetlike jerky gait, results from deletion of the maternally derived copy. As the p gene lies within the same region, many patients with deletions show iris transillumination and other signs of hypopigmentation. The p gene is expressed from both alleles. In approximately 1%, if the remaining p gene allele is also hypopigmentary, then the patient may show type 2 oculocutaneous albinism (Chapter 15: Dermatology, Figure 15.20). In both syndromes ophthalmic manifestation includes ocular hypopigmentation.

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Figure 13.6 Deletion 18q (de Grouchy Syndrome)

The de Grouchy syndrome phenotype is associated with deletion distal to and including 18q21. Systemic findings are usually severe developmental delay, failure to thrive, palmar creases, and hearing loss with or without abnormal external ears. Other reported features include cleft lip/palate, microcephaly, absent labia minora, cutaneous hemangiomas, congenital heart disease, and minor distal skeletal anomalies, in particular cutaneous dimples in the fossae overlying the extensor surfaces of joints. Poor vision due to pigmentary retinal dystrophy, optic atrophy, and nystagmus is the cardinal ophthalmic feature. Strabismus (shown here), high myopia, microcornea/microphthalmia, corneal opacity, iris defects, corectopia, and straightening of the retinal vessels and ptosis have also been observed.

 

Figure 13.7 Trisomy 21 (Down Syndrome)

Down syndrome is caused by trisomy 21, the most common chromosomal aberration in liveborn children. Features can also be seen as a result of partial trisomy, mosaicism, or translocation. There is an associated risk with rising maternal age. Children have a typical facies and variable developmental delay, often in combination with congenital heart disease, gastrointestinal malformations such as duodenal atresia, single palmar crease, immune system abnormalities, and a higher risk of developing leukemia. The patients may have prominent or even floppy eyelids (right image), nasolacrimal obstruction, high refractive error, hypoaccommodation, strabismus, nystagmus, keratoconus, and blepharitis. The optic nerve may show an increased number of retinal vessel branching or a spoke-wheel configuration of the vessels (as shown here).

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Figure 13.8 Trisomy 21 (Down Syndrome)—Anterior Segment

Patients with trisomy 21 may show many cataract phenotypes (Chapter 7: Lens), including total white cataract, nuclear, posterior subcapsular, and the more common “snowflake” opacities (left image), which may be variable in size and color. Brushfield spots of iris(right image) are areas of hyperplasia of the iris always white and symmetrically distributed circumferentially on the peripheral iris. Similar iris lesions can also be seen in normal children, but the eponym is not used. Congenital glaucoma is a very rare association. Ophthalmic follow-up throughout the developmental years is therefore essential to discover emerging and treatable ocular pathology such as cataracts.

 

Figure 13.9 Supernumerary 22q (Cat Eye Syndrome)

The critical region for cat eye syndrome is 22q11. The supernumerary chromosome results in trisomy or tetrasomy of the involved area. Systemic associations with this condition include mental retardation, preauricular skin tags or pits, micrognathia, hearing impairment, growth retardation, hemivertebra, and cleft palate. Cardiac defects are present in approximately one third of patients. Iris coloboma is common but not obligatory and gives the syndrome its name. Less frequent ophthalmic findings may include hypertelorism, epicanthus, and downslanting palpebral fissures. Microphthalmia and Duane syndrome (Chapter 1: Strabismus) have also been reported.

 

Figure 13.10 Fragile X Syndrome (Martin-Bell Syndrome)

This syndrome is usually caused by the expansion of a repeat nucleotide sequence on the X chromosome. Fragile X has variable expression in the hemizygote and the female heterozygote. One of the most common chromosomal causes of mental retardation, fragile X is estimated to occur in 1 in 2,000 male births. Systemic findings also include macrocephaly, prognathism, thickening of the nasal bridge extending down to the nasal tip, large ears, and macroorchidism. Ophthalmic findings are epicanthus, pale blue irides, and, less commonly, strabismus, nystagmus, myopia, and, as shown here, ptosis (see also Chapter 2: Lids and Adnexa, Figure 2.9). Visual avoidance behavior is common. (Anisocoria shown here is a pharmacologic artifact.)