Oculofacial Manifestations of Chromosomal Aberrations



Fig. 6.1
Normal Male Karyotype : 46, XY (courtesy of Genomic Pathology Program at Thomas Jefferson University Hospital)



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Fig. 6.2
FISH panel for chronic lymphocytic leukemia (CLL) : Results from a peripheral blood sample hybridized with the Abbott Molecular CLL panel. Left panel shows a deletion of ATM (11q22) (single green) and a normal signal pattern for TP53 probe at 17p13. Right panel shows a deletion of 13q14 (single red signal and two aqua signals for the locus on 13q34), and a normal signal pattern for chromosome 12 centromere (courtesy of Genomic Pathology Program at Thomas Jefferson University Hospital)


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Fig. 6.3
Normal Male Virtual Karyotype by SNP Microarray: Top panel shows Karyoview without gain or loss of any regions in the genome; Bottom panel shows detailed view of chromosome 1: log2Ratio of sample/normal, SNP allele tracks (AA, AB & BB) and copy number of the chromosome 1 (courtesy of Genomic Pathology Program at Thomas Jefferson University Hospital)


Chromosomal microarray (CMA) technology now allows for more sensitive detection of copy number variation (CNV) throughout the genome, which may or may not be pathogenic. This level of analysis provides for another dimension of genetic diagnosis [2]. CMA is now used for genetic testing of patients with unexplained developmental delays or disabilities, or multiple congenital anomalies. CMA offers a 20 % higher diagnostic yield over karyotyping . Balanced translocations cannot be detected as array does not evaluate chromosome structure but rather, dosage. The reported submicroscopic copy number variations are to numerous to count and well beyond the scope of this chapter. Clinicians are encouraged to consult on-line databases (e.g., ​genome.​ucsc.​edu/​) to unravel the clinical significance of these microscopi CNVs .

Trisomy 13 and 21 are the most common chromosomal aberrations associated with congenital ocular malformations identified in newborns [1]. In addition, some systemic malformations associated to ocular congenital malformation seem to predict a chromosomal abnormality (e.g.,: talipes-equinovarus, microcephaly, hydrocephalus, facial dysmorphism, and hypertelorism) [1]. Consideration of a chromosomal aberration should occur when there are other organ systems involved in addition to the eye, a recognized pattern of malformations, a pedigree that shows multiple prenatal losses or malformations, or a clinical scenario that is not likely explained by a single gene abnormality.

This chapter covers only non-complex chromosomal abnormalities . If a deletion of 13q is associated with duplication in 21p, it is hard to associate the phenotype to the 13q deletion and/or the 21p duplication. Only phenotypes associated with single chromosome deletions or duplications will be discussed.


Abnormalities of Chromosome Number


Polyploidy. The presence of one or more entire extra set of chromosomes is referred to as polyploidy. Polyploidy is usually not compatible with long-term viability. Triploidy (3 sets = 69 chromosomes) results mainly from dispermia (fertilization of a single haploid egg by two haploid sperms) while tetraploidy (4 sets = 92 chromosomes) is mainly generated by an abnormality in the first mitotic division after fertilization.

Aneuploidy. An additional chromosome, also known as trisomy, occurs when a meiotic non-disjunction result in two copies of the same chromosome in one germ cell. Trisomies 13, 18, 21 and those involving the sex chromosomes are the most common trisomies compatible with life. Monosomy is the presence of only one chromosome instead of a pair. The loss of an entire chromosome in human development usually results in spontaneous abortion. One common monosomy compatible with life is 45,XO, which causes Turner syndrome. Mechanisms for creating partial aneuploidy (partial trisomy or monosomy) include rearrangement, duplication, unbalanced segregation, or deletion within a chromosome.


Alterations of Chromosomal Structure


Translocations. A chromosome translocation is caused by rearrangement of parts between nonhomologous chromosomes. Translocations may be balanced, that is, an exchange without loss or gain of genetic information, and therefore functional, or unbalanced, where the exchange is unequal, and resulting in loss of functionality. Most translocations include two chromosomes ( reciprocal translocations ). Frequently, these are balanced although there are exceptions, as when the break in a reading frame or a regulatory region, or if the translocation is unbalanced at the molecular level. The six different products from meiosis when chromosomes have a balanced translocation are the normal copy of each chromosome, the balanced translocated chromosomes, and four with unbalanced segregation products. Balanced translocations are diagnosed by karyotype analysis. It has to be suspected in recurrent fetal loss or in children with malformations due to unbalanced translocation .

Other translocations are Robertsonian translocation and insertional translocation . In the former, translocations involve acrocentric chromosomes [1315, 21, 22], which have a small short arm. Translocations involving these chromosomes occur in 1 of 900 newborns. The most common involves chromosome 21 , resulting in Down syndrome , causing ~3 % to 5 % of Down syndrome. In insertional translocations, a chromosomal segment may be deleted from within a donor chromosome. Its removal may disrupt one or more genes at one or both breakpoints on the donor chromosome. When the donor chromosome fragment inserts into another recipient chromosome, it can disrupt a gene or insert between two genes. If no genes are disrupted, deleted, or duplicated on either the donor or recipient chromosome, the result is a balanced translocation .

Deletions and duplications. The organization of the human genome is highly complex. Throughout the human genome, there are repeated DNA sequences, some of which occur in tandem. Where these “tandem repeats” exist, there is a risk of slippage during meiosis. During recombination, segments of DNA within the chromosome can then delete or duplicate by unequal crossing-over.

If an interstitial deletion occurs, it may result loss of several genes located close together., resulting in a contiguous gene deletion syndrome (also known as a microdeletion syndrome ). If there is a deletion, the person is then monosomic for the deleted segment, which is called partial monosomy . Interstitial and terminal deletions can occur by other mechanisms such as missing segments after chromosomal breaks, or unbalanced transmission of a reciprocal translocation.

Similarly, interstitial duplication ( microduplication syndrome ) may occur, but the phenotypic effects tend to be less apparent.

Inversions. Inversions occur when two breaks within one chromosome invert and reinsert. “Tandem repeats” called segmental duplications predispose to these structural rearrangements. If the segment includes the centromere, the inversion is denoted as pericentric. If the inversion occurs within an arm and without involving the centromere it is denoted as paracentric. Pericentromeric inversion of chromosome 9 is frequent in general population and is considered as normal variant (heteromorphism). Only a small percentage of people carrying an inversion have a phenotype or related disease, usually due to disruption of a gene or a regulatory element. However, there is a risk of genetic imbalance for the offspring.

Ring chromosome. This abnormality can occur in two situations. First, when the two telomeric ends of a chromosome fuse , which usually result in no loss of chromosomal material. The other alternative is that a chromosome loses the tip of both short and long arms, with fusing of broken ends, which results in a partial monosomy.

Other structural abnormalities. There are other complex rearrangements. These are infrequent and beyond the scope of this chapter.


Other Abnormalities


Somatic and germinal mosaicism. A mosaic patient has cell lines that were derived from a single zygote, but that differs in genotype. Genetic mutations or chromosomal aberrations can arise in a single cell in either the prenatal or postnatal period, producing clones of cells that are genetically different from the original zygote. Thus, the effect of mosaicism is dependent on the stage at which the abnormality developed. If the aberration occurred early after conception ( somatic mosaicism ), one or more organs will be involved, mainly depending on the embryonic stage at which the aberration happened: the later in development, the more confined the abnormality (e.g., hypomelanosis of Ito). Molecular study or a karyotype of the affected tissue is helpful in diagnosing mosaicism. Genetic analysis from a blood sample may be normal, but an aberration will be detected on skin biopsy. Somatic chromosomal aberrations that occur postnatally cause many types of cancer.

Chromosomal aberrations have many opportunities to occur during germ cell development because of several mitotic divisions, and the result is referred to as germline mosaicism . Germline mosaicism does not necessarily produce any somatic abnormalities. Recurrence risk counselling for parents of a child with a chromosomal aberration but normal parental chromosomes must include a discussion of possible germline mosaicism. If the affected child is the product of an abnormal sperm or egg from a mosaic population of germ cells, then the risk of recurrence is increased as subsequent pregnancies can occur from additional abnormal eggs or sperm. The risk is estimated to be less than 1 %.

Genomic Imprinting anomalies. During embryonic development, a limited number of genes are unique in expressing only one of the two alleles, either the paternal copy or the maternal copy. The allele that should not be expressed is silenced by an epigenetic mechanism called genomic imprinting , which occurs by default in eggs and sperms. For example, the 15q11-q13 region is a complex chromosomal segment with genes affected by maternal imprinting and others with paternal imprinting. In this region, the paternal copy of the UBE3A gene is silenced in all sperms (paternal imprinting), while the SNRPN gene and other surrounding genes are silenced in all eggs (maternal imprinting). Consequently, any alteration that prevents the maternal allele expression of UBE3A gene cause Angelman syndrome, while any anomaly in the paternal expression of SNRPN and other genes causes Prader-Willi syndrome.

Uniparental disomy (UPD) happens when a patient inherits both copies of all or part of a chromosome from only one parent with no contribution for that chromosome from the other parent. When a single chromatid from a parent is present in duplicate, the term isodisomy is used. Heterodisomy refers to situations in which both homologs are present.

Prader-Willi syndrome can result from paternal deletion or maternal UPD of 15q11-q13, due to lack of allele inherited from the father. Conversely, Angelman syndrome can occur from maternal deletion or paternal UPD of 15q11-q13, due to lack of allele inherited from the mother. Mutations of maternally inherited UBE3A also cause Angelman syndrome. UPD should be considered in an autosomal recessive disorder with one identifiable carrier parent (assuming correct paternity); a known syndrome, but with uncommon features to the disorder; if the parent and patient have an autosomal recessive condition in the absence of consanguinity, founder effect, or incorrect paternity; and, male to male transmission of an X-linked recessive disorder. Disorders of imprinting are beyond the scope of this chapter as they are not detectable by karyotype , FISH or microarray



Chromosome 1


Balanced translocation rate is 1.39 per 1000 children [3] and chromosome 1 is involved in 43 % of these. In contrast, the rarity of deletions and trisomies in live children could be related to severity of their consequences.


Deletions of 1p



Definition and Epidemiology


Reported breakpoints of 1p result from interstitial deletions, malsegregation of balanced translocations, and de novo translocations [4, 5]. The majority of terminal deletions include 1p34 [4]. Interstitial proximal deletions cluster in the 1p22-p31 region [4, 5]. 1p36.3 is considered as a hot spot for breaks [6]. The estimated incidence for del(1)(p36) varies between 1:5000 to 1:10,000.


Systemic Manifestations


The reported phenotypes are variable and have not been clearly associated to particular break points [4]. Mental retardation, developmental delay, or psychiatric/behavioral symptoms have been found in all reported cases [4, 6, 7]. Reported survival ranges from 5 months to 30 years [8, 9]. Malformations include low set and or posteriorly rotated anomalous ears [810], short neck, bulbous nose, clinodactyly of the fifth finger as well as other less frequent anomalies, including absent thumb [812] and congenital heart disease [4, 5]. Mild ataxia or dysarthria as well as generalized hypotonia [7, 8] or seizures [6] may also occur. Other anomalies reported in some cases include high arched or cleft palate [8, 10], microcephaly [9, 10], hypertrichosis [9, 10], cryptorchidism [7, 10], dental anomalies [9], micrognathia [9, 11], preauricular tags [4], and deafness [6]. One child with del(1)(p21-p22.3) had a particularly severe phenotype in comparison to other similar deletions [5]. The patient presented with severe congenital heart disease, absent thumb, vertebral anomalies, and bilateral cleft lip and palate. Other patient with del(1)(p32.1-p32.3) had cherubic appearance, umbilical hernia and foot abnormalities [13].

1p36 deletion usually has moderate mental retardation, speech impairment and hypotonia [14]. Feeding problems and poor weight gain are more common findings [14]. The del(1)(p36) phenotype also includes large anterior Fontanelle, pointed chin, seizures, flat nasal bridge, clinodactyly and short fifth finger, low set ears, hearing deficits, and abusive behaviour [15]. Brain atrophy has been also reported in 1p36.3-pter deletion [16]. Congenital heart disease and cleft lip/palate are infrequent [15, 16]. One child with del(1)(p36.22) had hydrocephalus, small face with midline hypoplasia, frontal bossing, microstomia, polydactyly [17]. Other patient presented with gastroesophageal reflux, brachycephaly and telangiectatic and hypopigmented skin lesions [17].


Ophthalmic Manifestations


The most frequent oculofacial feature reported is small or narrow palpebral fissures (30 %) [4]. Other findings reported include almond shaped eyes [7], fissure upslanting [8], epicanthal folds [7, 10], hypertelorism and hyperopia [10]. Two patients with del(1)(p22.1-p22.2) had bilateral coloboma [4, 9]. One patient with bilateral microphthalmia had iris and choroidal coloboma [9]. One child was reported with cataracts [12]. Exotropia, hyperopia and long lashes were reported in a child with del(1)(p32.1p32.3) [13]. One patient with del(1)(p36.22) had bilateral iris coloboma and hypertelorism [17]. A patient with del(1)(p36.31-p36.33) had optic atrophy with impaired vision [6]. Case series of patients with del(1)(p36) revealed ophthalmological findings in up to 75 %, including strabismus, cranial nerve VI palsy, amblyopia, refractive errors, anomalous optic discs and lacrimal defects [14]. Other ocular problems observed in del(1)(p36) include nystagmus, visual inattention, unilateral cataract, fundus hypopigmentation and unilateral optic nerve coloboma [1820]. Terminal deletions may be associated with deep set eyes [6]. Both long eyelashes and synophyrs have been reported [4, 9].


Deletions of 1q



Definition and Epidemiology


Most frequent 1q deletions are del(1)(q21q25), del(1)(q25q32) and del(1)(q42qter) [21]. Del(1)(q42qter) is the most common 1q deletion and usually includes 1q42 and/or 1q43 [22]. Although approximately 30 % of patients with del(1)(q) die in the first 2 years of life, two reported survivors are a severely retarded 12 year old, and a 35 year old woman [22].


Systemic Manifestations


Findings of interstitial del(1)(q21q25) include developmental delay, hypotonia, microbrachycephaly, cleft palate, posteriorly rotated ears, club foot, transverse plamar crease and malformations of the heart, external genitalia and kidneys abnormalities [21]. One patient had myelomeningocele with hydrocephalus and anal atresia [21]. Autism and schizophrenia have been described in del(1)(q21.1) [23, 24]. Prune belly syndrome and Potter sequence were described in patients with del(1)(q25q32). Pancreatic anomalies have been reported in del(1)(q31.2q44) [25].

Terminal deletion of 1q present with profound mental retardation, growth deficiency, and microcephaly. Some individuals show genital and heart abnormalities [22, 26, 27]. Hypothyroidism and growth hormone deficiency have also been described [26]. Patients may also exhibit abnormal behavior or spontaneous laughter [22, 26]. Minor malformations may include a round facies with downturned mouth, flat philtrum with thin lips, low-set ears, micrognathia, short broad nose, short or thick neck, and clinodactyly [22, 26, 27].

Del(1)(q41q42) has been recently described with characteristic features, including developmental delay, dismorphic features and seizures, suggesting an association with FBXO [28]. One case with del(1)(q42) syndrome was reported with congenital cardiac disease, genital anomalies, neural tube defects and abnormalities of hands and feet [29]. Del(1)(q44) has been associated with hemiconvulsion, hemiplegia and epilepsy [30]. Six additional cases were reviewed from a literature search. Del(1)(qter) has been associated to short stature, developmental delay and mental retardation, microcephaly, seizures, abnormal corpus callosum , and abnormal ear shape [31]. A 6-year-old girl and de novo interstitial del(1)(q24.3-q31.1) had multiple pituitary hormone deficiency, severe cognitive impairment, bilateral cleft lip and palate, midline facial capillary malformation, erythema of hands and feet and dysplastic cranial vessels, low anti-thrombin III activity, hemifacial overgrowth due to progressive infiltrating lipomatosis with bone overgrowth [32].

A case with interstitial deletion of 1q having delayed psychomotor development, mid face hypoplasia, low set ears and tapering fingers was reported [33]. MRI showed hypoplasia of the corpus callosum.


Ophthalmic Manifestations


Epicanthal folds are a frequent feature of the distal 1q deletions. Upward-slanting palpebral fissures [22], strabismus [22], “protruberant eyes” [27], and “upper eye fullness” have also been described [32].

A case with interstitial deletion of 1q had ptosis and Duane syndrome . Microphthalmia, strabismus, Duane syndrome and bilateral congenital cataracts were described in patients with del(1)(q21.1) [34].

One patient with an unbalanced translocation with a partial trisomy of 4q and a terminal deletion of 1q was reported with sparse eyebrows and lashes, and bilateral retinal and optic nerve colobomas [35]. In addition, a patient with del(1)(q) and bilateral iris coloboma has been reported, although that the patient’s sibling had the same 1q deletion, but did not have coloboma [36]. Recent reports of del(1)(q41q42) and del(1)(q44) also include hypertelorism [28, 30].


Duplications of 1p



Definition and Epidemiology


Is a rare condition, with few cases reported in the literature.


Systemic Manifestations


Congenital heart disease , hand anomalies, growth retardation, microcephaly, flat nasal bridge, cleft lip/cleft palate, ear anomalies, micrognathia, and cryptorchidism have been reported [37]. An 8 year old male patient with dup(1)(p 13.1p22.1) was reported with clinical findings of Nikawa-Kuroki syndrome , including mental retardation, microcephaly, syndactyly, persistant fetal finger pads , flat nose with short columella [38].


Ophthalmic Manifestations


Ocular manifestations consistent with Nikawa-Kuroki syndrome , including flare of lateral eyebrows, euryblepharon, long lashes, epicanthal folds, bilateral ptosis and blue sclera were observed in the patient with dup(1)(p13.1-p22.1) [38].


Duplications of 1q



Definition and Epidemiology


Complete trisomy of chromosome 1 usually results in embryonic death [39], although there is a patient that lived at least to 4 years of age [27]. Few cases have been reported with duplication 1q.


Systemic Manifestations


Reported findings include severe mental retardation, congenital heart disease , micrognathia cleft lip and palate, hirsutism, cryptorchidism, renal dysplasia and hypoplasia, low set ears, high arched palate, nasal skin hemangioma, hearing defects, and absence of the gall bladder [27, 3942]. The brain may have microgyria, absent olfactory nerves, cerebral dysgenesis or hydrocephalus [41, 42]. It may also predispose to neoplasia formation [43].


Ophthalmic Manifestations


Reported oculofacial findings include “small and wide-set” eyes [27, 39] and downslanting of the palpebral fissures [41]. One case with dup(1)(q31q32) had infantile glaucoma associated with iris stromal dysgenesis and vascularized iris processes in an otherwise open angle [44]. GLC1 gene was identified in the duplicated region. One neonate with trisomy (1)(q32qter) was reported with goniodysgenisis, persistent tunica vasculosa lentis, hyaloid vessels, hypopigmentation of the posterior iris pigment epithelium, ectopia of ciliary processes, abnormal insertion of ciliary muscle and cataract [45]. One child had congenital glaucoma and dup(1)(q41qter), but this was attributed to an associated del(9)(p23pter) because of an earlier report [46].

Optic disc hypoplasia have been reported with dup(1)(q32.1q44) [47]. Other ocular manifestations of partial trisomy (1)(q42qter) include hypertelorism, shallow orbits with exophthalmic appearance, arched eyebrows, narrow palpeberal fissure, bilateral iris coloboma, punctate cataract and optic nerve coloboma [48].


Ring Chromosome 1



Definition and Epidemiology


This is a rare condition. One patient had ring 1 in all cells but mosaic for an absence of either chromosome 1 or 3 [49]. Another patient was also mosaic, with some cells having a normal karyotype and others having one or more ring 1 chromosomes [50]. Survival was described at least to 9 years old [51].


Systemic Manifestations


Ring 1 exhibit microcephaly, mental retardation, and short stature [12, 49, 51]. “Elfin” facies with upturned mouth, left palate, abnormal ears, congenital hip dislocation, preauricular sinuses, clinodactyly [51], and ascites have been described [4951].


Ophthalmic Manifestations


One publication did not report any ocular abnormalities [49]. One patient had small palpebral fissures, epicanthal folds, and down-slanting palpebral fissures [50]. Slight up-slanting of the fissures have also been reported.


Chromosome 2



Deletion 2p



Definition and Epidemiology


Deletion 2p is a rare condition, with few cases reported in the literature.


Systemic Manifestations


Lobar holoprosencephaly, microcephaly, short neck, large ears, clinodactyly, protuberant abdomen, cognitive impairments and cardiac defects have been reported with del(2)(p21p22.2) [52, 53]. One 5 year old male with 2p11.2 deletion showed mental retardation and bilateral clubfoot [54]. Two siblings with del(2)(p21) showed severe hypotonia, feeding problems, micrognathia, increased serum lactate, mild intellectual disability, hypospadias and cleft palate [55]. Urogenital abnormalities , psychomotor retardation and vitiligo were reported in del(2)(p11.2p13) [56]. A patient with del(2)(p16.3) presented with diaphragmatic hernia, developmental delay and short stature [57]. Nine patients have been reported with del(2)(p15p16.1), including severe developmental delay, intellectual disability, microcephaly, complex craniosynostosis and facial dysmorphism [58].


Ophthalmic Manifestations


Epicanthal folds, long palperal fissures, wide spaced eyebrows and synophthalmia/cyclopia have been reported with del(2)(p21p22) [52, 53]. Arched eyebrows, telecanthus and ptosis were reported with del(2)(p11.2p13) [56] as well as blepharophimosis [59]. A patient with del(2)(p21) had ptosis and epicanthal folds [55]. A 9 year old female patient with del(2)(p16.3) presented with bilateral ptosis, downslanting palpebral fissures and long eyelashes [57]. Patients with delayed psychomotor development and del(2)(p16.1) had ptosis, telecantus and epicanthal fold [60, 61]. In patients with del(2)(p15p16.1), optic nerve hypoplasia, strabismus, ptosis and telecanthus have been described [58].


Deletion 2q



Definition and Epidemiology


Different 2q deletions with varying phenotypic features have been reported in several cases [6063]. Over 100 patients with interstitial deletion of 2q have been reported. Frequently, these deletions are proximal to or include 2q33. Del(2)(q36) is rare [64]. Approximately 50 % of the reported deletions involve a chromosome region between 2q24.3-31.1 [63] or are terminal 2q37.3 deletions [65].


Systemic Manifestations


Deletion of 2q is associated with developmental delay, mental retardation, gonadal cysts, digital anomalies, hyperactivity with autistic traits and dysmorphic features including Pierre Robin sequence and temporal bone abnormalities. Hypoplastic lungs have been described [66]. Del(2)(q32) syndrome has been reported with growth retardation, microcephaly, facial dysmorphism, cleft palate, campodactyly, severe intellectual disability and ectodermal anomalies [67]. Del(2)(q33.3-q34) has been associated with Seckel syndrome , which includes intrauterine and postnatal growth retardation, developmental delay, microcephaly, receding forehead, large beaked nose, micrognathia, radial head dislocation, clinodactyly, and absent ear lobes. Hypotonia and hypospadius may also be present. Myelomeningocele, mild congenital heart disease, developmental delay, and minor dysmorphic features, including long philtrum , hypoplastic nasal bridge, prominent anteverted nasal tip, and mild abnormalities of the fingers have been reported with del(2)(q36). One patient with del(2)(q37.3) had speech delay, hyperactivity, mental retardation, autism, and brachydactyly [68].

Interstitial del(2)(q14.1q22.1) is rare. To the date, nine patients have been reported with deletions either within the region 2q13 or 2q14 to 2q22.1, having a combination of cognitive disability, growth retardation, hypotonia, craniofacial and limb abnormalities, and cardiac, renal and/or brain malformations, suggesting that there may be a recognizable phenotype. In this specific region there are 14 known disease-associated genes [69].

A recent publication reports the first familial case of interstitial del(2)(q37.3) affecting two genes, HDAC4 and TWIST2. Patients presented with brachydactyly and short stature without intellectual disability, which is usually described in brachydactyly-mental retardation syndrome, also known as Albright hereditary osteodystrophy [70]. Mutations in TWIST2 are usually associated with Settleis bitemporal forceps mark syndrome .


Ophthalmic Manifestations


Frequent findings of del(2)(q21q24) include microphthalmia, ptosis and cataract [71, 72]. Bilateral iris coloboma have been reported in individuals with del(2)(q21-q23.2) [73] or del(2)(q23.3-q24.2) [74] suggesting two separate critical areas. One child with del(2)(q24q32) had bilateral down-slanting palpaberal fissures, blepharophimosis, bilateral microphthalmia, iris coloboma, corneal opacities, and large chorioretinal coloboma involving the macula [75]. Thick eyebrows, synophrys, and hypertelorism are reported with del(2)(q31.2) and del(2)(q32.3) and optic nerve hypoplasia with del(2)(q31q33) [76]. Prominent supraorbital ridges, thick eyebrows, synophrys and proptosis were seen in a patient with del(2)(q31.2-q32.3) [77]. One patient with del(2)(q36) was described with hypertelorism, and in addition, “narrowness” of the palpebral fissures, although this is not evident in the associated photographs [64].

Epicanthal folds, Brushfield spots, and short palpaberal fissures have been described in terminal del(2)(q37.1). Coloboma has been described with del(2)(q37.3) [78] Seckel phenotype can present with down-slanting palpebral fissures. “Small eyes” have been described in a case of del(2)(q37.1qter), although there was concomitant duplication of part of the 1q [40]. Progressive keratoconus have been reported in a patient with del(2)(q37.3) [68]. Narrow palpebral fissures , deep set eyes and upslanting palpebral fissures have also been reported [79].


Duplication 2p



Definition and Epidemiology


There is no typical hotspot region in 2p duplication. Few cases with ophthalmic findings have been reported in the literature.


Systemic Manifestations


One patient with an inverted duplication of 2p and terminal 2p deletion presented with developmental delay, cardiac anomalies, pulmonary stenosis, micrognathia, low set ears, prominent forehead and depressed nasal bridge [80]. Two boys with microduplications 2p16 and 2p22 were reported with severe growth retardation, macrocephaly and broad forehead [81].


Ophthalmic Manifestations


The individual with inverted duplication of 2p and terminal 2p deletion showed hypertelorism, short palpebral fissures and nasolacrimal duct obstruction [80]. The two male patients with microduplications 2p16 and 2p22 had sparse eyebrows and hypertelorism [81].


Duplication 2q



Definition and Epidemiology


Most duplications of 2q result from unbalanced translocations resulting in trisomy for the entire q arm [82]. Different interstitial duplications of distal 2q have been reported including two siblings with dup(2)(q24.3q32.1)[71]. Their father had a balanced translocation and was clinically normal. There are five reports of patients with 2q duplication and ophthalmic findings.


Systemic Manifestations


There is evidence that the extent of the trisomic region correlates with phenotypic severity. Features common to virtually all distal trisomies of 2q include developmental delay, prominent forehead, depressed nasal bridge, anteverted nares, and long philtrum with thin upper lip. Ear anomalies include ear lobe creases [82]. Other reported findings include inguinal hernia, brahcycephaly, clinodactyly and pectus excavatum [82]. A patient with dup(2)(q32.1-q33.3) showed epilepsy, developmental delay and autistic behavior [83].


Ophthalmic Manifestations


Hypertelorism has been reported in all cases of distal dup2q. Some patients also had upslanting palpebral fissures and epicanthal folds [82]. One of the sibling pair had esotropia. A patient with dup(2)(q32.1q33.3) had hypertelorism, but not coloboma or epicantal folds reported in other dup2q patients [83]. Hypertrichosis, shallow orbits with prominent eyes, and blue sclera have been also reported in patients with dup(2)(q32q37) [84]. Nystagmus has also been reported.


Trisomy 2



Definition and Epidemiology


Complete trisomy of chromsome 2 has been reported in live born patients only as mosaicism . Less than 50 cases have been described in the literature.


Systemic Manifestations


One individual was reported with multiple non hepatic malformations including growth failure, congenital heart disease, hydronephrosis, gastrointestinal dysfunction, brain dysgenesis, hypotonia, microcephaly and developmental delay [85]. The child had cholestasis and hepatic fibrosis. The trisomy was only detected on liver biopsy, but was not found in intestinal mucosa, skin, ascitic fluid, or blood. Caudal dysgenesis and Hirschsprung disease have also been described.


Ophthalmic Manifestations


Lower canthal folds [85] and anophthalmia have been described in a patients with trisomy 2 mosaicism. Hypertelorism and nasolacrimal duct obstruction have been reported with dup(2)(p23pter) [86].


Chromosome 3



Deletion 3p



Definition and Epidemiology


Distal deletion of 3p is infrequent, with less than 50 patients reported.


Systemic Manifestations


Patients with distal 3p deletion show developmental delay, low birth weight, growth retardation, feeding problems, cardiac septal defects, seizures, hypothyroidism, micro- and brachycephaly, broad and flat nose, long philtrum, micrognathia, low set ears and syndactyly [8789]. Individuals with del(3)(p21-p31) are characterized by developmental delay, dysmorphisms, elevated serum creatine kinase levels and white matter involvement [90].


Ophthalmic Manifestations


Patients with del(3)(p14) have several oculofacial findings, including up-slanting fissures, deep set eyes, almond shaped eyes, eyebrows with medial flare, and epicanthal folds. Nasolacrimal duct stenosis have been also reported with del(3)(p14) [91]. One case with del(3)(p12p21.2) and a CHARGE phenotype was reported with iris coloboma, heart defect, choanal atresia, growth retardation and development delay, genital hypoplasia and ear anomalies with hypertelorism and bilateral microphthalmia [92]. Hypotelorism has also been reported [89]. Oculofacial findings associated with del(3)(p25-pter) are down-slanting palpaberal fissures, bushy eyebrows with synophrys, blepharophimosis, hypertelorism , epicanthal folds , ptosis and periorbital fullness [87, 88, 9395]. Patients with del(3)(p21p31) have arched eyebrows, hypertelorism and upslanting palpebral fissure [90].


Deletion 3q



Definition and Epidemiology


Mutations in the FOXL2 gene (located in 3q23 region) are responsible for the blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) , a condition that mainly affects development of the eyelids. Approximately 20 % of these patients exhibit BPES as part of a contiguous gene deletion syndrome [96]. 3p25 and q23 are two locations on chromosome 3 which may give rise to BPES [97]. This syndrome is typically inherited in an autosomal dominant pattern. The prevalence of BPES is unknown. In females, the eyelid malformation may be associated (type I BPES) with premature ovarian failure. Type I BPES is associated with female infertility and transmitted only by males, whereas males and females transmit type II. Bilaterally shortened horizontal palpaberal fissures, epicanthus inversus, and congenital ptosis with poor levator function characterize BPES .


Systemic Manifestations


An individual with BPES associated with diaphragmatic hernia was reported with del(3)(q21-q23) [98] and with microcephaly and developmental retardation in del(3)(q22.2-q23) [99] One neonate was reported with blepharophimosis, iris coloboma, hearing loss, post axial polydactyly, aplasia of corpus callosum, hydroureter and developmental delay [100]. Del(3)(q29) includes intellectual disability, schizophrenia, autism, bipolar disorder, depression and facial dysmorphism [101]. An 18 month old female with del(3)(q21.3-q22.1) presented features of Aicardi Syndrome [102]. A female newborn with del(3)(q26) had anal atresia, nasal skin tag, low set and protruding ears and growth delay [103].


Ophthalmologic Manifestations


A patient with del(3)(q26) encompassing SOX2 had bilateral microphthalmia, iris coloboma and cataract [103]. Del(3)(q29) microdeletion has been associated with slight pale optic disc, although no further investigation is provided [101]. A peripapillary chorioretinal lacunae was reported in a 18 month old female with del(3)(q21.3-q22.1) [102].


Duplication 3p



Definition and Epidemiology


Duplication 3p is a rare chromosomal aberration with few cases reported.


Systemic Manifestations


Developmental delay, dolicocephaly, low set and abnormal ears, cavernous hemangioma over the lumber spine, sacral dimple, clinodactyly and hypotonia were reported in an individual with dup(3)(p11.1-p14.2).


Ophthalmic Manifestations


The patient described above had ptosis and hypertelorism [104].


Duplication 3q



Definition


Dup(3)(q21qter) has been reported in patients with a phenotype that looks like Cornelia de Lange syndrome (CdLS) [105].


Systemic Manifestations


Patients having the CdLS phenotype associated with 3q duplications have hirsuitism, anteverted nares, carp shaped mouth with downturned corners, ear deformities, cardiac defects, mental retardation, and growth abnormalities. Limb reduction malformations are less frequent, whereas craniosynostosis, urinary malformations, and cleft palate more common in dup(3)(q) [105]. Two patients with dup(3)(q25q26) were reported with this phenotype [105]. Dup(3q)(13.2q13.31) has been associated with microretrognathia, cleft palate, septal defect, pulmonary hypertension , severe gastrointestinal reflux and mild hearing impairment [106].


Ophthalmic Manifestations


The dup(3)(q) CdLS -like phenotype has been associated with hypertelorism, synophyrs, epicanthal folds thick and long lashes, down-slanting palpebral fissures, nasolacrimal duct obstruction, and strabismus [107, 108]. In proximal interstitial duplication, high arched eyebrows and upslanting palpebral fissures have been reported [105]. Other ocular abnormalities seen in patients with CdLS, are frequently absent in dup(3)(q), although glaucoma, iris coloboma, cataract and anophthalmia, all uncommon or absent in CdLS, have been described [108]. Microphthalmia and corneal opacity were described in an individual with dup3q21-27 in the context of anomalous cerebellar development and Dandy-Walker malformation [109]. Dup(3)(q13.2-q13.31) has shown hypertelorism [106].


Pericentric Inversion of Chromosome 3



Definition and Epidemiology


This is a rare chromosomal abnormality, with two breaks on either side of the centromere .


Systemic Manifestations


One newborn with pericentric inversion of chromosome 3 showed atrial septal defect, polycystic kidney, clubbed feet, umbilical hernia, mental retardation, long and narrow hands and subluxation of the elbows [110].


Ophthalmic Manifestations


This patient with pericentric inversion of chromosome 3 presented several ophthalmological findings, including epicanthal folds, exotropia, microcornea, miotic pupil, iris neovascularization, cataract, glaucoma, hazy vitreous, subretinal hard exudates, exudative detachment, posterior hyaloid detachment with elevated neovascularization of the disc, and aneurysmal dilation of the peripheral retinal vessels, resembling Coats disease [110]. Some of these ocular findings may have been secondary to the primary retinal vascular malformation. Other patients reported with pericentric inversion of chrosome 3 had bilateral coloboma of the iris [111], upward slanting palpebral fissures, and hypertelorism.


Chromosome 4



Deletion 4p



Definition and Epidemiology


The most characteristic phenotypes for del4p are Wolf-Hirschorn syndrome (WHS) and Pitt-Rogers-Danks syndrome (PRDS) , now recognized as part of the same spectrum due to a deletion of 4p16.3 region [112]. The critical region for WHS, referred to as WHSCR-2, falls within a 300–600 kb interval in 4p16.3 [112] and contains the candidate gene NELFA. Small deletions could result in milder phenotypes. About 50 % of patients with WHS have a de novo pure deletion of 4p16 and nearly 40 % have an unbalanced translocation.

One author described patients who lacked the characteristic facial features, but showed non-specific manifestations of WHS [113]. The patients had deletions distal to WHSCR. Others developed a numerical scoring system for phenotypic features which may be helpful in identifying patients with normal karyotypes , on whom further molecular analysis might be indicated [114].

The critical region lies distal to the Huntington disease (HD) locus [115, 116]. No patient with both syndromes has been reported, maybe because of death before the typical adult onset for HD. WHS is caused by haploinsuficiency and Huntington disease results from an expanded CAG repeat leading to a pathologic gain of function.

Growth retardation and developmental delay have not been attributed to a specific gene, suggesting that more than one loci may be contributing [117]. It is apparent that WHS represents a contiguous gene deletion syndrome.

Interstitial deletion of the p14-16 region of chromosome 4 may present a distinct phenotype which is different from that of Wolf-Hirschhorn syndrome, with multiple minor anomalies and mental retardation [118].

The incidence of WHS is 1:50,000 live births [119]. About 90 % of cases are de novo, while 10–15 % arise from balanced translocations. De novo deletions are usually on the paternal chromosome [119, 120].


Systemic Manifestations


The distinctive WHS phenotype is defined by the presence of typical facial appearance consisting of ‘Greek warrior helmet appearance’ of the nose (the broad bridge of the nose continuing to the forehead) microcephaly, high forehead with prominent glabella, ocular hypertelorism, epicanthus, highly arched eyebrows, short philtrum, downturned mouth, micrognathia, and poorly formed ears with pits/tags. Patients have mental retardation, growth delay, congenital hypotonia and seizures.

Major manifestations are developmental delay growth retardation, cleft lip and/or palate, micrognathism, genital abnormalities, congenital heart disease, and seizures [114116, 119, 121123]. When the deletions involve the LETM1 gene , seizures are more likely to be observed [113]. Other less frequent features include low-set posteriorly rotated ears , preauricular tags, hearing loss, short philtrum, bowed or carp-shaped mouth, scalp defects, hypotonia, decreased tendon reflexes and abnormalities of the corpus callosum [114116, 119, 121]. Skeletal anomalies include tapered fingers, scoliosis, concave or hyperconvex nails and clinodactyly [114, 115, 119]. Other associations are congenital heart disease, fused teeth, and hypospadias [124, 125]. In addition, extensive Mongolian spots have been reported in del(4)(p16.3) [126]. Most individuals with WHS die in the first 2 years of life. In those who survive longer, severe retardation may be present [125]. Common causes of death are respiratory and cardiac [125]. Interstitial deletions proximal to the WHS region are usually found within 4p12-p16 and have a somewhat different phenotype [118].

One author demonstrated that there was a deletion in 4p16 region that overlapped and extended beyond the WHS critical region in each direction, considering likely that PRSD and WHS result from deletion in the same region [127]. Others had the same conclusion at a molecular level. Currently, WHS and PRDS represent clinical variation of a single disorder and the prognosis will be determined by the range and severity of symptoms present in the individual cases.

Developmental delay, hypotonia, high arched palate, thick lower lip, micrognathia, and prominent nose are seen in deletions that involve 4p14-p16 region, proximal to the WHS region. They vary from WHS individuals mostly because of their tall thin habitus, myopathic facies, and nipple abnormalities [118].


Ophthalmic Manifestations


Minor oculofacial manifestations include hypertelorism [128, 129], arched eyebrows, epicanthus, and upslanting or downslanting of the palpebral fissures. Less frequent findings are periorbital swelling, proptosis, shallow orbits, or blue sclera [114, 115, 117, 119, 121, 122, 124, 125]. Centrally distributed Brushfield-like spots on the iris [120] and iris heterochromia are could be seen [114], with a different distribution than those seen in Down syndrome. Cataracts may also occur [114, 125]. Possibly the most frequent ocular malformation of WHS is coloboma (30 %) or corectopia with or without microphthalmia [125]. Microcornea, disc abnormalities and foveal hypoplasia have been described in del(4)(p14p16.3) [130]. Microphthalmia, Peters anomaly and congenital cataract have also been reported with del4p. One patient with WHS was reported with early onset glaucoma involving a 165-kb segment within 4p16.3 region [131]. Coloboma can be unilateral [120, 122, 125] or bilateral. There have been reports of nasolacrimal duct obstruction, esotropia [115], exotropia [120, 125], and nystagmus in WHS [114, 117, 119]. Strabismus is seen in approximately one to two-thirds of patients [117, 119, 125]. Some traits, such as strabismus and epicanthus, may also show variable penetrance [117]. Ptosis has also been described (20–25 %) [117, 119, 125]. On a report of 10 patients severe ocular manifestations occurred in association with large 4p deletions, with the most frequent finding of exotropia (90 %) [132]. In one publication that included 22 patients with WHS, strabismus and nasolacrimal obstruction were found in patients with small or intermediate deletion, whereas ocular anomalies were found in patients with intermediate and large deletions [128]. Deletions that extend more proximally to 4p16 are associated with strabismus, hypertelorism, epicanthal folds. Abnormalities of the eyebrows occur as well. Less proximal involvement may still result in ptosis [117]. Abnormal slanting of the palpebral fissures appears to map to a 150 kb region between D4F26 and D4S9050.

Nystagmus has been associated to isolated terminal deletions and interstitial deletions proximal to the WHS region [117, 118]. The WHS critical region also includes the phosphodiesterase beta subunit gene. Biallelic mutations in this gene may be associated with retinal dystrophy. However, to our knowledge, retinal dystrophy has not been seen with WHS .


Deletion 4q



Definition and Epidemiology


Distal interstitial deletions are more often than proximal deletions. Most of proximal interstitial deletions are de novo [133]. Estimated incidence is 1 in 100.000.


Systemic Manifestations


Clinical presentation of 4q deletion is variable. Major deformities are infrequent but include renal malformations, congenital heart disease, or seizures. Dysmorphic features are a high forehead, flat nasal bridge, and receding chin [133]. Minor anomalies of the digits and nipples can be seen. Deafness and cleft palate are unusual associations. Del(4)(q12q13.1) results in mild mental retardation and dental anomalies, as well as hypotonia [133]. Piebaldism may be seen due to hemizygosity of the c-kit gene (4q12 region) [133]. Del(4)(q21q22) is associated with growth retardation, short stature, dolicocephaly and deafness [134]. One patient with del(4)(q21.22q23) was reported having micrognathia, clinodactyly genital malformation, cardiac anomalies, mental retardation, seizures, and a liver tumor [135]. Three patients with Axenfeld-Rieger syndrome and del(4)(q25) had mild learning difficulties, which is not typically seen in patients with this syndrome [136]. Del(4)(q27q31) is associated with mild mental retardation, micrognathia and dental malocclusion but no other systemic findings [137]. Cardiac malformations, Pierre Robin sequence, microcephaly, genito-urinary anomalies, short stature, and learning disability characterizes a deletion syndrome involving 4q31qter region . One author reported the “tail of a nail” sign in the fifth finger which is stiff with a hypoplastic distal phalanx and hooked or volar nail in del(4)(q34) [138]. Recent cases with del(4)(q21) have been associated with severe intellectual disability, lack of speech, hypotonia, facial dysmorphisms and significant growth retardation [139, 140].


Ophthalmic Manifestations


Eyebrow hypopigmentation and iris color abnormalities can be seen in individuals with del(4)(q12) and piebaldism [133]. In a patient with del(4)(q12q13.1), esotropia, refractive error, and epicanthus were reported [133]. Dystopia canthorum have also been reported. Other ocular abnormalities associated with proximal interstitial deletions include colobomatous microphthalmia, pigmentary retinopathy, and exotropia. Hypertelorism has been described in del(4)(q21.3q23) [141]. One case of bilateral Type II Duane syndrome with ptosis has been reported in a patient with del(4)(q27q31) [137]. One case of Axenfeld-Rieger syndrome and glaucoma was reported in a series of 20 patients with 4q deletions [142]. Four patients with overlapping microdeletions including PITX2 at 4q25 region were reported having Axenfeld-Rieger syndrome [136]. One author reported bilateral optic disc swelling in tail of the nail syndrome with del(4)(q34) [143]. Narrow palpebral fissure has been described in del(4)(q21) [139, 140].


Duplication 4p



Definition and Epidemiology


4p duplication syndrome is a rare condition, with few cases reported in the literature.


Systemic Manifestations


Trisomy 4p is also associated with microcephaly, mental and growth retardation, abnormal ears, bulbous nose, congenital heart defects, flexion contractures, microphthalmia, and seizures [144, 145].


Ophthalmic Manifestations


Microtia, ocular coloboma and nasolacrimal duct obstruction have been associated with dup(4)(p16) [144].


Duplication 4q



Definition and Epidemiology


Partial trisomy 4q is a rare genetic abnormality.


Systemic Manifestations


One author reported cardiac and renal defects, craniofacial malformation and mental retardation [146]. Mild intellectual disability, cranial malformation, facial dysmorphism and digital anomaly has been also reported with dup(4)(q32.2q34.3).


Ophthalmic Manifestations


One author reported morning glory disc anomaly [146]. Microphthalmia has been also associated to trisomy 4q [147]. Epicanthic folds have been reported in patients with dup(4)(q31.1q32.3) [148] and hypertelorism in an individual with dup(4)(q32.2q34.3) [149].


Chromosome 4 Inversion



Definition and Epidemiology


Chromosome 4 inversion is a rare condition with few cases reported.


Systemic Manifestations


One patient with inv(4)(q12q13.3) showed cleft lip and palate, cardiac abnormalities, meningocele, ear malformations, normal stature, normal cognitive development and otitis media [150].


Ophthalmic Manifestations


This patient had microphthalmia, cataract, retinal dysplasia, and Peters anomaly [150].


Chromosome 5



Deletion 5p



Definition and Epidemiology


The Cri du chat (CdCS) phenotype is due to partial terminal or interstitial deletion of 5p15.2. The incidence of cri du chat syndrome is estimated as 1 in 20,000–50,000 [151]. About 85 % of the patients show a de novo deletion. Up to 15 % present a familial cause, with a parental translocation in more than 90 %, or a para/pericentric inversion of chromosome 5 in 5 %.

The telomerase reverse transcriptase (hTERT ) gene is located in the critical 5p15.33 region for the CdCS phenotype. hTERT is a limiting component for telomerase activity that is essential for telomeric length maintenance and sustained cell proliferation [152].


Systemic Manifestations


Infants with CdCS characteristically show a distinct cat-like high pitched cry, psychomotor retardation, microcephaly, growth rate failure, microcepahly, round face, and broad nasal bridge [151]. When they become older, the face lengthens and becomes coarse with prominent supraorbital ridges, deep set eyes, hypoplastic nasal bridge, severe dental anomalies and comparatively large mouth will a full lower lip (Fig. 6.4). Hemizygosity of delta-catenin (CTNND2) is associated with severe intellectual disability in some patients with CdCS . Although lack of speech was considered a characteristic of the syndrome, it is not yet know whether language comprehension is impaired to the same extent as language production [153]. MRI of these patients shows atrophy of the brain stem, mainly at the pontine level associated with atrophic middle cerebellar peduncles and cerebellar white matter [154].

A318522_1_En_6_Fig4_HTML.jpg


Fig. 6.4
Patient with Cri du chat syndrome with del(5)(p15.2) and mild dysmorphic findings (courtesy of Mariana Aracena MD)


Ophthalmic Manifestations


Exotropia, myopia, upward slanting palpebral fissures, hypertelorism, and epicanthic folds have been reported in CdCS [151].

Telecanthus, epicanthal folds, antimongoloid palpebral fissures, optic atrophy, and tortuosity of the retinal vasculature have also been associated to CdCS.


Deletion 5q



Definition and Epidemiology


Few cases with 5q deletion and eye findings have been reported.


Systemic Manifestations


Del(5)(q14.3) has recently been recognized as a clinical entity presenting with severe intellectual disability, epilepsy and brain malformations [155]. One patient with del(5)(q22.1q31.1) was reported with mental retardation, craniofacial abnormalities and typical features of Gardner syndrome , including several adenomatous polyps of colon, osteomas of facial and long bones, and soft tissue tumors [156]. Three previously reported 5q deletion patients had also adenomatous polyposis coli [156] The adenomatous polyposis coli gene (APC) is located at 5q21-q22 region. Schizophrenia mental retardation and dysmorphic features were seen in a patient with del(5)(q21q23.1) [157]. One case had dysmorphic features and mewing cry associated with a de novo del(5)(q31.1q31.2) [158]. Marked hypotonia, apnea and developmental delay have also been reported in 5q31.3 microdeletion [159]. Neonatal lymphedema, short neck hypotonia, delayed development, and congenital heart defects have been reported with del(5)(q35.1q35.2) [160].

Recently, definition of 5q11.2 microdeletion syndrome based in 6 patients revealed an overlap with CHARGE syndrome and 22q11 deletion syndrome phenotypes, including choanal atresia, developmental delay, heart defects, external ear abnormalities, and short stature [161].


Ophthalmic Manifestations


Del(5)(q14.3) has been associated with hypertelorism [155], and iris coloboma in interstitial del(5)(q14.3q21) [162] Upslanting palpebral fissures with ptosis, exophthalmos and hypertelorism occur consistently with del(5)(q22.1q31.1) [156158]. Sparse eyebrows, hypertelorism and ptosis have been reported in del(5)(q31.3) [159, 163]. Bushy eyebrows, synophyrs , and irregular lashes have been reported with del(5)(q35.1) and del(5)(35.3) [164].


Duplication 5p



Definition and Epidemiology


There are only few reports on patients with duplications of the short arm of chromosome 5 [165168].


Systemic Manifestations


Dup(5)(p11p13.2) shows a severe phenotype that includes macrodolicocephaly, craniofacial anomalies, hypotonia, mental retardation, and malformations of the heart, kidneys, intestine and brain. When the duplication is distal to 5p13.3 region, only minor features have been reported, including developmental delay and learning difficulties [166].


Ophthalmic Manifestations


One patient with partial trisomy 5p had atypical Peters anomaly along with down-slanting eye fissures and epicanthal folds [167]. Microphthalmia, coloboma and strabismus have been associated with dup(5)(p13pter) [168].


Paracentric Inversion of Chromosome 5



Definition and Epidemiology


This is a rare condition, with few cases reported. Haplo insufficiency of NR2F1 has been proposed as the cause of deafness and other associated anomalies based on a similarity with the Nr2f1 null mouse [169].


Systemic Manifestations


A 4-year-old girl presented with profound deafness, feeding difficulties, facial dysmorphism, developmental delay, and a de novo paracentric chromosome 5 inversion, inv(5)(q15q33.2) [169].


Ophthalmic Manifestations


Upslanted palpebral fissures and strabismus were reported in the previously described patient [169].


Partial Tetrasomy with Triplication of 5p



Definition and Epidemiology


This is an extremely rare aberration with few cases reported in the literature.


Systemic Manifestations


Microcephaly, hypertonia seizures, dysplastic kidneys, cardiac abnormalities and clinodactyly have been reported in a patient with partial tetrasomy with triplication of 5p affecting the 5p14p15.33 region [170].


Ophthalmic Manifestations


The patient had hypoplastic supraorbital ridges, prominent eyes, chorioretinal coloboma and dysplastic retinal tissue at the optic nerve head [170].


Supernumerary Ring Chromosome 5



Definition and Epidemiology


This condition is an extremely rare chromosomal abnormality.


Systemic Manifestations


Convulsions, laryngomalacia, preauricular tags and high arched palate have been reported [171].


Ophthalmic Manifestations


The only reported oculofacial abnormality is telecanthus [171].


Chromosome 6



Deletion 6p



Definition and Epidemiology


Most deletions of 6p are terminal deletions. The 6p23 breakpoint is more common than 6p24. Other significant breakpoint is 6p25, where the forkhead transcription factor FOXC1 is located. This gene is associated with Axenfeld-Rieger syndrome (ARS) , characterized by specific ocular anomalies with or without systemic abnormalities . More than 40 6p deletion cases have been reported.


Systemic Manifestations


6p23 deletion is characterized in most of patients by craniosynostosis, with or without microcephaly, small pinched nose with flat bridge and anteverted nostrils [172]. Majority of these patients have congenital heart disease [172]. Associated hepatosplenomegaly and thrombocytopenia could be related to heart failure. Other authors have described hydrocephalus, hypotonia, malar hypoplasia, high/cleft palate, minor ear abnormalities with or without hearing loss, micrognathia, downturned mouth, and webbed/redundant loose neck skin, hypoplastic nails , minor extremity malformations, and genitourinary abnormalities [172, 173]. Nipple abnormalities have also been reported [172, 173]. Del(6)(p21.3) has been recently reported with severe speech impairment, seizures and behavioral abnormalities [174]. In addition, white matter abnormalities and periventricular heterotopia have been reported on MRI from patients with del(6)(p25) [175]. The 6p25 deletion syndrome is characterized by Dandy-Walker malformation, congenital heart defects, developmental delay, and dysmorphic facial features. When 6p25 is involved (FOXC1) Axenfeld-Rieger syndrome features can be seen, including craniofacial dysmorphism with maxillary hypoplasia, hypodontia, and umbilical anomalies; hearing loss, heart abnormalities , and developmental delay.


Ophthalmic Manifestations


Eye abnormalities are seen in up to 70 % of individuals with 6p23 deletions . Reported findings include microphthalmia, iris coloboma, Peters anomaly/corneal opacification, optic atrophy, bilateral optic disc coloboma, nystagmus, and epicanthal folds [172]. Up- or down-slanting palpebral fissures, mild synophyrs, and hypertelorism have been reported [172, 173]. One child had a hemangioma involving the brow [172]. Blepharophimosis, esotropia, high hyperopia and Brushfield spots have also been reported [172, 173]. One patient with del(6)(p21.3) was reported with strabismus, downslated palpebral fissures and mildly dysplastic papillae [174].

Anterior segment disorders such as Axenfeld-Reiger spectrum and/or iris hypoplasia associated with glaucoma are associated to del(6)(p25) [176, 177]. Other ocular findings include posterior embryotoxon, corectopia/polycoria and irido-corneal adhesions. One patient with del(6)(p24pter) [24] had bilateral posterior embryotoxon and, in one eye, progressive corectopia and ectropion uveae. The patient did not present glaucoma but there was bilateral optic nerve hypoplasia. Electroretinogram was normal. Grey-blue sclera can be associated with del(6)(p24p25). Telecanthus, divergent squint, hyperopia, Peters anomaly and mild pigmentary retinopathy were also reported with del(6)(p25) [178].


Deletion 6q



Definition and Epidemiology


Deletions of the long arm of chromosome 6 are rare and are characterized by clinical heterogeneity according to the deletion breakpoint. Interstitial deletions are rare. Approximately 80 cases have been reported.


Systemic Manifestations


Proximal deletions 6cen-q15 region have been associated with umbilical hernia and developmental delay. These children also show palmar creases, hyperextensible skin, joint laxity, microcephaly, and short stature. Individuals with del(6)(q13q15) present ectopic kidney and short necks, and also can have congenital heart disease [179]. Other less common features include genitourinary anomalies, joint contractures, syndactyly, club foot, micrognathia, and large/low-set ears. One author reported absent pulmonary valve in a patient with del(6)(q15q21). One patient with del(6)(q16.1q21) involving SIM1 had Prader-Willi Syndrome-like features, including obesity, short stature, hypotonia and hypopituarism [180]. One case with a small interstitial del(6)(q24q26) presented with developmental delay, low birth weight, hypotonia, heart murmurs, respiratory distress, craniofacial malformations and genital anomalies [181]. In del(6)(q25.3qter), mental retardation, seizures, microcephaly and cortical dysplasia have been reported [182].


Ophthalmic Manifestations


One child presented with del(6)(q13q15) and hypotelorism, nystagmus, and blue sclera [179]. Other series of children with proximal deletions, reported down-slanting fissures, epicanthal folds, small palpebral fissures and less commonly strabismus, but none of these features were localized to a particular locus. Other ophthalmological findings reported with terminal deletions are macular abnormalities, epicanthal folds, and strabismus [173]. One individual with del(6)(q13q15) was reported with “ocular albinism” [183]. His initial examination at 7 weeks showed iris transillumination but no transillumination was found by 34 weeks. Posteriorly, he developed nystagmus and exotropia. Fundus examination was hypopigmented, and also had macular hypoplasia. Electroretinogram was reported with normal rod but delayed cone response to 30 Hz flicker testing. One patient with del(6)(q16.1q21) with Prader-Willi syndrome -like features, just had downslanting and small palpebral fissures but no other ophthalmological findings were reported [180].

Deletion of 6q24q26 region is associated with epicanthic folds, downslanting palpebral fissures, hypertelorism, and retinal as well as macular abnormalities. A patient with del(6)(q25qter) presented with a crescent shaped hypopigmented area traversing the macula [184]. Strabismus , nasolacrimal duct obstruction, cataract and microphthalmia were associated to 6q deletion [181, 185188]. In del(6)(q25.3qter) deletion, strabismus, congenital nystagmus and high myopia have been reported [182]. An individual with del(6)(q26qter) was reported a bilateral small oval area of macular degeneration. The absence of retinal changes in a case of interstitial del(6)(q23q25) suggests that the critical area for retinal degeneration could be 6q26. This is a known locus for both rod-cone and cone-rod dystrophy [187].


Duplication 6p



Definition and Epidemiology


Less than 60 cases of partial duplication of 6p have been reported.


Systemic Manifestations


Partial trisomy of 6p is characterized by failure to thrive, low birth weight, craniosynostosis, feeding problems, recurrent respiratory tract infections, and psychomotor retardation [189]. One 11 year old female patient with interstitial tandem 6p duplication presented with mild dysmorphic features, moderate intellectual disability with behavioral disturbances, immunodeficiency and epilepsy [190].


Ophthalmic Manifestations


One patient with dup(6)(p12p21.3) had long lashes, down-slanting palpaberal fissures, blepharophimosis and corneal clouding [191]. The patient with 6p trisomy from interstitial tandem duplication had abnormal palpebral fissures [190]. One female infant with de novo partial 6p trisomy (dup(6)(p12.3p21.1)) presented with palpebral fissures abnormalities, long eyelashes, epicanthus, ptosis and blepharophimosis, although there is one case of dup(6)(p12p21.3) that was reported with cataract and corneal clouding [189, 191].


Duplication 6q



Definition and Epidemiology


6q duplication is a rare condition. Dup(6)(q26) could be a critical breakpoint for the 6q phenotype [192]. Most cases result from malsegregation of a reciprocal translocation that leads to a terminal 6q duplication and partial monosomy of another chromosome. Less than 15 cases of de novo pure duplication have been reported.


Systemic Manifestations


The dup(6)(q) syndrome is characterized by developmental delay, feeding difficulties, microcephaly, prominent forehead, midfacial hypoplasia, micrognathia with carp-shaped mouth, short webbed neck, and club foot. Abnormal palmar creases is less commonly seen. One individual with dup(6)(q23.3q25.3) was reported with microcephaly , delayed Fontanelle closure, dolicocephaly, congenital cardiac malformations, flexion contractures, abnormal palmar creases, midfacial hypoplasia, and a carp-shaped mouth [192]. Arthrogryposis has been described in a patient with de novo dup(6)(q24.2q25.3).


Ophthalmic Manifestations


Oculofacial features of del(6)(q) syndrome include down-slanting palpebral fissures and epicanthal folds. The patient reported with proximal dup(6)(q23.3q25.3) had infraorbital creases, hypertelorism, epicanthal folds, and almond shaped palpebral fissures without down-slanting [192]. This patient also had blue tinted sclera. Brushfield-like spots have been also reported with dup(6)(q21q23.3) [193]. One patient with de novo dup(6)(q26q27) presented with up-slanting palpebral fissures and congenital glaucoma [194].


Ring 6



Definition and Epidemiology


Ring chromosome 6 is a rare aberration that generally occurs de novo. The associated phenotype is variable, ranging from an almost normal phenotype to severe malformations and mental retardation. The severity seems to be related to the size of the deletion. About 25 cases have been reported.


Systemic Manifestations


Ring 6 manifestations include flat nasal bridge, well formed ears, short neck, microcephaly, micrognathia, bilateral simian crease, seizures, and mental and growth retardation [195].


Ophthalmic Manifestations


Eye findings associated with Ring 6 apparently are related to concomitant deletion of 6p, specially 6p25 region. Reported malformations include anterior segment defects (aniridia, coloboma, ectropion uveae), glaucoma, optic atrophy, and retinal abnormalities [173]. Hypertelorism and epicanthal folds were also reported [195].


Pericentric inversion of Chromosome 6



Definition and Epidemiology


Pericentric inversion of chromosome 6 is a rare condition with few reports in the literature.


Systemic Manifestations


This condition was reported in different generations of a family with several phenotypic findings including hearing loss, dental anomalies, ear anomalies, and mild mental retardation [172].


Ophthalmic Manifestations


Strabismus, coloboma and congenital cataract were reported [172]. Rieger’s syndrome has also been described.


Chromosome 7



Deletion 7p



Definition and Epidemiology


7p deletion is a rare condition, with less than 50 cases reported.


Systemic Manifestations


Psychomotor retardation, craniosynostosis, skull abnormalities, broad flat nasal bridge, digital anomalies, cardiac defects, urogenital anomalies and immunodeficiency have been reported in patients with del(7)(p15p22) [196].


Ophthalmic Manifestations


Ptosis and microphthalmia have been associated with del(7)(p15p22) [196]. Hypertelorism was reported in the context of craniosynostosis in a patient with del(7)(p21.1) [197].


Deletion 7q



Definition and Epidemiology


The most frequent deletions of 7q can be classified into 7q11q21, 7q21q32, 7q32q34 and 7q32qter.


Systemic Manifestations


Terminal and interstitial deletions of the long arm of chromosome 7 have been associated with developmental delay, growth retardation, hypotonia, seizures, microcephaly, prominent forehead, nasal dysmorphism , micrognathia, chest anomalies, abnormal hand creases and male genital malformation [198].

Williams-Beuren syndrome is a continuous gene deletion syndrome caused by a del(7)(q11q23). It is characterized by a characteristic facies, supravalvular aortic stenosis, connective tissue abnormalities, clinodactyly, mental retardation and precocious puberty. Patients with Williams-Beuren syndrome and del(7)(q11.23) show disorganized pre-elastic and mature elastic fibers. Skin biopsies may be used to find extracellular matrix anomalies. When associated with infantile spasms, it has been attributed to MAGI2 gene hemizygosity. One patient with del(7)(q11.21q11-23) and without disruption of MAGI2 has been reported with infantile spasm [199].

A recent report of del(7)(q36.2q36.3) included short stature, craniofacial dysmorphism in the absence of intellectual disability [200]. Low birth weight, cleft lip and palate, cryptorchidism and complex heart disease have been reported in del(7)(q34qter) [201]. Patients with terminal deletion of 7q have presented with anencephaly and holoprosencephaly due to hemizygosity for the SHH gene at 7q3A r [202].

It has been estimated that approximately 20 % of 7q deletion have either cleft lip and/or palate or congenital heart defect [201].


Ophthalmic Manifestations


Ophthalmologic features in patients with Williams-Beuren síndrome include strabismus (50 %), a typical stellate iris pattern of the anterior stroma, retinal vascular tortuosity (20 %) and hyperopia. One patient with del(7)(q11.21q11.23) has been reported with oculofacial findings, including periorbital fullness and downslanting palpebral fissures [199]. Hypertelorism and epicanthus have also been described in proximal 7q deletion [203]. A patient with del(7)(q22.1q32.2) deletion was reported with optic nerve coloboma [204]. Hypertelorism has been reported in del(7)(q34qter) [201]. A recent report of del(7)(q36.2q36.3) deletion included pale optic disc, coloboma, chorioretinal lesions and retinal pigmentary epithelium changes [200].

A patient with del(7)(q36) presented with nystagmus in the context of holoprosencephaly; SHH , HOX1 and HTR5A were deleted [205]. Other reports of 7q deletion includes enophthalmos, exophthalmos, strabismus, optic nerve atrophy and glaucoma [198].

One 13 year old boy with 7q terminal deletion syndrome showed holoprosencephaly with microcephaly, facial dysmorphism, severe intellectual disability, behavior problems, seizures, short stature, penoscrotal transposition, and ulnar ray deficiency. These findings were attributed to dosage expression of the SHH gene , although the region includes more than 40 genes [206].


Duplication 7p



Definition and Epidemiology


Isolated duplication 7p is a rare condition, with few cases reported in the literature.


Systemic Manifestations


Dup(7)(p13p22.1) has been described with hypotonia [207]. Dup(7)(p22.1) was associated with macrocephaly, low-set ears and speech delay. The ACTB gene is a strong candidate gene for the alteration of craniofacial development [208, 209].


Ophthalmic Manifestations


Patients with dup(7)(p22.1) can present with ocular hypertelorism. Ptosis has been also reported with dup7(p21.1p14.2) [210].


Duplication 7q



Definition and Epidemiology


Few reports describe the ophthalmological findings in 7q duplication.


Systemic Manifestations


Developmental delay, altered dermatoglyphics, low set ears, micrognathia, high arched palate, joint hyper flexibility, and small penis have been reported [211]. Dup(7)(q11.23), involving the Williams-Beuren syndrome deletion region, is an emerging phenotype characterized by dysmorphic facies, hypotonia, developmental delay with variable speech delay and autistic features. One series of eight pediatric patients and one adult all had aortic dilation, being the opposite vascular phenotype of the typical aortic stenosis found in Williams-Beuren syndrome [212].


Ophthalmic Manifestations


Hypertelorism, epicanthus, strabismus, palpebral fissure abnormalities, retinal pigment epithelium alteration, optic nerve anomalies, myopia, anophthalmos, abnormal extraocular muscles, iris coloboma, long eyelashes, microcornea and limbal dermoid have been described in 7q duplication [211, 213223].


Ring 7



Definition and Epidemiology


Less than 29 cases have been reported in the literature.


Systemic Manifestations


Most common manifestations are growth retardation, microcephaly and dermatological abnormalities. Holoprosencephaly has been reported [224].


Ophthalmic Manifestations


Hypertelorism , epicanthal folds and palpebral fissures abnormalities are the most frequent findings, although proptosis, ptosis, microcornea, cataracts and strabismus have been reported [224, 225].


Chromosome 8



Deletion 8p



Definition and Epidemiology


Most of 8p deletions include 8p23.1 region [226]. Less than 50 cases have been described in the literature.


Systemic Manifestations


Most of individuals with a deletion of the short arm of chromosome 8 are characterized by significant developmental delay, low birth weight, and short stature [226, 227]. The degree of mental retardation may be associated to deletion size [226]. Less frequently, severe behavioral problems may be seen [226]. The most frequent systemic abnormality is congenital heart disease , particularly atrioventricular canal defects [226, 227], although there are patients without heart defects [228]. Dolichocephaly and microcephaly associated to a high forehead may be present [226, 227]. In patients with del(8)(p22) or del(8)(p21) microcephaly is more common [226]. Other common facial features are low-set and/or malformed ears, micrognathia, arched palate, flat nasal bridge, short neck, and short nose [226] Microstomia is seen in less than half of cases [226]. Individuals can also present with abnormal genitalia, cryptorchidism, puffy hands and feet and a broad chest with widely set nipples [226, 227]. Gastrointestinal malrotation has also been observed in patients with terminal 8p deletion [226]. If the deletion extends centromeric to 8p23.1, comprising 8p21 region, other findings may be seen, including trigoncephaly, dysplastic ears, short neck, hypotonia, elbow dimples and narrow thorax [226].


Ophthalmic Manifestations


Ophthalmic findings are relatively frequent in patients with deletion 8p [227229] A common oculofacial abnormality is epicanthal folds, present in up to 90 % of patients [227]. Hypertelorism is less frequent [227]. One male patient with del(8)(p11.2p21) was reported with “visual impairment”, nystagmus, pale optic discs, moderate macular atrophy and a patchy retinal pigment epithelium disturbance. Visual evoked potential was significantly reduced but full field electroretinogram was normal [230]. Strabismus and nystagmus has been described with del(8)(p11.1p21.1) [231] and also microcornea, iris and choroid coloboma, and bilateral retinal dysplasia in a boy with del(8)(p11.2p21.1) [232]. One patient with del(8)(p21.1p23.1) had long, thin sparse eyebrows and deep set eyes. Other authors reported hypertrichosis and synophyrs in a child with del(8)(p23.1pter) [226]. One patient with terminal deletion of 8p was reported to have aniridia and nystagmus, but no further description is provided [228].


Deletion 8q



Definition and Epidemiology


Few cases have been reported in the literature. An important breakpoint is 8q22.


Systemic Manifestations


Del(8)(q22.1) has been associated with Nablus Mask-Like Facial syndrome : tight and glistening facial skin, abnormal ear architecture, upswept frontal hairline and sometimes microcephaly, cryptorchidism, cleft palate and neurological spectrum findings [233]. It has been suggested that del(8)(q22) is not sufficient by itself to cause the Nablus Mask-Like Facial phenotype [234].

Five patients with interstitial del(8)(q22.2q22.3) had intellectual disability, seizures, and dysmorphic features [235]. One patient had a de novo deletion in 8q22.3, presenting with seizures, intellectual disability and autistic behavior. In addition, she had mild dysmorphic features, including telecanthus and thick vermilion border of the lips. Array comparative genomic hybridization detected a 1.36 Mb deletion in 8q22.3, including RRM2B and NCALD [236].

Types I and II of the autosomal dominant tricho-rhino-phalangeal syndrome (TRPS) have been associated to del(8)(q24.1) [227]. Type 1 is characterized by early baldness , large nose, and cone-shaped epiphyses of the middle phalanges whereas Type II (Langer-Giedion syndrome ) also have mental retardation, microcephaly, and multiple exostoses. A deletion, disruption or point mutation of TRPS1 causes TRPS Type I, while simultaneous deletion of EXT1 cause Type II. The latter therefore represents a contiguous gene syndrome.


Ophthalmic Manifestations


One author reported hypertelorism , deep set eyes with upslanting palpebral fissures associated to del(8)(q21) [237]. One individual with TRPS phenotype and del(8)(q24.1) had bushy eyebrows without synorphyrys [227]. Nablus Mask-Like Facial syndrome associated with del(8)(q22.1) has been reported with blepharophimosis, hypertelorism and sparse eyebrows.


Duplication 8p



Definition and Epidemiology


Duplication of the short arm of chromosome 8 can present as a complete trisomy or mosaicism (Warkany syndrome), or tetrasomy. Phenotype usually does not have a good correlation with degree of mosaicism. 8p23.1 duplication syndrome has an estimated population prevalence of 1 in 58,000.


Systemic Manifestations


Trisomy 8p is characterized by short wide neck, as well as deep hand and foot creases [238]. One individual with an inverted terminal dup(8)(p21.2p23.2) had triangular facies, growth and developmental delay, large ears, and a café au lait spot [239]. Supernumary isochromosome 8p present with agenesis of the corpus callosum, developmental delay, rib anomalies, congenital heart disease, high/cleft palate, enlarged cerebral ventricles with or without gyral anomalies and vertebral anomalies with or without scoliosis [238, 240243]. Development delay has been reported, although motor delays due to hypotonia seem to be more frequent [240244]. The most frequent cause of death during the neonatal period is heart disease [238].

Although dysmorphism may be absent [243], the appearance may be characterized by a high forehead/frontal bossing, sparse temporal hair, and mild ear abnormalities [240242]. A shy behavioural phenotype with obesity has been described [244]. As seen in trisomy 8 , abnormal nails [240], clinodactyly [242], or gastrointestinal problems such as duodenitis, hamartomata (intestinal, liver, adrenal), and malrotation may rarely occur [241]. Nevus flammeus may be seen [241]. Although rare, children with virtually none of the clinically detectable malformations above have also been reported [244]. One female patient with dup(8)(q23q24) presented with dysmorphic features, retrognathia, hirsutism and developmental delay [245]. Mild or moderate developmental delay, mild dysmorphism and congenital heart disease are frequent in dup(8)(p23.1) [246] Other reported findings are behavioral problems, cleft lip and/or palate, macrocephaly, seizures, attention deficit hyperactivity disorder, balance problems, hypotonia, and hidrocele [246].


Ophthalmic Manifestations


Glaucoma, epicanthal folds [240, 242] and pseudoesotropia [240] has been reported. The eyebrows and eyelashes may be sparse [241]. Dup(8)(p21.2p23.2) has been associated with hypertelorism [239].


Duplication 8q



Definition and Epidemiology


Duplication 8q is a rare condition with few cases reported in the literature.


Systemic Manifestations


Dup(8)(q22q24) present mental retardation, short stature, broad short neck, cardiac malformations, cryptorchidism, hemangiomas, kyphoscoliosis, EEG abnormalities and muscular hypotonia [247].


Ophthalmic Manifestations


Dup(8)(q22q24) has been associated to hypertelorism, epicanthal folds, strabismus and lid hemangioma [247]. One patient with dup(8)(q23q24) presented with hypertelorism, hypoplastic eyebrows and significant hyperopic astigmatism [245].


Trisomy 8



Definition and Epidemiology


Warkany syndrome is usually mosaic or the result of a translocation. The average peripheral blood and fibroblast mosaicism is nearly 60 % and 70 %, respectively [248]. Degree of mosaicism and severity are not correlated. It seems that dup8q2 is the critical region for the trisomy 8 phenotype [248].

More than 100 cases have been reported in literature. Complete trisomy 8 is usually an early lethal condition. Of spontaneous abortions, 0.7 % are caused by trisomy 8 [249]. It has an estimated frequency of approximately 1:25,000–50,000 births.


Systemic Manifestations


Trisomy 8 is characterized by variable mental retardation, prominent anteverted nasal tip, prominent lower jaw (Fig. 6.5a), absent or dysplastic patella, joint contractures, vertebral defects, urinary abnormalities, a distinctive toe posture (flexed and turned towards midline of foot with digits 2 and 3 having equal length) (Fig. 6.5b), and deep furrows in the palms and soles [248]. Other typical features include cleft or high palate, sacral dimple/spina bifida occulta, congenital heart disease, clinodactyly/long fingers, slender pelvis, abnormal ears, hip dysplasia, everted lower lip, sternum abnormalities, or abnormal nails [248]. Seizures and gastrointestinal anomalies such as anus abnormalities are less frequent [248]. Birth weight is usually normal [248]. Patients with trisomy 8 can present temper tantrums. Hemihyperplasia and a discordant bone age of both hands have also been reported [249]. Trisomy 8 mosaicism is frequently found in patients with acute promyelocytic leukemia [250, 251].

A318522_1_En_6_Fig5_HTML.jpg


Fig. 6.5
(a) Patient with Trisomy 8 mosaic with mental retardation and dysmorphic facies characterized by prominent anteverted broad nasal tip, dysplastic ears and prominent lower jaw. Note patient also has hyperopia, exotropia, and telecanthus. (b) Deep creasesof the sole, and flexed digits 2 and 3 having equal length and turned towards midline of foot (courtesy of Mariana Aracena MD)


Ophthalmic Manifestations


Trisomy 8 is usually associated with abnormal slanting [248]. Strabismus is frequent, with esotropia being most common [248]. Duane syndrome has also been described [252], perhaps due to duplication of the DURS1 locus at 8q12-13. One author reported bilateral asymmetrical corneal opacities consistent with choristoma [253]. Other findings include cataract, corneal clouding, nasolacrimal duct obstruction, microcornea, iris heterochromia, ptosis, microphthalmia and macular hypoplasia . There is a report of Axenfeld-Reiger spectrum but with no glaucoma [254]. One patient with congenital pendular nystagmus and macular hypoplasia was reported. Electrodiagnostic tests confirmed cone function [252]. A pre term patient (8 months gestation) had congenital cataract and retinopathy of prematurity. He later developed acute angle closure glaucoma in one eye, and chronic uveitis, band keratopathy, posterior embryotoxon and small optic disc in the other eye [248].


Chromosome 8 Inversion


One female patient with inv(8)(q21.3q24.13) who had Moebius syndrome was reported [255].


Ring 8


Craniofacial anomalies, growth and mental retardation, epicanthal folds, deep set eyes and hypertelorism have also been observed in ring chromosome 8 [256, 257].


Chromosome 9



Deletion 9p



Definition and Epidemiology


Deletion 9p syndrome is a rare structural chromosomal disorder. Estimated frequency is 1 in 50,000 births. Deletion of the distal portion of chromosome 9p is associated to a characteristic phenotype . Frequent breakpoints are at 9p21 or 9p22 and arise de novo. Patients derived from a parental balanced translocation carrier more commonly involve 9p24 region [258].


Systemic Manifestations


Clinical features include severe mental retardation, craniosynostosis/trigononcephaly, midfacial hypoplasia, posterior rotated poorly formed ears, foot positioning defects, long middle phalanges, cardiac abnormalities, inguinal and umbilical hernia, scoliosis, cryptorchidism, and choanal atresia [257, 259].


Ophthalmic Manifestations


One patient with congenital glaucoma was reported having del(9)(p23pter) associated with dup(1)(q41qter) [46]. One author reported a case of congenital glaucoma associated with del(9)(p22.3) [257]. These reports may suggest a gene implicated in this condition. Other ophthalmic findings include epicanthal folds and up-slanting palpebral fissures [259, 260]. Exorbitism and esotropia have also been described [260].


Deletion 9q



Definition and Epidemiology


The chromosome 9q subtelomeric deletion syndrome is the most common clinically recognizable phenotype [261]. Most patients have deletions of the 9q34.3 that range from <400 kb to >3 Mb [262]. More than 50 cases have been reported.


Systemic Manifestations


Clinical characteristics of del(9)(q22q32) include hirsutism, brachycephaly, dysmorphic ears, urogenital abnormalities, finger and toe anomalies, cardiac abnormalities, psychomotor retardation, seizures, dilation of cerebral ventricles and cerebral atrophy [263]. Reported phenotypic features of 9q subtelomeric deletion syndrome are mental retardation hypotonia, autism, sleep disturbances, epilepsy, urogenital abnormalities, obesity, microcephaly, brachcephaly, flat facies, mid facial hypoplasia cardiac defects, abnormalities of hands and feet, deafness, abnormalities of the teeth, and anal atresia [262, 264]. A newborn with del(9)(q34.1) from a paracentric inversin had malformed ears, micrognathia, bilateral webbing of the neck, widely spaced nipples, and complex heart anomalies [265]. Mental retardation, dental hypoplasia and deafness have been described as well [266]. In a 16 year old female patient with del(9)(q34.11q34.13), demonstrated severe intellectual disability, congenital hydrocephalus, cleft lip and palate, talipes equinovarus, epilepsy, kyphoscoliosis , severe short stature and facial dysmorphism were reported [267].


Ophthalmic Manifestations


Patients with interstitial del(9)(q22q32) have been associated to supraorbital ridge hypoplasia, synorphrys, hypertelorism, telecanthus, hypotelorism, downward slanting, narrow palpebral fissures, epicanthal folds, ptosis, strabismus, and sclerocornea [263]. Deep set eyes, hypertelorism , synophrys, arched eyebrows/straight eyebrows, long lashes, down or upslanted palpabral fissures, and hypertropia have been reported with del(9)(q34.3) [262]. Blepharophimosis and ptosis has also been reported [266]. In a female patient with del(9)(q34.11q34.13) with several systemic findings, strabismus was reported [267]. A patient with del(9)(q34.1) presented hypertelorism [265].


Duplication 9p



Definition and Epidemiology


It has been suggested that 9p22 could be a critical region for the duplication 9p syndrome [268]. More than 150 cases have been reported in the literature.


Systemic Manifestations


One patient had de novo dup(9)(p22p24) with mental retardation, small stature, microcephaly/brachycephaly, globular nose, down turned mouth, low set ears, single palmar crease, hypoplasia of some phalanges, nail dysplasia or hypoplasia [268]. Vocal cord paralysis has also been associated with dup(9)(q34) [269].


Ophthalmic Manifestations


An individual with a de novo dup(9)(p22p24) presented with down-slanting palpebral fissures, deep set eyes and hypertelorism [268].


Duplication 9q



Definition and Epidemiology


Duplication 9q has been infrequently described. Significant breakpoints include 34.1-34.3 segment [270]. One individual with dup(9)(q34) was reported with 18 year follow up [271].


Systemic Manifestations


Duplication of proximal 9q has been associated with microcephaly and developmental delay, whereas dup(9)(q34) has been reported with vertebral abnormalities and large low-set ears [272]. Variable findings have been observed in patients who present dup(9)(q32): deep-set eyes, beaked nose, micrognathia, long fingers, and stiff joints. Mental retardation, dolicocephaly, microstomia, retrognathia, arachnodactyly, and camptodactyly are clinical manifestations of dup(9)(q34.1q34.3) [270].


Ophthalmic Manifestations


Esotropia, epicanthal folds, narrow palpebral fissures, synophrys, and deep-set eyes are variably present. One patient with dup(9)(q12q33), had all these findings [272]. Microphthalmia, deep set eyes, small and narrow horizontal palpebral fissures and hypotelorism were described in a female patient with dup(9)(q33.3q34.1) [271].


Trisomy 9



Definition and Epidemiology


Trisomy 9 is rare in live born children. In fact, it may be that many live born children actually have cryptic mosaicism with non mosaic cases succumbing prenatally [273]. This severe chromosomal aberration is not consistent with survival beyond the neonatal period. Over 50 cases have been reported in the literature .


Systemic Manifestations


Live born infants with trisomy 9 may present with intrauterine growth retardation, skeletal abnormalities, congenital heart disease, congenital kidney disease and genitourinary malformations [273]. Other reported minor abnormalities include rocker bottom feet, joint contractures, overlapping fingers, and hypoplastic nails. Described craniofacial malformation include low set ears with possible absent external canals, cleft/arched palate, migrognathia, bulbous nose, wide fontanelles, and small mouth [273]. Less frequently, abnormalities of the palmar crease, low hairline, anomalies of the gall bladder or diaphragmatic hernia , and microcephaly have been described [273].


Ophthalmic Manifestations


Microphthalmia is the most common ocular manifestation of trisomy 9 (61 %) [273275]. Bilateral microphthalmia, cataracts, corneal clouding, deep-set eyes and a depressed right globe were described in one live born infant with trisomy 9 [273]. Although not described further, the latter may be related to the facial asymmetry seen in approximately one third of affected babies. Microphthalmia is less frequently seen in patients with mosaic versus non mosaic trisomy 9 [274, 276]. One case reported on the ocular pathology in a patient with mosaic trisomy 9 had sclerocornea, no recognizable anterior chamber, colobomatous ciliary body on one side, and detached and dysplastic retina and atrophy of optic nerve [277].


Ring Chromosome 9



Definition and Epidemiology


This is a rare condition with less than 30 patients ever reported in the literature. Most break points are found in 9p24-p22 and 9q33-q34. Estimated frequency is 1 in 50,000.


Systemic Manifestations


Ring chromosome 9 has been associated with growth defects, failure to thrive, patchy skin pigment changes, developmental delay, facial dysmorphism, microcephaly, genital abnormalities, cardiac malformations and limb and skeletal anomalies.


Ophthalmic Manifestations


Reported ophthalmic findings include upslanting and small palpebral fissures, epicanthal folds and hypertelorism [278].


Chromosome 9 Inversion



Definition and Epidemiology



Systemic Manifestations


There is a report in a 3 month old female with esotropia, nystagmus and optic nerve hypoplasia, associated with inv(9)(p12q13) and facial dysmorphism, including frontal bossing, cupped ears and prominent deep set eyes [279] MRI confirmed an arachnoid cyst in a perimesencephalic cistern with no other brain abnormalities [279]. This inversion can be found in more than 1 % of general population, making this finding most likely a coincidence rather than an effect of the chromosomal abnormality.


Ophthalmic Manifestations


The patient with inv(9)(p12q13) had an MRI that showed optic nerve hypoplasia [279].


Chromosome 10



Deletion 10p



Definition and Epidemiology


10p deletion is a rare chromosomal condition. The deletion results in a variable phenotype depending on the size of the deletion. A frequent breakpoint is 10p13, although the deletion may include only the terminal 10p15 band, or extend towards the centromere to 10p14. Less than 50 cases have been reported.


Systemic Manifestations


Interstitial del(10)(p13) present a facies similar to DiGeorge sequence (more typically associated with del22q11). Other malformations include posterior cleft palate, tracheomalacia, ventricular septal defect, and a small thymus [280]. Finger contractures can also be present. Hypoparathyroidism, sensorineural deafness, and renal dysplasia have also been associated with del(10)(p13) [281]. One case of a de novo del(10)(p11.21p12.1) microdeletion had copper beaten skull (gyral impressions on the inner table of the skull) and pseudoarthrosis of the clavicle [282].

Interstitial del(10)(p11.23p12.1) is associated with developmental delay, mild craniofacial abnormalities, and cryptorchidism [283]. This region involves three genes: MKX, ARMC4, and MPP7. Previous reports suggest that haploinsufficiency of the MKX gene may affect the developmental process during testis migration or serve as a genetic susceptibility locus for cryptorchidism.


Ophthalmic Manifestations


Del(10)(p13) has been associated with down-slanting short narrow palpebral fissures, deep set eyes, epicanthal folds and hypertelorism [281, 284]. Del(10)(p11.21p12.1) has been associated with myopia with astigmatism, optic nerve hypoplasia, abnormal eletroretinogram and delayed visual evoked potential responses [282].


Deletion 10q



Definition and Epidemiology


Deletion (10)(q23.2q24.1) , involving the PTEN gene , can cause a spectrum of phenotypes including PTEN Hamartoma Tumor syndrome , Bannayan-Riley-Ruvalcaba síndrome and Cowden disease . Mutations of this gene are known to cause manifestations including macrocephaly, intellectual disability, mucocutaneous abnormalities, and hamartomatous neoplasms [285].


Systemic Manifestations


Deletion (10)(q23.2q24.1) associated features may include midfacial hypoplasia, prominent forehead, developmental delay and hypotonia. Dermatologic lesions particularly characteristic of Cowden disease include facial tricholemmas in the majority of cases, as well as acral keratosis and papillomas. Skin lesions usually do not occur until adulthood [285].

Patients with del(10)(q26pter) show microcephaly, brachycephaly, broad nasal bridge, malformed ears, webbed neck, micrognathia, congenital heart defects, urinary tract anomalies, hypertonia, respiratory distress, growth retardation and mental delay [286].

A novel interstitial del(10)(q24.3q25.1) is associated with lobar holoprosencephaly, cleft lip and palate, and hypoplastic kidneys [287].


Ophthalmic Manifestations


Hypertelorism and strabismus with del(10)(q11.1q21.1) have been reported [288]. Hypertelorism may be associated with midfacial hypoplasia in del(10)(q23.2q24.1) [285]. Pseudopapilledema is a typical finding of del(10)(q23.2q24.1). Anisometropia has also been associated to this deletion [285]. Patients with del(10)(qter) present hypertelorism, down-slanting palpebral fissure and strabismus [286].


Duplication 10p



Definition and Epidemiology


The majority of duplication 10p cases result from translocation . There are few reports of isolated pure trisomy [289]. A common proximal is 10p11 [289]. Approximately 60 cases have been described in the literature.


Systemic Manifestations


Duplication 10p has a variable clinical spectrum. Hypotonia, high-arched/cleft palate, frontal bossing, clubfoot, and nasal anomalies have been oftenly reported. Dolichocephaly, delayed suture closure, and mouth abnormalities are seen in less than half of cases [289]. Cardiac malformations and cystic dysplasia of the kidney are seen less frequently [289]. Agenesis of the gallbladder can also be present [289]. From all these findings, hypotonia has been associated with isolated trisomy of the largest trisomic segment (10)(p11pter) [289]. High arched/cleft palate and clubfoot are frequently present in pure trisomy .

Common findings in full trisomy 10p include developmental delay, dolicocephaly, low birth weight, ear abnormalities, micrognathia, cleft palate, club foot and renal and cardiac malformations [290]. One case with facio-auriculo–vertebral syndrome and dup(10)(p14p15) had complete absence of external ear, hemifacial microsomia and high arched palate [290].


Ophthalmic Manifestations


Approximately 20 % of trisomy 10p individuals have ocular abnormalities. A common finding is colobomatous microphthalmia [289]. Oculofacial findings, such as epicanthal folds and/or down-slanting palpebral fissures have been reported in about one third [289]. Hypertelorism has been seen in a patients with trisomy 10p [291, 292].


Duplication 10q



Definition and Epidemiology


Proximal 10q duplication is a well-defined, but rare syndrome and is often derived from a balanced translocation in a parent. Frequent breakpoints include 10q11q22 or 10q21q22 regions [293]. Less than 50 cases of duplication 10q have been reported in the literature.


Systemic Manifestations


The partial proximal trisomy 10q consists of mild to moderate developmental delay, growth retardation, microcephaly, prominent forehead, upturned nose, bow-shaped mouth, micrognathia, thick and flat helices of the ears and long, slender limbs. Other findings of dup(10)(q11q22) are anteverted nares, ear pits and/or hearing loss [293]. Duplication size has not been associated to any particular phenotype. A patient with an inverted terminal dup(10)(q25.1qter) had a flat occiput, flat face, small nose and mouth, congenital hip dislocation, abnormal thumbs, developmental delay, microcephaly, and hypotonia [239].


Ophthalmic Manifestations


Dup(10)(q11q22) has been associated to small deep set eyes [293]. Epicanthal folds have been reported in dup(10)(q11.2q22.3) [293], although proximal duplications to q11.2 region has been associated to strabismus. One patient with dup(10)(q11.2q22.3) had downslanting palpebral fissures [293]. Iris coloboma and retinal dysplasia are infrequent findings [293]. Blepharophimosis has also been reported in patients with dup(10)(q21q22) [293]. Dup(10)(q25.1qter) is associated with upslanting palpebral fissures and epicanthal folds [239].


Ring Chromosome 10



Definition and Epidemiology


Ring chromosome 10 is a rare condition, with few cases reported. Breakpoints at p13-15 and q26 have been reported.


Systemic Manifestations


One newborn with ring 10 presented with aganglionic megacolon, renal hypoplasia, stubby nose, long philtrum, micrognathia, ear abnormalities, short neck, pectus excavatum, severe hypotonia , seizures, hypocalcaemia and progressive renal failure [294].


Ophthalmic Manifestations


The patient had down-slanting palpebral fissures, hypertelorism and microphthalmia (no further description is provided) [294].


Chromosome 11



Deletion 11p



Definition and Epidemiology


Wilms tumor, Aniridia, Genitourinary anomalies, and Retardation characterize WAGR syndrome . It is a contiguous gene deletion syndrome at 11p13 region involving PAX6 and extending distally into the Wilms tumor gene , WT1. Patients with deletion of PAX6 and WT1 have a 50 % risk of developing Wilms tumor. The reported prevalence of WAGR syndrome ranges from 1 in 500,000–1,000,000.


Systemic Manifestations


Hypotonia , trigonocephaly, hearing deficits, midline brain anomalies, and minor abnormalities of the fingers have been reported. Patients with del(11)(p) had genitourinary abnormalities, mental retardation, Wilm’s tumor, short neck, dysmorphic facies, ear abnormalities, cranial asymmetry , scoliosis, inguinal hernia, and clinodactyly [295]. Other systemic features are mental retardation, facial asymmetry, asymmetric calcification of coronal sutures, skeletal anomalies, heart defects and anal stenosis [293]. A 1.6 Mb critical region has been described in del(11)(p13) for severe developmental delay and autistic features characteristic of WAGR syndrome [296]. If the deletion does not involve WT1 then there is no risk of Wilm’s tumor .

Potocki-Shaffer syndrome is a contiguous gene deletion syndrome caused by hemizygous del(11)(p11.2p12) and includes multiple exostoses, hypotonia, developmental delay, intellectual disability, micropenis and dysmorphic features. A patient with a 137 kb deletion in the Potocki-Shaffer syndrome interval on 11p11.2 presented with developmental delay and hypotonia , providing a possible critical region for those features [297].


Ophthalmic Manifestations


The most recognized ocular manifestation of del(11)(p13.3) is aniridia which is caused by involvement of the PAX6 gene . Aniridia is a panocular disorder that may present with a any combination of cataracts, macular hypoplasia, glaucoma, keratopathy and nystagmus. Dry eyes and ptosis have also been observed [298]. Isolated ocular disorders associated with PAX6 mutations, such as autosomal dominant keratitis, macular hypoplasia, cataract and Peters anomaly , would not be expected in del(11)(p13.3) as they occur due to point mutations. One group reported aniridia, cataract, nystagmus and gonadoblastoma but no Wilm’s tumor in a patient with del(11)(p12p13) [299]. Severe myopia, strabismus and nystagmus have been associated to 11p deletion syndrome [300]. Del(11)(p15.1p13) has been seen with aniridia, ptosis, cataract, glaucoma, nystagmus and pale optic nerve [295]. A patient with a del(11)(p11.2) was noted to have epicanthal folds [297].


Deletion 11q



Definition and Epidemiology


The eponym Jacobsen syndrome is often used for all cases of terminal 11q deletion with a breakpoint including or distal to 11q23. It has been suggested that deletion of 11q24.1 is critical for the full phenotype [301304]. Although the original report described the deletion in the setting of a familial 11;21 translocation, over 85 % of terminal deletions occur de novo [305], and 15 % cases arise as a result of parental translocations. Jacobsen síndrome has a female predominance of 2:1. Usually, the deletion size varies from 7 to 20 Mb in size but could be as small as 2.9 Mb in some patients. The significance of a breakpoint at 11q23.3 (nearly 80 %) has been attributed to a fragile site (FRA11B) at this locus [306, 307]. It has been suggested that cases presumed to be terminal deletions may have some preservation of telomeric sequences [306, 308]. A frequent translocation also involves a breakpoint at 11q23.3 and 22q11.2 [309]. The incidence of Jacobsen syndrome has been estimated at less than 1 in 100,000 [308]. Fewer than 40 cases of interstitial deletions of 11q have been described. The phenotype tends to be less severe than terminal deletions [310, 311].


Systemic Manifestations


Patients with Jacobsen syndrome present with distinctive clinical findings. Terminal deletions from 11q23 frequently present with developmental delay, trigonocephaly, a flat bulbous nose, depressed nasal bridge, ear abnormalities, micrognathia with or without abnormal palate, carp-shaped mouth (Fig. 6.6), pre- and postnatal growth retardation, cardiac abnormalities, and minor distal limb anomalies or joint contractures [302, 303, 307, 308, 310, 312319]. Transient thrombocytopenia or pancytopenia can also be seen in less than 40 % of cases. The KIRREL3 gene has been proposed as a candidate gene for neurocognitive delay and autism spectrum disorder in the setting of a small deletion of 11q [320]. This is based in a child with clinical manifestations consistent with Jacobsen syndrome who had a 2.899 Mb del(11)(q24.2q24.3). Pseudoachondroplasia was observed in a patient with del(11)(q21q22.2) [312]. Other findings are less commonly seen in patients with Jacobsen syndrome. One case of mosaic del(11)(q21) presented with characteristic findings but also with holoprosencephaly, cyclopia and arhinencephaly [321].

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Fig. 6.6
Girl with Jacobsen syndrome and del(11)(q23.3), having developmental delay, a flat bulbous nose, depressed nasal bridge, and telecanthus (courtesy of Mariana Aracena MD)

About 25 % of patients with Jacobsen syndrome die before 2 years of age [308].

It has been suggested that recurrent respiratory infections could be related to the hematologic abnormalities that are seen in these patients [305, 317, 322] This can be a significant cause of mortality. Other important morbidity associated to death is cardiac abnormalities.

There was an attempt to define the critical regions in patients with terminal deletions including or distal to 11q23, but the findings were not absolute as the particular regions did not have the expected clinical manifestation [308]. Deletion size was correlated with the severity of dysmorphism and developmental delay. Other uncommon findings, such as minor structural brain defects and genitourinary abnormalities are correlated with more proximal deletions [305, 307, 308, 315]. Deafness has been reported in del(11)(q22qter) [322].

Interstitial deletions phenotype is variable. One patient with del(11)(q14q22) [323] had transient hypocalcemia , hypotonia , severe growth and developmental retardation, dolichocephaly, anteverted nares, flat nasal bridge, high palate, carp-shaped mouth, micrognathia, recurrent respiratory infections and a normal immunologic evaluation.

Patients with more distal breakpoints to Jacobsen’s critical region show milder phenotypes [308, 324]. For example, an individual presented with del(11)(q24.2qter), developmental delay minimal structural brain anomalies, but no other systemic findings [324].


Ophthalmic Manifestations


Patients with terminal deletions including 11q23 usually have telecanthus and/or hypertelorism , ptosis, and epicanthal folds [305, 310, 313316, 322, 325, 326]. Hypertelorism can be present when the deletion starts at the 11q24.1 critical region [304]. Bilateral Peters anomaly was reported in an individual with del(11)(q14q22) [325]. Interstitial del(11)(q14q21) has been associated to strabismus, myopia and optic nerve colobomas [327]. One patient reported with subterminal deletion had also exorbitism [310]. Another individual with del(11)(q23) presented with hypoplastic orbital roofs [318], which was previously described [305]. Bilateral optic atrophy has been reported in del(11)(q23q25) [328].

Epicanthus has not been associated to a particular breakpoint [302, 304, 305, 308, 313, 315, 317, 319, 322, 326, 329] whereas ptosis can present in deletions that include 11q23 [302, 305, 308, 313, 319, 322, 326]. The ptosis may be mild, unilateral or bilateral, with or without levator function [314, 318, 330]. Downslanting [307, 317, 322, 329] or upslanting [302, 303, 305, 308, 315, 318, 319, 330] of the palpebral fissures has also been reported. Ectropion has been described in del(11)(q23qter) [308]. Lid colobomas with normal eyes were present in a child with del(11)(q22qter). Short or long eyelashes have been reported in del(11)(q23) as well. Del(11)(q23.3) has been associated to exotropia, hyperopia and chorioretinal coloboma [311].

Other reported ocular abnormalities seen in terminal deletions are unilateral or bilateral coloboma with or without microphthalmia with del(11)(q23) [305, 308, 316, 318, 322, 331], correctopia with del(11)(q23) [313], nuclear cataract del(11)(q23) [305, 331], and persistent pupillary membrane del(11)(q23) [331]. Juvenile glaucoma [305], and strabismus has been associated to del(11)(q23) [308, 317, 318], del(11)(q23.3) [319], and del(11)(q24.1) [308].

Retinal findings are unusual. The first reports of Jacobsen syndrome reports describe a normal fundoscopy [315, 318]. One child with del(11)(q23.3qter) born after a full-term gestation had peripheral avascular temporal retina, temporal dragging of retinal vessels, and peripheral vasculopathy [319]. Familial exudative vitreoretinopathy (FEVR) was suspected. Autosomal dominant FEVR has been mapped to this region (11q13-q23), which is proximal to the breakpoint for terminal deletions [332]. Both the FZD4 and LRP5 genes, which when mutated can result in FEVR, are located in this region.

One patient with interstitial del(11)(q14q22) had telecanthus and bilateral ptosis with normal globe examination [323]. Patients with breakpoints distal to 11q24.1 may have hypertelorism, ptosis, esotropia, and hypertrichosis of the eyebrows [308, 324].


Duplication 11p



Definition and Epidemiology


Complete or partial trisomy of 11p are rare conditions, with few cases reported. Most of cases result from unbalanced segregation of a balanced familial rearrangement [333]. An important breakpoint is 11p12-p13.


Systemic Manifestation


Described clinical manifestations of trisomy 11p are growth retardation, hypotonia/hypertonia, prominent forehead, broad nasal bridge, abnormal ears, cleft lip/ palate, overriding toes, clinodactyly, absent or hypoplastic thumbs, cardiac abnormalities, hernia, omphalocele, urogenital abnormalities, intestinal malrotation and cryptorchidism [333]. Majority of patients usually die early in childhood.


Ophthalmic Manifestation


Patients with trisomy 11p have been associated with different oculofacial findings, such as flat supraorbital ridges, epicanthal folds, hypertelorism , small down-slanted palpebral fissures, as well as other clinical manifestations, including strabismus, nystagmus, anophthalmia, microphthalmia, myopia, hyperopia, eccentric fixation, eccentric pupils, conjunctival telangiectasia, “Brushfield-like” spots, retinal detachment and rod dysfunction [333].


Duplication 11q



Definition and Epidemiology


Partial Trisomy 11q syndrome is a rare disorder. Band q23.3 contains a fragile site that predisposes to breaks and recombination between chromosomes. Few patients with “pure” 11q duplication have been reported.


Systemic Manifestations


Clinical manifestations in individuals with trisomy 11q are prominent occiput, hearing loss, micrognathia, café-au-lait spots, brain abnormalities, inguinal hernia, and thrombocytopenia. One patient with dup(11)(q11q13.3) presented with multiple craniosynostoses, congenital heart defect and developmental delay [334]. Dup(11)(q13.3q11.21) has been observed in individuals with mental retardation, microcephaly, abnormal ears, high arched palate, congenital heart disease and micrognathia [335]. A patient with dup(11)(q22qter) and a phenotype that resembled Pitt-Rogers-Danks syndrome , presented with manifestations not seen in that condition, such as severe kyphoscoliosis, prognathism, severe leg edema, hypertonicity, and spina bifida occulta [336].


Ophthalmic Manifestations


Dup(11)(q13q25) has been associated to bilateral iris coloboma and myopia, dup(11)(q13.5q21) with arched eyebrows, and dup(11)(q11q13.3) with blue sclera, strabismus and nystagmus [334]. Epicanthal folds , short palpebral fissures and strabismus have been seen in patients with dup(11)(q21q23.1) [335], and ptosis with dup(11)(q23) [337]. One case reported with dup(11)(q22qter) had mild ptosis and hypertelorism [336].


Ring 11



Definition and Epidemiology


Reports of ring chromosome 11 are rare. There are cases that resembled Jacobsen syndrome phenotype. Patients usually die early in infancy.


Systemic Manifestations


One case with del(11)(q24qter) had trigonocephaly, heart defects, micrognathia and minor ear anomalies [301], although this breakpoint is distal to Jacobsen’s critical region. Another patient with breakpoints at 11p15 and 11q25 had prenatal growth and psychomotor retardation, micrognathia, arched palate, microbrachycephaly, short nose, low nasal bridge, low-set ears, heart anomaly, genital anomaly, short neck, café au lait spots, hirsutism and deformity of nails, and pancytopenia [338]. Short neck has also been described in del(11)(q23.1qter) [303].


Ophthalmic Manifestations


Narrow downslanting palpebral fissures, telecanthus, epicanthus hypertelorism , telecanthus, and exotropia have been reported [301, 338].


Pericentric Inversion of Chromosome 11



Definition and Epidemiology


This condition is rare, with few cases reported in the literature.


Systemic Manifestations and Ophthalmic Manifestations


One family had pericentric inv(11)(p15:q12). All affected members had congenital glaucoma and two also presented epithelial and stromal corneal opacities with peripheral pannus [339].

A 12 month old boy had inv(11)(p11p23) and sporadic unilateral retinoblastoma. His father had the same chromosomal inversion but no retinal findings [340]. The 11q23 breakpoint has been associated to several malignant hematological diseases and may be relevant in malignant transformations [340]. Chromosome 11 aberrations have been associated with leukemia, Wilms’ tumor, malignant lymphoma and Ewing sarcoma [341].


Chromosome 12



Deletion 12p



Definition and Epidemiology


Monosomy for the distal short arm of chromosome 12 is rare [342].


Systemic Manifestations


A 15 year old patient and his mother had a del(12)(p13.33). After a normal karyotype analysis, FISH study revealed a 1.65 Mb terminal deletion. Clinical manifestations were microcephaly, facial dysmorphism, developmental and growth delay, dental anomalies and digital anomalies. The boy also had ventricular septal defect, attention deficit disorder, kyphoscoliosis and behavioral problems [342].


Ophthalmic Manifestations


The patient with del(12)(p13.33) had deep set eyes and strabismus [342].


Deletion 12q



Definition and Epidemiology


Few cases with deletion of 12q have been reported in the literature [343, 344].


Systemic Manifestations


Del(12)(q12q13.12) has been associated to mental and psychomotor retardation, intrauterine growth retardation, dental abnormalities, micrognathia, cleft palate, low set ears, sparse hair, short and webbed neck, widely set nipples, chest anomalies, mild scoliosis, and clinodactyly of the fifth finger [345]. Del(12)(q15q21.2) has been reported with intrauterine growth retardation, facial dysmorphism, developmental delay, delayed speech, ectodermal abnormalities, cleft palate, micrognathia, sacrococcygeal anomalies, and cardiac and renal anomalies [343]. An individual del(12)(q24.31q24.33) had developmental delay, tracheomalacia, coarse facial features, ambiguous genitalia, hypotonia, and apnea triggered by feeding or airway manipulation [346].

Reported findings of 12q subtelomeric deletions are developmental delay, food seeking behaviour, obesity, abnormal hair whorl pattern, brachydactyly and clinodactyly, short stature, mild dysmorphic facial features, polycystic kidneys and unilateral cryptorchidism [347]. In siblings with del(12)(q13.13q13.2) partially involving the HOXC gene cluster, minor facial dysmorphic features and developmental delay have been reported [348]. Deletion completely the entire HOXC gene cluster have skeletal abnormalities [348]. One girl with del(12)(q24.31) presented with intellectual disability, seizures and facial dysmorphisms [349].


Ophthalmic Manifestations


One case was reported with del(12)(q12q13.12) . The patient had bilateral ptosis, hypertelorism, strabismus, downward slant of the palpebral fissures and epicanthal folds [345]. Del(12)(q15q21.2) has been associated to hypertelorism, downslanted/upslanted palpebral fissures, arched eyebrows and crescent shaped eyes [343]. Short palpebral fissures and ptosis were also reported in a case with del(12)(q24.31q24.33) [346]. In a patient with del(12)(q13.13q13.2) partially involving the HOXC gene cluster, deep eye sets and epicanthal fold have been reported [348].


Duplication 12p



Definition and Epidemiology


Pallister-Killian syndrome (PKS) is a rare, sporadic, condition that often has highly distinctive features. It is caused by mosaic tetrasomy of chromosome 12p often due to a supernumerary isochromosome 12p [350356]. It is a dysmorphic disorder involving most systems, but also has a tissue-limited mosaicism in which most fibroblasts have 47 chromosomes with an extra small metacentric chromosome, while the karyotype of lymphocytes is normal. The grade of mosiacism in peripheral blood does not correlate with severity of the phenotype [353]. Estimated prevalence is 1 in 20,000. About 150 have been reported in the literature [356]


Systemic Manifestations


Patients with PKS present with coarse facial features, broad high forehead with sparse anterior hair, ear abnormalities, macrostomia, and a short broad nose with anteverted nares and a flat bridge [351353]. They also have profound developmental delay, seizures and hypotonia in addition to pigmentary anomalies of the skin [350, 353]. Other features may include anogenital abnormalities, thin upper lip and protruding lower lip, finger anomalies, hearing loss, cleft palate, and hemihypertrophy. Mosaicism may be associated to streaks of hyper/hypopigmentation [351]. If multiple organ malformations are present, patients die in early infancy. Dup(12)(p11.2p13.3) has been reported with craniofacial dysmorphy, cleft palate, mental deficiency, severe mental and motor delay, hypotonia, seizures, corpus callosum agenesis, preaxial polydactyly and diabetes insipidus [355].

One mosaic patient with Pallister-Killian syndrome had a 12p triplication and dysmorphic features, poor tone, respiratory distress, brachycephaly, and premature balding. The tetrasomy of 12p was only diagnosed by cultured skin fibroblasts [357].


Ophthalmic Manifestations


Hypertelorism is a usual feature of PKS [350352]. Approximately half of duplication 12p patients present epicanthal folds [350]. Other lid abnormalities are ptosis, lower lid entropion, and up-slanting or down-slanting of the palpebral fissures. About 30 % of individuals with PKS show sparse hair (particularly bitemporal alopecia), as well as sparse eyebrows. Patients with strabismus usually have exotropia although there are reports of esotropia [350, 352]. Other ophthalmic findings include myopia [350, 352], coloboma [353], cloudy corneas [353] nystagmus [352], patchy fundus hypopigmentation (as an expression of chromosomal mosaicism) [352].

A publication including 59 affected individuals with PKS , showed that 87 % had ophthalmological involvement, (most frequent were up-slanting or down-slanting of the palpebral fissures in 72 %) and other less frequent findings (proptosis, ptosis, epicanthal folds, telecanthus) [356].

One author reported depressed supra orbital ridges, possible microphthalmia, upslanting palpebral fissures and epicanthal folds with dup(12)(p11.2p13.3) [355].

One mosaic patient with Pallister-Killian syndrome had a 12p triplication and upslanting palperbral fissures [357].


Duplication 12q



Definition and Epidemiology


Duplication 12q is a rare condition with few cases reported in the literature.


Systemic Manifestations


One patient with a phenocopy of Wolf-Hirschhorn syndrome was reported with dup(12)(q13.3q14.1). Clinical manifestations were hypotonia, weak cry, developmental delay, tall forehead, receding anterior hair line, prominent glabella, highly arched eyebrows, hypertelorism , wide palperable fissures, prominent eyes, and a bulbous nasal tip with wide nasal bridge suggesting the Greek warrior helmet facies [358]. Dup(12)(q13.2q13.3) was reported in a patient that presented dysmorphism , developmental delay, seizures and hypospadias [359].

Low set ears, downturned mouth, micrognathia, short neck with loose skin at the nape, wide set nipples, palmar crease, subluxation of hips, sacral dimple, cryptorchidism, heart defects, and ulnar deviation of hands with clinodactyly have been reported with dup(12)(q24.1q24.5) [360].


Ophthalmic Manifestations


Epicanthal folds [359] and hypertelorism have been reported with dup(12)(q24.1q24.5) [360].


Trisomy 12



Definition and Epidemiology


Few cases of live born patients with trisomy 12 have been reported.


Systemic Manifestations


One case had dysmorphic features including malar hypoplasia, linear pigmented streaks on the forearms and lower legs , normal mental development, motor delay, short stature, scoliosis, and cardiac anomalies. Other reported features were infertility and situs inversus [361] Chromosome analysis of blood showed low incidence of trisomic cells (0.4 %) but cultured fibroblast presented trisomy 12 in 9 % and 13 % of cells from two skin biopsies [361].


Ophthalmic Manifestations


No ocular findings were reported in this case [361].


Chromosome 13



Deletion 13q



Definition and Epidemiology


The long arm of Chromosome 13 has several tumor suppressor genes, many of them involved in different types of malignancies such as breast cancer (BRCA2), alveolar rhabdomyosarcoma (FOXO1A) and retinoblastoma (RB1). 13q deletion has a wide clinical spectrum, and therefore, there has been a special interest in defining genotype-phenotype correlations. Depending on the size and position of the deleted region, partial deletion of 13q leads to distinct phenotypes [362364]. The q32 region is a reference point for is categorizing 3q deletions into 3 groups: Group 1, proximal deletions usually not involving 13q32; Group 2, distal deletions involving at least part of 13q32; and, Group 3, with more distal deletions involving 13q33-34. In addition, some of the phenotypic differences may also be due to imprinting [364].


Systemic Manifestations


Various phenotypic findings can be mapped to deleted loci: short stature with del(13)(q31.3), microcephaly with del(13)(q33.3q34), cortical development malformations with del(13)(q33.1qter), Dandy Walker malformation with del(13)(q32.2q33.1), corpus callosum agenesis with del(13)(q32.3q33.1), meningocele/encephalocele with del(13)(q31.3qter), cleft lip/palate, lung hypoplasia and thumb aplasia/hypoplasia with del(13)(q31.3q33.1) and distal limb anomalies with del(13)(q31.3q33.1). Patients with del(13)(q21qter) showed similar facial dysmorphic features. Prominent nasal collumella is mapped between [13](q31.3q33.3), and micrognathia between [13](q21.33q31.1) [363].

In Group 1 patients, there is mild or moderate mental retardation, growth retardation, hypotonia , and variable minor anomalies although microcephaly may also occur. In addition, several gastrointestinal anomalies have been reported, including Hirschprung disease with del(13)(q13q22) and del(13)(q14.1q22.3), jejunal atresia with del(13)(q14q21), agenesis of colonic mesenteries with del(13)(q14q31), duodenal and jejunal atresia with del(13)(q21.2q22), and jejunal and ileal atresia with del(13)(q14) [365367].

In Group 2, there can be one or more major malformations, in particular microcephaly, brain malformations such as anencephaly or encephalocele, cardiac malformations, absent distal limb abnormalities, and gastrointestinal tract malformations. Posterior encephalocele, holoprosencephaly, absent thumbs and genitourinary tract malformations have also been reported [364]. In Group 3, there is severe mental retardation without major malformations and usually without growth retardation.

Thumb and /or big toe anomalies are associated with deletion of 13q32 as is Hirschsprung disease . It appears that there may be more than one locus on 13q that affect limb development and colonic innervation. The EDNRB gene , which when mutated causes recessive Hirschprung disease, is located at 13q22. Minor dysmorphic abnormalities such as large ears, beaked nose, facial asymmetry, and protruding upper incisors occur in patients from both groups 2 and 3 [364].


Ophthalmic Manifestations


Retinoblastoma is caused by inactivation of the RB1 gene , a tumor suppressor located on 13q14.2 region. Patients with a 13q deletion involving this region often have pleiotropic manifestations. Group 1 have minor anomalies such as hypertelorism and iris heterochromia with or without retinoblastoma. Patients with Moebius syndrome with del(13)(q12.2q13), Axenfeld-Rieger spectrum with del(13)(q14), retinoblastoma with del(13)(q14.2), and Wilson disease with del(13)(q14.3q21.1) have been reported [365]. Strabismus has been observed with del(13)(q12.3) [366]. Hypertelorism, deep set eyes, strabismus and hypermetropia have been reported with del(13)(q32.3qter) [363]. Bilateral retinoblastoma (Fig. 6.7) have been reported with del(13)(q13q22) and del(13)(q14.1q22.3), bilateral retinoblastoma with del(13)(q14q21), unilateral retinoblastoma with del(13)(q14q31), bilateral optic nerve hypoplasia with del(13)(q21.2q22), and bilateral microphthalmia with del(13)(q14) [367]. Group 2 present minor anomalies including hypertelorism , down-slanting of the palpebral fissures and major ocular malformations including fixed and dilated pupils, microphthalmia and retinal coloboma have been reported [364] Group 3 present minor oculofacial findings, such as hypertelorism .

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Fig. 6.7
Patient with del(13)(q12.3q22) and bilateral low grade retinoblastoma, hypotonia and partial dysgenesis of corpus callosum (courtesy of Diego Ossandón MD and Federica Solanes MD)

Large deletions involving 13q have also been observed. Rieger syndrome , nasolacrimal duct obstruction and mild dysplastic optic nerve heads have been associated with del(13)(q14q31). Optic nerve hypoplasia and retinal dysplasia have also been described [368] A patient with del(13)(q14q32) had bilateral microphthalmia, bilateral iris and fundus coloboma, and bilateral retinoblastoma. In a large series of retinoblastoma patients (n = 1265) only 0.3 % had microphthalmia [369]. Iris heterochomia, iris stromal hypoplasia and depigmentation of retinal pigment epithelium were seen in a case with del(13)(q21.1q31.3) [370]. One patient with del(13)(q21.2q32) was reported with features of Waardenburg syndrome [371]. Anophthalmia/microphthalmia spectrum has been associated to del(13)(q31.3qter) [363].


Duplication 13q



Definition and Epidemiology


Partial 13q duplication cases can be classified as either proximal (pter-q22.1) or distal (qter-q22.2) Duplication of the proximal part of chromosome 13 is more phenotypically variable. Few cases have been reported.


Systemic Manifestations


Partial trisomy for the segment 13pter-q14 is characterized by a nonspecific pattern of malformations. Patients with partial trisomy for the distal segment of 13q have severe mental deficiency and a characteristic facies. One patient with dup(13)(q31.3q32.3) had developmental delay, autistic spectrum disorder, unexplained muscle cramp, dysmorphic appearance, elongated columella, bilateral low-set ears, short-webbed neck. One author reported a female patient with tetrasomy 13q mosaicism in the form of an inverted dup(13)(q21). The patient had developmental delay, pigmentary abnormalities known as phylloid hypomelanosis and precocious puberty [372].


Ophthalmic Manifestations


One patient with dup(13)(q31.3q32.3) presented elongated and wide palpebral fissures. A case with 13q mosaicism had hypertelorism [372].


Trisomy 13



Definition and Epidemiology


Trisomy 13, also known as Patau syndrome , has a significant frequency of congenital ocular malformations at birth. The incidence of trisomy 13 in live born infants is approximately 1 in 20,000 [373375]. Like many other trisomies, increased maternal age is associated. Trisomy 13 mosaicism is characterized by a less severe phenotype with a wide variation of clinical findings.


Systemic Manifestations


Central nervous system anomalies have been described in up to 50 % of patients [376]. Holoprosencephaly is the single most common cephalic disorder [376]. Seizures and severe mental deficiency are also very common. Abnormal facies and head and neck anomalies can be seen in up to 90 % of patients (Fig. 6.8). Microcephaly is frequently observed, particularly with wide sagittal suture and fontanelles. Cardiovascular abnormalities occur in about 80 % of patients, cleft lip and/or palate in 60 %–80 % of cases, and external ears anomalies with/without deafness in nearly 50 %. Capillary hemangiomas, particularly affecting the forehead, have been observed. Localized scalp defects in the parieto-occipital area may be seen. Other frequent reported findings infants include intrauterine growth retardation, polydactyly, cryptorchidism , bicornuate uterus, a single umbilical artery, and persistence of embryonic and/or fetal hemoglobin. Polycystic kidneys and other genitourinary abnormalities have been described.

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Fig. 6.8
Patient with trisomy 13 mosaicism. Note mild facial findings such as, low-set ears and capillary hemangioma

Full trisomy 13 is usually a lethal condition. One study reported that 28 % of surviving newborn infants die in the first week of life, 44 % within 1 month and 86 % in infancy [377]. Another study reports a median of survival of 10 to 26 days [378, 379], with a 3 month survival of 18 % [379]. One year survival for live births with trisomy 13 mosaicism was 80 % and for those with partial trisomy 13 was 29 % [379]. One child survived 146 months [380]. Although there is a very high frequency of congenital heart disease, these malformations are usually not lethal. One publication suggested that primary apnea was the most common cause of death [375].


Ophthalmic Manifestations


Ocular malformations have been found in almost 80 % of patients with trisomy 13 [381, 382]. These abnormalities are frequently severe and incompatible with vision. Because of the poor systemic prognosis, treatment of ocular conditions has to be carefully pondered.

Bilateral manifestations are seen in nearly all children. Trisomy 13 is the most common chromosomal aberration associated with microphthalmia or anophthalmia [276]. Although the first report describes apparent anophthalmia [383], severe microphthalmia as colobomatous microphthalmia is a known presentation of trisomy 13, in up to 60 % [378, 384]. Intraocular cartilage or other choristomatous tissue may be associated to iris and ciliary body coloboma. Anterior segment malformations are also common, occasionally similar to Axenfeld-Rieger spectrum or less frequently, Peters anomaly. Secondary glaucoma to angle dysgenesis may also occur. The cornea can be vascularized and with dysgenesis of Descemet or Bowman membranes. Cataract is a frequent feature. Optic nerve hypoplasia has also been described. Retinal dysplasia can be present, with features that include folds or intraocular cartilage. Full trisomy 13 is often associated with persistent ocular fetal vasculature [384]. A premature infant with trisomy 13, confirmed by karyotype analysis had microphthalmia, extensive colobomata, retinal dysplasia, and a heterotopic ciliary body [381].

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Jul 20, 2017 | Posted by in OPHTHALMOLOGY | Comments Off on Oculofacial Manifestations of Chromosomal Aberrations
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