Blepharophimosis syndrome is a recognizable ocular phenotype (blepharophimosis, telecanthus, ptosis, and epicanthus inversus) caused by heterozygous (dominant) intragenic mutation in FOXL2 (chromosome 3q23), which can also cause premature ovarian failure. A deletion that involves not only FOXL2 but also adjacent genes can result in additional clinical features (“blepharophimosis syndrome plus”). The authors describe a boy with blepharophimosis syndrome plus from a de novo heterozygous 3q22.3-q24 11.2 Mb microdeletion.
A 3-year, 4-month-old boy, the second child of non-consanguineous parents, was referred for evaluation of strabismus noted since soon after birth. There was no family history for strabismus or significant congenital abnormality. Soon after birth, he underwent cardiac and neurological evaluation because of perceived dysmorphism; reports were not available, but, according to the parents, cardiac imaging was normal and neuroimaging showed a “benign brain cyst” for which neither treatment nor follow-up were recommended. In the first year of life, he underwent bilateral surgery for talipes equinovarus (club foot). In the second year of life, he underwent bilateral eyelid surgery (frontalis sling) for congenital ptosis.
Examination at 3 years, 4 months old revealed a cheerful child who was small for his age. Height was 92 cm (25th percentile), weight was 11.15 kg (10th percentile), and head circumference was 44 cm (< 3rd percentile).1 He was developmentally delayed in that he had limited speech. Facies were consistent with those of blepharophimosis syndrome (Online Mendelian Inheritance in Man [MIM] #110100); in addition, there was microcephaly and micrognathia (Figure 1). Vision was central, steady, and maintained in either eye. There was an esophoria at near of 12 prism diopters. Ocular motility was significant for bilateral limited elevation and abduction (−3 for both), which persisted with Doll’s head maneuvering (Figure 1). Bell’s phenomenon (ie, elevation of the eye while the examiner forces the eyelids open and the patient attempts to close them) could not be assessed accurately because of cooperation issues. Anterior segment and fundus examinations were unremarkable. Cycloplegic refraction with cyclopentolate 1% was −4.50 +1.00 × 180 in the right eye and −4.50 +2.00 × 180 in the left eye. Fundus examination was unremarkable.
In primary position, blepharophimosis, telecanthus, ptosis, and epicanthus inversus can be appreciated. In side profile, the child’s micrognathia can be appreciated. He attempted to look to his right in the side profile image, but he was unable.
Because a chromosomal deletion encompassing FOXL2 (MIM*605597) was suspected, a molecular karyotype (ie, array comparative genomic hybridization [CGH]) was performed on the boy and his parents. DNA was extracted from the patient and his parents’ peripheral blood using a commercially available DNA isolation kit (FlexiGene DNA Kit, Qiagen, Limburg, The Netherlands), according to the manufacturer’s instructions. Molecular karyotyping was performed using Agilent Human Genome CGH 244A (Agilent Technologies, Santa Clara, CA), according to the manufacturer’s instructions. Genomic positions were defined using NCBI37/hg19. Copy number variations were considered if at least five contiguous oligonucleotides presented an abnormal log ratio. To identify microdeletions and microduplications, high-resolution array-CGH was performed for the patient and his parents. This revealed a 3q22.3-q24 microdeletion of 11.2 Mb between oligomeres 136,190,357 bp and 147,409,802 bp, which was not detected in the parents (Figure 2). The deleted region encompasses 54 genes, among them FOXL2, ATR (MIM *601215), ZIC1 (MIM *600470), and ZIC4 (MIM *608948) (Figure 3). In addition, a duplication of 53 kb in 22q12.3 between oligomers 33,903,854 bp and 33,956,620 bp, affecting intron 6 of the gene LARGE (MIM *605445), was detected in the patient and father, who was asymptomatic.
(A) A scatterplot view of chromosome 3 shows the deletion in 3q22.3-q24. The region is surrounded by a dotted blue box. (B) A zoomed-in gene view of the 11.2 Mb deletion.
A screenshot of the UCSC Genome Browser (GRCh37/hg19) Assembly (http://genome.ucsc.edu/cgi-bin/hgGateway) indicates the deleted genes in the region 3q22.3-q24. The red bar on top corresponds to the size of the deletion.
In addition to having classic features of blepharophimosis syndrome, this child was small, developmentally delayed, and had microcephaly, micrognathia, talipes equinovarus, and limited ocular motility. Other than limited ocular motility, these additional clinical features have been previously noted in children with blepharophimosis plus syndrome.2 Molecular karyotyping confirmed a de novo heterozygous deletion that included FOXL2 and adjacent genes, suggesting that one or more genes in the deleted region could have a role in ocular motility.
Whereas strabismus has been reported in up to 20% of cases of blepharophimosis syndrome,3 incomitant strabismus is not typical. There is one case report of a child with blepharophimosis syndrome related to an intragenic FOXCL1 duplication who also had bilateral Duane’s syndrome.4 We do not consider the clinical motility phenotype of the current patient to be Duane’s syndrome because of concurrent vertical gaze limitation and the absence of palpebral fissure narrowing during adduction; however, the underlying etiology is likely the same (ie, congenital cranial dysinnervation disorder).5 Duane’s syndrome is the most common congenital cranial dysinnervation disorder and recent reports have highlighted that high-resolution molecular karyotyping can reveal chromosomal copy number variations in syndromic forms.6–8
The current case is an example of a continuous gene syndrome, in which multiple unrelated genes are affected by a chromosomal abnormality that is associated with a complex phenotype.9,10 Contiguous gene syndrome is sometimes also termed “microdeletion syndrome,” which emphasizes that the affected chromosomal segment is often small on a cytogenetic scale.11 When an ophthalmic phenotype known to be associated with autosomal dominant single gene mutation (eg, blepharophimosis syndrome) occurs with additional clinical findings outside of those associated with the classic ophthalmic phenotype, a contiguous gene syndrome should be suspected.9,10 Genetic copy number analysis is needed to molecularly confirm such cases because standard genetic sequencing of the gene associated with the ophthalmic phenotype would be misleadingly normal if the gene is completely deleted.12 With the advent of high-resolution molecular karyotyping, an increasing number of contiguous gene syndromes are being recognized, particularly in patients with developmental delay.13 Virtually any gene associated with autosomal dominant disease can be part of a contiguous gene syndrome. Other than blepharophimosis syndrome plus, two of the more common contiguous gene syndromes in ophthalmology occur in association with aniridia (11p13; WAGR syndrome; MIM #194072) and retinoblastoma (13q14; chromosome 13q14 deletion syndrome; MIM #613884).
It is important to note that not all gene deletions are pathogenic. Although certain gene deletions clearly cause disease, all normal individuals have some degree of copy number variation.14 It can thus be challenging to determine in contiguous gene syndromes exactly which gene deletions are responsible for additional clinical features, especially when multiple genes are affected. In the current case, 53 known genes adjacent to FOXL2 are in the deleted region (Figure 3). It is unclear which of these could be associated with normal ocular motility. Other than FOXL2, genes in this region that, when deleted, have most clearly been implicated in additional phenotypic features of blepharophimosis plus syndrome include ATR, ZIC1, and ZIC4. ATR is important for cell cycle checkpoint signaling and DNA repair, and heterozygous deletion of the gene seems to cause developmental delay and microcephaly.15ZIC1 and ZIC4 are cerebellar zinc finger protein genes and their deletion is correlated with Dandy–Walker syndrome and ventricular enlargement,16 one or both of which may explain the benign “brain cyst” that was previously diagnosed in our patient but for which no report was available. Regarding contribution of the duplication in the current patient to his motility phenotype, the same duplication was also present in his unaffected father and thus probably was an unrelated variant; however, we cannot rule out the possibility that it had an effect that interacted with the deletion in the patient, thereby having some contribution to the motility phenotype.
The eight previously published cases of blepharophimosis plus syndrome that underwent high-resolution molecular karyotyping and were confirmed to be associated with heterozygous interstitial deletions of 3q22-23 were summarized by Brett et al.2 The authors highlighted clinical features other than those associated with blepharophimosis syndrome alone, such as microcephaly, micrognathia, and cardiac abnormalities. Limited ocular motility was not mentioned, even though most of these cases had a microdeletion that overlapped with the deletion in the current case.2 However, ocular versions were probably not carefully assessed in these previously published cases, which appeared mostly in the genetics literature,2 and thus limited ocular motility may have been overlooked. We encourage careful ocular motility assessment and high-resolution molecular karyotyping in children with blepharophimosis syndrome plus to assess whether limited ocular motility is a recurrent feature and to further phenotype–genotype correlations.
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- Brett MS, Ng IS, Lim EC, et al. De novo 3q22.1 q24 deletion associated with multiple congenital anomalies, growth retardation and intellectual disability. Gene. 2013;517:82–88. doi:10.1016/j.gene.2012.12.082 [CrossRef]
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- Gutowski NJ, Bosley TM, Engle EC. 110th ENMC International Workshop: the congenital cranial dysinnervation disorders (CCDDs). Naarden, The Netherlands, 25–27 October, 2002. Neuromuscul Disord. 2003;13:573–578. doi:10.1016/S0960-8966(03)00043-9 [CrossRef]
- Abu-Amero KK, Kondkar AA, Al Otaibi A, et al. Partial duplication of chromosome 19 associated with Syndromic Duane Retraction Syndrome [published online ahead of print August 19, 2013]. Ophthalmic Genet.
- Abu-Amero KK, Bosley TM, Kondkar AA, Oystreck DT, Khan AO. CCDD phenotype associated with a small chromosome 2 deletion [published online ahead of print January 29, 2014]. Semin Ophthalmol. 2014. doi:10.3109/08820538.2013.874474 [CrossRef]
- Abu-Amero KK, Kondkar AA, Oystreck DT, Khan AO, Bosley TM. Microdeletions involving chromosomes 12 and 22 associated with Syndromic Duane Retraction Syndrome [published online ahead of print May 27, 2014]. Ophthalmic Genet.
- Schmickel RD. Contiguous gene syndromes: a component of recognizable syndromes. J Pediatr. 1986;109:231–241. doi:10.1016/S0022-3476(86)80377-8 [CrossRef]
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- Shaffer LG, Bejjani BA, Torchia B, Kirkpatrick S, Coppinger J, Ballif BC. The identification of microdeletion syndromes and other chromosome abnormalities: cytogenetic methods of the past, new technologies for the future. Am J Med Genet C Semin Med Genet. 2007;145C:335–345. doi:10.1002/ajmg.c.30152 [CrossRef]
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- Grinberg I, Northrup H, Ardinger H, Prasad C, Dobyns WB, Millen KJ. Heterozygous deletion of the linked genes ZIC1 and ZIC4 is involved in Dandy-Walker malformation. Nat Genet. 2004;36:1053–1055. doi:10.1038/ng1420 [CrossRef]