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Reported ocular findings in the 22q11.2 deletion syndrome (which encompasses the phenotypes of DiGeorge, velocardiofacial, and Takao (conotruncal-anomaly-face) syndromes) have included posterior embryotoxon (prominent, anteriorly displaced Schwalbe’s line at the corneal limbus or edge), retinal vascular tortuosity, eyelid hooding, strabismus, and astigmatism. We present seven 22q11.2 patients from multiple centers with sclerocornea, an eye finding previously unreported in the literature. Four boys and three girls were identified with sclerocornea, systemic DGS/VCFS findings, and fluorescence in situ hybridization (FISH)-confirmed microdeletion at chromosome 22q11.2. FISH diagnosis was perinatal in six patients but at 2 years of age in one child. Sclerocornea was bilateral in five patients. Findings included descemetocele (five eyes), microophthalmos (one eye), iridocorneal adhesions (one bilateral case), and severe anterior segment dysgenesis (one eye). Two patients underwent bilateral corneal transplantation; another two were scheduled for possible unilateral transplant. Sclerocornea is a static congenital condition in which the cornea is opaque and vascularized and resembles the sclera. The novel finding of sclerocornea suggests that a genetic locus at 22q11.2 may be involved in anterior segment embryogenesis. In most of our patients, the diagnostic process was underway, but in one patient 22q11.2 deletion was not suspected until after the child had already been undergoing treatment for sclerocornea for 2 years. Sclerocornea should be added to the clinical manifestations of the 22q11.2 deletion syndrome. Ophthalmologists diagnosing sclerocornea in children with systemic findings suggestive of 22q11.2 deletion should ensure appropriate genetic referral.
The chromosome 22q11.2 deletion syndrome encompasses phenotypes previously called DiGeorge syndrome, velocardiofacial (Shprintzen) syndrome, Conotruncal anomaly face (Takao) syndrome, and some cases of autosomal dominant Optiz G/BBB syndrome and Cayler cardiofacial syndrome. [Driscoll et al., 1993; Wilson et al., 1993; Matsuoka et al., 1994; McDonald-McGinn et al., 1995; LaCassie and Arriaza, 1996; Wulfsberg et al., 1996; McDonald-McGinn et al., 1997a,b, 1999]. The 22q11.2 deletion syndrome occurs in about 1 in 4,000 live births. [Devriendt et al., 1998; Oskarsdottir et al., 2004] and is a contiguous gene deletion syndrome detected by fluorescence in situ hybridization (FISH) in 95% of the cases.
The clinical manifestations are varied and include congenital heart malformations (74%), in particular conotruncal malformations (tetralogy of Fallot, interrupted aortic arch, ventricular septal defect, and truncus arteriosus), palatal abnormalities (69%) such as velopharyngeal incompetence, submucous cleft palate and overt cleft palate, characteristic facial features in the majority of Caucasians (e.g., overfolded/squared-off helices, bulbous nasal tip, small mouth and chin), learning difficulties (70–90%), and thymus and parathyroid hypoplasia with immune (T-cell) deficiency (77%) and hypocalcemia (50%). [McDonald-McGinn et al., 1996,1997a, 1999a, 2001; Sullivan, 2004; Bassett et al., 2005; McDonald-McGinn et al., 2005, 2006] Other findings include feeding problems, growth hormone deficiency, autoimmune disorders, hearing loss, seizures, and renal, musculoskeletal, and laryngotracheoesophageal abnormalities.
Ophthalmologic findings in the 22q11.2 deletion syndrome have included posterior embryotoxon (a prominent, anteriorly displaced Schwalbe’s line at the corneal limbus or edge), retinal vascular tortuosity, eyelid hooding, strabismus, and astigmatism. [Fitch, 1983; Shprintzen et al., 1985; Beemer et al., 1986; Mansour et al., 1987; Ryan et al., 1997; Forbes et al., 2006] We present a multicenter case series of seven patients with the 22q11.2 deletion syndrome and sclerocornea, a finding previously unreported in the literature.
Clinical data were collected on seven patients with sclerocornea and the 22q11.2 microdeletion diagnosed by FISH presenting to the Children’s Hospital of Philadelphia, Philadelphia, PA; Children’s Healthcare of Atlanta at Egleston, GA; the University of Iowa, Iowa City, IA; the Lucile Salter Packard Children’s Hospital, Palo Alto, CA; and the Marshfield Clinic, Saint Joseph’s Hospital, Marshfield, WI. All patients were examined by an ophthalmologist. FISH diagnosis was carried out using the N25 probe or the TUPLE 1 probe in the chromosome 22q11.2 region to demonstrate a single 22 homolog signal, contrasted with a control probe, for example, ARSA in 22q12.3, present on both chromosome 22 homologs.
The study was approved by the Institutional Review Board of the University of Pennsylvania/Children’s Hospital of Philadelphia as part of studies on patients with the Chromosome 22q11.2 deletion syndrome, and the study data were handled in compliance with HIPAA regulations.
Four boys and three girls were identified with sclerocornea, systemic 22q11.2 deletion findings, and FISH-confirmed microdeletion at 22q11.2 (Table I). Diagnosis of the 22q11.2 deletion was perinatal in six patients and at 2 years of age in one patient (Patient 3), who had undergone corneal transplantation earlier in life and presented with a perforated corneal ulcer requiring surgical repair, after which a post-operative fever work-up led to the discovery of systemic abnormalities and the 22q11.2 microdeletion. Sclerocornea was bilateral in five patients. Additional ocular findings included descemetocele (five eyes), microophthalmos (one eye), iridocorneal adhesions (one bilateral case), and severe anterior segment dysgenesis (one eye). Three patients underwent corneal transplantation (two bilateral, one unilateral), and another patient was scheduled for a possible unilateral transplant. Figure 1
Sclerocornea is a congenital, non-progressive, non-inflammatory condition in which one or both corneas demonstrate some degree of opacification coupled with flattening of the normal corneal curvature. In all patients, opacification is more pronounced in the corneal periphery with varying involvement of the visual axis, in contrast with the primarily central opacification found in Peter anomaly. Sclerocornea is most commonly bilateral and asymmetric, although unilateral cases have been reported. [Krachmer et al., 1997] Flattening of corneal curvature may be severe; indeed, corneal curvatures equal to or less than scleral curvature are pathognomonic for the condition. [Desvignes et al., 1967] The association between opacification and flattening is so strong that most authors consider sclerocornea and cornea plana to be phenotypic manifestations of the same condition.
Sclerocornea may be sporadic or familial, without gender predilection, and when inherited, the recessive form typically demonstrates a more severe phenotype than the dominant form. [Bloch, 1965; Howard and Abrahams, 1971; Eliott et al., 1985; Tahvanainen et al., 1995] Associated genetic loci that have been reported include Xp22.31 when sclerocornea is present with microphthalmia and dermal aplasia as part of the MIDAS syndrome [Happle et al., 1993]; 18q21.3 in a 12-year-old child with autism, anophthalmia, microphthalmia, and sclerocornea and a mutation in the RAX gene [Voronina et al., 2004]; and 6p22-24 in a dysmorphic infant with an interstitial deletion [Moriarty and Kerr-Muir, 1992].
The finding of sclerocornea in association with the chromosome 22q11.2 deletion syndrome suggests that a genetic locus at 22q11.2 influences anterior segment embryogenesis. The anterior segment of the eye includes the cornea, anterior chamber, iris, lens, ciliary body, and related structures. The embryologic basis for sclerocornea lies in the absence of normal migration of neural crest cells between weeks seven and ten of gestation. Lack of migration results in failure of formation of the limbal anlage, resulting in absence of the limbus, lack of differentiation between corneal and scleral architecture, and development of corneal opacification and flattening. [Friedman et al., 1975; Townsend, 1998] The link between the 22q11.2 deletion and anterior segment embryogenesis is also supported by a recent report of Peter anomaly in a patient with a 22q11.2 deletion. [Casteels and Devriendt, 2005] Further, posterior embryotoxon has been reported to be the most common ocular finding in patients with the chromosome 22q11.2 deletion syndrome, present in half of patients. [Forbes et al., 2006] Posterior embryotoxon is characterized by an anteriorly displaced and thickened Schwalbe’s ring, which is the anterior boundary of the trabecular meshwork and the posterior boundary of Descemet’s membrane, and is seen at greater frequency in patients with anterior segment dysgenesis anomalies (e.g., Axenfeld anomaly and Rieger syndrome). It is possible that 22q11.2 and the other genetic loci reported in association with sclerocornea play multifactorial and interrelated roles in neural crest migration and differentiation.
Based upon our report of isolated cases from multiple hospitals, it is not possible to accurately report the prevalence of sclerocornea in patients with the 22q11.2 deletion syndrome. However, sclerocornea is likely to be infrequent, as it was not an identified ocular finding in a recent series of 90 patients with the 22q11.2 deletion at the Children’s Hospital of Philadelphia. [Forbes et al., 2006]. Extrapolating upon the number of patients with 22q11.2 deletion syndrome examined by one of the ophthalmologist authors (B. J. F.), we estimate the prevalence of sclerocornea to be approximately 1 in 240 patients.
Treatment of sclerocornea is often complex, and outcomes may be poor. Correction of refractive errors, monitoring and treatment of amblyopia, clearing of central opacification via corneal transplantation, treatment of glaucoma, and management of other associated ocular abnormalities result in lifelong relationships with many different ophthalmic subspecialists. Allografts have a high rate of rejection in the cases of sclerocornea, especially when performed in the pediatric population, and the treatment of glaucoma in these cases is most often surgical due to abnormalities of the anterior chamber angle, which contains the aqueous outflow tracts of the eye. [Gregersen, 1981; Kampik et al., 1986] In six of our seven reported patients, the 22q11.2 genetic diagnostic process was already underway. However, in one patient (Patient 3) the 22q11.2 deletion was not suspected until after the child had already been undergoing treatment for sclerocornea for 2 years, including bilateral corneal transplantation. The delay in diagnosis in this case underscores the importance of recognizing this new syndromic association for sclerocornea and ensuring that pediatric ophthalmologists ask appropriate questions to determine if a systemic evaluation is indicated. Sclerocornea should be added to the clinical manifestations of the 22q11.2 deletion syndrome, and ophthalmologists diagnosing sclerocornea in children with systemic findings suggestive of 22q11.2 deletion should ensure appropriate genetic referral.
Heed Ophthalmic Foundation.
Data from this study were presented at the American Association of Pediatric Ophthalmology and Strabismus Annual Meeting in Keystone, Colorado, March 2006 and the Fifth International 22q11.2 Deletion Syndrome Conference, Marseilles, France, July 2006.