Congenital glaucoma as a presenting feature of Rubinstein-Taybi syndrome in an infant with a novel pathogenic variant in the CREBBP gene

Abstract

Rubinstein-Taybi syndrome, also known as broad thumb-hallux syndrome, is a rare autosomal dominant genetic disorder. This multiorgan syndrome is linked to a pathogenic mutation in the CREBBP or EBP300 genes.

We present a patient with a hitherto unreported constellation of anterior segment abnormalities, including congenital glaucoma, congenital corneal keloid, cataract, and distinct facial and systemic features including a high-arched palate, low-set posteriorly rotated ears, Café-au-lait spots on the back, broad terminal phalanges of hands and feet, and bilateral cryptorchidism. The characteristic dysgenetic angle features and ultrasound biomicroscopic findings described in this case report show the occurrence of concomitant congenital keloid with glaucoma.

Genetic testing revealed a heterozygous one-base pair duplication in exon 3 of the CREBBP gene (c.886dupC), a novel frameshift pathogenic mutation in the CREBBP gene that has not been previously reported in a clinical setting.

Background

Rubinstein-Taybi syndrome (RSTS) (OMIM#180849) is a rare autosomal dominant genetic disorder, with a reported prevalence of 1:125 000 live births. This multisystem genetic disorder is characterised by intellectual disability, distinctive facial features, dental and skeletal malformations, broad terminal phalanges of hands and foot, ocular abnormalities, undescended testes in males, and congenital cardiac and kidney disorders. Most patients present during the neonatal period (86%), with 69% during the first 24 hours of life. Prolonged hospital stay is typical.¹ The most frequently reported ocular features include down-slanted palpebral fissures, coloboma, nasolacrimal duct obstruction, ptosis and corneal abnormalities, including keloids.^2–4

We describe a patient with a constellation of anterior segment abnormalities, including congenital glaucoma, congenital corneal keloid, cataract and the first clinical report of a distinct frameshift variant in the CREBBP gene.

Case presentation

An infant was brought by his parents with complaints of a corneal opacity noticed since birth. He also had feeding difficulties with recurrent pneumonia, which may have delayed the referral. The birth and antenatal history were uneventful, with no similar family history. There was no history of ocular trauma or infection.

Ocular examination revealed telecanthus, epicanthus, bilateral buphthalmos (more prominent in the right eye) and a well-circumscribed raised corneal opacity with a prominent vessel in the left eye (figure 1, top left). B-scan ultrasonography of the left eye showed an echo-free vitreous cavity with a cupped optic disc.

Figure 1.

Top left: Ocular features showing telecanthus, epicanthus, bilateral buphthalmos, a well-circumscribed corneal opacity in the left eye. Top right: low set posteriorly rotated ears. Bottom left: broad halluces. Bottom middle: broad thumbs, Bottom right:Cafe-au-lait spots on the back (arrow)

On systemic evaluation, he also had frontal bossing, a depressed nasal bridge, long philtrum, small upper lip, high-arched palate, low-set posteriorly rotated ears (figure 1, top right), figure 1, broad halluces (figure 1, bottom left), broad thumbs(figure 1, bottom middle), Cafe-au-lait spots on the back (Figure 1, bottom right) and bilateral cryptorchidism. Echocardiography and MRI of the brain were normal.

On examination under anaesthesia, the horizontal corneal diameter was 13.1 mm and 12.0 mm in the right and left eyes, respectively. The intraocular pressure (IOP) measured by Perkins’s tonometer was 22 mm Hg in the right eye and 15 mm Hg in the left eye (measured in the clear upper portion). Both eyes showed a high iris insertion with prominent iris processes on gonioscopy (figure 2, left panel, top and bottom) and cupped optic discs in the right eye. The left eye had a well-defined circular dirty-white raised corneal lesion (figure 2, top right). Ultrasound biomicroscopy revealed the involvement of the entire thickness of the cornea and iris adhesion to its base and margin, with a cataract (figure 2, bottom right). B-scan ultrasonography revealed a cupped optic nerve head in the left eye. A clinical possibility of RSTS with bilateral congenital glaucoma with left eye keloid and cataract was considered.

Figure 2.

Left panel: gonioscopy showing a high iris insertion with prominent iris processes in superior and inferior angles (top and bottom) and clear cornea in the right eye (centre). Right panel: a well-defined circular dirty-white raised corneal lesion in the left eye, suggestive of a keloid (top). Ultrasound biomicroscopy image showing full corneal thickness involvement of lesion, with iris adhesion to its base and margin, and cataractous lens (bottom).

Investigations

Targeted next-generation sequencing revealed a heterozygous one-base pair duplication in exon 3 of the CREBBP gene (c.886dupC), resulting in a frameshift and premature truncation of the protein at codon 296 (p.Gln296ProfsTer54). This variant is predicted to cause premature truncation of the CREB-binding protein and thereby loss of its function. The observed variant has not been reported previously in 1000 genomes, ExAC and gnomAD Exomes databases, though it has been reported in the dbSNP database (rs1567331357). The reference base is conserved across species, and in-silico predictions (by CADD score) predict it to be deleterious. The variant has been previously classified as pathogenic in ClinVar (Variation ID 594609). According to the American College of Medical Genetics and Genomics guidelines, the observed variation was classified as pathogenic.⁵ The criteria being fulfilled were PVS1 (null variant in a gene where the loss of function is a known mechanism of disease), +PM4 (protein length changes due to deletions/insertions in a non-repeat region or stop-loss variants), +PM2 (absent from controls (or at extremely low frequency if recessive), in Exome Sequencing Project, 1000 Genomes or ExAC) and +PP3 (multiple lines of computational evidence support a deleterious effect on the gene or gene product). Though the parents could not be screened for this variant, in view of the above mentioned features, the variant is likely pathogenic. The child’s characteristic clinical features and this CREBBP pathogenic variant make RSTS the most likely diagnosis.

Differential diagnosis

Known causes of corneal clouding at birth include sclerocornea, mucopolysaccharidosis, congenital hereditary endothelial dystrophy, birth trauma, corneal ulcers, Peters anomaly and congenital glaucoma. The first three conditions are usually bilateral, while our patient had a unilateral localised white opacity. There was no history of birth trauma or intrauterine infection. Peters anomaly has a characteristic central clear area in the centre of the opacity signifying a Descemet’s defect. Congenital glaucoma has a characteristic diffuse hazy cornea rather than a localised white opacity. The unilateral raised white opacity on the cornea ruled out most of the common causes and was characteristic of a corneal keloid.

Treatment

The baby underwent a combined trabeculotomy-and-trabeculectomy in the left eye and a goniotomy in the right eye for the glaucoma.

Outcome and follow-up

Postoperatively, he was stable with IOP 15 and 10 mm Hg in the right eye and left eye, respectively. Since the left eye was likely to be densely amblyopic, we decided against extensive surgery in that eye with low visual potential.

Discussion

RSTS or broad thumb-hallux syndrome (RTS; OMIM 180849) is caused by a pathogenic heterozygous mutation in the gene encoding the transcriptional coactivator cyclic adenosine monophosphate response element-binding protein (CREBBP) on chromosome 16p13 and E1A-binding protein (EBP300).⁶ The CREBBP gene produces a protein called CREB-binding protein. This protein is crucial for regulating cell development, differentiation and maturation.⁷ In the majority of the cases where a molecular diagnosis is made, the mutation has been found in the CREBBP gene. Loss of one functional copy of the CREBBP gene has been reported to cause RSTS.⁸ The variant seen in our patient has not been reported previously in a patient with RSTS. Though it has been classified as pathogenic in ClinVar, no clinical condition has been specified.⁹

Congenital glaucoma is an infrequently reported condition in RSTS. In our patient, the corneal opacity was his parents’ primary complaint, and the coexisting glaucoma was entirely unnoticed. Because there was no history of corneal perforation and the ultrasound biomicroscopy findings showed adhesion of peripheral iris at the base and the borders of the scarred cornea, the possibility of adherent leucoma and Peters anomaly was ruled out. The thick, raised, scarred lesion was recognised as a corneal keloid.

Corneal keloids are hypertrophied scars that appear as a single, irregular, protruding mass lesion. It most commonly occurs after a penetrating injury. Congenital corneal keloid has also been reported but is relatively rare. Histopathologically, keloids are identified by a thickened corneal epithelium with keratinisation, a fragmented or absent Bowman’s membrane and irregular arrangement of collagen bundles, fibroblasts and blood vessels.^{10 11} It has been proposed that it develops during the healing process by proliferating fibrovascular tissue or iris stromal cells¹⁰ or as a result of the excessive synthesis of collagen in the scar tissue.¹²

The pathogenesis of congenital corneal keloids remains unclear. It may be a result of an abnormal healing process secondary to intrauterine corneal perforation due to raised IOP. Another hypothesis is the failure of normal differentiation of corneal tissue during embryogenesis, as corneal perforation is unlikely in utero.¹³

Café-au-lait spots were another unusual finding in our patient, which are not typically associated in this condition. We found an isolated report describing this finding in RSTS.¹⁴

We decided against extensive surgery in the left eye keeping in mind the iridocorneal adhesion and cataracts and a high likelihood of keloid recurrence following corneal transplantation.^{11 15} The diagnosis of bilateral congenital glaucoma was confirmed based on the characteristic dysgenetic angle features and bilateral optic disc cupping. A review of ocular findings in 614 patients with RTS reported glaucoma in 32 cases and corneal opacities in 25 cases.¹⁶ In a series of 24 patients with ocular features in RSTS, only one had bilateral congenital glaucoma.¹⁷ We found only one report of bilateral corneal keloids and anterior segment dysgenesis in a child with RSTS.¹¹

Genetic testing in our case revealed a frameshift variant in the CREBBP gene, possibly explaining the multiple ocular and systemic anomalies occurring together. This variant is predicted to cause premature truncation of the CREB-binding protein and thereby loss of its function. The observed variant has not been reported previously in 1000 genomes, ExAC and gnomAD Exomes databases, and in-silico predictions (by CADD score) predict it to be deleterious.

Our patient’s findings add to the spectrum of ocular abnormalities and the genetic variants described in RSTS. Careful ocular examination and early treatment of glaucoma may help preserve vision in this challenging disease.

Learning points.

• An elevated corneal opacity does not always indicate an adherent leucoma or Peters anomaly; it might be a corneal keloid.

• Ultrasound biomicroscopy is essential to assess the status of the underlying anterior segment, and a thorough systemic evaluation is imperative to detect other systemic abnormalities.

• A congenital corneal keloid may coexist with congenital glaucoma. A detailed gonioscopy assessment must be done to determine the angle pathology, and B-scan ultrasonography may be used to detect a cupped optic disc.

Ethics statements

Patient consent for publication

Consent obtained from parent(s)/guardian(s).