A 2 year old boy of Romanian descent was referred to the childhood glaucoma centre of the University Medical Centre of the Johannes Gutenberg- University, Mainz, Germany, for further evaluation and treatment. His mother had noticed corneal opacity of his left eye soon after birth and consulted ophthalmologists elsewhere. At the age of 1 year the boy’s left eye had been treated by cyclophotocoagulation due to constantly elevated intraocular pressure (IOP) with a maximum IOP of 43 mmHg (Tmax). Both eyes were treated with a topical hypotensive medication containing a prostaglandin, a beta-blocker, and a carbonic anhydrase inhibitor.\nDuring our first ophthalmologic examination at the age of 2 years and 8 months in June 2018 he frequently rubbed his eyes, showed Bell’s phenomenon and variable horizontal and vertical pendular nystagmus. Using his right eye, he could track movements and localize large objects at 10–15 cm distance. Direct fixation of the objects was only possible when adding an acoustic signal. The right eye also was photophobic. His left eye showed no light perception. Three months later, further exploration under general anaesthesia revealed the following signs on the right eye: microcornea, a small central corneal opacity, mild conjunctival vascularization of the cornea, central and paracentral corneal thinning, aniridia with small remnants of iris at the temporal side, cataract, and normal fundus reflex (Additional file Fig. A-C). Using a hand-held Goldmann applanation tonometer (GAT) IOP was 23 mmHg (mean value is 16.22 mmHg, 95% CI 15.48–16.97) []. It is well described that during general anaesthesia IOP levels may be artificially lowered due to the sedation drugs []. IOP above 21 mmHg is considered to be elevated []. Corneal diameters were 10 mm horizontal and 6 mm vertical (mean value is 11.71 mm ± 0.42 mm) []. Axial length was normal at 21.68 mm (mean value of normal 2–72 months old children without ophthalmological symptoms is 20.97 mm ± 1.48 mm) []. His left eye showed microcornea, buphthalmos, severe corneal vascularization, absence of clear limbus borders, cataract, and complete corneal opacity (Additional file Fig. D). IOP was 20 mmHg (GAT) and axial length was elevated at 22.98 mm. Corneal diameters were 9 mm horizontal and 4 mm vertical. Gonioscopy was not possible due to corneal opacities in both eyes. Using ultrasonography, the anterior chamber of both eyes was abnormal with iridocorneal peripheral and central synechiae. Pachymetry was 341 μm (RE) and 382 μm (LE), indicating extreme corneal thinning (mean value of normal children without glaucoma is 551 μm) [] as shown in the slit lamp image (Additional file Fig. C). A thin central cornea can result in erroneously low IOP when measuring with the Goldmann applanation tonometer []. Presumably the patient’s actual IOP was even higher than the measured values due to the corneal thinning and the pressure lowering effect of the anaesthesia. Four months later in January 2019, another exploration of both eyes under general anaesthesia showed fully attached retinae and normal vitreous bodies (Additional file Fig. A and B).\nUpon clinical genetic examination at the age of 3 years and 4 months, his height was 98 cm (34th percentile, − 0.41 SD), weight was 13 kg (9th percentile, − 1.33 SD) and occipitofrontal circumference was 47 cm (microcephaly, < 1st percentile, − 3.11 SD). He had a coarse facies showing microcephaly, sparse hair, arched eyebrows, depressed nasal bridge, short nose, anteverted nostrils, short philtrum, prominent upper lip, macrostomia, prominent and everted lower lip, open mouth appearance, and low-set ears (Additional file Fig. A and B). He also had abnormal fifth fingers showing clinodactyly and hypoplastic terminal phalanges (Additional file Fig. C), cryptorchidism, and severe developmental delay. He had achieved sitting alone at the age of 2 years and 10 months and was able to stand only with extensive support.\nMolecular genetic analysis was performed using peripheral blood as described previously []. Following normal findings using sequence analysis of 18 genes known to be associated with congenital glaucoma, we applied whole exome sequencing and identified a novel de novo heterozygous variant c.251G>T, p.(Gly84Val) in the SRY-related HMG-box gene 11 (SOX11). The variant had neither been described in the literature nor annotated in the ClinVar database and was absent in the parents and the general population. It alters a conserved codon and was predicted to be likely pathogenic by in silico prediction tools (MutationTaster, CADD, SIFT, Varsome).\nOur medical and surgical treatment concentrated on the child’s right eye, considering it to be the only eye being able to perceive light. We first performed a limbal cell transplantation combined with amniotic membrane transplantation at the age of 3 years and 1 month, followed by an allogenic simple limbal epithelial transplantation (AlloSlet) and conjunctival covering. Thereafter we stopped topical hypotensive medication on the right eye. On the left eye the use of topical carbonic anhydrase inhibitor was continued. Unfortunately, when last seen at the age of 3 years and 7 months the boy did not show any improvement in his visual ability compared to before the operations.
Case 4 is a 25-year-old woman, the third child of healthy non-consanguineous parents. Pregnancy was complicated by reduced fetal movements. Birth weight was 3130 g (25th centile). Choanal stenosis and persistent ductus arteriosus were present in the neonatal period. She first walked at 4 years and spoke at 3 years old. At the age of 25 years old, her height was 162 cm (25th centile), weight 50 kg (10th centile) and head circumference 49 cm (<0.4th centile). She has severe intellectual disability and aggressive behaviour. She is physically well but has hypermetropia. She has a flat face with upslanting palpebral fissures and wide mouth with thick lips. Short second fingers with bilateral fifth finger clinodactyly was present along with skin syndactyly of toes 2–3 and 4–5. CGH was reported as arr 2p25(5535091–16398225)(hg 19)x1 with deletion of SOX11 and MYCN. The deletion was not found in either parent.