Retinal vasculopathy in autosomal dominant dyskeratosis congenita due to TINF2 mutation

A four-year-old boy with autosomal dominant dyskeratosis congenita (DC) and bone marrow failure (BMF) underwent routine ophthalmological assessment prior to matched unrelated haematopoietic stem cell transplantation (HSCT). Visual acuity was reduced in both eyes. Fundus examination showed a vitreous haemorrhage in the right eye and the left eye displayed a large circinate exudate encroaching on the macula. In the left temporal retina, areas of retinal haemorrhage and extensive areas of arterial occlusion and vascular sheathing were seen (top left). Flourescein angiography of the left eye confirmed extensive and profound vascular shut down in the temporal retina and choroid. At the junction of perfused and nonperfused retina there were numerous arteriovenous shunts (top right). Bilateral laser photocoagulation was directed to the areas of retinal nonperfusion. The patient’s father had undergone a sibling-HSCT at the age of 13 years for BMF secondary to phenotypic DC that had been diagnosed 2 years previously. The patient presented at age 3 years with BMF. Telomere length, assessed by flow fluorescence in situ hybridization, showed both the patient and his two-yearold sister to be less than the first percentile for age. Molecular analysis showed both of them to be heterozygous for a TINF2 mutation: c.844C>T (amino acid substitution: p.Arg282Cys). Interestingly, TINF2 was not considered a candidate gene in the boy or his sister as a previous screen by denaturing high performance liquid chromatography analysis on their affected father had not revealed any abnormality. However, reinvestigating this same sample from the father, which had come from a buccal mouthwash (post-HSCT), there was a small proportion (10%) of the mutant allele visible on the sequencing trace, strongly suggesting that he is a mosaic for a TINF2mutation that causes DC and this mutation has been inherited by both children. TINF2, the second most commonly mutated gene in DC encodes TINF2 (also known as TIN2), a member of the telomere-associated shelterin complex, which plays integral roles in the structure and function of telomeres. TINF2 mutations are usually associated with extremely short telemeres, earlier onset of disease and bone marrow failure that usually occurs prior to manifestation of any signs of the classic triad of DC. All reported mutations, most of which arise de novo, are heterozygous. Retinal abnormalities are seen in about 20% of patients with DC. In Revesz syndrome (Mendelian Inheritance in Man #268130), a severe DC variant caused by TINF2 mutations, bilateral exudative retinopathy is a defining feature along with intrauterine growth retardation, intracranial calcification and cerebellar hypoplasia. The patient is 100% donor chimera 9 months after HSCT, continues to be neurologically normal and has developed finger and toe nail dystrophy (bottom left and right) some 7 years earlier than his father did. This phenotypic variability (BMF onset and nail dystrophy) between father and son most likely reflects the father’s TINF2 mosaicism.