Retinopathy of prematurity (ROP), first described in 1942 as retrolental fibroplasia, is a disorder of retinal blood vessel development in premature infants.1 The retinal vasculature begins maturation during the 16th week of gestation in a centrifugal pattern from the optic nerve to the periphery, becoming complete in almost all cases at term.2 ROP is a biphasic disease. In preterm infants, who require supplemental oxygen therapy from a postconceptual age (PCA) of 22 to 30 weeks, the developing retina becomes hyperoxic. Through complex cell signaling, this leads to the vaso-obliterative phase of ROP by suppression of vascular endothelial growth factor (VEGF) and inhibition of retinal vessel growth. A contrasting second vasoproliferative phase then occurs, usually with a PCA of 31 to 36 weeks, where the now ischemic peripheral retina produces an overabundance of growth factors, instigating abnormal and disorganized vessel proliferation. The neovascularization generates cicatricial tractional forces that culminate in retinal detachment in severe cases.2–4 The onset in most cases is established prior to a PCA of 40 weeks.5
Defined in 1979, Pearson syndrome is a multisystem disorder characterized by mutations of mitochondrial DNA.6 Clinical presentation is variable with reduced bone marrow production, exocrine pancreatic dysfunction, metabolic acidosis, and hepatic failure.7 Ocular findings comprise pigmentary retinopathy and ptosis, similar to Kearns-Sayre syndrome, as well as bilateral zonular cataracts and corneal opacification.8–11 Although not previously reported specifically with Pearson syndrome, optic neuropathy may also be a late sequela due to metabolic dysfunction.
With this case, we describe the first report of delayed onset of ROP in a patient with Pearson syndrome and discuss the possible pathophysiologic mechanisms in relation to mitochondrial disease and oxygen tension in the developing retina.
A female infant was born by emergency caesarean section at 29.5 weeks of gestation for non-reassuring fetal tracing with a birth weight of 1,245 g. Complications during pregnancy included suspected intrauterine growth restriction, polyhydramnios, bilateral choroid plexus cysts, ventriculomegaly, echogenic bowel, and a urinary tract infection. The family history was positive for problems in platelet aggregation and refractory iron deficiency anemia in her maternal aunt.
At birth, the Apgar scores were 4, 5, and 6 at 1, 5, and 10 minutes, respectively. Intubation was immediately performed with admission to the neonatal intensive care unit. The protracted hospital course was complicated by apnea, lactic academia, septic ileus, cholestasis, pancytopenia, hyperglycemia, multiple transfusions of blood products, grade III intraventricular hemorrhage, and abnormal electroencephalography.
On first eye examination at a corrected PCA of 32 weeks, both eyes reacted to light and were soft to palpation. Anterior segment slit-lamp examination was unremarkable in both eyes. Funduscopic examination was significant for attenuated vasculature of both eyes, but no ROP was detected. Follow-up examinations were performed at a PCA of 33, 34, 36, and 40 weeks, with no evidence of ROP but atypical peripheral retinal pigment epithelial mottling.
Funduscopic examination at a PCA of 42 weeks revealed stage 1 ROP in zone II with 6 clock hours of involvement and no plus disease in both eyes (Figure 1). Fluorescein angiography at a PCA of 46 weeks revealed progression to stage 2 ROP with 12 clock hours of involvement in zone II in both eyes (Figure 2). Further progression was noted 2 weeks later at a PCA of 48 weeks. At that time, fundus examination demonstrated stage 2 ROP, with 12 clock hours of involvement in zones II and III in both eyes (Figure 3).
Postconceptual age of 42 weeks: stage 1 retinopathy of prematurity in zone II with 6 clock hours of involvement and no plus disease in both eyes.
Postconceptual age of 46 weeks: stage 2 retinopathy of prematurity with 12 clock hours of involvement in zone II in both eyes.
Postconceptual age of 48 weeks: stage 2 retinopathy of prematurity with 12 clock hours of involvement in zones II and III in both eyes.
A genetic work-up was conducted for mitochondrial diseases given the persistent lactic acidemia, pancytopenia, and hyperglycemia (GeneDx Combined Mito Genome Plus Mito Nuclear Gene Panel). This revealed a 4.9 kb deletion of the mitochondrial genome. The mutation was m.8488_13441del4953 including the genes MT-ATP6, ATP8, CO3, TG, ND3, TR, ND4L, ND4, TH, TS2, and TL2, which was consistent with Pearson syndrome. The heteroplasmy of this deletion was estimated to be 75%. Repeat genetic testing sent to Cincinnati Children's Hospital 2 months later confirmed the results.
Outpatient follow-up with fundus photographs at a PCA of 62 weeks demonstrated regression of ROP with full vascularization (Figure 4). No treatment was given throughout this time period.
Postconceptual age of 62 weeks: regression of retinopathy of prematurity with full vascularization.
In this case of Pearson syndrome, the extent of the relationship between the mitochondrial disease and the delayed onset of ROP cannot be definitively known. We hypothesize that increased oxygen use, created by the impairments in retinal cellular respiration, may have counterbalanced the negative effects of supplemental oxygen during the post-gestational, vaso-obliterative stage of ROP.
The patient in this case presented with stage 1 ROP at a PCA of 42 weeks. In the setting of multiple prior normal examinations, this would be considered atypically late. Large clinical trials and retrospective reviews have established a timeline for the onset of ROP, which follows a schedule most closely related to the PCA, rather than the chronological age.5 The natural history group in the Cryotherapy for ROP study had a mean PCA at stage 1 diagnosis of 34.3 weeks. The study additionally calculated an average PCA of 37.7 weeks at the time of threshold disease.12 Quinn et al.13 later described an average PCA for the onset of ROP at 36.7 weeks. Palmer et al.5 and Flynn14 initially reported that most cases could be diagnosed between 32 and 44 weeks, and with subsequent statistical analysis, they calculated the 95th percentile of ROP onset to be less than 39.1 weeks. Although delayed presentation of ROP has been reported after a PCA of 40 weeks, it is atypical.
Associated with a late ROP presentation, this patient was found to have a mitochondrial DNA mutation and clinical findings consistent with Pearson syndrome. Pearson syndrome is a multisystem disease, with variable clinical presentations, resulting in extensive organ failure.8 There is an inconsistent relationship between the specific mitochondrial deletion and phenotype, partly due to pleioplasmatic rearrangements and heteroplasmy, whereby organelles can exist with varying proportions of wild-type and mutant DNA simultaneously.15–18 Mitochondrial disorders have a predilection for ocular involvement. This has long been postulated from the relatively high metabolic demand of the retina in comparison to other tissues.19 The pathophysiology of mitochondrial syndromes lies in the inability to undergo effective aerobic glycolysis. Defective genes and proteins impair the production of NADH required for oxidative phosphorylation and adenosine triphosphate generation. Ultimately, there is a shift to anaerobic glycolysis that increases the oxygen consumption per unit of energy produced.20,21
Both Pearson syndrome and ROP have a relationship to oxygen metabolism. In the early vasoobliterative phase of ROP, respiratory management with excess oxygen plays a significant role in the arrest of retinal vessel growth. Oxygen tension is detected by various mechanisms, including the oxygen-sensing transcription factor, HIF.22 HIF drives the expression of genes that encode for products that promote adaptations to a hypoxic state.23 Notably, VEGF and erythropoietin assist in the creation of vascular networks.24 With the supplemental oxygen often required for premature neonates, HIF and VEGF are inhibited, leading to suppression of vessel development. Additionally, the abnormally elevated retinal oxygen tension generates reactive free radicals that initiate cytotoxic peroxidation and nitration, to which the neonatal retina is prone.25–29
There is an increase in oxygen consumption by anaerobic cellular respiration in Pearson syndrome. Theoretically, this would offset some of the deleterious effects of hyperoxia in the vaso-obliterative phase of ROP. The decrease in local oxygen tension may improve HIF-mediated vessel maturation and inhibit harmful oxygen-induced free radical species. Thus, the mitochondrial dysfunction in this case may have been protective and led to a postponed onset of stage 1 disease.
Limitations of this report include the potential of confounding metabolic derangements that would have affected the onset of ROP. Additionally, despite the theoretical pathophysiology, the cause of delayed ROP from mitochondrial disease cannot be definitively proven without further experimentation.
This case is the first report of a mitochondrial dysfunction syndrome associated with late ROP development. Our theorized mechanism for the delay of ROP in this patient with Pearson syndrome is that a compromised cellular aerobic respiration system increased oxygen consumption, offsetting the vasculostatic signals and cytotoxic reactive molecules associated with supplemental oxygen therapy.
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