Persistent Fetal Vasculature (PFV) is a congenital eye disease in which the hyaloid vascular system formed during the fetal period fails to regress after birth and remains. It was formerly called “Persistent Hyperplastic Primary Vitreous (PHPV)”, but was renamed to PFV by Goldberg in 1997 to more accurately reflect the nature of the disease. Currently, both terms are used synonymously.
This disease is the second most common cause of leukocoria (white pupillary reflex). 70–90% of patients have unilateral involvement, and most cases are non-hereditary. However, bilateral cases may be associated with systemic diseases such as Norrie disease or trisomy 13. At the genetic level, associations with the ATOH7 gene and the NDP gene have been reported.
In full-term infants, remnants of the hyaloid artery are found in about 3% of fundus examinations, while in preterm infants, some remnants are observed in about 95%. However, the majority are minor remnants that are clinically insignificant.
QWhat is the difference between PHPV and PFV?
A
PHPV is the old name for PFV, and they now refer to the same disease. In 1997, Goldberg proposed renaming it to PFV to more accurately describe the condition, and PFV is now the international standard term. In Japan, both names are sometimes used interchangeably.
QHow much does visual prognosis differ between the anterior and posterior types?
A
It differs greatly. In the anterior type, useful vision may be obtained through lens surgery and anterior vitrectomy. In the posterior type, the macula is often involved in the retinal fold or degenerated, and visual prognosis is markedly poor. The median visual acuity after 5 years is 20/100 for the anterior type and 20/800 for the posterior type, a large difference 1).
The hyaloid artery (primary vitreous) formed around the 4th week of gestation regresses as the secondary vitreous (avascular transparent vitreous) develops from the 6th week onward. This regression process requires apoptosis and macrophage activation, and molecules such as Wnt7b, Ang2, p53, VEGF, and Arf have been shown to be involved. When these signals are disrupted, vascular regression becomes incomplete, leading to PFV.
A somatic mosaicism hypothesis has also been proposed, suggesting that post-fertilization somatic mutations may contribute to the development of some cases.
In bilateral PFV, actively search for associated systemic diseases. The main known associated diseases are as follows.
Norrie disease: X-linked hereditary disease. Mutation in the NDP gene. Associated with bilateral retinal dysplasia, hearing loss, and intellectual disability.
Trisomy 13 (Patau syndrome): Chromosomal abnormality. Associated with severe systemic malformations.
Dilated fundus examination: Confirms characteristic findings such as fibrovascular membrane, elongated ciliary processes, and retinal folds.
Ocular ultrasound (B-scan): Assesses ocular structure and evaluates the presence of calcification. PFV often shows no calcification, while the presence of calcification strongly suggests retinoblastoma.
CT scan: Excellent for detecting calcification (high density). Retinoblastoma shows calcification in over 90% of cases, while PFV typically does not.
MRI: Useful for evaluating soft tissues, visualizing the hyaloid vascular stalk, and differentiating from other diseases. It has no radiation exposure and is an excellent alternative to CT.
A white pupil (white pupillary reflex) is the most important ophthalmic emergency sign. Because it requires differentiation from retinoblastoma, an ophthalmology visit at a specialized facility should be made as soon as possible after detection.
The treatment goals for PFV are: (1) prevention of complications such as elevated intraocular pressure and corneal opacity, (2) achieving and maintaining as much vision as possible, and (3) amblyopia treatment.
For the anterior type, lens surgery plus anterior vitrectomy is the standard. For the posterior and mixed types, posterior vitrectomy is additionally performed. The surgical approach is usually an anterior limbal approach.
Early surgery is directly linked to visual prognosis.
In the PEDIG (Pediatric Eye Disease Investigator Group) cataract registry study (Haider et al., 2024), cases that underwent surgery before 77 days of age had 13 times higher odds of achieving counting fingers vision or better compared to cases after 77 days1).
Postoperative amblyopia treatment (occlusion therapy of the healthy eye) is essential for improving visual prognosis. Continuous occlusion training from preschool age is recommended.
In the PEDIG cataract registry (Haider et al., 2024), among 64 eyes with 5-year outcomes, 48% achieved VA 20/200 or better, and only 10% achieved age-appropriate vision (20/40 or better) 1). Median visual acuity was 20/100 in aphakic eyes and 20/400 in pseudophakic eyes (pseudophakic PFV had significantly worse prognosis, OR 0.14) 1). Median visual acuity was 20/100 in anterior type and 20/800 in posterior type, with posterior type being markedly worse 1).
QWill surgery restore normal vision?
A
Surgery offers the greatest opportunity to improve visual prognosis, but recovery of normal vision is often difficult. Only about 10% achieve age-appropriate vision (20/40 or better) at 5 years 1). The degree of visual recovery varies greatly depending on disease type (anterior vs. posterior), timing of surgery, and thoroughness of amblyopia treatment.
Around the 4th week of gestation, the hyaloid artery branching from the internal carotid artery enters the vitreous cavity and forms the main component of the primary vitreous. From the 6th week onward, the secondary vitreous, an avascular transparent gel, begins to form from the retinal side, and the primary vitreous is pushed to the periphery and regresses.
The regression process is completed from the late fetal period to after birth. Normally, the only remaining remnants are the Mittendorf dot on the posterior lens capsule, the Bergmeister papilla on the optic disc, and the Cloquet canal, which was the path of the hyaloid artery.
Regression of the hyaloid vessels requires apoptosis (programmed cell death) and phagocytosis by macrophages. Multiple molecules are involved in this process.
Wnt7b: A major signal responsible for inducing apoptosis by perivascular macrophages.
Ang2 (Angiopoietin-2): An angiogenic regulator that promotes vascular regression.
p53: A regulator of apoptosis.
VEGF: Involved in regulating vascular survival signals during regression.
Arf (p19Arf/p14ARF): Involved in apoptosis via the p53 pathway.
When these signals are impaired, fibrovascular tissue around the hyaloid vessels proliferates abnormally, leading to lens opacity, retinal dysplasia, and microphthalmia. Traction from residual tissue leads to elongation of ciliary processes and formation of retinal folds.
7. Latest research and future perspectives (research-stage reports)
The Pediatric Eye Disease Investigator Group (PEDIG) is collecting large-scale data on congenital cataracts, including PFV, through the pediatric cataract registry.
In the PEDIG registry study by Haider et al. (2024, 64 eyes, 5 years), the rate of achieving visual acuity of 20/200 or better was 48%, glaucoma 24%, and visual axis opacification 15–45% 1). Compared to previous single-center reports (Bata study 33%, Anteby study 16.7%), the visual acuity achievement rate has improved, suggesting the effectiveness of early intervention and systematic postoperative management 1). Additionally, the quantitative demonstration of poor prognosis in pseudophakic eyes (OR 0.14) provides important insights for future surgical strategies (aphakic management vs. intraocular lens implantation) 1).
The association between microcephaly, microphthalmia, pigmentary chorioretinopathy (MPPC syndrome) and PFV is being studied. Molecular genetic analysis is advancing the identification of gene mutations involved in the regression of the hyaloid vasculature.
Although many PFV cases have been considered non-hereditary, a hypothesis has been proposed that post-fertilization somatic mutations (mosaicism) are involved in the onset. With advances in next-generation sequencing technology, verification of this hypothesis is expected to progress in the future.
QIs it possible to recover vision in the future?
A
At present, complete recovery of vision impairment that has already occurred is difficult. However, the accumulation of long-term data is leading to optimization of surgical timing and postoperative management. Furthermore, elucidation of the molecular genetic pathogenesis is expected to lead to the development of future intervention targets.
Haider KM, Freedman SF, Greenwood M, et al. Visual outcomes and complications of surgery for persistent fetal vasculature: a registry study from the Pediatric Eye Disease Investigator Group. Am J Ophthalmol. 2024;260:29-35.
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