Persistent Fetal Vasculature

Clinical Presentation

Persistent fetal vasculature (PFV), historically termed “persistent hyperplastic primary vitreous,” is typically a unilateral condition caused by failure of the fetal hyaloidal vessels to regress during embryogenesis.¹ During ocular development, the hyaloid artery and its capillary network branches (the tunica vasculosa lentis) supply nutrients to the developing lens and additional branches fill the vitreous cavity and attach to the surface of the retina. It is from these numerous insertions of the branches of the hyaloid artery into the retina that retinal traction can develop and progress during axial length growth of childhood.

PFV is divided into 3 categories, based on the degree of involution of the hyaloid and the tunica vascular lentis: anterior, posterior, and combined anterior-posterior.² Examples of anterior PFV are cataracts, retrolenticular membrane, posterior lenticonus, Mittendorf dot, elongated ciliary process, shallow anterior chamber, poor pupil dilation, microcornea, secondary glaucoma, iridohyaloid blood vessels, and intralenticular hemorrhage. PFV is the second most common cause of acquired cataract during the first year of life.³

Examples of posterior PFV are retinal detachment, retinal dysplasia, retinal folds, optic nerve hypoplasia, Bergmeister papilla, macular anomalies, intravitreal hemorrhage, and vitreal membranes. Combined PFV cases (both anterior and posterior) are the most common and complicated form, accounting for approximately 60% of all cases.⁴ Combined PFV can lead to extremely severe ocular disorders, such as microphthalmos, buphthalmos, or phthisis bulbi.^5,6

Differential Diagnosis

The differential diagnosis for PFV includes causes of pediatric leukocoria. Diagnoses to be considered include retinoblastoma, advanced retinopathy of prematurity (ROP), familial exudative vitreoretinopathy (FEVR), Coats disease, Norrie disease, incontinentia pigmenti, congenital cataract, ocular toxocariasis, retinal dysplasias, and severe intermediate uveitis. Of these, it is most important to rule out retinoblastoma.

Several findings may be helpful in differentiating retinoblastoma from PFV. A small eye is more suggestive of PFV as it is uncommon to see retinoblastoma in a microphthalmic eye. Moreover, retinoblastoma can be either unilateral or bilateral, while PFV is typically a unilateral condition. Ancillary testing with radiologic findings and Doppler ultrasonography can also be helpful in distinguishing PFV from retinoblastoma.²

Diagnostic Examination

Fundus examination showing the presence of persistent congenital vessels from the optic disc to the posterior surface of the lens is diagnostic for PFV.⁷ In cases in which the diagnosis is uncertain or visualization of the retina is poor, it is important to perform additional imaging tests to confirm the diagnosis. High‐frequency ultrasonography,⁸ computed tomography scan (CT), magnetic resonance imaging (MRI),⁹ and intravenous fluorescein angiography (FA) can be helpful adjunctive tests. In PFV, ultrasonography can show an echogenic inhomogeneous band extending from the lens posterior capsule to the optic disc. Color Doppler can show arterial flow inside this band, which represents the persistent hyaloid artery.¹⁰ CT and MRI can show enhancement of abnormal intravitreal tissue, a linear structure suggestive of a hyaloid canal, shallow anterior chamber, irregular lens, or a retinal detachment or fold. The absence of intraocular calcification on computed tomography or ultrasonography is important to rule out retinoblastoma.⁷ FA can show a persistent anterior tunica vasculosa lentis extending to the margin of the iris.

Treatment

The severity of the disease determines the optimal therapy. Reasonable approaches to PFV range from observation to surgery. In either case, treating the amblyopia will be necessary. Isolated Mittendorf dot and Bergmeister papilla are examples of minimally affected PFV cases, in which surgery is not indicated and treatment consists of optimization of patching therapy for amblyopia.

Severe PFV requires surgery, as these eyes will progress to angle-closure glaucoma, vitreous hemorrhage, retinal detachment, and phthisis bulbi.¹¹ Indications for surgery are recurrent or severe intravitreal hemorrhage, progressive retinal detachment, progressive shallowing of the anterior chamber, or secondary glaucoma caused by closure of the anterior chamber angle.² Anterior PFV associated with a visually significant cataract should be treated with lensectomy and anterior vitrectomy with cautery of the tips of the hyaloid stalk. In addition, medical or surgical management of glaucoma may be required for anterior PFV cases with elevated intraocular pressures. The surgical approach for posterior PFV includes segmentation of the hyaloid stalk to release traction with or without lens extraction.^12,13 In the surgical management of posterior PFV, it is important to visualize the pars plana prior to trocar cannula insertion, as abnormal peripheral retinal insertion may be present. If the pars plana cannot be visualized, a transpupillary or translimbal approach may be safer to prevent iatrogenic retinal breaks.¹⁴

Incontinentia Pigmenti

Clinical Presentation

Incontinentia pigmenti (IP) is a rare, inherited, X-linked dominant disorder that affects multiple organ systems including the skin, teeth, hair, nails, eyes, and central nervous system.¹⁵ The principal finding in IP is characteristic progressive skin lesions beginning with vesicular bullous lesions that progress to whorl-like pigmentary changes over 4 stages. Ocular findings and the central nervous system anomalies are less frequent than skin disorders and vary from mild to severe presentations.

Ocular involvement is present in 35% of cases and is usually unilateral. Ocular findings are divided into retinal and non-retinal findings, with the majority involving the retina. The natural history of untreated retinal disease is progressive retinal ischemia, leading to neovascularization and retinal detachment.^{16, 22, 23} Macular findings include foveal hypoplasia and absence of a normal parafoveal vascular pattern, which is thought to be secondary to vascular occlusion and subsequent remodeling during macular development. Non-retinal findings include nystagmus, strabismus, microphthalmos, pigmentation of the conjunctiva, anterior segment dysgenesis, and optic atrophy.

Dental abnormalities are seen in 54%-80% of affected individuals and include missing, small, or abnormally peg-shaped teeth. Alopecia is present in 38% of patients and nail abnormalities (ridging, pitting, subungual tumors) are present in 7%-40% of patients. Although central nervous system abnormalities, which are present in 15% of cases, are not major or minor criteria of the condition, they are regarded as the most disabling conditions. Examples of CNS involvement are developmental delay, microcephaly, spasticity, and seizures.

Differential Diagnosis

The differential diagnosis for IP includes ROP, FEVR, Norrie disease, Eales disease, and sickle cell retinopathy.¹⁵ However, skin findings are unique to IP and are not present with the above-mentioned conditions.¹⁷

Diagnostic Examination

Landy and Donnai established the criteria for the diagnosis of IP, which is based on clinical features and whether there is a first degree relative with IP. If there is a first degree relative with IP, only 1 of the following features is required (Table 1). If there is no first degree relative with IP and no genetic testing is available, then 1 major and at least 2 minor criteria are required (Table 2).

Table 1. Criteria for diagnosis of IP in the presence of an affected first degree relative (Landy & Donnai, 1993)

Table 2. Criteria for diagnosis of IP in the absence of an affected first degree relative (Landy & Donnai, 1993)

In 2014, Minic and colleagues proposed adding 1 of the stages of IP skin lesions to the major criteria and adding dental, ocular (non-retinal), CNS, hair, nail (mild ridging/pitting of nail plate, subungual or periungual tumors), cleft palate, breast and nipple anomalies (supernumerary nipples, nipple hypoplasia, breast hypoplasia, and aplasia), and histological skin findings to the minor criteria. They also advocated taking into account genetic testing for the IKBKG mutation and family history of IP into consideration in the diagnosis of IP.

The skin findings in IP are very unique and usually appear in a distinct temporal sequence that progresses through 4 stages. Some stages may overlap and may not be present in some patients, so a skin biopsy may be helpful.¹⁸ Stage 1 (vesicular stage) is characterized by small papules, vesicles, and pustules over an erythematous base, usually measuring 1 mm to 1 cm and found on the head, neck, trunk. They are usually present at birth or develop shortly after birth within the first 1-2 weeks of life and disappear by 4 months of age. Stage 2 (verrucous stage) is characterized by warty papules over an erythematous base, following the lines of Blaschko. They are usually found on the extremities and trunk but can also appear on the head and neck. These lesions usually develop within 2 to 6 weeks of age and disappear by 6 months of age. In adulthood, these warty lesions can be seen on the palms and soles. Stage 3 (hyperpigmentation stage) is characterized by pigmented whorl lesions that are usually on the trunk and extremities, but can also be seen in skin folds in the head and neck region. These lesions can persist until the age of 40 but usually are seen during the first months of life and disappear during adolescence. Stage 4 (hypopigmentation stage) is characterized by hairless, hypopigmentaed linear skin lesions usually seen in the lower extremities. These lesions usually appear during adolescence and because they are subtle, careful dermatological assessment may be needed to find them.  

The IKBKG gene (Inhibitor of nuclear factor Kappa B Kinase subunit Gamma), also known as NEMO (Nf kappa b Essential MOdulator), regulates the activity of multiple genes that control the body’s immune responses and inflammatory reactions, and plays a role in the signaling pathway that is critical for the formation of ectodermal tissues including the hair, skin, teeth, and sweat glands. It also protects the cell from certain signals that would otherwise cause the cell to self-destruct (apoptosis). Although not a diagnostic criterion, identification of an IKBKG gene mutation is present in up to 80% of affected individuals and can be suggestive of IP.¹⁹ When IP is suspected, a genetics consult is recommended, because a professional in that field can help order genetic testing and counsel carriers regarding the risk of having affected children.

Treatment

Since IP is due to a genetic mutation, there is no cure for the disease, and treatment is limited to management of symptoms. Fluorescein angiography is required in all cases of IP, as the extension of avascular retina can be difficult to define by indirect ophthalmoscopy alone. Huang and colleagues²⁰ have recently proposed a management algorithm for IP patients based on a systematic review of IP. According to the authors, when no retinal abnormalities are found, patients should be followed every 3 to 6 months for 1 year. In cases of incomplete peripheral vascularization without neovascularization of the retina, the ophthalmologist can either treat the peripheral ischemic retina or observe. If treatment is performed with laser photocoagulation, the patient should be followed with fundus photography and fluorescein angiography in 6 to 8 weeks. If observation is chosen, close follow-up should be performed every 2 weeks for 3 months, and monthly for 6 months with fundus photography and intravenous fluorescein angiography (IVFA) at 3 months.

When retinal neovascularization or retinal hemorrhage occurs, patients should be treated with laser photocoagulation. Repeat examination with fundus photography and IVFA should be performed in 6-8 weeks. Intravitreal anti-VEGF can be considered as adjunct treatment following laser if there is refractory disease following laser treatment.^{17, 21-23} Retinal detachments should be treated with vitrectomy with or without a scleral buckle.

There should be a low threshold to bring the child in for an examination under anesthesia for imaging and treatment.

Norrie Disease

Clinical Presentation

Norrie disease is a rare X-linked disorder caused by a mutation in the Norrie disease pseudoglioma (NDP) gene that encodes the Norrin protein, which is important in normal vascular development.²⁴ In Norrie disease, there is incomplete regression of the hyaloidal vessels and retinal vascularization.²⁵ The genetic mutation in NDP is involved in other pediatric vitreoretinopathies. Norrie disease is characterized by sensorineural hearing loss, mental retardation, and blindness. Patients usually present with little to no light perception at birth or shortly thereafter by 3 months of age.^{26, 27}

Ocular manifestations are typically bilateral. Findings at presentation include cataract and retrolental fibroplasia, opaque cornea, iris atrophy, persistent fetal vasculature, vitreous hemorrhage, dysplastic retina with a gray or grayish-yellow pseudoglioma appearance, retinal folds, and hemorrhagic retinal detachments.

Differential Diagnosis

The differential for Norrie disease includes familial exudative vitreoretinopathy retinopathy (FEVR), persistent fetal vasculature (PFV), Coats disease, retinopathy of prematurity (ROP), retinoblastoma, endophthalmitis. It can be difficult to distinguish Norrie disease from these other diseases, especially advanced stage 5 ROP. Determining whether there is a history of severe vision loss at or near birth in male family members can be helpful in making the distinction. Although hearing loss and cognitive delay can be seen in preterm infants and Norrie disease, a birth history of prematurity and long clinical course can help distinguish between ROP and Norrie disease. Retinoblastoma can be distinguished often by clinical examination, but a CT or B-scan ultrasonogram may be necessary. Any infant presenting with severe vision loss and retinal dysplasia should be genetically tested for Norrie disease.^27,28

Diagnostic Examination

Diagnosis is based on birth and family history, ophthalmologic findings, and systemic findings (one-third develop hearing loss, two-thirds have mental retardation). The diagnosis can be supported by genetic mutations in the NDP gene. Audiologic evaluation and neurodevelopmental assessment are recommended once the diagnosis is established. Molecular analysis of amniocytes is the preferred approach for prenatal diagnosis. However, this method can only diagnose whether the fetus has inherited the genetic mutation, but does not predict the severity of the disease, given the gene expression variability. In this context, prenatal ultrasound findings during late pregnancy provide valuable information regarding disease phenotype.²⁹ The examination often reveals calcification of the ocular wall, massive vitreous opacity, and retinal detachment.³⁰

Treatment

Historically, no treatment was offered for Norrie disease other than managing a blind, painful eye. The natural history is no light perception, either at birth or by 3 months, and development of phthisis bulbi in the first decade of life.^31,32 Jacklin and colleagues reported that vitrectomy and lensectomy prevented phthisis bulbi at 2 years of age compared to the unoperated eye. Additional support for transection of the residual stalk tissue, a remnant of the hyaloidal vessel, has been shown to decrease progressive tractional retinal detachment and damage to the lens and ciliary body, thereby decreasing phthisis bulbi. Relief of the anterior posterior traction also permits eye growth, and in some cases allows for reattachment of the retina in the posterior pole.³²  For this reason, and the natural history of severe vision loss, vitrectomy and possible lensectomy--if there is significant lens opacity--is recommended as early as possible.

References

1. Haddad R, Font RL, Reeser F. Persistent hyperplastic primary vitreous. A clinicopathologic study of 62 cases and review of the literature. Surv Ophthalmol. 1978;23(2):123-134.
2. Trese MT, Capone Jr A. Diagnosis and Management of Persistent Fetal Vasculature Syndrome. In: Hartnett ME, editor. Pediatric Retina. 2nd ed. Philadelphia: Lippincott Williams & Wilkins; 2014:626-639.
3. Byrne SF. Ultrasound of the Eye and Orbit: Mosby Incorporated; 2002.
4. Pollard ZF. Persistent hyperplastic primary vitreous: diagnosis, treatment and results. Trans Am Ophthalmol Soc. 1997;95:487.
5. Sisk RA, Berrocal AM, Feuer WJ, Murray TG. Visual and anatomic outcomes with or without surgery in persistent fetal vasculature. Ophthalmology. 2010;117(11):2178-2183.e1-2.
6. Kartchner JZ, Hartnett ME. Familial exudative vitreoretinopathy presentation as persistent fetal vasculature. Am J Ophthalmol Case Rep. 2017;6:15-7.
7. Chen C, Xiao H, Ding X. Persistent Fetal Vasculature. Asia Pac J Ophthalmol (Phila). 2019;8(1):86-95.
8. Mackeen LD, Nischal KK, Lam WC, Levin AV. High-frequency ultrasonography findings in persistent hyperplastic primary vitreous. J AAPOS. 2000;4(4):217-224.
9. Wycliffe ND, Mafee MF. Magnetic resonance imaging in ocular pathology. Top Magn Reson imaging. 1999;10(6):384-400.
10. Sanghvi DA, Sanghvi CA, Purandare NC. Bilateral persistent hyperplastic primary vitreous. Australas Radiol. 2005;49(1):72-74.
11. Walsh MK, Drenser KA, Capone Jr A., Trese MT. Early vitrectomy effective for bilateral combined anterior and posterior persistent fetal vasculature syndrome. Retina. 2010;30(4 Suppl):S2-8.
12. Hu A, Pei X, Ding X, et al. Combined persistent fetal vasculature: a classification based on high-resolution B-mode ultrasound and color Doppler imaging. Ophthalmology. 2016;123(1):19-25.
13. Zahavi A, Weinberger D, Snir M, Ron Y. Management of severe persistent fetal vasculature: case series and review of the literature. Int Ophthalmol. 2019;39(3):579-587.
14. Goldberg MF. Persistent fetal vasculature (PFV): an integrated interpretation of signs and symptoms associated with persistent hyperplastic primary vitreous (PHPV). LIV Edward Jackson Memorial Lecture. Am J Ophthalmol. 1997;124(5):587-626.
15. Barañano D, Goldberg M. Incontinentia Pigmenti. In: ME H, editor. Pediatric Retina. 2nd ed. Philadelphia: Lippincott Williams & Wilkins; 2014:354-366.
16. Greene-Roethke C. Incontinentia Pigmenti: A Summary Review of This Rare Ectodermal Dysplasia With Neurologic Manifestations, Including Treatment Protocols. J Pediatr Health Care. 2017;31(6):e45-e52.
17. Swinney CC, Han DP, Karth PA. Incontinentia Pigmenti: A Comprehensive Review and Update. Ophthalmic Surg Lasers Imaging Retina. 2015;46(6):650-657.
18. Landy SJ, Donnai D. Incontinentia pigmenti (Bloch-Sulzberger syndrome). J Med Genet. 1993;30(1):53.
19. Fusco F, Pescatore A, Bal E, et al. Alterations of the IKBKG locus and diseases: an update and a report of 13 novel mutations. Hum Mutat. 2008;29(5):595-604.
20. Huang NT, Summers CG, McCafferty BK, Areaux Jr RG, Koozekanani DD, Montezuma SR. Management of retinopathy in incontinentia pigmenti: A systematic review and update. Journal of VitreoRetinal Diseases. 2018;2(1):39-47.
21. Cernichiaro-Espinosa LA, Patel NA, Bauer MS, et al. Revascularization after intravitreal bevacizumab and laser therapy of bilateral retinal vascular occlusions in incontinentia pigmenti (Bloch-Sulzberger syndrome). Ophthalmic Surg Lasers Imaging Retina. 2019;50(2):e33-e7.
22. Shah PK, Bachu S, Narendran V, Kalpana N, David J, Srinivas CR. Intravitreal bevacizumab for incontinentia pigmenti. J Pediatr Ophthalmol Strabismus. 2013;50 Online:e52-4.
23. Ho M, Yip WWK, Chan VCK, Young AL. Successful treatment of refractory proliferative retinopathy of Incontinentia Pigmenti by intravitreal Ranibizumab as adjunct therapy in a 4-years-old child. Retin Cases Brief Rep. 2017;11(4):352-355.
24. Berger W, Meindl A, Van de Pol TJ, et al. Isolation of a candidate gene for Norrie disease by positional cloning. Nature Genet. 1992;1(3):199.
25. Wu W-C, Drenser K, Trese M, Capone Jr A, Dailey W. Retinal phenotype-genotype correlation of pediatric patients expressing mutations in the Norrie disease gene. Arch Ophthalmol (Chicago, Ill : 1960). 2007;125(2):225-230.
26. Dresner KA. Norrie Disease. In: ME Hartnett, editor. Pediatric Retina. 2nd ed. Philadelphia: Lippincott Williams & Wilkins; 2014: 351-356.
27. Smith SE, Mullen TE, Graham D, Sims KB, Rehm HL. Norrie disease: extraocular clinical manifestations in 56 patients. Am J Med Genet. Part A. 2012;158(8):1909-1917.
28. Sims KB. NDP-related retinopathies. GeneReviews®[Internet]: University of Washington, Seattle; 2014.
29. Liu J, Zhu J, Yang J, Zhang X, Zhang Q, Zhao P. Prenatal diagnosis of familial exudative vitreoretinopathy and Norrie disease. Mol Genet Genomic Med. 2019;7(1):e00503.
30. Wu LH, Chen L-H, Xie H, Xie Y-J. Prenatal diagnosis of a case of Norrie disease with late development of bilateral ocular malformation. Fetal and Pediatr Pathol. 2017;36(3):240-245.
31. Walsh MK, Drenser KA, Capone Jr A, Trese MT. Early vitrectomy effective for Norrie disease. Arch Ophthalmol (Chicago, Ill : 1960). 2010;128(4):456-460.
32. Todorich B, Thanos A, Yonekawa Y, Capone Jr A. Repair of total tractional retinal detachment in Norrie disease: Report of technique and successful surgical outcome. Ophthalmic Surg Lasers Imaging Retina. 2017;48(3):260-262.